WO2025238147A1

WO2025238147A1 - Maintenance treatment of cardiac ttr amyloidosis using anti-transthyretin antibodies

Info

Publication number: WO2025238147A1
Application number: PCT/EP2025/063386
Authority: WO
Inventors: Aubin MICHALON; Peter Kahr
Original assignee: Neurimmune AG
Current assignee: Neurimmune AG
Priority date: 2024-05-15
Filing date: 2025-05-15
Publication date: 2025-11-20
Anticipated expiration: 2026-11-15

Abstract

Provided is a maintenance therapy for TTR amyloidosis in a subject.

Description

Maintenance treatment of cardiac TTR amyloidosis using anti-transthyretin antibodies

FIELD OF THE DISCLOSURE

The present disclosure generally relates to a novel maintenance therapy for TTR amyloidosis in a subject.

BACKGROUND OF THE DISCLOSURE

Systemic amyloidosis is an infiltrative disease caused by progressive deposition of amyloid fibrils in organs such as the heart, liver and pancreas. For cardiac amyloidosis, the most common forms include immunoglobulin light-chain and transthyretin amyloidosis. Transthyretin (TTR) is a soluble protein involved in thyroxin and retinol transport in the body. TTR is secreted in the blood by the liver and in the cerebrospinal fluid by the choroid plexus and is also expressed in specific tissues like the pancreatic alpha cells or retinal epithelium. Under specific conditions which have been poorly elucidated and may include acidic pH, oxidative stress and local factors, the TTR protein adopts misfolded, misassembled and/or aggregated TTR conformations and becomes toxic, which can lead to transthyretin-mediated amyloidosis (ATTR).

Current approved drugs either stabilize or block the production of amyloidogenic precursors, preventing further amyloid deposition. This approach, while reducing cell damage and disease progression, does not remove existing amyloid deposits. A therapeutic strategy based on a monoclonal antibody capable of selectively binding amyloid deposits and inducing their removal could represent a key treatment for systemic amyloidosis such as of the heart.

Human antibodies that target misfolded, misassembled and/or aggregated TTR have been developed and are currently investigated in clinical trials. In particular, a Phase 1, First-in- Human, Double-Blind, Placebo-Controlled, Multicenter, Single and Multiple Ascending Dose Study of antibody NI006 in Patients with Amyloid Transthyretin Cardiomyopathy has been successfully completed; see ClinicalTrials.gov ID NCT04360434 and Garcia-Pavia etal., Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. N. Engl. J. Med. 389 (2023), 239-250. However, there exists a need for further strategies for treating ATTR in a subject, with an acceptable benefit/risk profile and preferably dosing/administration as much convenient to the subject and the physician as possible.

In accordance with the present disclosure, the solutions to the above-described problems are provided by the embodiments characterized in the claims and as disclosed in the description and recited in the items preceding the claims.

SUMMARY OF THE DISCLOSURE

The present disclosure relates to a novel treatment approach, namely maintenance treatment of cardiac TTR amyloidosis using an anti-TTR antibody. In the field of cardiac diseases or amyloidosis in general, this treatment strategy has not been suggested and thus, the present disclosure opens a completely new field. The newly developed maintenance treatment strategy allows to maintain the treatment success of the initial full dose treatment, namely the removal of amyloid deposits from the heart, by preventing amyloid rebound. Put in other words, the present disclosure relates to the "re-treatment" of patients with an anti-TTR antibody in a patient population that has been previously treated with an TTR amyloid (ATTR) depleting agent which may be the same as the anti-TTR antibody or an equivalent thereof used for the retreatment. The re-treatment therapy is aiming at preventing re-occurrence of ATTR deposits or even further reducing the ATTR deposit load that remains after a previous treatment, if any. The present disclosure features an anti-TTR IgGl antibody dosing regimen selected to prevent, inhibit, or reduce amyloid reformation after initial depletion of 600 mg every 4 weeks (q4w). The establishment of a maintenance treatment has an enormous benefit for the patients since this avoids recurrence of the disease and alleviates the fear associated therewith and avoids the need of a further full dose treatment in case of recurrence. Maintenance treatment is administered less frequently than a full dose treatment, as will be outlined below, and thus, its administration is more convenient for the patient in comparison to another full dose treatment cycle.

Accordingly, the present disclosure relates to an anti-TTR antibody for use in cardiac TTR amyloidosis (ATTR) maintenance treatment in a subject in need of said treatment. In general, any dosing regime is suitable as maintenance treatment as long as TTR amyloid rebound is prevented, i.e., reformation of ATTR deposits is suppressed. Preferably, a maintenance treatment regimen based on a flat dose is applied since body weight- adjusted doses prove inconvenient in clinical practice since the administration of body weight- adjusted doses is complex and prone to mistakes, for example in the measurement of the body weight, calculation of the appropriate dose to administer, and extraction of the corresponding drug volume from the vials. In addition, this approach generates substantial drug wastage corresponding to the amount of drug remaining in the vial that is not administered to the patient.

Based on the results of a Phase 1, First-in-Human, Double-Blind, Placebo-Controlled, Multicenter, Single and Multiple Ascending Dose Study of anti-TTR antibody NI006 (renamed to ALXN2220) in Patients with Amyloid Transthyretin Cardiomyopathy (ClinicalTrials.gov ID NCT04360434 (also referred to as Study NI006-101 herein) and Garcia-Pavia et al., Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. N. Engl. J. Med. 389 (2023), 239-250) a maintenance treatment regime for antibody ALXN2220 was developed (see Example 2) and a corresponding Phase 2, randomized, open-label, multicenter study has been set up to evaluate the safety and tolerability of maintenance treatment with ALXN2220 (see Example 1).

The maintenance treatment regimen was developed with PK/PD modeling and a flat dose regime was established as maintenance treatment which is selected to achieve at least the same, preferably slightly higher, steady-state serum anti-TTR antibody average concentration (Cavg) in a patient which is achieved with the lowest body weight based full dose antibody treatment which was shown to reduce TTR amyloid at 12 months in a patient since achieving the same steady-state serum ALXN2220 average concentration (Cavg) that was shown to reduce cardiac TTR amyloid in the above-mentioned Study NI006-101 is expected to also prevent cardiac ATTR rebound. Particularly, a flat dose regime was established as maintenance treatment which is selected to achieve at least 5% of amyloid depletion per year to neutralize a putative amyloid rebound of 5% per year. This should assure that after a patient has received full dose treatment leading to the elimination or reduction of TTR amyloid, newly formed TTR amyloid is directly eliminated and neutralized by the maintenance treatment so that there is no disease recurrence. The amyloid reduction is preferably indicated by a reduction observed with either one of two imaging-based surrogate markers of cardiac amyloid load (extracellular volume (ECV) on cardiac MRI and cardiac tracer uptake on scintigraphy). 5% amyloid rebound per year in patients suffering from ATTR corresponds to the highest reported rate in the literature to date (Rettl et al., Eur Heart J Cardiovasc Imaging 23 (2022), 767-780). For antibody ALXN2220, also referred to as NI006, it was shown that a dose of 3 mg/kg (intravenously administered, IV) when administered once every 4 weeks (Q4W) was the lowest dose which led to TTR amyloid reduction in a patient after 12 months and that a dose of 30 mg/kg IV when administered once every 4 weeks (Q4W) achieved nearly maximal TTR amyloid reduction at 12 months (see Garcia-Pavia et al., Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. N. Engl. J. Med. 389 (2023), 239-250). Based on these values, median steady-state Cavg values after 3 to 30 mg/kg Q4W were used as target ALXN2220 exposure during maintenance treatment. Furthermore, PK/PD modeling indicated that 95% of patients treated at a putative dose of 5 mg/kg of antibody NI006/ALXN2220 administered intravenously once every 4 weeks (Q4W) would have an amyloid elimination rate of 5% per year or more based on the results of the Phase 1 study (see Garcia-Pavia et al., Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. N. Engl. J. Med. 389 (2023), 239-250). Therefore, preferably median steady-state Cavg values greater or equal to 5 mg/kg Q4W were used as target ALXN2220 exposure during maintenance treatment. Same steady-state serum ALXN2220 Cavg means that the same total serum ALXN2220 is achieved, once steady-state is reached. Based on the studies as outlined in Example 2, intravenous administration of 2400 mg Q16W was predicted to result in close to 100% of patients with steady-state serum ALXN2220 Cavg larger than median steady-state Cavg after 5 mg/kg Q4W and was thus predicted to prevent cardiac ATTR rebound.

The PK/PD modelling described in Example 2 was further refined and additional simulations were conducted for various maintenance dose regimens by integrating further data on amyloid homeostasis in ATTR-CM patients into model 1. In particular, the dosing regimen for this study was selected to prevent amyloid formation based on literature-derived assumptions about changes in extracellular volume (ECV) in treatment-naive patients. According to a recent review, ECV-cMR can be considered as gold standard for amyloid burden and can be used as primary imaging marker in ATTR-CM. For refining the PK/PD model, an annual absolute increase of 3.7% in ECV was considered, which was derived from data in the cMRI substudy of Attribute-CM, the pivotal Phase 3 study of acoramidis in patients with ATTR-CM. With this refined PK/PD model, intravenous administration of 2400 mg Q16W was also predicted to result in close to 100% of patients with steady-state serum ALXN2220 Cavg larger than median steady-state Cavg after 5 mg/kg Q4W and was thus predicted to prevent cardiac ATTR rebound, but it was also possible to model and predict further suitable maintenance dose regimens. A dosing regimen of 600 mg Q4W was selected to achieve an average steady-state serum concentration greater than 40 qg/mL, which is expected to achieve amyloid reduction > 3.7% ECV in the majority study participants. More specifically, based on an extended data set and published data (Razvi et al., JACC 83 (2024), (13_Supplement) 347), it was determined that ECV is expected to increase by less than 3.78% in 90% of patients over 12 months. A dosing regimen of 600 mg IV Q4W, as a maintenance treatment, was predicted to prevent amyloid reformation in the majority of NI006-102 study participants by achieving an average steadystate serum concentration greater than 43 pg/mL in >95% of treated patients, an exposure which achieved amyloid reduction > 3.78% ECV after 12 months in study NI006-101, i.e. by about 5%; see supra. Fig. 9 illustrates that reducing the dose while increasing the frequency of antibody administration results in equivalent steady-state levels. Specifically, administering 600 mg every four weeks is equivalent to 2400 mg every four months or 1200 mg every eight weeks. This allows for tailoring the dosing to the patient's needs and comfort. Personalized care plans that consider individual patient characteristics can lead to more effective and targeted treatments, enhancing overall patient satisfaction and outcomes. For example, in case of discomfort during administration of a high dose of the antibody, lower doses at more frequent intervals can be administered. Furthermore, administration of a lower dose at shorter intervals avoids strong fluctuations of serum antibody level and thus, could be more convenient for some patients (see Fig. 10). In addition, a lower dose allows for higher infusion rate and/or time, depending on to which extent the concentration of the antibody in the infusion dilution is lowered, if at all.

Based on the innovative idea of maintenance treatment in cardiac ATTR which was developed during the experiments made within the scope of the present disclosure and the corresponding PK/PD modeling presented in Example 2 and Example 3, a corresponding maintenance treatment regimen can be developed for further anti-TTR antibodies based on the lowest body weight-based dose, which was shown to reduce TTR amyloid, preferably at least 5% TTR amyloid per year and which leads to a reduction of extracellular volume (ECV), preferably of at least 3.7% ECV per year, respectively. Most preferably, an exposure to the ATTR depleter, e.g., anti-TTR antibody, achieves amyloid reduction of about > 3.78% ECV after 12 months.

Accordingly, the present disclosure relates in one embodiment to an anti-TTR antibody for use in TTR amyloidosis (ATTR) maintenance treatment, wherein the maintenance treatment preferably comprises administering a flat dose of an anti-TTR antibody at a dosing regimen suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which neutralized TTR amyloid formation, preferably at a rate of at least 5% per 12 months, in subjects which have been diagnosed with ATTR, wherein the amyloid neutralization is indicated as a reduction of extracellular volume (ECV), e.g., as measured by cardiac MRI and/or cardiac tracer uptake on scintigraphy.

In another embodiment, the maintenance treatment comprises administering a flat dose of an anti-TTR antibody at a dosing regimen suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which neutralized TTR amyloid formation, preferably at a rate of at least 3.7% ECV, most preferably at a rate of at least 3.78% ECV, in subjects which have been diagnosed with ATTR, wherein the reduction of ECV can be measured by cardiac MRI and/or cardiac tracer uptake on scintigraphy.

As mentioned, with the refined model, a dosing regimen of 600 mg Q4W was selected to achieve an average steady-state serum concentration greater than 40 pg/mL, which is expected to achieve amyloid reduction > 3.7% ECV in the majority of study participants. More specifically, the dosing regimen of 600 mg Q4W was selected to prevent, i.e., inhibit, amyloid reformation in the majority of study participants by achieving an average steady-state serum concentration greater than 40 ug/mL, which is expected to achieve amyloid reduction > 3.78% ECV. The average steady-state ALXN2220 serum concentrations will correspond to levels achieved with dosing at around 5 mg/kg Q4W in the expected study population (approximately corresponding to Cohorts 3 and 4 in Study NI006-101). In Fig. 9 it is illustrated that reducing the dose while increasing the frequency of antibody administration and 3.78% ECV, respectively, results in equivalent steady-state levels and thus, with this refined model, it was further confirmed that different maintenance doses can be applied. For example, administering 600 mg every four weeks is equivalent to 2400 mg every four months or 1200 mg every eight weeks. Accordingly, in a preferred embodiment, the maintenance treatment comprises administering a flat dose of 150 mg to 3000 mg, preferably of 300 mg to 3000 mg, more preferably of 600 mg to 2400 mg of an anti-TTR antibody at a dosing interval suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which was shown to reduce TTR amyloid by about 5% and to reduce TTR by about > 3.7% ECV, preferably at a rate of at least 3.78% ECV, respectively. In a preferred embodiment, the maintenance treatment comprises administering a flat dose of 2400 mg of an anti-TTR antibody at a dosing interval suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which was shown to reduce TTR amyloid by about 5%.

In another preferred embodiment, the maintenance treatment comprises administering a flat dose of 2400 mg of an anti-TTR antibody at a dosing interval suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which was shown to reduce TTR by about > 3.7% ECV, preferably about > 3.78% ECV, respectively

In a preferred embodiment, the maintenance treatment comprises administering a flat dose of 600 mg of an anti-TTR antibody at a dosing interval suitable to achieve at least the same steadystate serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which was shown to reduce TTR amyloid by about 5%.

In another preferred embodiment, the maintenance treatment comprises administering a flat dose of 600 mg of an anti-TTR antibody at a dosing interval suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which was shown to reduce TTR amyloid by about 5% and/or to reduce TTR of at least 3.7% ECV, preferably about > 3.78% ECV, respectively

In a preferred embodiment, the maintenance treatment comprises administering a flat dose of 1200 mg of an anti-TTR antibody at a dosing interval suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which was shown to reduce TTR amyloid by about 5%.

In another embodiment, the maintenance treatment comprises administering a flat dose of 1200 mg of an anti-TTR antibody at a dosing interval suitable to achieve at least the same steadystate serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which was shown to reduce TTR amyloid by about 5% and/or to reduce TTR by at least 3.7% ECV, preferably about > 3.78% ECV.

As shown in Example 2, the PK/PD model indicates that 95% of patients treated with 5 mg/kg Q4W of ALXN2220 would have an amyloid elimination rate of 5% per year or more (Fig. 2). As further shown in Example 3, the refined PK/PD model indicates that 95% of patients treated with 5 mg/kg Q4W of ALXN2220 would have an amyloid reduction rate of 3.7% ECV per year or more (Fig. 7). Accordingly, in one embodiment, the maintenance treatment comprises administering a flat dose of an anti-TTR antibody at a dosing regimen suitable to achieve a steady-state serum antibody average concentration (Cavg) in a subject above the median steadystate Cavg in subjects treated with 3 mg/kg to 10 mg/kg IV of the antibody Q4W, most preferably with 5 mg/kg IV Q4W.

In a preferred embodiment, the maintenance treatment comprises administering a flat dose of 150 mg to 3000 mg, preferably of 300 mg to 3000 mg, more preferably of 600 mg to 2400 mg of an anti-TTR antibody at a dosing interval suitable to achieve a steady-state serum antibody average concentration (Cavg) in a subject above the median steady-state Cavg in subjects treated with 3 mg/kg to 10 mg/kg IV of the antibody Q4W, most preferably with 5 mg/kg IV Q4W.

In a preferred embodiment, the maintenance treatment comprises administering a flat dose of 2400 mg of an anti-TTR antibody at a dosing interval suitable to achieve a steady-state serum antibody average concentration (Cavg) in a subject above the median steady-state Cavg in subjects treated with 3 mg/kg to 10 mg/kg IV of the antibody Q4W, most preferably with 5 mg/kg IV Q4W.

In another preferred embodiment, the maintenance treatment comprises administering a flat dose of 600 mg of an anti-TTR antibody at a dosing interval suitable to achieve a steady-state serum antibody average concentration (Cavg) in a subject above the median steady-state Cavg in subjects treated with 3 mg/kg to 10 mg/kg IV of the antibody Q4W, most preferably with 5 mg/kg IV Q4W. In another embodiment, the maintenance treatment comprises administering a flat dose of 1200 mg of an anti-TTR antibody at a dosing interval suitable to achieve a steady-state serum antibody average concentration (Cavg) in a subject above the median steady-state Cavg in subjects treated with 3 mg/kg to 10 mg/kg IV of the antibody Q4W, most preferably with 5 mg/kg IV Q4W.

As mentioned above, the PK/PD model shown in Example 2 indicates that 95% of patients treated with 5 mg/kg Q4W of ALXN2220 would have an amyloid elimination rate of 5% per year or more and in Fig. 2 it was further shown that dosing of 2400 mg Q16W allows an average exposure that is at or above 5 mg/kg Q4W.

Thus, in a preferred embodiment, the maintenance treatment comprises administering the antibody at a dosing regimen of 2400 mg Q16W, preferably via intravenous infusion.

Fig. 9 shows that a dose of 600 mg every four weeks achieves an equivalent steady-state level to a dose of 2400 mg every 16 weeks. It is further shown, for example in Fig. 11, that a dose of 600 mg every four weeks has been identified by the refined PK/PD model as reasonable to control ECV progression. Thus, in a further preferred embodiment, the maintenance treatment comprises administering the antibody at a dosing regimen of 600 mg Q4W, preferably via intravenous infusion.

Fig. 9 also shows that a dose of 1200 mg every eight weeks achieves an equivalent steady-state level to a dose of 2400 mg every 16 weeks. Thus, in a further preferred embodiment, the maintenance treatment comprises administering the antibody at a dosing regimen of 1200 mg Q8W, preferably via intravenous infusion.

It can be derived from Fig. 9 that doubling the dose corresponds to doubling the interval which suggest a direct proportionality between dose and interval and thus, based on the modelling provided in the present disclosure, the skilled person can calculate further administration intervals (r\tau) based on a given dose (D) with the following formula: T= 1/150 x D, wherein T (tau) is the administration interval in weeks and D is the dose in milligrams. In one embodiment, the dose ranges from 100 mg to 3000 mg. The maximum observed serum concentration (Cmax) and the area under the serum concentration-time curve (AUC) of these dosing regimens will be lower than the weight- bracketed flat doses as described in international application PCT/EP2023/08180 and is therefore expected to be safe. The average steady-state ALXN2220 serum concentrations will correspond to levels achieved with dosing at 5 to 10 mg/kg Q4W in almost all patients.

As described in the study protocol of the Phase II Clinical Trial (Example 1) and also in the study protocol of Example 3, the maintenance treatment is administered to patients who have completed full dose treatment with ALXN2220. Accordingly, in one embodiment, the maintenance treatment is started after completion of an initial full dose treatment with an anti- TTR antibody and preferably the same anti-TTR antibody as used for maintenance treatment.

As further described in the study protocol of the Phase II Clinical Trial (Example 1), the maintenance treatment is started after completion of a full dose treatment with antibody ALXN2220 and is only administered to those patients, which did not show amyloid rebound. Patients who show amyloid rebound must complete a further full dose treatment before start of the maintenance treatment.

Accordingly, in one embodiment, the maintenance treatment is started after completion of an initial full dose treatment with an anti-TTR antibody or after completion of a secondary full dose treatment with an anti-TTR antibody. Thus, the maintenance treatment may be either performed directly after the initial full dose treatment or between two full dose treatment cycles, wherein the secondary full dose treatment is performed if patients show amyloid rebound. In one embodiment, the maintenance treatment is applied to patients who did not experience amyloid rebound.

Full dose treatment with an anti-TTR antibody preferably comprises administering the antibody at a dose of 2400 mg to a subject weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a subject weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a subject weighing equal or more than 100 kg (> 100 kg), preferably one every four weeks via IV infusion. Full dose treatment is preferably performed for 12 to 48 months and/or it is performed until amyloid depletion has been achieved. Details concerning the full dose treatment, in particular concerning the dosing regimen and duration of the treatment are described in international application WO 2024/105062 Al, which content is herein incorporated by reference.

In case of amyloid rebound, a relatively short cycle of full dose treatment with the antibody will be applied. This dosing regimen was optimized for safety and efficacy to reduce cardiac amyloid swiftly, with average steady-state ALXN2220 serum concentrations between 30 mg/kg Q4W and 60 mg/kg Q4W. At these dose levels in the Study NI006-101, amyloid reductions were observed already after 4 administrations and were more pronounced after 8 and 12 administrations. For the purpose of the present study, a duration of 32 weeks of full dose treatment was chosen (corresponding to 8 Q4W infusions).

Accordingly, in one embodiment, the secondary full dose treatment, which is administered after amyloid rebound has been detected in the patient and before start of the maintenance treatment, is administered at the same dosing as described for the (initial) full dose treatment, but is only administered over a period of about 8 to 32 weeks, preferably the secondary full dose treatment is completed after a maximum of 32 weeks,

In particular, the present disclosure relates in one aspect to an anti-TTR antibody for use in the treatment of cardiac ATTR, wherein the treatment comprises:

(i) assessing amyloid rebound and classifying the subject with amyloid rebound or without amyloid rebound,

(ii)(a) treating a subject with amyloid rebound with a full dose treatment of an anti-TTR antibody for a duration of 32 weeks in the subsequent cycle and continue treatment of the subject with the maintenance treatment according to the present disclosure thereafter; or

(ii)(b) treating a subject without amyloid rebound with the maintenance treatment;

(iii) assessing amyloid rebound after step (ii)(a) or after step (ii)(b); and

(iv)(a) treating a subject with amyloid rebound with a full dose treatment of the anti-TTR antibody for a duration of 32 weeks in the subsequent cycle and continue treatment of the subject with the maintenance treatment thereafter; or

(IV)(b) continue treating a subject without amyloid rebound with the maintenance treatment, preferably wherein full dose and maintenance treatment are performed with the same anti-TTR antibody, preferably wherein the maintenance treatment is administered Q16W-Q26W, preferably Q16W and comprises 2400 mg of the anti-TTR antibody and the full dose treatment is administered Q4W and comprises a weight-bracketed flat dose regimen comprising: (i) 2400 mg to a subject having body weight of < 60 kg; (ii) 3200 mg to a subject having body weight of > 60 kg and < 100 kg; and (iii) 4800 mg to a subject having a body weight of > 100 kg.

The present disclosure also relates to an anti-TTR antibody for use in the treatment of cardiac ATTR, wherein the treatment comprises:

(iii) assessing amyloid rebound after step (ii)(a) or after step (ii)(b); and

(IV)(b) continue treating a subject without amyloid rebound with the maintenance treatment, preferably wherein full dose and maintenance treatment are performed with the same anti-TTR antibody, preferably wherein the maintenance treatment is administered Q2W-Q10W, preferably Q4W-Q8W, more preferably Q4W or Q8W, most preferably Q4W and comprises 300 mg to 1200 mg, preferably 600 mg to 1200 mg, more preferably 600 mg or 1200 mg, most preferably 600 mg of the anti-TTR antibody, preferably wherein maintenance treatment is administered at 600 mg Q4W or 1200 mg Q8W, most preferably 600 mg Q4W, and the full dose treatment is administered Q4W and comprises a weight-bracketed flat dose regimen comprising: (i) 2400 mg to a subject having body weight of < 60 kg; (ii) 3200 mg to a subject having body weight of > 60 kg and < 100 kg; and (iii) 4800 mg to a subject having a body weight of > 100 kg.

However, in a preferred embodiment, maintenance treatment is started after completion of the initial full dose treatment (no assessment whether a patient has experienced amyloid rebound or not is thus necessary), meaning that the maintenance treatment is preferably carried out following the full dose treatment without a treatment pause. Thus, the present disclosure relates in a preferred aspect to an anti-TTR antibody for use in the treatment of cardiac ATTR, wherein the treatment comprises:

(i) initial full dose treatment of the subject, which comprises administering a full dose of an anti-TTR antibody to the subject for at least 24 months, preferably for at least 48 months and/or until amyloid depletion has been achieved, preferably wherein the anti- TTR antibody is administered at a dose of 2400 mg to a subject weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a subject weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a subject weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion; and subsequently

(ii) maintenance treatment according to the present disclosure, preferably wherein the maintenance treatment comprises administering an anti-TTR antibody, which is preferably the same anti-TTR antibody used for the full dose treatment, at a concentration of 2400 mg every 16-26 weeks (Q16W-Q26W), preferably Q16W via IV infusion, or at a concentration of 300 mg to 1200 mg, preferably 600 mg to 1200 mg, more preferably 600 mg or 1200 mg, most preferably 600 mg every two to ten weeks, preferably two to eight weeks, more preferably four to eight weeks, more preferably four or eight weeks, most preferably four week, i.e. most preferably 600 mg Q4W or 1200 mg Q8W via IV infusion.

In the Clinical Trials referred to in Examples 1 and 3, antibody ALXN2220/NI006 is used as drug substance for the maintenance treatment. The parent antibody of NI006 has been first described in WO 2015/092077 Al (designated as antibody NI-301.37F1) and in Michalon et al.et al., Nat. Commun. 12 (2021), 3142 (designated as antibody NI301 A). As disclosed in WO 2015/092077 Al, NI006 (NI-301.37F1) is inter alia characterized by binding to aggregated human wild-type transthyretin (wtATTR), which is shown in Figures 2 to 4 and 6 and described in Examples 3 to 6, and further described at page 46, last paragraph. In addition, WO 2015/092077 Al discloses thatNI006 (NI-301.37F1) does not bind to monomers and dimers of the human native transthyretin (TTR) as shown in Example 5 and Figure 4. This binding profile is advantageous since the antibody binds selectively to aggregated wtTTR and thus allows prima facie to consider not only the treatment of hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy, FAP), which is due to mutations in the gene encoding TTR, but also the treatment of wild-type transthyretin amyloidosis (wtATTR), known as senile systemic amyloidosis (SSA). Moreover, the antibody is not at risk to interfere with native monomer assembly into physiological tetramers. Said antibody has been described by comprising in its variable region or binding domain the complementary determining regions (CDRs) and variable heavy (VH) and variable light (VL) chain having the amino acid sequences depicted in Fig. 1C and IM, respectively, of WO 2015/092077 Al. The disclosure in US Pat. No. 10,344,080 is incorporated by reference in parts pertinent thereto (e.g., sequences of VHCDR1-3 & VLCDR1-3, including, sequences of VH and VL chains).

In principle, any anti-TTR antibody, which recognizes the amyloidogenic form of TTR, i.e., aggregated TTR species, and preferably human aggregated TTR, but does not bind to physiological TTR species can be used in accordance with the present disclosure.

Preferably, the anti-TTR antibody as used in accordance with the present disclosure is NI006/ALXN2220 or an equivalent antibody that substantially has the TTR binding profile of NI006/ALXN2220 and preferably is of human origin. For example, WO 2015/092077 Al discloses two further human antibodies which show the mentioned bind profile, i.e., antibodies NI-301.59F1 and NI-301.35G11, and two human antibodies, NI-301.28B3 and NI301.12D3 which have the substantially same epitope as NI006/ALXN2220 (NI-301.37F7). More preferably, the equivalent antibody is derived from human antibody NI-301.37F1 as characterized in WO 2015/092077 Al and in Michalon et al., Nat Commun. 12 (2021), 3142; see also supra.

Accordingly, the antibody or antigen-binding fragment as used in accordance with the present disclosure comprises in one embodiment a heavy chain variable region comprising complementary determining regions (CDRs) comprising heavy chain CDR1-3 whose sequences are set forth in SEQ ID NOs: 1-3, respectively, and light chain CDR1-3, whose sequences are set forth in SEQ ID NOs: 4-6, wherein the anti-TTR antibody or the antigenbinding fragment thereof comprises a heavy chain variable region comprising at least 80% sequence identity to SEQ ID NO: 7 and light chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8.

The VH region my include an amino acid sequence having at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100% sequence identity) to SEQ ID NO: 7 and the VL includes an amino acid sequence having at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100% sequence identity) to SEQ ID NO: 8.

Alternatively, the VH region includes an amino acid sequence having at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100% sequence identity) to SEQ ID NO: 11 and the VL region includes an amino acid sequence having at least 80% sequence identity (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100% sequence identity) to SEQ ID NO: 12.

Preferably, the VH region includes the amino acid sequence of SEQ ID NO: 7 and the VL includes the amino acid of SEQ ID NO: 8, or the VH region includes the amino acid sequence of SEQ ID NO: 11 and the VL region includes the amino acid of SEQ ID NO: 8 or 12, preferably SEQ ID NO: 8.

To avoid generation of "anti-drug antibodies" (ADA) by a subject administered an antibody described herein, the antibody is preferably a human or humanized antibody, typically human IgG and most preferably a human IgGl. In a preferred embodiment, the antibody is a human IgGlm3 allotype.

Antibody NI006/ALXN2220 as used in accordance with the present disclosure is a fully human IgGlm3 allotype antibody and thus comprises the human constant heavy chain (HC) amino acid sequence as exemplified in SEQ ID NO: 9 and a corresponding human constant light chain (LC), here kappa light chain, as exemplified in SEQ ID NO: 10. As explained further below, IgG antibodies are made up as tetramers consisting of HC and two light LC chains linked by disulfide bridges. The theoretical molecular weight of antibody NI006/ALXN2220 is 144.2 kDa, and the weight determined by mass spectrometry (MS) is 144.2 kDa (deglycosylated) and between 147.0 and 147.6 kDa (intact IgGl), respectively.

Antibody NI006/ALXN2220 has been produced in Chinese hamster ovary (CHO)-Kl cells. CHO cells are the most widely used mammalian cells for the production of recombinant monoclonal antibodies due to their ability to perform post-translational modifications (PTMs) on the antibody molecules, which typically take place in the human body as well. Through genetic manipulation by mutagenesis, different CHO daughter cells with improved qualities have been established. Among those variants are CHO-K1, CHO-S, CHO-DXB11 and CHO- DG44. Thus, in one embodiment, the antibody for use in accordance with the present disclosure is produced in CHO cells, preferably in a CHO-K1 cell line and is purified from the cell culture medium for further use.

As shown in Example 7 of international application WO 2024/105062 Al, the major PTMs that have been identified in antibody NI006/ALXN2220 are the modification in the HC of glutamine at the N-terminus to pyro-glutamic acid, the loss of C-terminal lysine, and N-glycosylation. In this context, the N-glycosylation site was identified at position 300 (HC N300, SEQ ID NO: 9). Thus, in one embodiment, the antibody for use in accordance with the present disclosure has lost the C-terminal lysine, i.e., the antibody has undergone C-terminal lysine clipping. In particular, the C-terminal lysine as shown in SEQ ID NO: 9 is chopped off the heavy chain of the antibody, preferably of each heavy chain of the antibody. Alternatively, the glutamine at the N-terminal is modified as pyro-glutamic acid, i.e., the heavy chain of the antibody as shown in SEQ ID NO: 9 has undergone N-terminal glutaminyl cyclization. Said sequence, i.e., the sequence of the heavy chain which comprises cyclic pyroglutamic acid and no N-terminal glutamate is set forth in SEQ ID NO: 14.

Alternatively, the heavy chain of the antibody for use in accordance with the present disclosure has lost the C-terminal lysine and the glutamine at the N-terminal is modified as pyro-glutamic acid. Said sequence, i.e., the sequence of the heavy chain with a clipped off C-terminal lysine and which comprises cyclic pyroglutamic acid and no N-terminal glutamate is set forth in SEQ ID NO: 15.

In addition, or alternatively, the antibody is glycosylated, in particular N-glycosylated. More particularly, the heavy chain of the antibody is glycosylated and even more particularly N300 of the heavy chain.

In a preferred embodiment, the anti-TTR antibody for use in accordance with the present disclosure lacks the C-terminal cysteine, has a modified glutamine at the N-terminal as pyro- glutamic acid and comprises at least one N-glycosylation site.

Thus, in one preferred embodiment, the antibody as used in accordance with the present disclosure is composed of two heavy chains having SEQ ID NO: 9, and two light chains having SEQ ID: 10, and wherein in the heavy chain the glutamine at the N-terminus is modified as pyro-glutamic acid, the C-terminal lysine is lost, and the heavy chain is N-glycosylated. In other words, the antibody as used in accordance with the present disclosure is preferably composed of two heavy chains having SEQ ID NO: 15, and two light chains having SEQ ID NO: 10, and wherein the heavy chain is N-glycosylated.

As mentioned above, the anti-TTR antibody, as used in accordance with the present disclosure, depleted amyloid transthyretin from cardiac tissue in a dose- and time-dependent manner. Thus, in a preferred embodiment, the ATTR amyloidosis leads to Cardiomyopathy (CM) and thus, in a preferred embodiment, the subject to be treated in accordance with the present disclosure has ATTR amyloidosis with CM (ATTR-CM). In a further preferred embodiment, the subject to be treated has either variant ATTR (ATTRv/hATTR) or wild-type ATTR-CM (wATTR). Even more preferred, the subject to be treated has either variant ATTR-CM (ATTRv-CM/hATTR- CM) or wild-type ATTR-CM (wATTR-CM).

As outlined in international application WO 2024/105092 Alin detail, which content is herein incorporated by reference, a formulation comprising 50 mg/mL of the antibody, i.e., ALXN2220/NI006, in 20 mM histidine buffer, 65 or 80 mg/mL sucrose, and 0.3 mg/mL polysorbate 80, at pH 5.8 has been found to be particularly suitable to ensure long-term stability of the drug product. Thus, a formulation comprising 50 mg/mL of the antibody, i.e., ALXN2220/NI006, in 20 mM histidine buffer, 80 mg/mL sucrose, and 0.3 mg/mL polysorbate 80, at pH 5.8 has been used in the Clinical Trials as described in the Examples, below.

Thus, in one embodiment the antibody for use in accordance with the present disclosure, i.e., for the maintenance treatment of ATTR, is administered in a pharmaceutical formulation at 50 mg/mL in 20 mM histidine buffer (e.g., L-histidine and L-histidine monohydrochloride), 80 mg/mL sucrose, 0.3 mg/mL polysorbate 80, at pH 5.8.

Alternatively, the antibody for use in accordance with the present disclosure is administered in a pharmaceutical formulation at 50 mg/mL in 20 mM histidine buffer (e.g., L-histidine and L- histidine monohydrochloride), 65 mg/mL sucrose, 0.3 mg/mL polysorbate 80, at pH 5.8.

Preferably, the antibody for use in accordance with the present disclosure is administered as an intravenous (IV) infusion to the patient over 2 hours for initial administration and over 1 hour for subsequent administrations, i.e., the maintenance treatment comprises administering the antibody as an intravenous (IV) infusion to the patient over 2 hours for initial administration and over 1 hour for subsequent administrations, preferably in the formulation as referred to above.

The present disclosure further relates to an article of manufacture comprising one or more container(s) comprising (i) a formulation of an anti-TTR antibody in a total amount of 2400 mg or multiple doses of any one thereof; and (ii) a leaflet prescribing the maintenance treatment regimens of the present disclosure, preferably wherein the leaflet prescribes that the antibody is to be administered at a dosage of 2400 mg once every 16 to 26 weeks, preferably once every 16 weeks.

Even though the maintenance treatment approach has been exemplified based on cardiac ATTR, it is prudent to expect that it can be applied to further TTR amyloidoses in which treatment is based on the reduction of TTR amyloids. Thus, the present disclosure relates in its broadest aspect to an anti-TTR antibody for use in the treatment of TTR amyloidosis.

Further embodiments of the present disclosure will be apparent from the description and Examples that follow.

DEFINITIONS

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the exemplary methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples are illustrative only and not intended to be limiting. Unless otherwise stated, a term as used herein is given the definition as provided in the Oxford Dictionary of Biochemistry and Molecular Biology, Oxford University Press, 1997, revised 2000 and reprinted 2003, ISBN 0 19 850673 2; Second edition published 2006, ISBN 0-19-852917-1 978-0-19852917-0.

For the avoidance of any doubt, it is emphasized that the expressions "in some embodiments", "in a certain embodiments," "in certain instances," "in some instances," “in some aspects,” "in a further embodiment," "in one embodiment," "in a further aspect," "in a first aspect," "in a second aspect," etc., and the like are used and meant such that any of the embodiments described therein are to be read with a mind to combine each of the features of those embodiments and that the disclosure has to be treated in the same way as if the combination of the features of those embodiments and aspects would be spelled out in one embodiment. The same is true for any combination of embodiments and features of the appended claims and illustrated in the Examples, which are also intended to be combined with features from corresponding embodiments disclosed in the description, wherein only for the sake of consistency and conciseness the embodiments are characterized by dependencies while in fact each embodiment and combination of features, which could be construed due to the (multiple) dependencies must be seen to be literally disclosed and not considered as a selection among different choices. In this context, the person skilled in the art will appreciate that the embodiments and features disclosed in the Examples are intended to be generalized to any anti-TTR antibody and equivalents having substantially the same properties.

As used herein, the term "about," as used herein, refers to a value that is ± 10% of a recited value; preferably ± 5%.

In connection with the present disclosure, the term "and/or" is understood to mean that all members of a group which are connected by the term "and/or" are disclosed cumulatively in any combination, both alternatively to each other and in each case to each other. This means for the expression "A, B and/or C" that the following disclosure content is to be understood thereunder: a) A or B or C; or b) (A and B); or c) (A and C); or d) (B and C); or e) (A and B and C).

The term "antibody" as referred to herein includes whole antibodies and any antigen binding fragment (z.e., "antigen-binding portion") or single chain versions thereof. An "antibody" refers, in one embodiment, to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region (CH) is comprised of three domains, CHI, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and various complement proteins.

The exact boundaries of CDRs can be defined differently according to different methods. In some embodiments, the positions of the CDRs or framework regions within a light or heavy chain variable domain can be as defined by Kabat et al., NIH Publication 91 (1991), 3242. In such cases, the CDRs can be referred to as "Kabat CDRs" (e.g., "Kabat LCDR2" or "Kabat HCDR1"). In other embodiments, the positions of the CDRs of a light or heavy chain variable region can be as defined by Chothia et al., Nature 342 (1989), 877- 883). Accordingly, these regions can be referred to as "Chothia CDRs" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In other embodiments, the positions of the CDRs of the light and heavy chain variable regions can be as defined by a Kabat-Chothia combined definition. In such embodiments, these regions can be referred to as "combined Kabat-Chothia CDRs". Thomas et al., Mol Immunol 33 (1996), 1389-1401 exemplifies the identification of CDR boundaries according to Kabat and Chothia definitions. In other embodiments, the positions of the CDRs or framework regions within a light or heavy chain variable domain can be as defined by the International Immunogenetics database (IMGT) standard. Marie-Paule Lefranc et al., Developmental & Comparative Immunology 27 (2003), 55-77 exemplify the identification of and CDR boundaries according to IMGT standard. Accordingly, these regions can be referred to as "IMGT CDRs" (e.g., "IMGT-LCDR2" or "IMGT-HCDR3"). The term "antibody" includes corresponding binding fragments thereof and the doses mentioned herein refer to a molecular weight of NI006 with approximately 147 kDa for the intact IgGl antibody. Thus, for the use of antibodies which significantly differ in their MW the dose may be adjusted accordingly. Similarly, if an antibody is used with a lower or longer serum half-life, for example because of altered glycosylation and/or modification such as PEGylation, the dose and dosing interval, respectively, may be recalculated.

Furthermore, unless stated otherwise, terms and expressions used herein in order to characterize the present disclosure, in particular the anti-TTR antibody as used in accordance with the present disclosure are given in the definitions as provided in WO 2015/092077 Al, in particular in subsection "I. Definitions" at pages 16 to 42, the disclosure content of which is explicitly incorporated herein by reference. The same applies to the general embodiments disclosed in WO 2015/092077 Al for antibodies, pharmaceutical compositions, etc.

The term "between" as used herein includes the endpoints.

As used herein, the expressions "is capable of binding" and "binds to" refers to the capability of the antibody to bind to, for example aggregated TTR, under experimental conditions, for example in an ELISA assay.

"Maintenance treatment" is a dose that prevents amyloid formation based on the assumption that the ECV increases annually by 5% in treatment-naive [TTR-CM] patients. Thus, maintenance treatment is a dosing regimen that, when administered, (a) maintains LV wall thickness growth (e.g., <2 mm increase in end diastolic interventricular septum), or (b) maintains extracellular volume (ECV) (e.g., < 5% growth, e.g., per year); or (c) maintains Global longitudinal strain (e.g., < 1% increase, e.g., per year). The term "treatment" preferably refers to the prevention of rebound and reformation ATTR deposits in more than 50%, preferably more than 60%, more preferably more than 70%, still more preferably more than 80%, even more preferably more than 90% and most preferably more than 95% of the treated patient population after 1 year.

As used herein, the term "maintenance treatment" refers to the administration of a therapeutic agent or regimen subsequent to a prior completed course of treatment directed against ATTR amyloidosis, in particular transthyretin-related cardiac amyloidosis (ATTR-CM), with the objective of preventing the reformation or rebound of amyloid deposits and maintaining disease stability or remission. Maintenance treatment may also be referred to as "re-treatment", particularly where it involves renewed therapeutic intervention following a treatment-free interval; see also Example 3.

The maintenance treatment may be:

Initiated immediately upon conclusion of the initial full treatment course, or

Preferably initiated after a defined treatment-free interval, typically of up to twelve months or 2 years, during or at the end which the potential reformation of ATTR deposits is assessed through biomarker surveillance. It is understood that the prior (initial) treatment may have been conducted with the same or a different anti-TTR therapeutic agent, including but not limited to TTR stabilizers, TTR silencers or preferably ATTR depleters such as NI006/ALXN2220.

In one embodiment, maintenance treatment is initiated in response to evidence of ongoing or renewed progression of ATTR amyloid deposition, as determined by one or more quantitative surrogate imaging markers, such as:

Extracellular volume (ECV) quantified by cardiac magnetic resonance imaging (CMR); and/or

Heart retention (HR) or whole-body retention (WBR) ratios determined by bone scintigraphy.

Progression is preferably defined by an ECV, z.e., amyloid increase of > 1%, preferably > 2%, more preferably > 3%, and particularly equal to or greater than 3.7% or 3.78%, measured or estimated over a 12-month period.

Maintenance treatment may be applied prophylactically, preemptively, or in response to measurable progression, and is intended to not only halt further amyloid deposition, but optionally also to reduce the total amyloid load, including any residual deposits remaining after prior treatment.

The term "prevention of rebound or reformation of ATTR deposits", particularly following prior treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), is used herein to describe therapeutic effects that stabilize or reverse the deposition of amyloid fibrils in cardiac tissue. This outcome is preferably assessed by non-invasive imaging techniques that reliably quantify myocardial amyloid burden.

In particular, "prevention" encompasses one or more of the following measurable outcomes: Reduction of progression of cardiac amyloid deposition to an annual increase in extracellular volume (ECV), as measured by cardiac magnetic resonance imaging (CMR), of less than 3.78%, more preferably less than 3.7%, still more preferably less than 3% and ideally less than 2.0%, most preferably less than 1%;

Halting progression, z.e., amyloid reduction which compensates ATTR progression by achieving amyloid reduction of about 3.7%, preferably 3.78%, defined as no statistically significant increase in ECV, i.e., an annual ECV change of approximately 0%, typically within ±1%, accounting for imaging variability;

Reversal of amyloid burden, also referred to as cardiac reverse remodeling, defined as an ECV decrease (regression) of > 3.7%, preferably > 3.78%, more preferably >5% over a 12-month period;

Such responses are indicative of effective suppression of disease progression and correlate with improved cardiac structure and function. These outcomes are preferably confirmed by quantification of extracellular volume (ECV) using cardiac magnetic resonance imaging (cMRI); and/or Heart Retention (HR) or Whole-Body Retention (WBR) ratio as determined by bone scintigraphy (e.g., using 99mTc-DPD or 99mTc-PYP).

To accommodate varying degrees of therapeutic effect, treatment response may further be categorized as:

Minimal regression: ECV reduction >0.5% and <1.2%

Moderate regression: ECV reduction >1.2% and <3.0% Significant regression: ECV reduction >3.0% and <5.0% Substantial regression: ECV reduction >5.0%

As mentioned above and explained in Example 3, the Attribute-CM Phase 3 trial of acoramidis further confirmed the utility of ECV as a clinical endpoint. According to its cardiac MRI substudy, 90% of patients (treated and untreated) had an annual ECV progression below 3.78%, supporting this value as an upper boundary of expected natural disease progression in a well- characterized patient population (Razvi et al., JACC 83(13_Supplemant):347, 2024). This value also fits with the assessments made in other studies of TTR amyloid cardiomyopathy, for example the treatment response to partisan reported in Patel et al. (Journal of Cardiovascular Magnetic Resonance 26 (2024) 100229, 123-125; and Heart 2024; 110(Suppl 1): A1-A30), wherein in untreated patients disease progression at 1 year in terms of mean ECV increased by 4.0% and 6.8% at 2 years. In this study, the CMR response was categorized by changes in ECV as either: disease progression (>3% increase), stable (< 3% change) or regression (>3% decrease) over one year. An extracellular volume reduction of >5%, indicating cardiac amyloid regression and shown to be clinically meaningful, has been postulated in CM (Razvi et al., JACC 83 (2024), (13_Supplement) 347). In accordance with the present disclosure, the maintenance dose of the ATTR depleter, i.e., anti-TTR antibody, is preferably selected such that the amyloid elimination rate over 12 months is at least 5%, which is expected to be sufficient not only to compensate for any newly formed or rebounding amyloid deposits but is also expected to lead to net removal of residual amyloid that may persist following a prior course of treatment. Accordingly, in a preferred embodiment, the term "preventing” includes at least halting or compensating for rebound or reformed amyloid deposition and, advantageously, further comprises reduction of the total ATTR amyloid load, including any residual deposits remaining after earlier therapy.

Therefore, in accordance with the present disclosure, the term “preventing" also encompasses “inhibiting” the re-occurrence of ATTR amyloid deposition and/or “reducing” amyloid reformation and the overall amyloid load.

"Percent (%) sequence identity" with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to the nucleic acids or amino acids in the reference polynucleotide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid or amino acid sequence identity can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, percent sequence identity values may be generated using the sequence comparison computer program BLAST. As an illustration, the percent sequence identity of a given nucleic acid or amino acid sequence, A, to, with, or against a given nucleic acid or amino acid sequence, B, (which can alternatively be phrased as a given nucleic acid or amino acid sequence, A that has a certain percent sequence identity to, with, or against a given nucleic acid or amino acid sequence, B) is calculated as follows:

100 multiplied by (the fraction X/Y) where X is the number of nucleotides or amino acids scored as identical matches by a sequence alignment program (e.g., BLAST) in that program’s alignment of A and B, and where Y is the total number of nucleic acids in B. It will be appreciated that where the length of nucleic acid or amino acid sequence A is not equal to the length of nucleic acid or amino acid sequence B, the percent sequence identity of A to B will not equal the percent sequence identity of B to A.

As used herein, the terms "treat" or "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, in which the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development of cardiac deficiency. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (z.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival (e.g., prolonging survival of a human subject having ATTR for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more years, e.g., for the lifetime of the subject) as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the manifestation of the condition or disorder is to be prevented.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig- 1 : Schema of the Study design. *Participants demonstrating amyloid rebound will receive full dose treatment (weight-bracketed dose regimen; 2400 mg to a subject having body weight of < 60 kg; 3200 mg to a subject having body weight of > 60 kg and < 100 kg; and 4800 mg to a subject having a body weight of > 100 kg IV Q4W) for a duration of 32 weeks in the subsequent cycle and continue in the maintenance dose arm thereafter. Eligible participants without amyloid rebound at baseline will be randomized 1 : 1 to maintenance dose or observation arm. Participants demonstrating amyloid rebound at the end of cycle 1 or 2 in the maintenance dose or observation arm will receive full Dose treatment for a duration of 32 weeks in the subsequent cycle and continue in the maintenance dose arm thereafter. Over the course of the study, each participant can only receive full dose treatment for 32 weeks once. q4w = every 4 weeks; ql6w = every 16 weeks.

Fig- 2 : Predicted percentage of patients with steady-state serum ALXN2220 (=NI006) Cavg above target median steady-state Cavg for 2400 mg administered according to different dose intervals. Fig. 3: Predicted % change in cardiac ATTR after 12 months of Q4W IV doses of 0.3 to 60 mg/kg. Percentiles from 1000 simulations.

Fig. 4: Predicted steady-state serum ALXN2220 (=NI006) exposure after Q4W IV doses of 3 to 30 mg/kg. Circles indicate median steady-state Cavg used as target exposure for maintenance dose interval selection. Percentiles from 1000 simulations. Triangles are the individual AUC28days at the end of the open -label extension in study NI006-101 and were calculated from the simulated individual PK profiles using individual parameter estimates (mode) and individual dosing history.

Fig- 5 : Predicted steady-state serum ALXN2220 (=NI006) exposure after 2400 mg flat dose for different dose intervals. Percentiles from 1000 simulations. Horizontal lines represent the target median steady-state Cavg values.

Fig- 6 : Schema of the study design: * Previous participants of the Study NI006-101 will be eligible. Participants will be allowed to be on standard therapy, as determined by treating physician and study Investigator(s), which may include conventional heart failure therapies and approved disease modifying agents for ATTR amyloidosis. Abbreviations: IV = intravenous, pts = participants, q4w = every 4 weeks, w= week

Fig- 7 : Predicted % mid change of cardiac ECV after 12 months of Q4W IV doses of 0.3 to 60 mg/kg. Percentiles from 1000 simulations.

Fig. 8: Predicted steady-state serum ALXN2220 (=NI006) exposure after Q4W IV doses of 0.3 to 60 mg/kg. Percentiles from 1000 simulations.

Fig. 9: Predicted steady-state serum ALXN2220 (=NI006) exposure after 2400 mg, 1200 mg, and 600 mg flat dose for different dose intervals.

Fig. 10: Predicted steady-state serum ALXN2220 (=NI006) exposure after Q16W flat doses of 2400 mg and Q4W flat doses 600 mg. Fig. 11: Predicted ECV progression after exposure of 600 mg Q4W ALXN2220 (=NI006) over 48 weeks.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure generally relates to maintenance treatment of TTR amyloidosis, preferably cardiac TTR amyloidosis. More specifically, the present disclosure relates to the embodiments as characterized in the claims, disclosed in the description and illustrated in the Examples and Figures further below.

Specifically, the present disclosure relates to a human anti-transthyretin (TTR) antibody, which is capable of binding mutated, misfolded, misassembled and/or aggregated TTR species and/or fragments thereof and does not substantially recognize physiological TTR species, for use in maintenance treatment of a TTR amyloidosis (ATTR), preferably of cardiac ATTR. In a preferred embodiment, the anti-TTR antibody does not bind to the physiological TTR tetramer and more preferably also not the wild type TTR monomer and preferably also not to the wild type TTR dimer. Since the anti-TTR antibody is used in the treatment of ATTR in human subjects in accordance with the present disclosure, in one embodiment the anti-TTR antibody is human-derived and non-immunogenic in human.

As explained in detail above, maintenance treatment in cardiology and in the field of amyloidoses treatment is a completely new approach and based on the experiments made within the scope of the present disclosure, the feasibility of such kind of treatment was shown for the first time. As explained in detail above, the maintenance treatment is administered after completion of a full dose treatment to avoid amyloid rebound.

Accordingly, the present disclosure relates to an anti-TTR antibody for use in TTR amyloidosis (ATTR) maintenance treatment, preferably in cardiac ATTR, in a subject in need of said treatment. In general, any maintenance dosing regimen is suitable as long as TTR amyloid rebound is prevented. It is described that up to 5% amyloid rebound can be observed per year in patients suffering from amyloidosis (Rettl et al., Eur Heart J Cardiovasc Imaging 23 (2022), 767-780) and thus, for the prevention of amyloid rebound, a maintenance treatment regimen should be chosen which depletes about 5% amyloid per year to neutralize the amyloid which may be formed after completion of the initial full dose treatment. Accordingly, in one embodiment the maintenance treatment comprises administering a dose of an anti-TTR antibody, preferably in a range between 150 mg to 3000 mg, preferably between 300 mg and 2400 mg, preferably between 600 mg and 2400 mg, preferably 600 mg, 1200 mg, or 2400 mg, preferably via intravenous infusion, at a dosing regimen suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which neutralized TTR amyloid formation, preferably at a rate of at least 5% per 12 months, in subjects suffering from ATTR and which have been diagnosed with ATTR, respectively, wherein the amyloid neutralization is indicated as a reduction of extracellular volume (ECV), e.g., as measured by cardiac MRI and/or cardiac tracer uptake on scintigraphy.

A subj ect suffering from ATTR or which has been diagnosed with ATTR includes, in particular, a subject which has completed initial full dose treatment and thus, which is either (temporarily) cured from the disease or in which cardiac parameters have been improved; see details further below as regards the aspect of completion of full dose treatment.

In one embodiment, the maintenance treatment comprises administering a dose of an anti-TTR antibody, preferably in a range between 150 mg to 3000 mg, preferably between 300 mg and 2400 mg, preferably between 600 mg and 2400 mg, preferably 600 mg, 1200 mg, or 2400 mg, preferably via intravenous infusion, at a dosing regimen suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body weight based full dose antibody treatment which reduces amyloid formation as measured by reduction of ECV, preferably at a rate of at least 3.7% ECV, preferably about > 3.78% ECV per 12 months, in subjects suffering from ATTR and which have been diagnosed with ATTR, respectively, wherein the reduction of ECV is measured e.g., by cardiac MRI and/or cardiac tracer uptake on scintigraphy.

In one embodiment, the administration interval (r\tau) can be calculated based on a given dose (D) with the following formula: T= 1/150 x D, wherein r (tau) is the administration interval in weeks and D is the dose in milligrams. In one embodiment, the dose ranges from 100 mg, preferably from 150 mg to 3000 mg as referred to above.

Preferably, the diagnosis is based either on the presence of symptomatic ATTR, preferably ATTR-CM or on an NT-proBNP level of > 2000 pg/mL. The use of NT-proBNP as biomarker in ATTR is recognized in the art and based on the level of said biomarker (either in combination with the level of cardiac troponin T (cTnT) (Grogan et al., J Am Coll Cardiol 68 (2016), 1014- 1020) or in combination with estimated glomerular filtration rate (eGFR) (Gillmore et al., European Heart Journal 39 (2018), 2799-2806)) staging systems have been developed with a cut off for NT-proBNP of 3000 pg/mL; see also Perfetto et al., Internal and Emergency Medicine 17 (2022), 957-969. Thus, dependent on the level of cTnT and eGFR, and only with a view to the level of NT-proBNP, the subject has Grade I, II and III cardiac ATTR. Thus, the subject to be treated is preferably either symptomatic for ATTR, preferably ATTR-CM and/or has an NT-proBNP level of > 2000 pg/mL. In case of symptomatic ATTR, diagnosis is preferably based on evidence of cardiac amyloidosis by echocardiography or cMRI and one of the following: (a) endomyocardial biopsy with confirmatory TTR amyloid typing by either immunohistochemistry or mass spectrometry; or (b) grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP) in the absence of monoclonal gammopathy; or (c) grade 2 or 3 cardiac uptake on 99mTc scintigraphy (99mTc DPD, 99mTc PYP, or 99mTc HMDP), and confirmatory TTR amyloid typing by either immunohistochemistry or mass spectrometry in non-cardiac tissue in the presence of monoclonal gammopathy.

In one embodiment, the maintenance treatment as used in accordance with the present disclosure comprises administering a flat dose of an anti-TTR antibody at a dosing regimen suitable to achieve a steady-state serum antibody average concentration (Cavg) in a subject above the median steady-state Cavg in subjects treated with 3 mg/kg to 10 mg/kg IV of the antibody Q4W, preferably with 5 mg/kg to 10 mg/kg IV Q4W, or with 3 mg/kg IV Q4W, 4 mg/kg IV Q4W, 5 mg/kg IV Q4W, 6 mg/kg IV Q4W, 7 mg/kg IV Q4W, 8 mg/kg IV Q4W, 9 mg/kg IV Q4W or 10 mg/kg IV Q4W, more preferably with at least 3 mg/kg IV Q4W, more preferably with 3 mg/kg IV Q4W or 5 mg/kg IV Q4W, most preferably with 5 mg/kg IV Q4W.

The average steady-state serum concentration is preferably greater than about 40 pg/mL, which is expected to achieve amyloid reduction at a rate of at least 5% per year or of > 3.7% ECV, preferably about > 3.78% ECV per year, respectively, in the majority study participants. The average steady-state serum concentration is preferably between about 40 pg/mL and 160 pg/mL, preferably between about 40 pg/mL and about 100 pg/mL, preferably between about 40 pg/mL and about 90 pg/mL, preferably between 44 pg/mL and 91 pg/mL, most preferably greater than 40 pg/mL, still more preferably greater than 43 pg/mL. In one embodiment, the administration interval (r\tau) for the maintenance treatment as used in accordance with the present disclosure can be calculated based on a given dose (D) with the following formula: T= 1/150 x D, wherein r (tau) is the administration interval in weeks and D is the dose in milligrams. In one embodiment, the dose ranges from 100 mg to 3000 mg as referred to above, e.g., 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg, 2000 mg, 2025 mg, 2050 mg, 2075 mg, 2100 mg, 2125 mg, 2150 mg, 2175 mg, 2200 mg, 2225 mg, 2250 mg, 2275 mg, 2300 mg, 2325 mg, 2350 mg, 2375 mg, 2400 mg, 2425 mg, 2450 mg, 2475 mg, 2500 mg, 2525 mg, 2550 mg, 2575 mg, 2600 mg, 2625 mg, 2650 mg, 2675 mg, 2700 mg, 2725 mg, 2750 mg, 2775 mg, 2800 mg, 2825 mg, 2850 mg, 2875 mg, 2900 mg, 2925 mg, 2950 mg, 2975 mg, 3000 mg, and all values in between, or from 100 mg to 3000 mg as referred to above, e.g., 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg,

220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg,

430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg,

640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg,

850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, 1200 mg, 1210 mg, 1220 mg, 1230 mg, 1240 mg, 1250 mg, 1260 mg, 1270 mg, 1280 mg, 1290 mg, 1300 mg, 1310 mg, 1320 mg, 1330 mg, 1340 mg, 1350 mg, 1360 mg, 1370 mg, 1380 mg, 1390 mg, 1400 mg, 1410 mg, 1420 mg, 1430 mg, 1440 mg, 1450 mg, 1460 mg, 1470 mg, 1480 mg, 1490 mg, 1500 mg, 1510 mg, 1520 mg, 1530 mg, 1540 mg, 1550 mg, 1560 mg, 1570 mg, 1580 mg, 1590 mg, 1600 mg, 1610 mg, 1620 mg, 1630 mg, 1640 mg, 1650 mg, 1660 mg, 1670 mg, 1680 mg, 1690 mg, 1700 mg, 1710 mg, 1720 mg, 1730 mg, 1740 mg, 1750 mg, 1760 mg, 1770 mg, 1780 mg, 1790 mg, 1800 mg, 1810 mg, 1820 mg, 1830 mg, 1840 mg, 1850 mg, 1860 mg, 1870 mg, 1880 mg, 1890 mg, 1900 mg, 1910 mg, 1920 mg, 1930 mg, 1940 mg, 1950 mg, 1960 mg, 1970 mg, 1980 mg, 1990 mg, 2000 mg, 2010 mg, 2020 mg, 2030 mg, 2040 mg, 2050 mg, 2060 mg, 2070 mg, 2080 mg, 2090 mg, 2100 mg, 2110 mg, 2120 mg, 2130 mg, 2140 mg, 2150 mg, 2160 mg, 2170 mg, 2180 mg, 2190 mg, 2200 mg, 2210 mg, 2220 mg, 2230 mg, 2240 mg, 2250 mg, 2260 mg, 2270 mg, 2280 mg, 2290 mg, 2300 mg, 2310 mg, 2320 mg, 2330 mg, 2340 mg, 2350 mg, 2360 mg, 2370 mg, 2380 mg, 2390 mg, 2400 mg, 2410 mg, 2420 mg, 2430 mg, 2440 mg, 2450 mg, 2460 mg, 2470 mg, 2480 mg, 2490 mg, 2500 mg, 2510 mg, 2520 mg, 2530 mg, 2540 mg, 2550 mg, 2560 mg, 2570 mg, 2580 mg, 2590 mg, 2600 mg, 2610 mg, 2620 mg, 2630 mg, 2640 mg, 2650 mg, 2660 mg, 2670 mg, 2680 mg, 2690 mg, 2700 mg, 2710 mg, 2720 mg, 2730 mg, 2740 mg, 2750 mg, 2760 mg, 2770 mg, 2780 mg, 2790 mg, 2800 mg, 2810 mg, 2820 mg, 2830 mg, 2840 mg, 2850 mg, 2860 mg, 2870 mg, 2880 mg, 2890 mg, 2900 mg, 2910 mg, 2920 mg, 2930 mg, 2940 mg, 2950 mg, 2960 mg, 2970 mg, 2980 mg, 2990 mg, or 3000 mg.

In one embodiment, the maintenance treatment as used in accordance with the present disclosure comprises administering the antibody at a dosing regimen ofl50 mg every week (150 mg Q1W) to 2400 mg every 32 weeks (2400 mg Q32W), preferably of 300 mg every two weeks (300 mg Q2W) to 2400 mg every 26 weeks (2400 mg Q26W), preferably of 600 mg every four weeks (600 mg Q4W) to 2400 mg every 16 weeks (2400 mg Q16W), e.g., 300 mg every 2 weeks (300 mg Q2W), 600 mg every 4 weeks (600 mg Q4W), 900 mg every 6 weeks (900 mg Q6W), 1200 mg every 8 weeks (1200 mg Q8W), 1500 mg every 10 weeks (1500 mg Q10W), 1800 mg every 12 weeks (1800 mg Q12W), 2100 mg every 14 weeks (2100 mg Q14W), 2400 mg every 16 weeks (2400 mg Q16W), 2700 mg every 18 weeks (2700 mg Q18W), or 3000 mg every 20 weeks (3000 mg Q20W), wherein further dosing regimens can be calculated, preferably with the formula presented above.

In one embodiment, the maintenance treatment as used in accordance with the present disclosure comprises administering the antibody at a dosing regimen of 2400 mg every 44 to 8 weeks (2400 mg Q8W to Q44W), preferably at a dosing regimen of 2400 mg Q8W to Q32W, preferably of 2400 mg Q8W to Q26W, preferably of 2400 mg Q8W to Q28W, preferably of 2400 mg Q12W to Q26W, preferably of 2400 mg Q12W to Q28W, preferably of 2400 mg Q28W to Q18W, preferably of 2400 mg Q18W to Q26W, of 2400 mg Q26W to Q16W, or of 2400 mg Q24W to Q16W, or at a dosing regimen of 2400 mg Q44W, Q42W, Q40W, Q38W, Q36W, Q34W, Q32W, Q30W, Q28W, Q26W, Q24W, Q22W, Q20W, Q18W, Q16W, Q14W, Q12W, Q10W, or Q8W, more preferably at a dosing regimen of 2400 mg Q16W, Q24W, Q26W, or Q28W, most preferably at a dosing regimen of 2400 mg Q16W.

In one embodiment, the maintenance treatment as used in accordance with the present disclosure comprises administering the antibody at a dosing regimen of 600 mg every 2 to 8 weeks (600 mg Q2W to Q8W), preferably at a dosing regimen of 600 mg Q2W to Q6W, preferably of 600 mg Q4W to Q6W or of 600 mg Q2W to Q4W, or at a dosing regimen of 600 mg Q8W, Q6W, Q4W, Q2W, most preferably at a dosing regimen of 600 mg Q4W.

In one embodiment, the maintenance treatment as used in accordance with the present disclosure comprises administering the antibody at a dosing regimen of 1200 mg every 4 to 16 weeks (1200 mg Q4W to Q16W), preferably at a dosing regimen of 1200 mg Q4W to Q12W, preferably of 1200 mg Q4W to Q8W or of 1200 mg Q8W to Q16W, or at a dosing regimen of 1200 mg Q16W, Q12W, Q8W, Q4W, most preferably at a dosing regimen of 1200 mg Q8W.

The antibody is preferably administered via intravenous infusion (IV). Thus, the maintenance treatment as used in accordance with the present disclosure comprises preferably administering the antibody via intravenous (IV) infusion, preferably wherein the antibody is administered at a concentration and dosing regimen referred to above, preferably of 2400 mg every 16 to 28 weeks (Q16W to Q28W), preferably Q16W to Q26W, more preferably Q16W via IV infusion, or of 600 mg every two to six weeks (Q2W to Q6W), preferably Q4W via IV infusion.

As mentioned in Example 1, the antibody is formulated at 50 mg/mL and infusion of 2400 mg antibody is performed over 1 hour; thus with an infusion rate of 48 mL/hour. In Example 3, the antibody which is formulated at 50 mg/mL is administered at an amount of 600 mg within 30 min and thus, with an infusion rate of 24 mL/hour. The lower infusion rate could be more convenient for the patient.

The maintenance treatment is administered until the responsible physician considers that the patient is cured from the disease and no amyloid rebound is expected. For example, the patient may be considered cured if the progression of cardiac amyloid deposition remains reduced or inhibited relative to an annual increase in extracellular volume (ECV), as measured by cardiac magnetic resonance imaging (CMR), of less than 3.78%, more preferably less than 3.7%, still more preferably less than 3% and ideally less than 2.0%, most preferably less than 1%. Preferably the maintenance treatment comprises administering the anti-TTR antibody for at least 48 weeks, preferably at least 144 weeks, and most preferably lifelong.

In one embodiment, the maintenance treatment is administered concurrently with a TTR tetramer stabilizer, meaning that the patient receiving the maintenance treatment is concurrently receiving a TTR tetramer stabilizer. For example, the TTR tetramer stabilizer is selected from the group consisting of diflunisal, Tafamidis, and Acoramidis (AGIO), and is preferably Tafamidis.

As mentioned above, the maintenance treatment is preferably administered after completion of a full dose treatment with an anti-TTR antibody, which is preferably the same antibody that is used for the maintenance treatment. Thus, the subject has completed initial full dose treatment with the anti-TTR antibody before starting the maintenance treatment. A full dose treatment can be regarded as being completed upon amyloid depletion.

Furthermore, parameters which define a completed full dose treatment can be derived from the Phase I NI006 Study (ClinicalTrials.gov ID NCT04360434 and Garcia-Pavia et al., Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. N. Engl. J. Med. 389 (2023), 239-250), which is also described in detail in Example 1 of international application PCT/EP2023/08180, which content is herein incorporated by reference. In particular, in one embodiment, a full dose treatment with the anti-TTR antibody is completed when composite of all-cause mortality (ACM) and total cardiovascular (CV) clinical events are lowered. In addition or alternately, full dose treatment can be regarded as completed when at least one of the following symptoms are improved:

(a) symptoms, functionality, and health-related quality-of-life (QoL) as measured by the change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score;

(b) time to cardiovascular (CV)-related mortality;

(c) six-minute walk test (6MWT) score compared to baseline;

(d) rate of cardiovascular (CV) clinical events;

(e) time to all-cause mortality (ACM).

In addition or alternately, full dose treatment can be regarded as completed when at least one of the following effects are observed, i.e., when full dose treatment with the anti-TTR antibody (a) reduces NT-proBNP levels in the subject compared to baseline;

(b) reduces rate of heart failure (HF) events;

(c) reduces incidence of intensification of oral diuretic therapy, which optionally includes outpatient augmentation of oral diuretic therapy;

(d) reduces incidence of changes in disease modifying therapy;

(e) reduces incidence of hospitalization for atrial fibrillation;

(f) induces change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score beyond 24 months of study treatment;

(g) induces change from baseline in six-minute walk test (6MWT) beyond 24 months of study treatment;

(h) induces change from baseline in ATTR-CM disease severity based on the Mayo, NAC, and Columbia disease stage, and NYHA classification;

(i) induces change from baseline in GLS;

(j) induces change from baseline in stroke volume;

(k) induces change from baseline in echocardiography parameters of interest;

(l) induces change from baseline in hs-cTnT;

(m) induces change from baseline in DPD/PYP/ HMDP cardiac scintigraphy cardiac uptake and/or cMRI-derived ECV, T1 and T2 mapping;

(n) induces change from baseline in eGFR

(o) induces change from baseline in EQ-5D-5L score and/or induces change from baseline in SF-36 scores;

(p) induces change from baseline in a marker selected from CRP, IL IL lb, IL6, IL8, IFNg, TNF-a, IL10, IL1RA, C3 and C4, serum amyloid A, and ferritin; preferably a marker which is CRP;

(q) induces change from baseline in a marker selected from serum carboxy-terminal PICP, PIIINP, serum CITP, and plasma PRO-C6;

(r) induces change from baseline in a marker selected from TTR (prealbumin), TSH, RBP and fT4;

(s) induces change from baseline in (1) PND score and FAP stage; (2) Norfolk QoL-DN total score; and/or (3) sNFL levels;

(t) induces change from baseline in NIS and/or induces a change in NC studies.

In one embodiment, the full dose treatment is completed after 12 to 48 months, preferably after 24 to 48 months. Furthermore, in a preferred embodiment, full dose treatment, which precedes the maintenance treatment used in accordance with the present disclosure, is performed with an anti-TTR antibody, which is preferably the same anti-TTR antibody used for the maintenance treatment and comprises administering the antibody at a dose of (a) 2000 mg to 2500 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3000 mg to 3500 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4000 mg to 5000 mg to a patient weighing equal or more than 100 kg (> 100 kg). In a preferred embodiment, the antibody is administered at a dose of 2400 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg), at a dose of 3200 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg), or at a dose of 4800 mg to a patient weighing equal or more than 100 kg (> 100 kg). These flat doses are used in the Phase 3 Clinical Trial Protocol (CTP) as outlined in Example 8 of international application WO 2024/105062 Al.

Preferably, full dose treatment comprises administering the antibody once every four weeks (Q4W) via IV infusion.

In one embodiment, the maintenance treatment is administered to a subject which has not experienced amyloid rebound after the initial full dose treatment. Accordingly, in one embodiment, before commencement of the maintenance treatment, the subject is tested for amyloid rebound. If the subject has experienced amyloid rebound and has been tested for amyloid rebound, respectively, a second cycle of full dose treatment is applied before commencement of the maintenance treatment. Thus, in one embodiment, the maintenance treatment is started after completion of a secondary full dose treatment and is thus performed between two full dose treatment cycles, respectively.

In one embodiment, the secondary full dose treatment is administered at the same dosing as described for the (initial) full dose treatment, but is only administered over a period of about 8 to 32 weeks, preferably the secondary full dose treatment is completed after a maximum of 32 weeks.

A patient is classified as amyloid rebound if, after completion of the full dose treatment, new TTR amyloids are formed so that the disease phenotype recurrences. More specifically, a patient is classified as amyloid rebound if at least one criterion in each of the following three parameter (a) to (c) is fulfilled:

(a) Cardiac Structure

(1) Increased left ventricle (LV) wall thickness (e.g., as measured by > 2 mm increase in end diastolic interventricular septum (ED-IVS)), or

(2) Increased extracellular volume (ECV) (e.g., as measured by > 5 % absolute increase), or

(3) Worsened global longitudinal strain (GLS) (e.g., as measured by > 1% absolute increase)

(b) Cardiac Function

(1) Decreased left ventricular ejection fraction (LVEF) (e.g., as measured by > 5 % absolute increase), or

(2) Increased N-terminal pro b-type natriuretic peptide (NT-proBNP) (e.g., as measured by > 30% relative increase, or > 1000 ng/mL absolute increase)

(c) Overall Function

(1) Unplanned ATTR-CM related hospitalization, or

(2) Increased New York Heart Association (NYHA) class.

The subjects to be treated in accordance with the present disclosure are the subjects which have been considered amendable for the full dose treatment and which have been treated with the full dose treatment, respectively, as described in the study protocol of the First Clinical Trials (see ClinicalTrials.gov ID NCT04360434 and Garcia-Pavia et al., 2023), as well as Example 1 of international application WO 2024/105062 Al). Preferably, the subject is an adult human patient, preferably an adult patient with clinically established cardiomyopathy (ATTR-CM) whose body weight is at least 39 kg.

As mentioned above, the anti-TTR antibody, as used in accordance with the present disclosure, is known to deplete amyloid transthyretin from cardiac tissue in a dose- and time-dependent manner. Thus, in a preferred embodiment, the maintenance treatment according to the present disclosure can be applied to avoid amyloid rebound in ATTR-Cardiomyopathy (CM) (ATTR- CM). In a further preferred embodiment, the subject to be treated has either variant ATTR (ATTRv/hATTR) or wild-type ATTR-CM (wATTR). Even more preferred, the subject to be treated has either variant ATTR-CM (ATTRv-CM/hATTR-CM) or wild-type ATTR-CM (w ATTR-CM). However, also other diseases related to TTR amyloid can be subject to the maintenance treatment in accordance with the present disclosure, e.g., ATTR polyneuropathy (ATTR-PN), Familial Amyloid Polyneuropathy (FAP), Familial Amyloid Cardiomyopathy (FAC), Senile Systemic Amyloidosis (SSA), systemic familial amyloidosis, leptomeningeal/Central Nervous System (CNS) amyloidosis including Alzheimer disease, TTR-related ocular amyloidosis, TTR-related renal amyloidosis, TTR-related hyperthyroxinemia, TTR-related ligament amyloidosis including carpal tunnel syndrome, rotator cuff tears and lumbar spinal stenosis, and preeclampsia

In a preferred embodiment, the subject to be treated has been diagnosed with hereditary ATTR- CM for a known pathogenic TTR mutation or has sporadic, wild-type- ATTR-CM (WT-ATTR- CM) (e.g., a wild type ATTR gene that codes for TTR proteins that form deposits in the heart) and a negative genetic testing for a TTR mutation. Preferably, the diagnosis is based either on the presence of symptomatic ATTR, preferably ATTR-CM or on an NT-proBNP level of > 3000 pg/mL

To evaluate the effects of maintenance treatment with the anti-TTR antibody on the rate of amyloid rebound, the following endpoints are evaluated:

• Change from baseline in cardiac MRI and/or scintigraphy parameters of interest

• Change from baseline in echocardiography parameters of interest

• Change from baseline in cardiac biomarkers

• Change from baseline in NYHA class

• Change from last assessment in NI006-101 to baseline in NI006-102 in above mentioned parameters

• Incidence of participants demonstrating Amyloid Rebound

As mentioned above, the parent antibody of NI006/ALXN2220 is also described in WO 2015/092077 Al (designated as antibody NI-301.37F1) and in Michalon et al., Nat Commun. 12 (2021), 3142 (designated as antibody NI301A) and is capable of binding a human TTR epitope which comprises or consists of the amino acid sequence TTR41-45 (SEQ ID NO: 51 of WO 2015/092077 Al). Characterization of the binding properties of the antibody demonstrated that it presents high binding affinity to misfolded TTR in the sub-nanomolar range, is highly selective for the amyloid conformation of TTR, i.e., binds selectively with high affinity to the disease associated ATTR aggregates, exerts similar binding to wild type TTR and variant TTR related to sporadic or hereditary disease, respectively, and does not bind physiological TTR monomers. Furthermore, the anti-TTR antibody binds ATTR deposits in cardiac tissues obtained at autopsy from ATTR-CM patients. Accordingly, in one embodiment, the antibody as used in accordance with the present disclosure is an antibody, which is equivalent to the above-characterized antibody having a heavy chain and a light chain variable region including the amino acid of SEQ ID NO: 7 and SEQ ID NO: 8 meaning that the equivalent antibody has substantially the same binding characteristics than the above-characterized antibody having a heavy chain and a light chain variable region including the amino acid of SEQ ID NO: 7 and SEQ ID NO: 8. In particular, the equivalent antibody

(i) binds a human TTR epitope which comprises or consists of the amino acid sequence TTR41-45,

(ii) presents high binding affinity to misfolded TTR in the sub-nanomolar range,

(iii) is highly selective for the amyloid conformation of TTR, i.e., binds selectively with high affinity to the disease associated ATTR aggregates

(iv) exerts similar binding to wild type TTR and variant TTR. Related to sporadic or hereditary disease,

(v) does not bind physiological TTR monomers, and/or

(vi) binds ATTR deposits in cardiac tissues obtained at autopsy from ATTR-CM patients.

In one embodiment, the equivalent antibody shows one of the binding characteristics (i) to (vi). In one embodiment, the equivalent antibody shows at least two of the listed binding characteristics. In one embodiment, the equivalent antibody shows at least three of the listed binding characteristics. In one embodiment, the equivalent antibody shows at least four of the listed binding characteristics. In one embodiment, the equivalent antibody shows at least five of the listed binding characteristics. In a preferred embodiment, the equivalent antibody shows all of the binding characteristics (i) to (vi). The binding characteristics can be determined with conventional methods in the art, for example ELISA assays, Surface plasmon resonance (SPR) analyses, dot blot analyses, time-course aggregation studies, immunoprecipitation experiments, and immunohistochemistry (H4C) as for example described in Mi chai on et al., Nat Commun. 12 (2021), 3142.

Antibody NI006/ALXN2220 is a fully human IgGlm3 allotype antibody and thus comprises the human constant heavy chain (HC) amino acid sequence as exemplified in SEQ ID NO: 9 and a corresponding human constant light chain (LC), here kappa light chain, as exemplified in SEQ ID NO: 10.

As shown in Example 7 of international application WO 2024/105062 Al, the major PTMs that have been identified in antibody NI006/ALXN2220 are the modification in the HC of glutamine at the N-terminus to pyro-glutamic acid, the loss of C-terminal lysine, and N-glycosylation. Thus, in a preferred embodiment, the heavy chain of the anti-TTR antibody for use in accordance with the present disclosure lacks the C-terminal cysteine, has a modified glutamine at the N-terminal as pyro-glutamic acid and comprises at least one N-glycosylation site.

Another class of anti-TTR antibodies that could be used in accordance with the present disclosure is described in international applications by Prothena Biosciences Limited (Prothena). In particular, embodiments of the disclosure relate to the use of anti-TTR antibody NN-6019 of Novo Nordisk (formerly known as PRX004 from Prothena Biosciences) in the treatment of a human subject in need of such treatment, as provided herein. NN-6019 (PRX004) corresponds to and is the humanized version of antibody 14G8 described in Higaki et al., Amyloid 23 (2016) 86-97 and which is disclosed in WO 2016/120810 Al and WO 2018/007922A2 and more specifically in WO 2019/108689 Al, the disclosure in these documents being incorporated by reference. NN-6019 (PRX-004) is an investigational monoclonal antibody designed to specifically target and clear the misfolded (toxic) forms of the TTR amyloid protein found in ATTR. Accordingly, antibody PRX004 would be another preferred anti-TTR antibody for use in the treatment method in accordance with the present disclosure among others which recognize the same epitope as PRX004, i.e. amino acids TTRs9- 97 or an epitope comprising amino acids TTR101-109, and which are humanized versions of the originally cloned mouse monoclonal antibodies 14G8, 9D5, 5A1, 6C1 disclosed in WO 2016/120810 Al, WO 2018/007924 A2, WO 2018/007924 A2 and WO 2018/007923 Al, the disclosure in these references, including, the antibody sequences, e.g., full-length and/or CDRs thereof, relating to these antibody clones and/or deposits thereof are incorporated herein by reference.

Thus, in one embodiment, the antibody for use in accordance with the present disclosure is a monoclonal antibody comprising a mature heavy chain variable region comprising three CDRs of SEQ ID NO:61 as set forth in WO 2019/108689 Al and a mature light chain variable region comprising three CDRs of SEQ ID NO:70 as set forth in WO 2019/108689 Al, except that positions H52 and L26 by Kabat numbering can each be independently N or S, or a monoclonal antibody comprising a mature heavy chain variable region comprising three CDRs of SEQ ID NO: 1 as set forth in WO 2019/108689 Al and a mature light chain variable region comprising three CDRs of SEQ ID NO: 16 as set forth in WO 2019/108689 Al, In one embodiment, the antibody is characterized by comprising a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO:65 as set forth in WO 2019/108689 Al, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO:76 as set forth in WO 2019/108689 Al. More preferably, the antibody is characterized as in claims 26 to 35 of WO 2019/108689 Al, which content is herein incorporated by reference.

The sequences of heavy chain variable (VH) regions, light chain variable (VL) region, and complementarity determining regions (CDRs) of anti-TTR antibodies and antigen-binding fragments thereof which are preferably used in accordance with the present disclosure are shown in Table 1 below. CDR sequences were defined by the Kabat system (bioinf.org.uk/abs/). SEQ ID NO: 1 (VH-CDR1) represents residues 31-35 (Kabat numbering) of SEQ ID NO: 7 (VH). SEQ ID NO: 2 (VH-CDR2) represents residues 52-67 (Kabat numbering) of SEQ ID NO: 7 (VH). SEQ ID NO: 3 (VH-CDR3) represents residues 100-109 (Kabat numbering) of SEQ ID NO: 7 (VH). SEQ ID NO: 4 (VL-CDR1) represents residues 31-35 (Kabat numbering) of SEQ ID NO: 8 (VL). SEQ ID NO: 5 (VL-CDR2) represents residues 52-67 (Kabat numbering) of SEQ ID NO: 8 (VL). SEQ ID NO: 6 (VL-CDR3) represents residues 100-109 (Kabat numbering) of SEQ ID NO: 8 (VL).

Table 1: Anti-TTR antibody sequences

CDR = complimentary determining region; VH = heavy chain variable region; VL = light chain variable region, HC = heavy chain; LC = light chain.

** the N-terminal glutamate has been modified to pyroglutamic acid

The anti-TTR antibody or antigen binding fragment thereof may include one or more CDR sequences including an amino acid sequence having about 80%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and/or SEQ ID NO: 6. Further, the anti-TTR antibody or antigen binding fragment thereof may include one or more CDR sequences having an amino acid sequence with 1, 2, or 3 mismatches relative to the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and/or SEQ ID NO: 6. In a particular example, the anti- TTR antibody or antigen binding fragment thereof includes six CDR amino acid sequences with 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6.

The anti-TTR antibody or antigen-binding fragment thereof may have a VH region including an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 7. In a particular example, the anti-TTR antibody or antigen-binding fragment thereof has a VH region including an amino acid sequence with 100% sequence identity to the amino acid sequence of SEQ ID NO: 7.

The anti-TTR antibody or antigen-binding fragment thereof may have a VL region including an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 8. In a particular example, the anti-TTR antibody or antigen-binding fragment thereof has a VL region including an amino acid sequence with 100% sequence identity to the amino acid sequence of SEQ ID NO: 8.

The anti-TTR antibody or antigen-binding fragment thereof may have a VH region including an amino acid sequence with at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 11. In a particular example, the anti-TTR antibody or antigen-binding fragment thereof has a VH region including an amino acid sequence with 100% sequence identity to the amino acid sequence of SEQ ID NO: 11.

The anti-TTR antibody or antigen-binding fragment thereof may have a VL region including an amino acid sequence with at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 12. In a particular example, the anti-TTR antibody or antigen-binding fragment thereof has a VL region including an amino acid sequence with 100% sequence identity to the amino acid sequence of SEQ ID NO: 12.

Preferably, the anti-TTR antibody or antigen-binding fragment thereof may have a VH region including an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or preferably 100% sequence identity to the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 11, and a VL region including an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or preferably 100% sequence identity to the amino acid sequence of SEQ ID NO: 8. Also, within the scope of the present disclosure are anti-TTR antibodies and antigen-binding fragments thereof, in which specific amino acids have been substituted, deleted, or added. These modifications do not have a substantial effect on the anti-TTR antibody’s biological properties such as binding activity; see also infra. For example, antibodies may have amino acid substitutions in the framework region (FR), so as to improve binding to the antigen. In another example, a number of acceptor framework residues can be replaced by the corresponding donor amino acids. The donor framework can be a mature or germline human antibody framework sequence or a consensus sequence. Guidance concerning how to make phenotypically silent amino acid substitutions is provided in, e.g., Bowie et al. (Science, 247: 1306-1310, 1990), Cunningham et al. (Science, 244: 1081-1085, 1989), Ausubel (ed.) (Current Protocols in Molecular Biology, John Wiley and Sons, Inc., 1994), T. Maniatis, E. F. Fritsch and J. Sambrook (Molecular Cloning: A Laboratory Manual, Cold Spring Harbor laboratory, Cold Spring Harbor, N.Y., 1989), Pearson (Methods Mol. Biol. 243:307-31, 1994), and Gonnet et al. (Science 256: 1443-45, 1992); each of which is incorporated herein by reference.

The variant antibodies or antigen-binding fragments thereof are functionally active and may have, e.g., fewer than about 30%, about 25%, about 20%, about 15%, about 10%, about 5% or about 1% amino acid of the number of residues substituted or deleted while retaining essentially the same immunological properties including, but not limited to, binding to TTR, as described herein, i.e., equivalent antibodies having substantially the same binding properties to TTR as the exemplarity antibody comprising a heavy chain variable region with the amino acid sequence of SEQ ID NO: 7 and the light chain variable region with the amino acid of SEQ ID NO: 8, which is characterized in international application WO 2015/092077 Al, where the antibody is named NI-301.37F1) as well as in Michal on et al., Nat. Commun. 12 (2021), 3142 (designated as antibody NI301A) by (i) binding selectively with high affinity to the disease associated ATTR aggregates, (ii) binding to misfolded/aggregated wild type TTR and variant TTR related to sporadic and hereditary disease, respectively, as well as to ATTR deposits in cardiac tissues obtained at autopsy from ATTR-CM patients, but not substantially binding native TTR monomers, and, importantly, being capable of removing ATTR fibrils by macrophage-mediated phagocytosis. The latter property can be easily tested as described in international application WO 2020/094883 Al; see also Michalon et al. (2021), supra.

The antibodies or antigen-binding fragments thereof may also include variants, including, e.g., humanized or chimeric antibodies or antigen-binding fragments thereof, analogs, orthologs, homologs and derivatives of the exemplified antibody, that exhibit a biological activity, e.g., binding of an antigen such as TTR. The antibodies may contain one or more analogs of an amino acid (including, for example, non-naturally occurring amino acids, amino acids which only occur naturally in an unrelated biological system, modified amino acids from mammalian systems etc.), antibodies with substituted linkages, as well as other modifications known in the art.

The anti-TTR antibody fragment can be selected from the group consisting of bis-Fab, Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.

In certain embodiments, the anti-TTR antibody is a monoclonal antibody (mAb). The anti-TTR antibody may be a human or chimeric antibody. The anti-TTR antibody may be an IgG antibody. The anti-TTR antibody may be a recombinant human IgGl antibody.

In an embodiment, the human anti-TTR antibody or antigen-binding fragment thereof does not elicit an anti-drug antibody (ADA) response in a human subject. The anti-TTR antibody or antigen-binding fragment thereof may have a VH region including an amino acid sequence with 100% sequence identity to the amino acid sequence of SEQ ID NO: 7 and a VL region including an amino acid sequence with 100% sequence identity to the amino acid sequence of SEQ ID NO: 8.

In this context, the person skilled in the art is aware that effector function and intensity can, inter alia, depend on the IgG class or isotype and that IgG2 and IgG4 have only attenuated effector functions compared to IgGl or IgG3. Therefore, in an embodiment, the anti-TTR antibody described herein can be of the IgGl or IgG3 class or isotype, for example, IgGl. Of course, besides using native IgG immunoglobulins corresponding effector functions can be genetically engineered; see, e.g., Saunders KO (2019) Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life. Front. Immunol. 10: 1296. doi: 10.3389/fimmu.2019.01296.

The five primary classes of immunoglobulins are IgG, IgM, IgA, IgD and IgE. These are distinguished by the type of heavy chain found in the molecule. IgG molecules have heavy chains known as gamma-chains; IgMs have mu-chains; IgAs have alpha-chains; IgEs have epsilon-chains; and IgDs have delta-chains; see for review, e.g., Schroeder et al., J. Allergy Clin. Immunol. 125 (2010), S41-S52. Furthermore, different subclasses exist, wherein the IgAs are further divided into subclasses IgAl and IgA2, and wherein IgGs are further divided into subclasses IgGl, IgG2, IgG3, and IgG4. Furthermore, two types of light chain, kappa (K) and lambda ( ) exist.

In principle, the antibody as used in accordance with the present disclosure may be of any kind of class and subclass, respectively, and may comprise any kind of light chain, as long as the antibody binds to misfolded and preferably aggregated forms of TTR, and preferably as long as binding specificity towards TTR as indicated in the Examples of WO 2015/092077 Al for antibody NI-301.37F1 remains unaffected in kind and as long as no adverse effects occur when administering said antibody to a patient, wherein the adverse effects can be determined as described in Example 1. However, preferably complete IgG antibodies are used, wherein the antibody comprises a constant domain. Accordingly, in one embodiment, the immunoglobulin heavy and/or light chain constant domain present in the antibody as used in accordance with the present disclosure is of the IgG type, the IgM type, the IgA type, the IgD type or the IgE type, preferably of the IgG type. In one embodiment, the immunoglobulin heavy and/or light chain constant domain present in the antibody as used in accordance with the present disclosure is of the IgAl, IgAl, IgGl, IgG2, IgG3, or IgG4 subclass, preferably of the IgGl, IgG2, IgG3, or IgG4 subclass and most preferably of the IgGl subclass.

As mentioned above, NI006/ALXN2220 induces antibody-mediated phagocytosis of ATTR fibrils by phagocytic immune cells such as macrophages, resulting in the clearance of ATTR deposits from tissues. Thus, in one embodiment, the antibody comprises a region equivalent to the human IgG constant region, and which is capable of mediating phagocytosis, like a IgA subclass or engineered Fc regions as for example described in Liu et al., Antibodies 9 (2020), 64.

Recombinant expression of complete human IgGl antibodies with a human or mouse constant domain can be performed substantially as described in the Examples of WO 2015/092077 Al. Preferably, the antibody is a monoclonal antibody or derived from a monoclonal antibody.

There are not only the above-mentioned four subclasses of IgGs but human heavy and light chain genes also exhibit extensive structural polymorphism(s) and, being closely linked, are inherited as a haplotype. Allotypic variants can be immunogenic and provoke antibody responses as a result of allo-immunization. Thus, switching the allotype can be of particular interest to provide non-immunogenic antibody therapeutics. So far, extensive allotypes (polymorphisms) are known, but focus is put on the serologically defined allotypes. Allotypes of IgG proteins are defined by the expression of unique epitope(s) recognized by unique serologic reagent(s). Allotypes expressed on the constant region of IgG heavy chain are designated as Gm (Genetic marker) together with the subclass, e.g., Glm, and the allotype number (or letter), e.g., Glml [or Glm(a)], G3m5 [or G3m(bl)]. Human immunoglobulin allotypes are listed in Table 1 of Jefferis and Lefrance, mAbs 1 (2009), 1-7 and in Fig. 1A of Irani et al., Molecular Immunology 67 (2015), 171-182, which content is herein incorporated by reference. Accordingly, in one embodiment, the antibody as used in accordance with the present disclosure is of any one of the following allotypes, but not limited thereto: Glml, Glm2, Glm3, Glml7, G2m23, G3m21, G3m28, G3ml l, G3m5, G3ml3, G3ml4, G3ml0, G3ml5, G3ml6, G3m6, G3m24, G3m26, G3m27, A2ml, A2m2, A2m3, Eml, Kml, Km2, and Km3, but preferably of Glm2, Glm3, or Glm 17, and most preferably of Glm3.

As explained above, antibody NI006/ALXN2220 is a fully human IgGlm3 allotype antibody and composed of two identical heavy chains of the IgGl subclass and the IgGlm3 allotype. In addition, as mentioned above, original human antibody NI-301.37F1 is of the kappa type and thus, NI006/ALXN2220 is composed of two identical light chains of the kappa subclass. The sequences of the variable heavy (VH) and variable light (VL) chains of NI006/ALXN2220 are set forth in SEQ ID NOs: 7/11 and 8, respectively, and each isotype like the IgGlm3 isotype has a unique amino acid sequence of the constant regions of their heavy chains; see Jefferis and Lefrance (2009), supra. Thus, in one embodiment, the antibody as used in accordance with the present disclosure is characterized by two heavy chains, wherein each heavy chain (HC) comprises a amino acid sequence set forth in SEQ ID NO: 9, and by two light chains, wherein each light chain (LC) comprises a amino acid sequence set forth in SEQ ID NO: 10. Each heavy chain is comprised of 450 amino-acid residues, and each light chain consists of 214 amino acid residues. The four chains are stabilized by intra-chain and inter-chain disulfide bonds, wherein the positions of the disulfide bridges, which have been identified per Lys-C and trypsin digestion and subsequent LC-MS (see Example 2) are the following:

LC:C23-LC:C88

LC:C134-LC:C194

LC:C214-HC:C223

HC:C22-HC:C97 HC:C147-HC:C203

HC1:229-HC2:229 and HC1:232-HC2:232

HC:C264-HC:C324

HC:C370-HC:C428.

(amino acid numbering corresponds to the heavy and light chain sequence set forth in SEQ ID NOs: 9 and 10)

Thus, in one embodiment, the antibody for use in accordance with the present disclosure comprises at least 8 disulfide bridges, preferably at the above-identified positions.

Furthermore, each heavy chain of antibody NI006/ALXN2220 contains a single N-linked glycosylation site at Asn300. The N-linked glycosylation structure is predominantly a fucosylated, complex biantennary glycan with 0 galactose residues (GOF) (about 49 %) or with 1 galactose residue (GIF) (about 25 %). The detailed glycosylation profile is shown in Example 2. Glycosylation plays a vital role in the stability, in vivo activity, solubility, serum half-life and immunogenicity of many therapeutic proteins. N-glycan analysis determines the relative distribution of N-glycans released from the glycoprotein, and provides insightful information on the safety and efficacy of bio-therapeutics.

Thus, in one embodiment, the antibody for use in accordance with the present disclosure has a heavy chain which is N-glycosylated, preferably wherein the N-linked glycosylation site is Asn300, preferably wherein the antibody comprises a N-linked glycosylation structure which is predominantly a glycan with 0 galactose residues (GOF) (about 49 %) or with 1 galactose residue (GIF) (about 25 %). Most preferably, the antibody has the glycosylation profile as shown in Example 2.

Furthermore, one or several amino acids at the amino or carboxy terminus of the light and/or heavy chain, such as the C-terminal lysine of the heavy chain, may be missing or derivatized in a proportion or all of the molecules.

Thus, in one preferred embodiment, the antibody for use in accordance with the present disclosure has a heavy chain that does not comprise a C-terminal lysine. For example, in such embodiment, the C-terminal lysine included in SEQ ID NO: 9 is missing. The sequence of such a heavy chain is set forth in SEQ ID NO: 13. In addition, or alternatively, the antibody for use in accordance with the present disclosure has a heavy chain, in which the glutamine at the N-terminal is derivatized, preferably substituted with pyroglutamate. This pyroglutamate formation is also referred to as N-terminal cyclization. The sequence of such a heavy chain is set forth in SEQ ID NO: 14 or SEQ ID NO: 15, in which the N-terminal glutamine is absent.

Most preferably, the antibody for use in accordance with the present disclosure has a heavy chain that does not comprise a C-terminal lysine, i.e., which C-terminal lysine has undergone C -terminal lysine clipping, in which the glutamine at the N-terminal is substituted with pyroglutamate, i.e., which has undergone N-terminal glutaminyl cyclization (see SEQ ID NO: 15), and which is N-glycosylated.

The amino acid sequences of the heavy and light chains are shown below:

QLQLQESGPGLVKPSETLSLTCSVSGGSIISRSSYWGWIRQPPGKGLEWIGGIYHSGNTYD NPSLKSRLTMSVDTSKNQFSLNLRSVTAADTAVYYCARIVPGGDAFDIWGQGTMVTVSS

(SEQ ID NO: 9, NI006/ALXN2220, heavy chain amino acid sequence, wherein the amino acids of the constant region are underlined, and wherein the C-terminal lysine (K) is optional and/or the N-terminal glutamine (Q) undergoes intramolecular cyclization, resulting in the formation of pyroglutamic acid)

DIQMTQSPSSLSASVGDRVTIACRASQSVGTYLNWYQQKRGKAPKLLIFAASSLQSGVPS RFSGSGSGTDFTLTISSLOPEDFATYYCOQSYSSPPTFGOGTKVEIKRTVAAPSVFIFPPSDE

(SEQ ID NO: 10, NI006/ALXN2220, light chain amino acid sequence, wherein the amino acids of the constant region are underlined) In addition, but to a minor extent and preferably in negligible amounts, some antibody species may have undergone other post-translational modifications (PTMs) such as partial cleavage, oxidation, deamidation, succinimide or pyroglutamate formation and isomerization. The PTMs identified to be present in NI006/ALXN2220 are referred to in Example 2. In particular, next to the above-mentioned C-terminal lysine clipping and cyclization of the N-terminus, the antibody as used in accordance with the present disclosure may show methionine (M) oxidation, preferably at HC position 255; asparagine (N) deamidation, preferably at HC position 318 and/or at HC position 387; asparagine (N) succinimide formation, preferably at HC position 318; and/or amidation of the C-terminal proline (P) after the loss of the C-terminal lysine and glycine.

Furthermore, the theoretical molecular weight of antibody NI006/ALXN2220 is 144.2 kDa, and the weight determined by mass spectrometry (MS) is 144.2 kDa (deglycosylated) and between 147.0 and 147.6 kDa (intact IgGl), respectively. Thus, in one embodiment, the antibody comprised in the pharmaceutical composition of the present disclosure has a molecular weight of about 150 kDa, preferably of about 147 kDa.

Thus, the present disclosure relates in one aspect to an anti-TTR antibody for use in the treatment of cardiac ATTR, wherein the treatment comprises:

(i) assessing amyloid rebound and classifying the subject with amyloid rebound or without amyloid rebound in accordance with the criteria mentioned above,

(ii)(a) treating a subject with amyloid rebound with a full dose treatment of an anti-TTR antibody for a duration of 32 weeks as defined hereinbefore and continue treatment of the subject with the maintenance treatment according to the present disclosure thereafter; or

(ii)(b) treating a subject without amyloid rebound with the maintenance treatment in accordance with the present disclosure;

(iii) assessing amyloid rebound after step (ii)(a) or after step (ii)(b) and classifying the subject with amyloid rebound or without amyloid rebound in accordance with the criteria mentioned above; and

(iv)(a) treating a subject with amyloid rebound with a full dose treatment of the anti-TTR antibody for a duration of 32 weeks as defined hereinbefore and continue treatment of the subject with the maintenance treatment in accordance with the present disclosure thereafter; or (IV)(b) continue treating a subject without amyloid rebound with the maintenance treatment in accordance with the present disclosure, preferably wherein full dose and maintenance treatment are performed with the same anti-TTR antibody, preferably with antibody NI006/ALXN2220, preferably wherein the maintenance treatment is administered at any of the dosing regimens described above, preferably Q16W- Q26W, preferably Q16W and comprises 2400 mg of the anti-TTR antibody; or Q2W-Q6W, preferably Q4W and comprises 600 mg of the anti-TTR antibody, and the full dose treatment is administered Q4W and comprises a weight-bracketed flat dose regimen comprising: (i) 2400 mg to a subject having body weight of < 60 kg; (ii) 3200 mg to a subject having body weight of > 60 kg and < 100 kg; and (iii) 4800 mg to a subject having a body weight of > 100 kg.

In a preferred embodiment, maintenance treatment is started after completion of the initial full dose treatment (no assessment whether a patient has experienced amyloid rebound or not is thus necessary), meaning that the maintenance treatment is preferably carried out following the full dose treatment without a treatment pause. Thus, the present disclosure relates in a preferred aspect to an anti-TTR antibody for use in the treatment of cardiac ATTR, wherein the treatment comprises:

(i) initial full dose treatment of the subject as defined hereinbefore, wherein the full dose treatment comprises administering a full dose of an anti-TTR antibody, preferably the anti-TTR antibody as defined hereinbefore, to the subject for at least 24 months, preferably for at least 48 months and/or until amyloid depletion has been achieved, or until one of the above-mentioned symptoms has been improved or the above-mentioned treatment effects have been achieved, preferably wherein the anti-TTR antibody is the antibody as defined hereinbefore, preferably NI006/ALXN2220, and is administered at a dose of 2400 mg to a subject weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a subject weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a subject weighing equal or more than 100 kg (> 100 kg) every four weeks (q4w) via IV infusion; and subsequently

(ii) maintenance treatment according to the present disclosure, preferably wherein the maintenance treatment comprises administering an anti-TTR antibody, which is preferably the same anti-TTR antibody used for the full dose treatment, at a concentration of 2400 mg every 16-26 weeks (Q16W-Q26W), preferably Q16W via IV infusion, or of 600 mg every 2-6 weeks (Q2W to Q6W), preferably Q4W via IV infusion, preferably wherein the antibody is administered lifelong. The present disclosure relates in a further aspect to an anti-TTR antibody for use in the treatment of TTR amyloidosis (ATTR), preferably of cardiac ATTR in a subject, preferably wherein the antibody is the antibody as defined hereinbefore, wherein the treatment comprises:

(i) initial full dose treatment of the subject, which comprises administering a full dose of an anti-TTR antibody to the subject for at least 24 months, preferably for at least 48 months and/or until amyloid depletion has been achieved, or until one of the above- mentioned symptoms have been improved or the above-mentioned treatment effects have been achieved, preferably wherein the anti-TTR antibody is the antibody as defined hereinbefore, preferably antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a subject weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a subject weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a subject weighing equal or more than 100 kg (> 100 kg) every four weeks (q4w) via IV infusion;

(ii) pausing the treatment until amyloid rebound is detected in the subject and the subject is classified as amyloid rebound in accordance with the criteria mentioned above, and

(iii) full dose treatment of the subject with amyloid rebound, which comprises administering a full dose of an anti-TTR antibody to the subject for a maximum of 32 weeks, preferably for 8 to 32 weeks and/or until amyloid depletion has been achieved, or until one of the above-mentioned symptoms have been improved or the above-mentioned treatment effects have been achieved, preferably wherein the anti-TTR antibody is the anti-TTR antibody as defined hereinbefore, preferably antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a subject weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a subject weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a subject weighing equal or more than 100 kg (> 100 kg) every four weeks (q4w) via IV infusion; optionally

(iv) repeating steps (ii) and (iii), and/or switching to the maintenance treatment after a full dose treatment.

As outlined in international application WO 2024/105092 Al in detail, which content is herein incorporated by reference, a formulation comprising 50 mg/mL of the antibody, i.e., NI006/ALXN2220, in 20 mM histidine buffer, 80 mg/mL or 65 mg/mL sucrose, and 0.3 mg/mL polysorbate 80, at pH 5.8 has been found to be particularly suitable to ensure longterm stability of the drug product. Thus, a formulation comprising 50 mg/mL of the antibody, i.e., NI006/ALXN2220, in 20 mM histidine buffer, 80 mg/mL sucrose, and 0.3 mg/mL polysorbate 80, at pH 5.8 has been used in the Clinical Trials as described in the Examples, below.

Accordingly, in one embodiment, the anti-TTR antibody used in accordance with the present disclosure is administered to the subject by intravenous infusion in an aqueous formulation, in which the aqueous formulation has a pH of about 5.0 to 6.5, includes a histidine buffer, a sugar such as sucrose, and a surfactant such as polysorbate 80 (PS80), and in which the anti-TTR antibody is present in the aqueous formulation at a concentration of about 25 to 125 mg/mL.

Preferably, the aqueous formulation has a pH of about 5.8 and includes 20 mM histidine (e.g., histidine hydrochloride, e.g., L-histidine and/or L-histidine monohydrochloride), 6.5% weight per volume (w/v) sucrose, and 0.03% PS80 w/v, and in which the antibody is present in the aqueous formulation at a concentration of about 50 mg/mL or about 100 mg/mL preferably of about 50 mg/mL.

More preferably, the aqueous formulation has a pH of about 5.8 and includes 20 mM histidine (e.g., histidine hydrochloride, e.g., L-histidine and/or L-histidine monohydrochloride), 8% weight per volume (w/v) sucrose, and 0.03% PS80 w/v, and in which the anti-TTR antibody is present in the aqueous formulation at a concentration of about 50 mg/mL or about 100 mg/mL, preferably of about 50 mg/mL.

In one embodiment, the anti-TTR antibody as used in accordance with the present disclosure is administered to the subject in a diluted form including a diluent. Preferably, the diluent is glucose or a polymer thereof (e.g., the polymer is dextran). The glucose or polymer thereof (e.g., dextran) may be used as a diluent at a concentration of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/v, and preferably of about 5%.

The intravenous infusion can be performed with a syringe pump with an infusion syringe or an infusion pump. In an embodiment, a total antibody dose of up to 100 mg is administered by infusion, for example, a syringe pump with an infusion syringe. In an embodiment, a total antibody dose greater than 100 mg is administered with an infusion pump. In an embodiment, the anti-TTR antibody is diluted into an infusion bag prefilled with the diluent. In some embodiments, the infusion syringe includes a minimum administration volume of 10 mL of the aqueous formulation. In some embodiments, a total volume of the diluted form administered to the subject does not exceed 200 mL (e.g., about 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 55 mL, 60 mL, 65 mL, 70 mL, 75 mL, 80 mL, 85 mL, 90 mL, 95 mL, 100 mL, 105 mL, 110 mL, 115 mL, 120 mL, 125 mL, 130 mL, 135 mL, 140 mL, 145 mL, 150 mL, 155 mL, 160 mL, 165 mL, 170 mL, 175 mL, 180 mL, 185 mL, 190 mL, 195 mL, or 200 mL), including a flushing volume. For example, in some embodiments, the total volume of a single administration does not exceed 200 mL. In some embodiments, at least for a first infusion, the aqueous formulation is administered over approximately 2 hours (±10 minutes). In some embodiments, the aqueous formulation is administered over approximately 1 hour (±10 minutes).

In a preferred embodiment, the anti-TTR antibody will be administered intravenously using a dosing syringe in a syringe pump or an infusion bag. An aqueous formulation as defined hereinbefore of the anti-TTR antibody should be brought to room temperature before use. Immediate use after opening a single-use vial containing anti-TTR antibody is recommended. The anti-TTR antibody should be clear or slightly opalescent and colorless or slightly yellow. Aqueous anti-TTR antibody formulations which are cloudy or with deposits must not be used.

The present disclosure further relates to an article of manufacture or kit used for maintenance treatment of ATTR, preferably cardiac ATTR, comprising one or more container(s) comprising a formulation of an anti-TTR antibody in a total amount of 2400 mg or multiple doses of any one thereof, and a leaflet prescribing that the antibody is to be administered at a dosage of 2400 mg once every 16 to 26 weeks, preferably once every 16 weeks.

The present disclosure further relates to an article of manufacture or kit used for maintenance treatment of ATTR, preferably cardiac ATTR, comprising one or more container(s) comprising a formulation of an anti-TTR antibody in a total amount of 150 mg or multiple doses of any one thereof, e.g., 600 mg, 1200 mg, 2400 mg, and a leaflet prescribing that the antibody is to be administered at a dosage between 150 mg to 3000 mg, wherein the administration interval is calculated based on the following formula: T= 1/150 x D, wherein r (tau) is the administration interval in weeks and D is the dose in milligrams, preferably wherein the leaflet describes that the antibody is to be administered at a dosage of 2400 mg once every 16 to 26 weeks, preferably once every 16 weeks, or at a dosage of 600 mg once every two to six weeks, preferably once every four weeks, or at a dosage of 1200 mg once every six to ten weeks, preferably once every eight weeks. As mentioned above, the dosage regime can be adapted in view of the tolerance in the patient.

The antibody is preferably the anti-TTR antibody as defined hereinbefore, and most preferably antibody NI006/ALXN2220 as characterized by its CDRs and its VH and VL region, respectively, and most preferably by its two heavy chains and two light chains.

The present disclosure further relates to an ATTR maintenance treatment method, preferably cardiac ATTR, wherein the treatment comprises administering of an anti-TTR antibody as defined herein in the treatment regimen as defined hereinbefore to a subject in need thereof.

The present disclosure further relates to a method of treating TTR amyloidosis in a human patient in need thereof, the method comprising:

(i) assessing amyloid rebound and classifying the patient with amyloid rebound or without amyloid rebound according to the criteria as defined hereinbefore;

(ii)(a) treating a patient with amyloid rebound with a full dose treatment of an anti-TTR antibody, preferably NI006/ALXN2220 for a duration of 32 weeks in the subsequent cycle and continue treatment of the patient with maintenance treatment in accordance with the present disclosure, with the anti-TTR antibody, preferably NI006/ALXN2220 thereafter; or

(ii)(b) treating a patient without amyloid rebound with maintenance treatment in accordance with the present disclosure, with the anti-TTR antibody, preferably with NI006/ALXN2220; and

(iii) assessing amyloid rebound at the end of cycle 2 in the maintenance treatment of (ii)(a) or cycle 1 in the maintenance treatment of (ii)(b); and

(iv)(a) treating a patient with amyloid rebound with a full dose treatment with the anti-TTR antibody, preferably with NI006/ALXN2220 for a duration of 32 weeks in the subsequent cycle and continue treatment of a patient with the maintenance treatment in accordance with the present disclosure, with the anti-TTR antibody, preferably with of NI006/ALXN2220 thereafter; or

(iv)(b) continue treating a patient without amyloid rebound with the maintenance treatment in accordance with the present disclosure, with the anti-TTR antibody, preferably with of NI006/ALXN2220, wherein the maintenance treatment is administered at any of the doses and administration intervals as referred to above and the full dose treatment is administered Q4Q and comprises a weight- bracketed flat dose regimen comprising: (i) 2400 mg to a patient having body weight of < 60 kg; (ii) 3200 mg to a patient having body weight of > 60 kg and < 100 kg; and (iii) 4800 mg to a patient having a body weight of > 100 kg.

(iv)(b) continue treating a patient without amyloid rebound with the maintenance treatment in accordance with the present disclosure, with the anti-TTR antibody, preferably with of NI006/ALXN2220, wherein the maintenance treatment is administered Q16W-Q26W, preferably Q16W and comprises 2400 mg of NI006/ALXN2220 and the full dose treatment is administered Q4Q and comprises a weight-bracketed flat dose regimen comprising: (i) 2400 mg to a patient having body weight of < 60 kg; (ii) 3200 mg to a patient having body weight of > 60 kg and < 100 kg; and (iii) 4800 mg to a patient having a body weight of > 100 kg. Alternatively, the present disclosure relates to a method of treating TTR amyloidosis in a human patient in need thereof, the method comprising:

(iv)(b) continue treating a patient without amyloid rebound with the maintenance treatment in accordance with the present disclosure, with the anti-TTR antibody, preferably with of NI006/ALXN2220, wherein the maintenance treatment is administered Q2W-Q6W, preferably Q4W and comprises 600 mg of NI006/ALXN2220 and the full dose treatment is administered Q4Q and comprises a weight- bracketed flat dose regimen comprising: (i) 2400 mg to a patient having body weight of < 60 kg; (ii) 3200 mg to a patient having body weight of > 60 kg and < 100 kg; and (iii) 4800 mg to a patient having a body weight of > 100 kg.

Alternatively, the present disclosure relates to a method of treating TTR amyloidosis in a human patient in need thereof, the method comprising:

(iv)(b) continue treating a patient without amyloid rebound with the maintenance treatment in accordance with the present disclosure, with the anti-TTR antibody, preferably with of NI006/ALXN2220, wherein the maintenance treatment is administered Q6W-Q10W, preferably Q8W and comprises 1200 mg of NI006/ALXN2220 and the full dose treatment is administered Q4Q and comprises a weight-bracketed flat dose regimen comprising: (i) 2400 mg to a patient having body weight of < 60 kg; (ii) 3200 mg to a patient having body weight of > 60 kg and < 100 kg; and (iii) 4800 mg to a patient having a body weight of > 100 kg.

In a preferred embodiment, the patient only receives full dose treatment for 32 weeks once during the treatment cycle.

(i) initial full dose treatment of the patient, which comprises administering a full dose of an anti-TTR antibody to the patient for at least 24 months, preferably for at least 48 months and/or until amyloid depletion has been achieved, or until one of the above- mentioned symptoms have been improved or the above-mentioned treatment effects have been achieved, preferably wherein the anti-TTR antibody is the antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a patient weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion; and subsequently

(ii) maintenance treatment of the patient according to the present disclosure, preferably wherein the maintenance treatment comprises administering an anti-TTR antibody, preferably the same antibody as used during full dose treatment, most preferably antibody NI006/ALXN2220 at a concentration of 2400 mg every 16-26 weeks (Q16W- Q26W), preferably Q16W via IV infusion; or a concentration of 600 mg every 2-6 weeks (Q2W-Q6W), preferably Q4W via IV infusion, most preferably 2400 mg Q16W via IV infusion.

Optionally, the method further comprises assessing amyloid rebound in the patient during the maintenance treatment and classifying the patient according to the above-mentioned criteria to be amyloid rebound or not. In case the patient is classified as amyloid rebound, a secondary full dose treatment is applied as explained above, and preferably followed by maintenance treatment in accordance with the present disclosure. In case a patient has no amyloid rebound, maintenance treatment is continued.

Several documents are cited throughout the text of this specification. The contents of all cited references (including literature references, issued patents, published patent applications as cited throughout this application including the background section and manufacturer's specifications, instructions, etc.) are hereby expressly incorporated by reference; however, there is no admission that any document cited is indeed prior art as to the present disclosure.

A more complete understanding can be obtained by reference to the following specific examples which are provided herein for purposes of illustration only and are not intended to limit the scope of the disclosure.

EXAMPLES

Example 1: A Phase 2, Randomized, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of Maintenance Treatment with ALXN2220 in Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

This is a Phase 2, randomized, open-label, multicenter study ("NI006-102") to evaluate the safety and tolerability of maintenance treatment with ALXN2220 compared to active observation in patients with ATTR-CM treated with standard of care therapy. In the unique population of previous participants of the Phase 1 Study ("NI006-101 ") of ALXN2220, changes in amyloid burden after treatment pause (between NI006-101 completion and NI006-102 baseline, average time of treatment pause is approximately 1-2 years) and the safety and immunogenicity of treatment re-start will also be investigated. Participants demonstrating Amyloid Rebound based on a combination of structural and functional parameters will have the opportunity to temporarily receive full dose treatment. All participants will be treated according to the available standard of care at the discretion of the Investigator. Adjustments in the standard of care during the study period will be allowed.

The study consists of a Screening Period and a Primary Evaluation Period. During the Screening Period, participants will be screened for eligibility and eligible participants will undergo a comprehensive baseline assessment of their cardiac status. Results of the baseline assessment in Study NI006-102 will be compared to previous assessments in Study NI006-101. When eligibility is confirmed, participants who do not demonstrate Amyloid Rebound will be randomized in a 1 : 1 ratio to the Maintenance Dose arm or the Observation arm (Figure 1).

The Primary Evaluation Period is split into three cycles of 48 weeks each. During the Primary Evaluation Period, participants in the Maintenance Dose arm will receive infusions of ALXN2220 every 16 weeks (ql6w). In the Observation arm, participants will be actively monitored with on-site visits every 16 weeks without infusions. At the end of each cycle, a comprehensive assessment of the cardiac status will be repeated to identify participants with Amyloid Rebound.

Amyloid Rebound will be assessed according to modified criteria based on the 2021 European Society of Cardiology (ESC) expert criteria for disease progression (Garcia-Pavia et al. 2021, Eur Heart J 42(16): 1554-1568). Participants demonstrating Amyloid Rebound based on these criteria at baseline (compared to last assessment in Study NI006-101) or at the end of Cycle 1 or 2 (compared to the baseline in Study NI006-102), will be treated with Full Dose infusions every 4 weeks (q4w) for 32 weeks. Thereafter, participants will continue in the Maintenance Dose arm until the end of the Primary Evaluation Period. Over the course of the study, each participant can only receive Full Dose treatment for 32 weeks once. STUDY POPULATION

All surviving participants of the Study NI006-101 will be contacted and asked to participate in this study. It is anticipated that some participants who discontinued Study NI006-101 early or who have significant physical limitations, may not be interested in participating in this study. Therefore, the expected number of participants is approximately 30.

STUDY DURATION

The duration of the Primary Evaluation Period will be approximately 144 weeks (2.7 years) depending on the time interval between the three cycles. The total study duration, including Screening Period is expected to be approximately 149 weeks (2.9 years).

SCHEDULE OF ACTIVITIES

Table 2: Schedule of Activities (So A) ^a All screening and baseline assessments are to be performed within 35 days from signing the informed consent form. Screening period can be prolonged in case full assessment of Amyloid Rebound criteria cannot be completed within the 35 days Screening period. ^b Participants who prematurely discontinue ALXN2220 infusions in the Full Dose or Maintenance arm should be encouraged to complete all scheduled visits and assessments according to the Observation arm. Participants withdrawing from the study prior to completion of the Primary Evaluation Period, regardless of cause, will be asked to complete an Early Discontinuation (ED) Visit 16 weeks (± 7 days) post last dose or as soon as possible in case of participation in Observation arm only. ^c The first visit in each cycle should be performed as early as possible, when an assessment of Amyloid Rebound has occurred to determine the eligibility for Full Dose treatment. All subsequent visits should be timed according to the first visit in the respective cycle. The minimum allowed time window between 2 infusions is 21 days within a cycle. The maximum interval between two consecutive cycles is 90 days. ^d The first infusion in the Maintenance arm (clvl) or any first Full Dose infusion (cYvl) is to be administered over 2h (± 15min) intravenously. If this infusion is well-tolerated, further infusions should be administered over 45 min to Ih; infusion durations up to 2h are allowed at Investigators discretion. The postinfusion observation duration should be at least 2h long for the first 3 infusions in the Maintenance Dose or Full Dose arm; thereafter observation durations can be shortened to Ih depending on the Investigator's assessment. ^e Visit clv2 is to be performed approximately 48h after the initial infusion in the Full Dose arm and the Maintenance arm. Visits c2v2 and c3v2 are to be performed in participants receiving an initial infusion at the Full Dose level at c2vl and c3v2, respectively. ^f Includes detailed data of clinical events, laboratory tests, ECGs and imaging collected during clinical routine follow-up at sites after participant's completion in the NI006-101 study. Imaging data may be subject to central re-analysis if specific informed consent is given by the participant.

⁸ A full physical examination includes inspection of general appearance, skin, nose, ears, eyes, neck, throat, heart, abdomen, lungs, vascular system, nervous system, musculoskeletal system, and extremities. Medical standard procedures will be applied. On treatment days, a full physical examination will be performed before the start of the infusion and an abbreviated physical examination, inclusive of general appearance, heart, lungs, skin, musculoskeletal system and extremities and other organs or body systems as clinically indicated should be performed prior to the participant's discharge. On non-treatment days, a full physical examination will be performed. ^h Vital sign measurements will be recorded at each visit and include systolic and diastolic BP, heart rate, respiratory rate, oxygen saturation (SpO2, pulse oximetry), and body temperature. Measurements of systolic and diastolic BP, heart rate and respiratory rate should be made after the participant has been resting for at least 5 minutes. On treatment days, vital signs are to be measured within 15 minutes before of start of infusion (SOI), then every 30 minutes after SOI (± 10 minutes) during the infusion and at the EOI. During the postinfiision observation, vital signs are to be measured 30 and 60 minutes after EOI (± 10 minutes), and then periodically as clinically indicated, until the participant is discharged.

¹ For women of child-bearing potential (WOCBP), serum HCG performed by the central laboratory is required at Screening. Subsequent pregnancy tests should be performed locally using urine dipsticks (up to 1 day prior to infusion), unless otherwise specified by local regulations. A negative test result has to be available before every infusion start.

^J On visits with dosing, a preinfusion ECG and a postinfusion ECG (to be performed up to 30 minutes post EOI) are to be performed. Participants should be resting for at least 5 minutes prior to ECG recording. ^k For participants with dosing visits, blood sampling should be performed before the start of the infusion.

¹ For participants with dosing visits, an additional PK sample should be taken after EOI (to be performed up to 30 minutes post EOI).

“Time window forthese assessments is ± 10 days. ⁿ Not applicable in Germany. Only in participants with contraindications to cMRI and/or longitudinal scintigraphy in Study NI006- 101.

⁰ Optional cardiac, salivary or fat tissue biopsy to be collected in participants who provided separate informed consent during Screening Period and once during Primary Evaluation Period. Time window is ±14 days.

Abbreviations: 6MWT = 6 minute walk test; ADA = antidrug antibodies; AE = adverse event; ATTRv = variant ATTR; BP = blood pressure; cMRI = cardiac magnetic resonance imaging; D = day; ECG = electrocardiogram; ED = Early Discontinuation; EOI = End of infusion; HIV = Human Immunodeficiency Virus; KCCQ = Kansas City Cardiomyopathy Questionnaire; NYHA = New York Heart Association; PK = pharmacokinetic; SAE = Serious Adverse Event; SOI = Start of Infusion;

V = visit; WOCBP = women of childbearing potential OBJECTIVES AND ENDPOINTS

Table 3: Objectives and Endpoints

PLAN OF THE STUDY

SCREENING

Consenting participants will be screened for study eligibility for up to 35 days prior to Day 1. Eligibility of a participant must be confirmed within 35 days. However, Screening Period can be prolongated in case assessment of rebound criteria cannot be completed within the 35 days Screening Period to complete the rebound criteria assessment. Participants who satisfy all the inclusion criteria and meet none of the exclusion criteria will be either randomized or will be allocated to the full dose arm.

RANDOMIZATION

Participants demonstrating Amyloid Rebound at baseline will be allocated to Full Dose treatment during the first cycle and will subsequently continue in the Maintenance Dose arm. All other participants will be centrally randomized to Maintenance Dose or Observation arm in a 1 : 1 ratio using an interactive web response system (IWRS).

Randomization will occur in a block size of 4 and will not be stratified.

PRIMARY EVALUATION PERIOD

During the Primary Evaluation Period, participants will receive study intervention (ALXN2220 2400 mg ql6w) or active observation for three cycles of 48 weeks duration each, resulting in a total duration of 144 weeks (approximately 3 years).

Participants in the Maintenance Dose arm will receive intravenous infusions of ALXN2220 every 16 weeks (ql6w). In the Observation arm, participants will be actively observed with on- site visits every 16 weeks without infusions. At the end of each cycle, a comprehensive assessment of the cardiac status will be repeated to identify participants with Amyloid Rebound.

Amyloid Rebound will be assessed by the Investigator and Sponsor according to modified criteria based on the 2021 European Society of Cardiology (ESC) expert criteria for disease progression (Garcia-Pavia et al. 2021, Eur Heart J 42(16): 1554-1568) summarized in Table 4. At least one criterion in each of the three domains (cardiac structure, cardiac function, overall function) needs to be fulfilled for a participant to be classified as Amyloid Rebound. In case of disagreement between the Investigator and the Sponsor, the DEC will be asked to provide a recommendation whether a case should be classified as Amyloid Rebound or not. The final decision is with the Sponsor.

Table 4: Amyloid Rebound Criteria

Abbreviations: ATTR-CM = Amyloid transthyretin cardiomyopathy; ECV = Extracellular volume; EDIVS = End diastolic interventricular septum; GLS = Global longitudinal strain; LV = Left ventricle; LVEF = Left ventricular ejection fraction; NT-proBNP = N-terminal pro b-type natriuretic peptide; NYHA = New York Heart Association

Participants demonstrating Amyloid Rebound based on these criteria at baseline (compared to last assessment in Study NI006-101) or at the end of Cycle 1 or 2 (compared to the baseline in Study NI006-102), will be treated with Full Dose infusions every 4 weeks (q4w) for 32 weeks. Thereafter, participants will continue in the Maintenance arm until the end of the Primary Evaluation Period. Over the course of the study, each participant can only receive Full Dose treatment for 32 weeks once, irrespective of whether the collected data indicates an Amyloid Rebound a second time. Participants completing the Primary Evaluation Period will have their last visit at Visit c3vl 1. RATIONALE FOR STUDY DESIGN

RATIONALE FOR STUDY POPULATION

Previously treated participants in the Study NI006-101 are a unique population to investigate changes in amyloid burden after a treatment pause (between the end of NI006-101 and the start of Study NI006-102) and the safety and immunogenicity of treatment resumption. In addition, previously treated participants are the most appropriate population to study a maintenance treatment regimen.

RATIONALE FOR TREATMENT AND ACTIVE OBSERVATION ARMS

It is currently unknown, whether treatment with ALXN2220 can be stopped after amyloid depletion has been achieved or if maintenance treatment is beneficial.

Participants who have not experienced Amyloid Rebound at baseline will be randomized in a 1 :1 ratio to the Maintenance Dose arm or the Observation arm. An active Observation arm where participants receive standard of care therapy will allow comparison with ALXN2220 maintenance treatment on top of standard of care. Adaptations in the standard of care, e.g., after approval of novel therapies for ATTR-CM, will be allowed in both arms. The Declaration of Helsinki mandates the use of standard of care treatments as controls.

The Full Dose arm was added to allow participants experiencing Amyloid Rebound to receive 8 administrations of the same dose of ALXN2220 as in Study ALXN2220-ATTRCM-301. This duration corresponds to the treatment duration of the Open-Label Extension in Study NI006- 101, during which amyloid reduction could be achieved.

RATIONALE FOR STUDY DURATION

Assessment of Amyloid Rebound will be performed approximately every 12 months. Based on previously published data (Damy et al, ESC 2023), Amyloid Rebound was calculated to occur in approximately 5 - 10% of participants per year. Therefore, a total duration of 3 years will allow a comparison of Amyloid Rebound between the Maintenance Dose and Observation arm.

JUSTIFICATION FOR DOSE

The justification for the dose is described in Example 2 below.

INCLUSION CRITERIA

Eligible participants must meet all of the following criteria for inclusion: 1. Must have received at least a partial dose of ALXN2220 in Study NI006-101 and, in the opinion of the Investigator, tolerated the study drug

2. Able to understand and sign an informed consent form prior to initiation of any study procedures, and willing and able to comply with all study procedures

3. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and must agree to use highly effective physician-approved contraception from screening to 5 months after ending study participation

4. Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 7 months after the last dose of study intervention:

• Refrain from donating fresh unwashed semen

Plus, either:

• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent

OR

• Must agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception

EXCLUSION CRITERIA

Participants who meet any of the following criteria will not be able to participate in the study:

1. Any new or uncontrolled condition after completion of Study NI006-101 that could make the participant unsuitable for participation in this study, per Investigator's assessment

2. Suspected or known intolerance/allergy to proteins or any components of the study drug

3. Treatment or study discontinuation in Study NI006-101 due to a treatment-related adverse event that was serious, severe or life-threatening (on CTCAE scale)

4. Participation in another investigational clinical study or intake of investigational drug within 30 calendar days or 5 half-lives of Day 1, whichever is longer

5. Acute coronary syndrome, unstable angina, stroke, transient ischemic attack, coronary revascularization, cardiac device implantation, cardiac valve repair, or major cardiac surgery within 3 months of screening

6. Average resting systolic BP < 90 mm Hg or symptomatic orthostatic hypotension at screening per Investigator's assessment

7. Uncontrolled clinically significant cardiac arrhythmia, per Investigator's assessment 8. Hemoglobin < 8 g/dL for women or < 9 g/dL for men measured at screening

9. Platelet count < 100000/mm3 or other disorder associated with clinically significant thrombocytopenia measured at screening

10. Current unstable liver or biliary disease per Investigator's assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Participants with severe hepatic impairment (e.g., Child Pugh Class C) are not eligible a. Note: Stable chronic liver disease (including Gilbert's syndrome, asymptomatic gallstones, and chronic stable hepatitis B e.g., the presence of HBsAg, or positive hepatitis C antibody test result without evidence of active infection at screening or within 3 months prior to starting study intervention) is acceptable if the participant otherwise meets entry criteria

11. Lymphoma, leukemia, or any malignancy within the past 5 years except for: a. Adequately treated basal cell or squamous epithelial carcinomas of the skin, or cervical carcinoma in situ that have been resected curatively with no evidence of metastatic disease b. Adequately treated stage I cancer from which the participant is currently in remission c. Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen

12. Participants with renal failure requiring dialysis or who have an estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease epidemiology collaboration (CKD- EPI) formula < 20 mL/min/1.73 m2 measured at screening

13. Polyneuropathy requiring a wheelchair (ie, Polyneuropathy disability score IV)

14. Known medical or psychological condition(s) or risk factor that, in the opinion of the Investigator or Sponsor, might interfere with the participant's full participation in the study, pose any additional risk for the participant, or confound the assessment of the participant or outcome of the study

15. Body weight < 40 kg at screening

16. Use of disallowed medication

17. History of HIV or positive HIV antibody test

18. History of bleeding diathesis or coagulopathy e.g., antiphospholipid antibody syndrome, congenital disorders such as hemophilia A, B, and Von Willebrand disease) STUDY INTERVENTION AND CONCOMITANT THERAPY

The study intervention composition and doses to be administered in this study are presented in

Table 5.

Table 5: Study intervention

Abbreviations: IV = intravenous, ql6w = every 16 weeks, q4w = every 4 weeks

ASSIGNMENT OF STUDY INTERVENTION

Participants demonstrating Amyloid Rebound at baseline will be allocated to Full Dose treatment during the first cycle and will subsequently continue in the maintenance arm. All other participants will be centrally randomized to Maintenance Dose or Observation arm in a 1 :1 ratio using an IWRS.

Randomization will occur in a block size of 4 and will not be stratified.

ALXN2220 will be dispensed at the study visits as summarized in the SoA (Table 2).

STUDY INTERVENTION ADMINISTRATION A participant's initial dose [Day 1, clvl] and any later first infusion at the Full Dose level (c2vl or c3vl) will be delivered over approximately 2 hours (±10 minutes). If these infusions are tolerated without safety issues (e.g., grade 2 or higher infusion related reactions or other acute hypersensitivity events), subsequent infusions should be delivered over 45 min to 1 hour; infusion durations up to 2h are allowed at Investigator's discretion. End of infusion (EOI) is defined as completing the whole IMP infusion plus flushing the entire infusion line.

The window for treatment administration is the scheduled date ± 7 days.

The minimal interval between two study intervention administrations is 21 calendar days in the Full Dose and the Maintenance Dose arm.

The maximum interval between two consecutive cycles is 90 days.

ALLOWED MEDICINE AND THERAPY

Participants are to be treated according to the standard therapy, as determined by treating and study physician(s). This includes ATTR-adapted conventional heart failure treatment (including diuretics) and may include approved disease modifying agents for ATTR amyloidosis.

Treatment with locally approved TTR gene silencing agent for ATTR amyloidosis (except as listed in Section Disallowed Medicine and Therapy) is permitted if given prior to enrollment in this study at a stable dose for at least 90 calendar days prior to signing the ICF. New treatment initiation of a TTR gene silencer is allowed at the locally approved dosage regimen, but not during the first 90 days after randomization.

The use of locally approved TTR stabilizers for ATTR amyloidosis and new treatment initiation of a TTR stabilizer are permitted without restrictions, at the locally approved dosage regimen.

The Medical Monitor should be notified if an ATTR disease modifying agent will be started or changed during the duration of the study and detailed information about the reason for change should be provided. If progression of ATTR-CM per Investigator's assessment is the reason for a change in disease modifying agent, this should be recorded in the eCRF.

DISALLOWED MEDICINE AND THERAPY

The following concurrent medications are prohibited during the study, unless taken at a stable dose during Study NI006-101. If use during the study is medically required, treatment needs to be interrupted, at least temporarily for the time of treatment with the disallowed medicine. Inotersen. If previously used, a minimum wash-out period of 180 days prior to Day 1 must be respected.

ATTR amyloid depleter (ie, monoclonal anti-ATTR antibody) approved or in clinical development other than ALXN2220/NI006.

Diflunisal unless prescribed as local standard therapy (for ATTR-CM, pain, or arthritis) under appropriate safety precautions as per Investigator's assessment.

Doxycycline or tauroursodeoxycholic acid (TUDCA). If previously used, a minimum washout period of 14 days prior to Day 1 is required. Short-term usage of doxycycline during the study for indications other than ATTR-CM (e.g., bacterial infection) may be permitted with the agreement of the Medical Monitor.

Non-dihydropyridine calcium channel blockers with conduction system effects e.g., verapamil, diltiazem). If previously used, a minimum wash-out period of 14 days prior to Day 1 is required.

Treatment with systemic immunosuppressive or immune modulating drugs including, but not limited to, antimetabolites e.g., mycophenolate mofetil, azathioprine), calcineurin inhibitors (e.g., cyclosporine, tacrolimus) and non-calcineurin inhibitors (e.g., everolimus, sirolimus), biologic agents and cytokine modulators (e.g., alemtuzumab, basiliximab, daclizumab, muromonab, rituximab, adalimumab, infliximab, etanercept, tocilizumab, stiltuximab). Treatment regimens for multiple myeloma and/or Light Chain (AL) amyloidosis such as cyclophosphamide, bortezomib and dexamethasone, and daratumumab are also not permitted. Short-term use of systemic corticosteroids (e.g., prednisone) may be permitted with the agreement of the Medical Monitor. In particular, systemically administered steroids may be permitted provided that:

1. The dose is < 20 mg/day prednisone or equivalent if administered chronically, or

2. The dose is > 20 mg/day, and the administration is limited to no more than 5 consecutive days.

IV or subcutaneous human immunoglobulins (e.g., IVIG or SCIG).

Cytotoxic chemotherapy (e.g., cyclophosphamide).

STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Table 2). Protocol waivers or exemptions are not allowed. IMAGING AND BIOMARKERS (EFFICACY) ASSESSMENTS

Planned timepoints for all efficacy assessments are provided in the SoA (Table 2). cMRI

Cardiac MRI can be utilized to visualize and indirectly quantify the full continuum of amyloid deposition in the heart (Martinez-Naharro et al. 2017, J Am Coll Cardiol 70(4): 466-477) using advanced cMRI protocols with contrast agents. ECV on cMRI correlates with other markers of ATTR disease status, is predictive of mortality (Martinez-Naharro et al. 2017, J Am Coll Cardiol 70(4): 466-477) and can be considered a surrogate marker of cardiac amyloid load (Garcia-Pavia et al., Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. N. Engl. J. Med. 389 (2023), 239-250). Approximately half of the participants in Study NI006-101 underwent longitudinal cMRI assessments. In Study NI006-102, participants are planned to be followed longitudinally with cMRI, unless the participant does not consent to the procedure, contraindications are present or the participant underwent longitudinal scintigraphic assessment in Study NI006-101. Images will be acquired according to a harmonized acquisition protocol and evaluated by a central laboratory. Results from the central reading will be used to determine whether an Amyloid Rebound criterion is met. Efforts will be made to compare the cMRI assessment in Study NI006-102 with cMRI assessments collected during Study NI006-101 or during routine clinical follow-up after NI006-101 completion.

CARDIAC SCINTIGRAPHY

Cardiac scintigraphy using 99m technetium (99mTc)- 3, 3 -diphosphono- 1,2- propanodicarboxylic acid (DPD), 99mTc-hydroxymethylene diphosphonate (HMDP) and 99mTc-pyrophosphate (PYP) tracers has been established as sensitive and specific tool to identify patients with cardiac ATTR amyloid deposits, has become a cornerstone in the diagnostic algorithm for ATTR-CM (Garcia-Pavia, et al. 2021, Eur Heart J 42(16): 1554-1568; Kittleson et al. 2023, J Am Coll Cardiol 81(11): 1076-1126) and can be used as a surrogate marker for the cardiac amyloid load in patients with ATTR CM (Garcia-Pavia et al., Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. N. Engl. J. Med. 389 (2023), 239-250). Approximately half of the participants in Study NI006-101 underwent longitudinal scintigraphic assessments. Participants with contraindications to cMRI and/or longitudinal scintigraphy in Study NI006-101 should undergo cardiac scintigraphy in Study NI006-102. If possible, the scintigraphic tracer should not be changed across both studies for any participant. Efforts will be made to compare the scintigraphic assessment in Study NI006- 102 with scintigraphic assessments collected during Study NI006-101 or during routine clinical follow-up after NI006- 101 completion. Cardiac scintigraphy will not be performed in Germany, where all participants underwent cMRI during the Study NI006-101.

ECHOCARDIOGRAPHY

Cardiac structure and function in patients with ATTR-CM can be assessed non-invasively with echocardiography, and an increased left ventricular wall-thickness is a component in the diagnostic algorithm of ATTR-CM (Garcia-Pavia et al. 2021, Eur Heart J 42(16): 1554-1568; Kittleson et al. 2023, J Am Coll Cardiol 81(11): 1076-1126). Longitudinal changes in cardiac structure and function will be assessed using serial echocardiograms across all sites and following a harmonized acquisition protocol. Evaluation of all echocardiograms will be performed by a central reader. Results from the central reading will be used to determine whether an Amyloid Rebound criterion is met. Efforts will be made to compare the echocardiographic assessments in Study NI006-102 with echocardiographic assessments collected during Study NI006-101 or during routine clinical follow-up after NI006-101 completion.

CARDIAC BIOMARKERS

Natriuretic peptide (NT-proBNP) and cardiac troponin T (hs-cTnT) are two widely established blood biomarkers of cardiac stress and cardiomyocyte damage with prognostic relevance in ATTR-CM (Grogan et al. 2016, J Am Coll Cardiol 68(10): 1014-1020; Gillmore et al. 2018, Eur Heart J 39(30): 2799-2806). Both will be used to assess ATTR-CM disease status and to evaluate changes in cardiac structure and function over time in response to treatment with ALXN2220. See Section Clinical Laboratory Tests for the list of clinical efficacy laboratory tests to be performed and the SoA (Table 2) for the timing and frequency.

PHARMACOKINETIC S

Blood samples of approximately 2 mL will be collected for measurement of ALXN2220 serum concentrations as specified in the SoA (Table 2).

Instructions for the collection and handling of biological samples will be provided by the Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded.

All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. PHARMACODYNAMIC S

PD measurements of interest include cardiac scintigraphy, echocardiography, and cMRI as well as cardiac markers NT -proBNP and hs-cTnT.

The actual date and time (24-hour clock time) of each sample will be recorded. All efforts will be made to obtain the PD samples at the exact nominal time relative to dosing.

EXPLORATORY (EFFICACY) ASSESSMENTS

KCCQ

The KCCQ is a 23-item questionnaire developed to measure health status and health-related QoL in participants with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their QoL (Table 2). The KCCQ overall summary score (KCCQ-OS) is a valid and reliable health status measure for patients with heart failure and has been employed in randomized controlled studies, including in ATTR-CM (Maurer et al. 2018, N Engl J Med 379(11): 1007-1016; Nativi-Nicolau et al. 2021, ESC Heart Fail 8(5): 3875-3884).

6MWT

The 6MWT measures the distance a participant can quickly walk on a flat, hard surface in a period of 6 minutes. It evaluates the global and integrated response of all the systems involved during exercise. This is a self-paced test; participants choose their own exercise intensity and are allowed to stop and rest during the test (Crapo and Laboratories 2002, Am J Respir Crit Care Med 166(1): 111-117). If the participant has a need for a walking aid (e.g., cane) or supplemental oxygen at baseline, it must be consistently used at each subsequent 6MWT throughout the study.

DISEASE STAGE

Several models using different surrogate markers of disease severity and/or prognosis in ATTR CM are available (Garcia-Pavia et al. 2021, Eur Heart J 42(16): 1554-1568). Although NYHA class has been shown to be prognostic in ATTR-CM, it lacks sensitivity as a standalone tool for detecting more subtle progression of ATTR-CM, and therefore should be interpreted in a multiparametric approach. The Mayo Clinic (Grogan et al. 2016, J Am Coll Cardiol 68(10): 1014-1020), and the UK NAC (Gillmore et al. 2018, Eur Heart J 39(30): 2799-2806) cardiac staging system for patients with ATTR-CM are 2 relatively simple applicable staging systems using universally employed biomarkers NT-proBNP and eGFR or cTnT. Another staging score for ATTR-CM is the Columbia score (Cheng et al. 2020, JACC CardioOncol 2(3): 414-424) which includes NYHA and daily dose of diuretic therapy besides biomarker-based staging.

INTENSIFICATION OF DIURETIC THERAPY

Besides daily dose of diuretic therapy, intensification of diuretic therapy in the outpatient setting is increasingly being recognized as an important prognostic factor in patients with chronic heart failure (Chatur et al., 2023, Eur Heart J 44(31): 2930-2943). In this study, intensification of oral diuretic therapy (e.g., urgent intravenous infusion for decompensated heart failure, initiation of new or combination diuretic therapy, significant augmentation of existing diuretic therapy) is an exploratory endpoint. Details of diuretic therapy will be proactively collected by site personnel at each study visit and reported in the eCRF.

INFLAMMATORY BIOMARKERS

Inflammatory biomarkers will be evaluated to further characterize the degree of immune activation by ALXN2220. Assessments will include the following:

• Complement factors C3 and C4

• ILlb, IL6, IL8, IFNg, tumor necrosis factor a (TNF-a) (proinflammatory cytokines)

• IL10, IL1RA (anti-inflammatory cytokines)

• C-reactive protein (CRP), serum amyloid A (SAA), ferritin (positive acute phase proteins)

CARDIAC, SALIVARY GLAND OR FAT TISSUE BIOPSY (OPTIONAL)

Endomyocardial biopsy has historically been considered the gold standard for establishing the diagnosis of ATTR-CM and continues to be required in the diagnostic algorithm in case of inconclusive results on scintigraphy and hematological tests (Garcia-Pavia et al. 2021, Eur Heart J 42(16): 1554-1568).

If the participant has provided separate informed consent, cardiac, salivary or fat tissue biopsies will be obtained according to a Laboratory Manual. Target engagement of ALXN2220, antibody-mediated amyloid depletion and related biological processes will be explored on tissue from cardiac or extracardiac biopsies.

DONATION OF ADDITIONAL BIOLOGICAL SAMPLES (OPTIONAL) Immunogenicity Assessments Serum samples for ADA (approximately 3 mL blood per sample) will be collected at timepoints according to SoA (Table 2). All efforts will be made to obtain the immunogenicity samples at the exact nominal time relative to dosing.

The detection and characterization of ADA to ALXN2220 will be performed using a validated assay method by or under the supervision of the Sponsor. For ADA positive samples antibody titers will be determined and further characterization may be performed.

Samples may be stored for a maximum of 25 years (or according to local regulations) following the last participant's last visit for the study at a facility selected by the Sponsor.

STATISTICAL CONSIDERATIONS

This section contains a brief summary of the planned statistical analyses.

The statistical analysis of the data obtained from this study will be the responsibility of the Sponsor or designee. A version 1.0 of the Statistical analysis plan (SAP) will be finalized before the first participant will be allocated to study intervention and include a more technical and detailed description of the statistical analyses described in this section. Any analysis that deviates from this plan will be documented in the clinical study report (CSR). The primary analysis will be conducted at the end of the Primary Evaluation Period.

STATISTICAL HYPOTHESES

The primary objective of the study is to evaluate the safety and tolerability of long-term maintenance therapy with ALXN2220. As such, there are no formal statistical hypotheses that will be tested.

ANALYSIS SETS

The following participant analysis sets are defined:

STATISTICAL ANALYSES

Statistical methods described in this section will be further elaborated in the separate SAP.

Descriptive statistics will be used to provide an overview of the results and will be displayed by treatment arm and by visit (or cycle), where applicable. Descriptive statistics for continuous variables will minimally include the number of participants, mean, standard deviation (SD), median, minimum, and maximum. For categorical variables, frequencies, and percentages will be presented. The denominator for percentages will be based on the number of participants appropriate for the purpose of analysis.

GENERAL CONSIDERATIONS

Baseline is defined as the last measurement prior to Day 1 of the first cycle. If the Day 1 assessment is missing, invalid, or collected after administration of study treatment, the latest non-missing assessment prior to Day 1 of the first cycle will be considered instead. In addition, a pre-Full Dose baseline is defined as the last measurement prior to the first Full Dose treatment administration.

Treatment-emergence will be defined as those events which started on or after the date of Day 1 of the first cycle, or whose severity worsened on or after the date of Day 1 of the first cycle. Where applicable, data from Study NI006-101 (e.g., baseline or dosing information) will be used in the Study NI006-102 analyses. Details will be specified in the SAP.

All data and all outcomes derived from the data will be presented in detailed data listings and/or summary tabulations. Graphical displays may also be provided when appropriate.

EFFICACY ENDPOINT ANALYSES

Efficacy analyses will be performed for secondary and exploratory endpoints, as listed below, using descriptive statistics.

For continuous endpoints, these will be presented using absolute values at each visit and change from baseline (or change from last assessment in Study NI006-101 to baseline in Study NI006- 102, as applicable). For categorical endpoints, these will be presented using the number and percentage of participants at each visit. Furthermore, to account for participants who demonstrate Amyloid Rebound at the end of Cycle 1 or 2 and have one cycle of Full Dose treatment before continuing to the Maintenance arm, additional analyses will be performed for the secondary efficacy endpoints using pre-Full Dose baseline instead of baseline and will include all visits after pre-Full Dose baseline.

The Full Analysis Set will be used for analysis of all efficacy data, except for analyses using the pre-Full Dose baseline which will use the Full Dose Set. Additional analyses may be performed using the Completer Set or Per Protocol Set, where appropriate.

Additional sensitivity analyses will be presented with exclusion of data collected following Amyloid Rebound and last observation carried forward from the timepoint of Amyloid Rebound. Details will be specified in the SAP.

Secondary endpoints:

• Change from baseline in cMRI parameters of interest

• Change from baseline in cardiac scintigraphy parameters of interest

• Change from baseline in echocardiography parameters of interest

• Change from baseline in cardiac biomarkers

• Change from baseline in NYHA class

• Change from last assessment in Study NI006-101 to baseline in Study NI006-102 in the above mentioned parameters

• Incidence of participants demonstrating Amyloid Rebound

Exploratory endpoints:

• 6MWT

• KCCQ • Disease stage (NAC, MAYO, Columbia)

• Incidence of intensification of oral diuretic therapy

• Inflammatory biomarkers

• Immunohistochemistry on tissue samples

Further details and methods to be used will be specified in the SAP.

EXAMINATION OF SUBGROUPS

The expected sample size of 30 participants limits the number of potential subgroup analyses. Subgroup analyses may be performed according to specifications outlined in the SAP and may include:

• TTR genotype (variant vs wild-type) (data collected during Study NI006-101)

• Treatment with disease modifying agents (TTR stabilizer vs TTR silencer vs TTR stabilizer/silencer combination vs none)

• Baseline NT-proBNP (NT -proBNP > 3000 pg/mL vs NT-proBNP < 3000 pg/mL)

• NYHA Classification (II vs III-IV)

• Cumulative ALXN2220 dose/exposure in Study NI006-101

• Off-treatment duration between Study NI006-101 and Study NI006-102

CLINICAL LABORATORY TESTS

The tests detailed in Table 6 will be obtained according to the SoA (Table 2) and performed by local and central laboratories as indicated: clinical laboratory tests will be analyzed by local laboratories, biomarker tests will be performed by a central laboratory. Results from the laboratory assessments obtained on dosing days are not required prior to dosing the participants, except for serum or urine HCG pregnancy test as needed for WOCBP.

(Table 2).

Table 6: Protocol-required Laboratory Tests _ ^a Peripheral smear should be reviewed if platelet count < 75,000/mm³ OR if platelet count drops by > 50% compared to preinfusion value. ^b Details of liver chemistry stopping criteria and required actions and follow-up are: Liver Safety: Suggested Actions and Follow-up Assessments. All events of ALT > 3 x ULN and total bilirubin > 2 x ULN (> 35% direct bilirubin) or ALT > 3 x ULN and INR > 1.5 (if INR measured), which may indicate severe liver injury (possible Hy's law), must be reported to ICON in an expedited manner (within 24 hours) and as SAE if SAE criteria are met the INR stated threshold value will not apply to participants receiving anticoagulants. ^c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

Abbreviation Definition

6MWT 6 minute walk test

ADA Anti drug antibody

ADE Adverse Drug Event

AE Adverse event

AL Amyloid light chain

ALT Alanine transaminase

AST Aspartate aminotransferase

ATTR Amyloid transthyretin

ATTR-CM Transthyretin Amyloid Cardiomyopathy

ATTR-PN Transthyretin Amyloid Polyneuropathy

ATTRv Variant ATTR

ATTRwt Wild-type ATTR

AUC Area under the serum concentration-time curve

BMI Body mass index BP Blood pressure BSA Body surface area C Concentration

Cend of infusion End of infusion serum concentration Cmax Maximum observed serum concentration Cthrough Through serum concentration CFR Code Federal Regulation CIOMS Council for International Organizations of Medical Sciences CKD-EPI Chronic kidney disease epidemiology collaboration CL Serum clearance CM Cardiomyopathy cMRI Cardiac magnetic resonance imaging CRO Contract research organization CRP C-reactive protein CSR Clinical study report CTCAE Common terminology criteria for adverse events CTFG Clinical Trial Facilitation Group cYvl Cycle Y Visit 1

D Dav DEC Data evaluation committee DILI Drug-induced liver injury DNA Deoxyribonucleic acid DPD "mTc -3, 3 -diphosphono- 1,2-propanodicarboxylic acid EAPA Europe and Asia Pacific ECG El ectrocardi ogram eCRF Electronic Case report form ECV Extracellular volume ED Early Discontinuation EDC Electronic data capture Abbreviation Definition ED-IVS End diastolic interventricular septum eGFR Estimated Glomerular filtration rate EOI End of infusion ESC European Society of Cardiology EU CTR European Union Clinical Trials Regulation FAS Full Analysis Set FSH Follicle stimulating hormone fF3 Free Triiodothyronine fT4 Free Thyroxine FU Follow-up GCP Good Clinical Practice GDPR General Data Protection Regulation GLP Good Laboratory Practice GLS Global longitudinal strain GMP Good Manufacturing Practice hATTR Hereditary ATTR HBcAb Hepatitis B core antibody HBsAG Hepatitis-B -surf ace- Antigen HCG Human chorionic gonadotropin HIV Human immunodeficiency virus HMDP "mTc-hydroxyl-methylene-diphosphonate HRT hormone replacement therapy hs-cTNT Cardiac troponin T IB Investigator's Brochure ICF Informed Consent Form ICH International Council for Harmonisation IEC Independent Ethics Committee IFN Interferon

IgGl Immunoglobulin- 1 IgM Immunoglobulin M IL Interleukin IL1RA Interleukin-1 receptor antagonist IMP Investigational medicinal product INR International Normalized Ratio IP Intellectual property IRB Institutional Review Board IRR Infusion-related reactions IRT Interactive Response Technology ISF Investigator site file IV Intravenous IVIG Intravenous human immunoglobulins IWRS Interactive web response system KCCQ Kansas city cardiomyopathy questionnaire LV Left ventricle Abbreviation Definition LVEF Left ventricular ejection fraction mAB Monoclonal antibody MD Medical Doctor MedDRA Medical dictionary for regulatory activities MMRM Mixed model repeated measures n Absolute occurrence NAC National Amyloidosis Centre NCI National Cancer Institute NT-proBNP N-terminal pro b-type natriuretic peptide NYHA New York Heart Association PD Pharmacodynamic pH Potential of hydrogen PK Pharmacokinetics PYP "mTc-pyrophosphate ql6w every 16 weeks q4w every 4 weeks RBC Red blood cells REF Chronic heart failure RNA Ribonucleic acid SAA Serum amyloid A SADE Serious Adverse Device Effect SAE Serious adverse event SAF Safety Analysis Set SAP Statistical analysis plan SAS Statistical Analysis System SCIG Subcutaneous human immunoglobulins SCR Screening SD Standard deviation SoA Schedule of Activities SOI Start of infusion SpO2 Oxygen saturation T4 Thyroxine

TEAE Treatment emergent adverse event TNF-a Tumor necrosis factor alpha TSH Thyroid stimulating hormone TTR Transthyretin TUDCA Tauroursodeoxycholic acid UK United Kingdom ULN Upper limit of normal USADE Unanticipated Serious Adverse Device Effect V Visit WBC White blood cells WHO World Health Organization WHO-DD World Health Organization-Drug Dictionary Abbreviation Definition

WOCBP Women of child-bearing potential wt Wild-type

Example 2: Pharmacokinetic simulations for maintenance dose interval selection in the Phase 2 NI006-102 study in patients with transthyretin amyloid cardiomyopathy

ALXN2220 (formerly known as NI006) is a human monoclonal IgGl antibody binding with high affinity and exclusive selectivity to amyloid transthyretin (ATTR). It is being developed as an intravenous (IV) treatment for patients with ATTR-cardiomyopathy (CM). The therapeutic mode of action of ALN2220 involves antibody-dependent activation of the immune system to recognize and eliminate ATTR from tissue in a clearance process involving phagocytosis by immune cells. Elimination of cardiac ATTR is expected to result in reduced heart stiffness, better contractility, and likely in improved heart function.

Based on data from a phase 1, first-in-human, double-blind, placebo-controlled, multicenter, single and multiple ascending dose study of ALXN2220 in patients with ATTR-CM (NI006- 101), a population pharmacokinetic (PK)/pharmacodynamic (PD) model was developed describing ALXN2220 serum concentration and two proxy measurements of cardiac ATTR: short-axis extracellular volume (ECV Mid) by magnetic resonance imaging (MRI) and heart- by-whole body retention (HRWBR) by scintigraphy. The PK/PD analysis data set contained 844 serum ALXN2220 observations and 109 PD observations from 39 patients treated with intravenous (IV) doses ranging from 0.3 to 60 mg/kg administered once every four weeks (Q4W) for up to two years.

A phase 2 study NI006-102 was designed to evaluate the safety and efficacy of maintenance treatment with ALXN2220 compared to active observation in previous participants of study NI006-101. The aim of the current analysis was to select a dose interval that prevents cardiac ATTR rebound after initial amyloid depletion with ALXN2220. The key hypothesis was that achieving the same steady-state serum ALXN2220 average concentration (Cavg) that was shown to reduce cardiac ATTR in the phase 1 study NI006-101 will also prevent cardiac ATTR rebound and that preferably a minimal ALXN2220 dose regimen should be selected that allows the neutralization of a rebound of 5% per year in almost all patients (in about 95% of the patients). 5% amyloid rebound per year in patients suffering from ATTR corresponds to the highest reported rate in the literature to date (Rettl et al., Eur Heart J Cardiovasc Imaging 23 (2022), 767-780). 3 mg/kg IV Q4W was the minimal dose to achieve ATTR reduction at 12 months and 30 mg/kg IV Q4W achieved nearly maximal ATTR reduction at 12 months in study NI006-101. PK/PD modeling indicated that 95% of patients treated at a putative dose of 5 mg/kg administered intravenously Q4W would have an amyloid depletion rate of 5% per year or more (Figure 3). Based on this, median steady-state Cavg values greater or equal to 5 mg/kg Q4W were used as target ALXN2220 exposure. Same steady-state serum ALXN2220 Cavg means that the same total serum ALXN2220 is achieved, once steady-state is reached.

Figure 2 shows the percentage of patients that were predicted to be above the median target steady-state Cavg for different dose intervals, when administered with a dose of 2400 mg IV. 2400 mg IV Q16W was predicted to result in close to 100% of patients with steady-state serum ALXN2220 Cavg larger than median steady-state Cavg after 5 mg/kg IV Q4W and was thus predicted to prevent cardiac ATTR rebound in study NI006-102.

1. SIMULATION APPROACH

The goal of the analysis was to select a dose interval that prevents cardiac ATTR rebound and preferably achieves amyloid reduction of residual ATTR deposits. A limitation of the population PK/PD model was that it did not include ATTR synthesis. It therefore cannot be used to explicitly predict cardiac ATTR rebound. The current analysis used serum ALXN2220 exposure instead and was based on the key hypothesis that achieving the same average ALXN2220 concentration (Cavg) that was shown to reduce cardiac ATTR in the phase 1 NI006-101 study, in particular by at least 5% per year, will also prevent cardiac ATTR rebound of 5% per year.

The following steps were taken:

1. Define target ALXN2220 exposure for preventing cardiac ATTR rebound and amyloid reduction: a. Simulate cardiac ATTR reduction in study NI006-101 after 12 months of Q4W doses of 0.3 to 60 mg/kg IV. b. Select dose range between minimal dose that achieved cardiac ATTR reduction and dose that achieved close to maximal cardiac ATTR reduction. c. Calculate steady-state serum ALXN2220 Cavg achieved with these Q4W doses.

2. Define dose interval that achieves the target ALXN2220 exposure: a. Simulate serum ALXN2220 concentration after 2400 mg flat IV dose administered according to different dose intervals from Q4W to Q48W and calculate steady-state serum ALXN2220 Cavg. b. Calculate percentage of patients predicted to have Cavg larger than median target Cavg for the different dose intervals.

2. MATERIALS AND METHODS

2.1. Population PK/PD model

The population PK/PD model used for the current simulations was described in LYO-X-2023- 02-0001 Amendment 1; see below.

2.2. SIMULATION METHODOLOGY

PK/PD simulations were done in R using the Simulx mlxR library. With mlxR a simulation model file was automatically generated using the Monolix results as an input to the function monolix2simulx(). The simulations included inter-individual variability (IIV) and covariate effects. 1000 individuals were simulated. Predictions did not include the observational error. In all simulations, a 2-h IV infusion was used for the first dose and 1-h IV infusion for all subsequent doses, as in study NI006-101.

Body weights for the 1000 simulated patients were randomly sampled from a normal distribution with mean and standard deviation set to the mean (80.1 kg) and standard deviation (14.5 kg) reported by Huh 2021 (Brit Jnl Clinical Pharma. 2021;87:3574-3587) for an ATTR- CM population of 292 patients. Sampled body weights smaller than the minimum reported body weight (42 kg) or larger than the maximum reported body weight (133.8 kg) were excluded from the simulations. As the influence of age was previously found to be minimal without any clinical significance (LYO-X-2023 -02-0001 Amendment 1), age was fixed to the mean age (74.7 years) reported by Huh 2021 (Brit Jnl Clinical Pharma. 2021;87:3574-3587) for an ATTR-CM population of 292 patients.

For determining target ALXN2220 exposure (section 3.1), individual ECV Mid or HRWBR values, 500 of each, were randomly sampled from the NI006-101 population with replacement. For the simulations of the different maintenance dose intervals (section 3.2), 500 low baseline ECV Mid values of 45% and 500 low baseline HRWBR values of 0.03 were used: The rationale for the lower baseline values was that the maintenance study will be run in patients that were treated with ALXN2220 and already achieved cardiac ATTR reduction.

PK and ATTR profiles were simulated with a time step of 30 minutes for the first 4 hours after the start of each infusion, then with output times after 1, 2, 4 and 7 days, and then every 7 days. AUCtau, where tau is the dose interval, was calculated from the simulated PK profiles at steadystate using the “linear up/log down” trapezoidal rule. Visual inspection of the PK profiles confirmed that steady-state had been reached. Cavg was calculated as AUCtau / tau. Median Cavg from the different Q4W mg/kg doses was used as target exposure. The percentage of patients receiving 2400 mg who achieved a higher Cavg than this median target Cavg values was calculated for the different dose intervals.

2.3 SOFTWARE AND COMPUTER SYSTEM

All data analysis and simulations were done on a desktop computer (LOY-X internal name: PowerCrunch- 10) running Windows 10 Professional. For the PK/PD simulations, Simulx (Monolix Suite 2019R2 (Antony, France: Lixoft SAS, 2019 and update version Monolix Suite 2023R1, Antony, France: Lixoft SAS, 2023 for further dose justification in Example 3), mlxR 4.2.0 (Lavielle 2019, Lavielle M. mlxR: Simulation of longitudinal data. Version 4.2.0. 2019 (simulx.webpopix.org)) and a validated version of R 4.2.1 and update version of R 4.4.0 (R Development Core Team 2008, A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, 2008, (www.Rproject.org)) were used.

2.4 GUIDELINES

The data analysis was in accordance with Good Clinical Practice (GCP) guidelines and the LYO-X standard operating procedures (SOP) from the QMS Version 4.01.

3. RESULTS

3.1 DEFINITION OF TARGET ALXN2220 EXPOSURE

Figure 3 shows by how much cardiac ATTR was predicted to be reduced after 12 months of Q4W IV doses ranging from 0.3 to 60 mg/kg in study NI006-101. 3 mg/kg Q4W was the minimal dose to achieve ATTR reduction at 12 months and 30 mg/kg Q4W achieved nearly maximal ATTR reduction at 12 months. Furthermore, modeling results indicated that that 95% of patients treated at a putative dose of 5 mg/kg administered intravenously Q4W would have an amyloid depletion rate of 5% per year or more. Based on this, median steady-state serum Cavg values after 3 to 30 mg/kg Q4W were used as ALXN2220 exposure targets and finally - as 5% annual amyloid growth is the highest reported observation in the literature - a Cavg corresponding to 5mg/kg Q4W was selected as the exposure target for maintenance dose finding. Figure 4 shows the calculated steady-state (after 12^th dose) serum ALXN2220 AUC28days and corresponding Cavg values in study NI006-101.

3.2 PREDICTED REQUIRED DOSE INTERVAL TO ACHIEVE TARGET ALXN2220 EXPOSURE

Figure 5 shows the calculated steady-state (after last simulated dose) serum ALXN2220 AUCtau and corresponding Cavg for 2400 mg IV administered according to different dose intervals. Figure 2 shows the percentage of patients that were predicted to be above the target steady-state Cavg for different dose intervals and target exposures. For 2400 mg given Q16W, about 98% of patients were predicted to have a steady-state Cavg above the median Cavg of NI006-101 patients treated with 5 mg/kg Q4W; about 25% of patients were predicted to have a steady-state Cavg above the median Cavg of NI006-101 patients treated with 10 mg/kg Q4W.

4. DISCUSSION

Steady-state serum ALXN2220 Cavg was used to determine the maintenance dose interval that prevents cardiac ATTR rebound and optionally further reduces overall TTR amyloid load in patients treated with 2400 mg IV. The hypothesis was that achieving the same steady-state serum ALXN2220 Cavg that was linked with cardiac ATTR reduction in study NI006-101, and in particular that results in an annual cardiac ATTR reduction of at least 5% in study NI006- 101, should also prevent cardiac ATTR rebound in the same patients re-enrolled in study NI006-102. Same steady-state serum ALXN2220 Cavg means that the same total serum ALXN2220 is achieved, once steady-state is reached. As ATTR elimination is proportional to how ATTR is bound by ALXN2220, this should be a reasonable hypothesis. This approach did not consider other potentially important serum ALXN2220 characteristics like time above a certain concentration. In that perspective, for large dose intervals, even though Cavg is the same as a target Cavg, actual concentrations will be relatively low for the second half of the dosing interval which could impact cardiac ATTR rebound.

The current model did not contain ATTR synthesis and thus could not be used to explicitly predict cardiac ATTR rebound. This assumption of no ATTR synthesis was supported by the fact that almost all patients in study NI006-101 took tafamidis as co-medication, a TTR stabilizer preventing ATTR fibrils formation. Patients in study NI006-102 are expected to keep taking tafamidis, still supporting this hypothesis. However, it cannot be excluded that ATTR synthesis will be different now that patients have a lower total ATTR amount. It will need to be confirmed in study NI006-102 whether the target serum ALXN2220 exposure translates into prevention of cardiac ATTR rebound. In that perspective, the generated cardiac ATTR imaging data after treatment interruption and for the larger dose interval will be very valuable and might enable to estimate an ATTR synthesis rate.

5. CONCLUSION

3 mg/kg IV Q4W was the minimal dose showing cardiac amyloid reduction after 12 months in study NI006-101 and modeling results indicated that that 95% of patients treated at a putative dose of 5 mg/kg administered intravenously Q4W would have an amyloid depletion rate of 5% per year or more. 2400 mg IV Q16W was predicted to result in close to 100% of patients with steady-state serum ALXN2220 Cavg larger than median steady-state Cavg after 5 mg/kg IV Q4W and was thus predicted to prevent cardiac ATTR rebound, in particular of 5% per year, in study NI006-102. In particular, the expected average steady-state serum concentration is expected to be greater than 43 pg/mL in >95% of treated patients and resulting in an exposure which achieves amyloid reduction > 3.7% and 3.78% ECV, respectively after 12 months.

Example 3: A Phase 2, Single Arm, Multicenter Study to Evaluate the Pharmacodynamics and Safety of Re-Treatment with ALXN2220 in Patients with Transthyretin Amyloid Cardiomyopathy

The aim of the current study is to evaluate the pharmacodynamics and safety of re-treatment with ALXN2220 in the patient population of previous participants in Study NI006-101. To refine the ALXN2220 PK/PD model and confirm the estimated pharmacologically active dose of ALXN2220, a dosing regimen of 600 mg every 4 weeks (q4w) will be tested. The study will also evaluate the cardiac structure and function, and clinical function after a treatment-pause of approximately two years since conclusion of Study NI006-101, as well as the change from baseline in this study.

The study consists of a Screening Period and an Active Treatment Period as visualized in Fig.

6. During the Screening Period, participants will undergo a comprehensive assessment of their cardiac status including cardiac imaging. Results of the assessments in the Screening Period of Study NI006-102 will be compared to previous assessments in Study NI006-101. During the Active Treatment Period, eligible participants will receive 12 intravenous administrations of ALXN2220 600 mg every 28 days followed by an evaluation visit 28 days after the last administration. Between the first and second administration, three additional safety visits will be scheduled. The duration of the Active Treatment Period will be approximately 48 weeks (11 months). The total study duration, including Screening Period and Active Treatment Period is expected to be approximately 53 weeks (1 year). The 48 weeks treatment period is expected to be sufficient to characterize the pharmacodynamic effects and safety of re-treatment with ALXN2220 at a dose of 600 mg q4w in a population previously treated with ALXN2220 based on the PK/PD modelling results.

Previous participants of the Phase lb Study NI006-101 will be eligible for the present study. Participants will be allowed to be on standard therapy, as determined by treating and study physician(s), which may include conventional heart failure therapies and approved disease modifying therapies for ATTR amyloidosis.

The primary endpoint analysis will be performed on the Pharmacodynamic Analysis Set. The absolute change from baseline in midventricular ECV as measured by cardiac MRI and/or the HR/WBR as measured by cardiac scintigraphy will be analysed using descriptive statistics. In addition, changes in ECV and HR/WBR will also be analysed utilizing PK/PD modelling. The secondary endpoint will be performed on the Pharmocokinetics Analysis Set. The serum concentration (Ctrough and C_end of infusion) of ALXN2220 will be summarized descriptively by visit. Additional exploratory analysis, including any population PK modeling and PK/PD modeling, if performed, may be documented separately.

Analyses will also be performed for exploratory endpoints, as listed below, using descriptive statistics. For continuous endpoints, these will be presented using absolute values at each visit and change from baseline (or change from last assessment in Study NI006-101 to baseline in Study NI006-102, as applicable). For categorical endpoints, these will be presented using the number and percentage of participants at each visit. The Screening Analysis Set will be used for comparisons between Study NI006-102 and Study NI006-101. The SAF will be used for all other exploratory analyses. Additional analyses may be performed using the Per Protocol Set, where appropriate.

Exploratory endpoints:

Change from baseline in

• cMRI parameters of interest

• cardiac scintigraphy parameters of interest • echocardiography parameters of interest

• cardiac biomarkers (NT-proBNP, Trop)

• inflammatory biomarkers

• 6MWT

• KCCQ

• Disease stage (NYHA, NAC, MAYO, Columbia)

• CPET

• Incidence of intensification of oral diuretic therapy

• Immunohistochemistry on tissue samples

All safety analyses will be performed on the SAF. The safety and tolerability of ALXN2220 in participants with ATTR-CM will be assessed based on TEAEs, SAEs, ECG abnormalities, clinical laboratory data, physical examinations, and vital sign measurements, and will be presented using descriptive statistics. TEAEs will be summarized by MedDRA system organ class and preferred term. The incidence of TEAEs will be based on the number and percentage of participants with events and the number of events. TEAEs will be further summarized by NCI CTCAE v5.0 severity and relationship to study intervention. Separate listings will be provided for any AEs with an outcome of death, participants with SAEs, participants with an AE leading to IMP discontinuation and participants with an AE leading to study discontinuation. Clinical laboratory data (hematology, clinical chemistry, urinalysis [continuous parameters]), vital signs, and ECG parameters (continuous) will be presented using absolute values at each visit and change from baseline. Clinical laboratory data outside of the reference ranges will be listed. Summaries of abnormal ECG and physical examination data by visit will be presented using the number and percentage of participants with each finding. Furthermore, immunogenicity assessment will be performed. Serum samples for ADA (approximately 3 mL blood per sample) will be collected and the detection and characterization of ADA to ALXN2220 will be performed using a validated assay method. For ADA positive samples antibody titers will be determined and further characterization may be performed.

In the present study, the following Study Intervention is used: Table 7. Study Intervention

Abbreviations: IV = intravenous, q4w = every 4 weeks

JUSTIFICATION OF DOSE

The PK/PD modelling described in Example 2 (model 1) was further refined and additional simulations were conducted for various maintenance dose regimens by integrating further data on amyloid homeostasis in ATTR-CM patients into model 1. In particular, the dosing regimen for this study was selected to prevent amyloid formation based on literature-derived assumptions about changes in ECV in treatment-naive patients. For this purpose, an annual absolute increase of 3.7% in ECV was considered, which was derived from the most recently published data in the cMRI substudy of Attribute-CM, the pivotal Phase 3 study of acoramidis in patients with ATTR-CM. As can be seen in Fig. 7 and 8, a dose equivalent of 5 mg/kg q4w IV required to deplete newly forming amyloid. The PK/PD analysis data set has been extended to contain 1048 serum ALXN2220 observations and 142 PD observations from 43 patients treated with doses ranging from 0.3 to 60 mg/kg administered IV once every four weeks (Q4W) for up to two years. Based on the cardiac magnetic resonance imaging (MRI) sub-study of Attribute-CM, the pivotal Phase 3 study of acoramidis in patients with ATTR-CM (Razvi el al., J ACC 83 (2024), (13_Supplement) 347), 90% of patients are expected to have an annual absolute extracellular volume (ECV) increase below 3.78% as the rate of amyloid reformation, combining both treated and untreated patients. Similar to the Phase 3 dose regimen, a flat dose and a four week dosing interval were selected for this Phase 2 maintenance study. A dosing regimen of 600 mg intravenous (IV) every four weeks was predicted to prevent amyloid reformation in the majority of study participants by achieving an average steady-state serum concentration greater than 43 pg/mL in >95% of treated patients, an exposure which achieved amyloid reduction > 3.78% ECV after 12 months in study NI006-101. The underlying assumption in this analysis was that the steady-state average serum concentrations (Cavg) of ALXN2220 that resulted in a given cardiac ATTR reduction in study NI006-101 should also prevent/inhibit the corresponding cardiac ATTR regrowth and even further reduces residual ATTRT deposits. The population PK/PD model used for the current simulations for further refinement of the dose justification is described in LYO-X Report No.: LYO-X-2025-03-0001, Support of maintenance dosing regimen selection for ALXN2220 in ATTR-CM patients using PK/PD modeling, March 14, 2025 (LYO-X-2023 -02-0001 Amendment 1. L. Renaud. Population pharmacokinetic and pharmacodynamic analysis of NI006 in the Phase 1 NI006- 101 study and PK/PD simulations to support dose selection, Amendment 1. June 13, 2023 and update LYO-X-2024-05-0003. L. Renaud). Fig. 9 and 10 further illustrate that reducing the dose while increasing the frequency of antibody administration results in equivalent steadystate levels. Specifically, administering 600 mg every four weeks is equivalent to 2400 mg every four months or 1200 mg every eight weeks.

As can be seen from Fig. 11, simulated ECV reductions with 600mg q4w suggest that dose is effective in maintaining amyloid levels low and depleting residual amyloid and is thus, reasonable to control ECV progression.

The maximum observed serum concentration (Cmax) and the area under the serum concentration-time curve (AUC) of this dosing regimen will be lower than the one selected for Study ALXN2220-ATTRCM-301 (all participants of NI006-101 weighted > 60 kg and would receive 3200 mg or 4800 mg), so that no additional risks are anticipated. The average steadystate ALXN2220 serum concentrations will correspond to levels achieved with dosing at 5 to 8 mg/kg q4w.

Claims

1. An anti-TTR antibody for use in TTR amyloidosis (ATTR) maintenance treatment in a subject in need of said treatment, preferably wherein the ATTR is cardiac ATTR.

2. The anti-TTR antibody for use according to claim 1 , wherein the maintenance treatment comprises administering a flat dose of the antibody at a dosing interval suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body -weight based full dose antibody treatment which reduces TTR amyloid at 12 months in subjects which have been diagnosed with ATTR, particularly wherein the amyloid reduction is indicated as a reduction of extracellular volume (ECV), e.g., as measured by cardiac MRI and/or cardiac tracer uptake on scintigraph.

3. The anti-TTR antibody for use according to claim 1 , wherein the maintenance treatment comprises administering a flat dose of the antibody at a dosing interval suitable to achieve at least the same steady-state serum anti-TTR antibody average concentration (Cavg) in the subject which is achieved with the lowest body -weight based full dose antibody treatment which reduces extracellular volume (ECV) at 12 months in a subject which has been diagnosed with ATTR, wherein the reduction of ECV is measured, e.g., by cardiac MRI and/or cardiac tracer uptake on scintigraphy.

4. The anti-TTR antibody for use according to claim 1 or 2, wherein the maintenance treatment comprises administering a flat dose of the antibody at a dosing interval suitable to (a) achieve at least 5% of amyloid depletion per year and/or (b) neutralize a putative amyloid rebound of 5% per year, and/or (c) achieve an average antibody steadystate serum concentration equal to or greater than 40 pg/ml, wherein amyloid reduction is indicated as a reduction of extracellular volume (ECV), e.g., as measured by cardiac MRI and/or cardiac tracer uptake on scintigraphy.

5. The anti-TTR antibody for use according to claim 1 or 3, wherein the maintenance treatment comprises administering a flat dose of the antibody at a dosing interval suitable to (a) achieve at least amyloid reduction of 3.7% ECV per year and/or (b) to neutralize a putative amyloid formation by ECV of 3.7% per year; and/or (c) achieve an average antibody steady-state serum concentration equal to or greater than 40 pg/ml, wherein the ECV reduction is measured e.g., by cardiac MRI and/or cardiac tracer uptake on scintigraphy, preferably wherein the average steady-state serum concentration is greater than 43 pg/mL in >95% of treated patients, and/or the exposure achieves amyloid reduction > 3.78% ECV, preferably after 12 months..

6. The anti-TTR antibody for use according to any one of claims 1 to 5, wherein the maintenance treatment comprises administering a flat dose of the antibody at a dosing interval which results in a steady-state serum antibody average concentration (Cavg) in the subject above the median steady-state Cavg in subjects treated with 3 mg/kg to 10 mg/kg of the antibody via infusion every four weeks (3 mg/kg to 10 mg/kg IV Q4W), preferably with 5 mg/kg to 10 mg/kg IV Q4W, or with 3 mg/kg IV Q4W, 5 mg/kg IV Q4W, or 10 mg/kg IV Q4W, more preferably with at least 3 mg/kg IV Q4W, most preferably with 5 mg/kg IV Q4W.

7. The anti-TTR antibody for use according to any one of claims 1 to 6, wherein the maintenance treatment comprises administering the antibody at a flat dose between 150 mg and 2400 mg infusion, preferably between 300 mg and 2400 mg infusion, preferably between 600 mg and 2400 mg infusion, preferably 600 mg, 1200 mg, or 2400 mg infusion, most preferably 600 mg or 2400 mg infusion.

8. The anti-TTR antibody for use according to any one of claims 2 to 7, wherein the flat dose is 600 mg infusion.

9. The anti-TTR antibody for use according to any one of claims 2 to 7, wherein the flat dose is 1200 mg infusion.

10. The anti-TTR antibody for use according to any one of claims 2 to 7, wherein the flat dose is 2400 mg infusion.

11. The anti-TTR antibody for use according to any one of claims 1 to 10, wherein the maintenance treatment comprises administering the antibody at a dosing regimen of 150 mg every week (150 mg Q1W) to 2400 mg every 32 weeks (2400 mg Q32W), preferably of 300 mg every two weeks (300 mg Q2W) to 2400 mg every 26 weeks (2400 mg Q26W), preferably of 600 mg every four weeks (600 mg Q4W) to 2400 mg every 16 weeks (2400 mg Q16W); and/or wherein the maintenance treatment comprises administering the antibody at an administration interval which is calculated based on the following formula: T= 1/150 x D, wherein T (tau) is the administration interval in weeks and D is the dose in milligrams.

12. The anti-TTR antibody for use according to any one of claims 1 to 11, wherein the maintenance treatment comprises administering the antibody at a dosing regimen of 2400 mg every 8 to 44 weeks (2400 mg Q8W to Q44W), preferably at a dosing regimen of 2400 mg Q8W to Q32W, preferably of 2400 mg Q8W to Q26W, preferably of 2400 mg Q12W to Q26W, preferably of 2400 mg Q18W to Q26W, of 2400 mg Q16W to Q26W, or of 2400 mg Q16W to Q24W, or at a dosing regimen of 2400 mg Q44W, Q32W, Q26W, Q24W, Q18W, Q16W, Q12W, or Q8W, most preferably at a dosing regimen of 2400 mg Q16W.

13. The anti-TTR antibody for use according to any one of claims 1 to 12, wherein the maintenance treatment comprises administering the antibody at a dosing regimen of 600 mg every 2 to 8 weeks (600 mg Q2W to Q8W), preferably at a dosing regimen of 600 mg Q2W to Q6W, preferably of 600 mg Q4W to Q6W or of 600 mg Q2W to Q4W, or at a dosing regimen of 600 mg Q8W, Q6W, Q4W, Q2W, most preferably at a dosing regimen of 600 mg Q4W.

14. The anti-TTR antibody for use according to any one of claims 1 to 13, wherein the maintenance treatment comprises administering the antibody at a dosing regimen of 1200 mg every 4 to 16 weeks (1200 mg Q4W to Q16W), preferably at a dosing regimen of 1200 mg Q4W to Q12W, preferably of 1200 mg Q4W to Q8W or of 1200 mg Q8W to Q16W, or at a dosing regimen of 1200 mg Q16W, Q12W, Q8W, Q4W, most preferably at a dosing regimen of 1200 mg Q8W.

15. The anti-TTR antibody for use according to any one of claims 1 to 14, wherein the maintenance treatment comprises administering the antibody at a dosing regimen of 150 mg every week (150 mg Q1W) to 2400 mg every 32 weeks (2400 mg Q32W), preferably of 300 mg every two weeks (300 mg Q2W) to 2400 mg every 26 weeks (2400 mg Q26W), preferably of 600 mg every four weeks (600 mg Q4W) to 2400 mg every 16 weeks (2400 mg Q16W), preferably wherein the dosing regime is calculated based on the following formula: T= 1/150 x D, wherein T (tau) is the administration interval in weeks and D is the dose in milligrams.

16. The anti-TTR antibody for use according to any one of claims 1 to 15, wherein the maintenance treatment comprises administering the antibody via intravenous (IV) infusion.

17. The anti-TTR antibody for use according to claim 15 or 16, wherein the antibody is administered at a concentration of 2400 mg every 16-26 weeks (Q16W-Q26W), preferably Q16W via IV infusion.

18. The anti-TTR antibody for use according to claim 15 or 16, wherein the antibody is administered at a concentration of 600 mg every 2-6 weeks (Q2W-Q6W), preferably Q4W via IV infusion.

19. The anti-TTR antibody for use according to claim 15 or 16, wherein the antibody is administered at a concentration of 1200 mg every 4-12 weeks (Q4W-Q12W), preferably Q8W via IV infusion.

20. The anti-TTR antibody for use according to any one of claims 1 to 19, wherein the maintenance treatment comprises administering the antibody for at least 48 weeks, preferably at least 144 weeks, and most preferably lifelong.

21. The anti-TTR antibody for use according to any one of claims 1 to 20, wherein the maintenance treatment prevents TTR amyloid rebound.

22. The anti-TTR antibody for use according to any one of claims 1 to 21, wherein a TTR stabilizer, preferably tafamidis, is administered concurrently with the maintenance treatment.

23. The anti-TTR antibody for use according to any one of claims 1 to 22, wherein the subject has either variant ATTR-CM (ATTRv-CM/hATTR-CM) or wild-type ATTR- CM (wATTR-CM).

24.. The anti-TTR antibody for use according to any one of claims 1 to 23, wherein the maintenance treatment is started after completion of the full dose treatment with an anti- TTR antibody, preferably wherein the anti-TTR antibody is the same anti-TTR antibody as used for the maintenance treatment, preferably wherein full dose treatment with the anti-TTR antibody is completed after 12 to 48 months, preferably after 24 to 48 months, and/or upon amyloid depletion.

25. The anti-TTR antibody for use according to claim 24, wherein full dose treatment with the anti-TTR antibody comprises administering the antibody at a dose of 2400 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a patient weighing equal or more than 100 kg (> 100 kg).

26. The anti-TTR antibody for use according to any one of claims 1 to 25, wherein the maintenance treatment is started after completion of an initial full dose treatment with an anti-TTR antibody.

27. The anti-TTR antibody for use according to any one of claims 1 to 26, wherein the maintenance treatment is started after completion of a secondary full dose treatment with an anti-TTR antibody after amyloid rebound.

28. The anti-TTR antibody for use according to any one of claims 1 to 27, wherein the maintenance treatment is performed between two full dose treatment cycles with an anti- TTR antibody, preferably wherein the maintenance treatment is performed between the initial full dose treatment and the secondary full dose treatment after amyloid rebound, or between two secondary full dose treatment cycles after amyloid rebound.

29. The anti-TTR antibody for use according to any one of claims 1 to 28, wherein the subject has completed initial full dose treatment with an anti-TTR antibody before start of the maintenance treatment.

30. The anti-TTR antibody for use according to claim 29, wherein the subject has not experienced amyloid rebound after the initial full dose treatment with the anti-TTR antibody.

31. The anti-TTR antibody for use according to claim 29, wherein the subject has experienced TTR amyloid rebound after the initial full dose treatment with the anti-TTR antibody and has completed a secondary full dose treatment before start of the maintenance treatment.

32. The anti-TTR antibody for use according to claim 31, wherein the subject has not experienced amyloid rebound after the secondary full dose treatment with the anti-TTR antibody.

33. The anti-TTR antibody for use according to claim 31, wherein the subject has experienced TTR amyloid rebound after the secondary full dose treatment with the anti- TTR antibody and has completed a further secondary full dose treatment before start of the maintenance treatment.

34. The anti-TTR antibody for use according to any one of claims 27 to 33, wherein a subject is classified as amyloid rebound if at least one criterion in each of the following three parameter (a) to (c) is fulfilled:

(a) Cardiac Structure

(3) Worsened global longitudinal strain (GLS) (e.g., as measured by > 1% absolute increase);

(b) Cardiac Function

(2) Increased N-terminal pro b-type natriuretic peptide (NT-proBNP) (e.g., as measured by > 30% relative increase, or > 1000 ng/mL absolute increase); and

(c) Overall Function

(1) Unplanned ATTR-CM related hospitalization, or

(2) Increased New York Heart Association (NYHA) class.

35. The anti-TTR antibody for use according to any one of claims 26 to 34, wherein initial full dose treatment with an anti-TTR antibody is completed after 12 to 48 months, preferably after 24 to 48 months.

36. The anti-TTR antibody for use according to any one of claims 26 to 35, wherein secondary full dose treatment with an anti-TTR antibody is completed after a maximum of 32 weeks, preferably after 8 to 32 weeks.

37. The anti-TTR antibody for use according to any one of claims 26 to 36, wherein full dose treatment with an anti-TTR antibody is completed upon amyloid depletion.

38. The anti-TTR antibody for use according to any one of claims 26 to 37, wherein full dose treatment with an anti-TTR antibody is completed when composite of all-cause mortality (ACM) and total cardiovascular (CV) clinical events are lowered.

39. The anti-TTR antibody for use according to any one of claims 26 to 37, wherein full dose treatment with an anti-TTR antibody is completed when composite of all-cause mortality (ACM) and heart failure (HF) events are lowered.

40. The anti-TTR antibody for use according to any one of claims 26 to 39, wherein full dose treatment with an anti-TTR antibody is completed when at least one of the following symptoms are improved:

(b) time to cardiovascular (CV)-related mortality;

(c) six-minute walk test (6MWT) score compared to baseline;

(d) rate of cardiovascular (CV) clinical events; and

(e) time to all-cause mortality (ACM).

41. The anti-TTR antibody for use according to any one of claims 26 to 30, wherein full dose treatment with an anti-TTR antibody is completed when at least one of the following effects are observed:

(a) reduces NT-proBNP levels in the subject compared to baseline; (b) reduces rate of heart failure (HF) events;

(d) reduces incidence of changes in disease modifying therapy;

(e) reduces incidence of hospitalization for atrial fibrillation;

(i) induces change from baseline in GLS;

(j) induces change from baseline in stroke volume;

(k) induces change from baseline in echocardiography parameters of interest;

(l) induces change from baseline in hs-cTnT;

(n) induces change from baseline in eGFR

(r) induces change from baseline in a marker selected from TTR (prealbumin), TSH, RBP and fF4;

(s) induces change from baseline in (1) PND score and FAP stage; (2) Norfolk QoL-DN total score; and/or (3) sNFL levels; and

(t) induces change from baseline in NIS and/or induces a change in NC studies.

42. The anti-TTR antibody for use according to any one of claim 1 to 41, wherein full dose treatment with an anti-TTR antibody comprises administering the antibody at a dose of 2400 mg to a subject weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a subject weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a subject weighing equal or more than 100 kg (> 100 kg).

43. The anti-TTR antibody for use according to 42, wherein the antibody is administered once every four weeks (Q4W) preferably via IV infusion.

44. The anti-TTR antibody for use according to any one of claims 1 to 43, wherein the antibody comprises a heavy chain variable region comprising complementary determining regions (CDRs) comprising heavy chain CDR1-3, whose sequences are set forth in SEQ ID NOs: 1-3, respectively, and light chain CDR1-3, whose sequences are set forth in SEQ ID NOs: 4-6, respectively, wherein the anti-TTR antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8.

45. The anti-TTR antibody for use according to any one of claims 1 to 44, wherein the antibody comprises a human Ig constant region, preferably a human IgG constant region, preferably wherein the antibody comprises a human IgGl constant region comprising an antibody heavy chain constant region of human IgGlm3 allotype.

46. The anti-TTR antibody for use according to any one of claims 1 to 45, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 450 amino acid residues comprising the sequence of SEQ ID NO: 9, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO: 10.

47. The antibody for use according to any one of claims 1 to 45, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 449 amino acid residues comprising the sequence of SEQ ID NO: 13, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO: 10.

48. The antibody for use according to any one of claims 1 to 45, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 449 amino acid residues comprising the sequence of SEQ ID NO: 14, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO: 10.

49. The antibody for use according to any one of claims 1 to 45, wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises 448 amino acid residues comprising the sequence of SEQ ID NO: 15, and each light chain comprises 214 amino acid residues comprising the sequence of SEQ ID NO: 10.

50. The antibody for use according to any one of claims 1 to 49, wherein the antibody is NI006/ALXN2220 or comprises a binding fragment thereof.

51. The antibody for use according to any one of claims 1 to 50, wherein the antibody is a recombinant antibody produced in Chinese hamster ovary (CHO) cells, preferably wherein the antibody is produced in CHO-K1 cells.

52. The antibody for use according to any one of claims 1 to 46, and 48 to 51, wherein the heavy chain of the antibody comprises a cyclized N-terminal glutaminyl residue comprising pyroglutamate (pyro-Q).

53. The antibody for use according to any one of claims 1 to 46, and 50 to 51, wherein the antibody heavy chain further comprises a clipped C-terminal lysine.

54. The antibody for use according to any one of claims 1 to 53, wherein the antibody is N- glycosylated, preferably wherein the N-linked glycan is on N300 of the heavy chain of the antibody.

55. The antibody for use according to any one of claims 1 to 54, wherein the anti-TTR antibody is NI006/ALXN2220 which is administered in a pharmaceutical formulation at 50 mg/mL in 20 mM histidine buffer, 80 mg/mL sucrose, 0.3 mg/mL polysorbate 80, at pH 5.8.

56. An anti-TTR antibody for use in the treatment of TTR amyloidosis (ATTR) in a subj ect in need thereof, wherein the treatment comprises: (i) full dose treatment of the subject, which comprises administering a full dose of the antibody to the subject for at least 24 months, preferably for at least 48 months and/or until amyloid depletion has been achieved, wherein the antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a patient weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion; followed by

(ii) maintenance treatment of the subject, which comprises administering a maintenance dose of the antibody to the subject for at least 48 weeks, preferably at least 144 weeks, and most preferably lifelong, wherein the antibody is antibody NI006/ALXN2220 and is administered at a concentration of 2400 mg every 16-26 weeks (Q16W-Q26W), preferably Q16W via IV infusion, or at a concentration of 600 mg every 2-8 weeks (Q2W-Q8W), preferably Q4W via IV infusion.

57. An anti-TTR antibody for use in the treatment of TTR amyloidosis (ATTR) in a subj ect in need thereof, wherein the treatment comprises:

(i) full dose treatment of the subject, which comprises administering a full dose of the antibody to the subject for at least 24 months, preferably for at least 48 months and/or until amyloid depletion has been achieved, wherein the antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a patient weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion; followed by

(ii) pausing the treatment until amyloid rebound is detected in the subject; followed by

(iii) full dose treatment of the subject, which comprises administering a full dose of the antibody to the subject for a maximum of 32 weeks, preferably for 8 to 32 weeks and/or until amyloid depletion has been achieved, wherein the antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a patient weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion; and optionally

(iv) repeating steps (ii) and (iii) for at least one more time, and/or starting with maintenance treatment of the subject after full dose treatment, which comprises administering a maintenance dose of the antibody to the subject for at least 48 weeks, preferably at least 144 weeks, and most preferably lifelong, wherein the antibody is antibody NI006/ALXN2220 and is administered at a concentration of 2400 mg every 16-26 weeks (Q16W-Q26W), preferably Q16W via IV infusion, or at a concentration of 600 mg every 2-8 weeks (Q2W-Q8W), preferably Q4W via IV infusion.

58. The antibody for use according to claim 57, wherein a subject is classified as amyloid rebound if at least one criterion in each of the following three parameters (a) to (c) is fulfilled:

(a) Cardiac Structure

(b) Cardiac Function

(c) Overall Function

(1) Unplanned ATTR-CM related hospitalization, or

(2) Increased New York Heart Association (NYHA) class.

59. An anti-TTR antibody for use in the treatment of TTR amyloidosis (ATTR), preferably cardiac ATTR in a subject, the treatment comprising:

(I) assessing amyloid rebound and classifying the subject with amyloid rebound or without amyloid rebound, wherein the subject is classified as amyloid rebound if at least one criterion in each of the following three parameter (a) to (c) is fulfilled:

(a) Cardiac Structure

(b) Cardiac Function

(c) Overall Function

(1) Unplanned ATTR-CM related hospitalization, or

(2) Increased New York Heart Association (NYHA) class; and

(II)(a) treating a subject with amyloid rebound with a full dose treatment of

NI006/ALXN2220 for a duration of 32 weeks in the subsequent cycle and continue treatment of the subject with maintenance treatment of NI006/ALXN2220 thereafter; or

(II)(b) treating a subject without amyloid rebound at baseline with maintenance treatment of NI006/ALXN2220; and

(IV)(a) treating a subject with amyloid rebound with a full dose treatment of

NI006/ALXN2220 for a duration of 32 weeks in the subsequent cycle and continue treatment of the subject with maintenance treatment of NI006/ALXN2220 thereafter; or (IV)(b) continue treating a subject without amyloid rebound at baseline with maintenance treatment of NI006/ALXN2220, wherein the maintenance treatment is administered

(i) Q16W-Q26W, preferably Q16W and comprises 2400 mg of NI006/ALXN2220;

(ii) Q2W-Q6W, preferably Q4W and comprises 600 mg of NI006/ALXN2220; or

(iii) Q4W-Q12W, preferably Q8W and comprises 1200 mg of NI006/ALXN2220; and the full dose treatment is administered Q4W and comprises a weight-bracketed flat dose regimen comprising: (i) 2400 mg to a subject having body weight of < 60 kg; (ii) 3200 mg to a subject having body weight of > 60 kg and < 100 kg; and (iii) 4800 mg to a subject having a body weight of > 100 kg.

60. The anti-TTR antibody for use according to claim 59, wherein the subject only receives full dose treatment for 32 weeks once during the treatment cycle.

61. An anti-TTR antibody for use in the treatment of TTR amyloidosis (ATTR), preferably cardiac ATTR in a subject, the treatment comprises:

(i) initial full dose treatment of the subject, which comprises administering a full dose of an anti-TTR antibody to the subject for at least 24 months, preferably for at least 48 months and/or until amyloid depletion has been achieved, preferably wherein the anti-TTR antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a subject weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a subject weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a subject weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion; and subsequently

(ii) maintenance treatment of the subject according to any one of claims 1 to 21, preferably wherein the maintenance treatment comprises administering antibody NI006/ALXN2220 at a concentration of

(i) 2400 mg every 16-26 weeks (Q16W-Q26W), preferably Q16W via IV infusion;

(ii) 600 mg every 2-6 weeks (Q2W-Q6W), preferably Q4W via IV infusion; or

(iii) 1200 mg every 5-12 weeks (Q4W-Q12W), preferably Q8W via IV infusion.

62. The anti-TTR antibody for use according to claim 60, wherein the treatment comprises the following steps after step (ii) of claim 61,

(iii) assessing amyloid rebound in the subject, and classifying the subject with amyloid rebound or without amyloid rebound, wherein the subject is classified as amyloid rebound if at least one criterion in each of the following three parameter (a) to (c) is fulfilled:

(a) Cardiac Structure

(b) Cardiac Function

(c) Overall Function

(1) Unplanned ATTR-CM related hospitalization, or

(2) Increased New York Heart Association (NYHA) class; and

(iv)(a) secondary full dose treatment of a subject with amyloid rebound, which comprises administering a full dose of anti-TTR antibody to the subject for a maximum of 32 weeks and/or until amyloid depletion has been achieved, preferably wherein the anti-TTR antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a subject weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a subject weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a subject weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion, and optionally continue treatment of the subject with the maintenance treatment thereafter; or

(iv)(b) continue maintenance treatment of a subject without amyloid rebound; optionally wherein steps (iii) and (iv) can be repeated. I l l

63. An anti-TTR antibody for use in the treatment of TTR amyloidosis (ATTR), preferably of cardiac ATTR in a subject, wherein the treatment comprises:

(i) initial full dose treatment of the subject, which comprises administering a full dose of an anti-TTR antibody to the subject for at least 24 months, preferably for at least 48 months and/or until amyloid depletion has been achieved, preferably wherein the anti-TTR antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a subject weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a subject weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a subject weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion;

(ii) pausing the treatment until amyloid rebound is detected in the subject, and

(iii) full dose treatment of the subject with amyloid rebound, which comprises administering a full dose of anti-TTR antibody to the subject for a maximum of 32 weeks, preferably for 8 to 32 weeks and/or until amyloid depletion has been achieved, preferably wherein the anti-TTR antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a subject weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a subject weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a subject weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion; optionally

64. An article of manufacture comprising: one or more container(s) comprising (i) a formulation of an anti-TTR antibody in a total amount of 2400 mg or multiple doses of any one thereof; and (ii) a leaflet prescribing that the antibody is to be administered at a dosage of 2400 mg once every 16 to 26 weeks, preferably once every 16 weeks, or at a dosage calculated based on the following formula: T= 1/150 x D, wherein T (tau) is the administration interval in weeks and D is the dose in milligrams, wherein the antibody comprises a heavy chain variable region comprising complementary determining regions (CDRs) comprising heavy chain CDR1-3, whose sequences are set forth in SEQ ID NOs: 1-3, respectively, and light chain CDR1-3, whose sequences are set forth in SEQ ID NOs: 4-6, respectively, wherein the anti-TTR antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7 and light chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8, preferably wherein the antibody is the antibody as defined in any one of the preceding claims.

65. An article of manufacture comprising: one or more container(s) comprising (i) a formulation of an anti-TTR antibody in a total amount of 600 mg or multiple doses of any one thereof; and (ii) a leaflet prescribing that the antibody is to be administered at a dosage of 600 mg once every 2 to 8 weeks, preferably once every 4 weeks, or at a dosage calculated based on the following formula: T= 1/150 x D, wherein T (tau) is the administration interval in weeks and D is the dose in milligrams, wherein the antibody comprises a heavy chain variable region comprising complementary determining regions (CDRs) comprising heavy chain CDR1-3, whose sequences are set forth in SEQ ID NOs: 1-3, respectively, and light chain CDR1-3, whose sequences are set forth in SEQ ID NOs: 4-6, respectively, wherein the anti-TTR antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 7 and light chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8, preferably wherein the antibody is the antibody as defined in any one of the preceding claims.

66. An article of manufacture comprising: one or more container(s) comprising (i) a formulation of an anti-TTR antibody in a total amount of 1200 mg; and (ii) a leaflet prescribing that the antibody is to be administered at a dosage of 1200 mg once every 4 to 16 weeks, preferably once every 8 weeks, wherein the antibody comprises a heavy chain variable region comprising complementary determining regions (CDRs) comprising heavy chain CDR1-3 whose sequences are set forth in SEQ ID NOs: 1-3, respectively, and light chain CDR1-3, whose sequences are set forth in SEQ ID NOs: 4- 6, wherein the anti-TTR antibody comprises a heavy chain variable region comprising at least 80% sequence identity to SEQ ID NO: 7 and light chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8, preferably wherein the antibody is the as defined in any one of the preceding embodiments.

67. An article of manufacture comprising: one or more container(s) comprising (i) a formulation of an anti-TTR antibody in a total amount of 150 mg or a multitude thereof; and (ii) a leaflet prescribing that the antibody is to be administered at a dosage calculated based on the following formula T= 1/150 x D, wherein r (tau) is the administration interval in weeks and D is the dose in milligrams, wherein the dose preferably ranges from 150 mg to 3000 mg, wherein the antibody comprises a heavy chain variable region comprising complementary determining regions (CDRs) comprising heavy chain CDR1-3 whose sequences are set forth in SEQ ID NOs: 1-3, respectively, and light chain CDR1-3, whose sequences are set forth in SEQ ID NOs: 4-6, wherein the anti- TTR antibody comprises a heavy chain variable region comprising at least 80% sequence identity to SEQ ID NO: 7 and light chain variable region comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 8, preferably wherein the antibody is the as defined in any one of the preceding embodiments.

68. An article of manufacture comprising: one or more container(s) comprising (i) a formulation of an anti-TTR antibody in a total amount of 2400 mg or multiple doses of any one thereof; and (ii) a leaflet prescribing that the antibody is to be administered at a dosage of 2400 mg once every 16-26 weeks, preferably one every 16 weeks, wherein the anti-TTR antibody is antibody NI006/ALXN2220.

69. An article of manufacture comprising: one or more container(s) comprising (i) a formulation of an anti-TTR antibody in a total amount of 600 mg; and (ii) a leaflet prescribing that the antibody is to be administered at a dosage of 600 mg once every 2- 8 weeks, preferably one every 4 weeks, wherein the anti-TTR antibody is antibody NI006/ALXN2220.

70. An article of manufacture comprising: one or more container(s) comprising (i) a formulation of an anti-TTR antibody in a total amount of 1200 mg; and (ii) a leaflet prescribing that the antibody is to be administered at a dosage of 1200 mg once every 4-16 weeks, preferably one every 8 weeks, wherein the anti-TTR antibody is antibody NI006/ALXN2220.

71. The article of manufacture of any one of claims 64 to 70, wherein NI006/ALXN2220 is a recombinant human-derived immunoglobulin gamma 1 (IgGl) monoclonal antibody specifically recognizing aggregated wild type and mutant forms of TTR and is expressed in a Chinese hamster ovary cell line, preferably in the CHO-K1 cell line.

72. The article of manufacture of any one of claims 64 to 71, wherein NI006/ALXN2220 has an approximate molecular weight of 150 kDa.

73. The article of manufacture of any one of claims 64 to 72, wherein NI006/ALXN2220 is a concentrate for solution for infusion that is presented as sterile, colorless to slightly yellow, clear to slightly opalescent liquid, essentially free of visible particles for intravenous use by infusion after dilution.

74. The article of manufacture of claim 73, wherein each mL of solution contains 50 mg/mL NI006/ALXN2220 in 20 mM histidine buffer, 80 mg/mL sucrose, 0.3 mg/mL polysorbate 80, at pH 5.8.

75. The article of manufacture of any one of claims 64 to 74, wherein the recommended dosage of NI006/ALXN2220 on the label is 2400 mg that must be diluted then administered as an intravenous infusion over approximately one to two hours, once every 16 to 26 weeks, preferably once every 16 weeks.

76. The article of manufacture of any one of claims 64 to 74, wherein the recommended dosage of NI006/ALXN2220 on the label is 600 mg that must be diluted then administered as an intravenous infusion over approximately one to two hours, once every 2 to 8 weeks, preferably once every 4 weeks.

77. The article of manufacture of any one of claims 64 to 74, wherein the recommended dosage of NI006/ALXN2220 on the label is 1200 mg that must be diluted then administered as an intravenous infusion over approximately one to two hours, once every 4 to 16 weeks, preferably once every 8 weeks.

78. The article of manufacture of any one of claims 64 to 77, wherein prior to administration, NI006/ALXN2220 is diluted in 5% glucose solution.

79. The article of manufacture of any one of claims 64 to 77, wherein NI006/ALXN2220 is a clear to opalescent and colorless to pale yellow solution, available as solution 100 mg/2 mL (50 mg/mL) in a single-dose vial.

80. The anti-TTR antibody for use according to any one of claims 1 to 63, wherein the subject is an adult human patient, preferably an adult patient with clinically established cardiomyopathy (ATTR-CM) whose body weight is at least 39 kg.

81. A method of TTR amyloidosis (ATTR) maintenance treatment in a subject in need thereof, wherein the maintenance treatment is performed as defined in any one of the preceding claims.

82. A method of treating TTR amyloidosis in a human patient in need thereof, the method comprising:

(I) assessing amyloid rebound and classifying the patient with amyloid rebound or without amyloid rebound, wherein the patient is classified as amyloid rebound if at least one criterion in each of the following three parameter (a) to (c) is fulfilled:

(a) Cardiac Structure

(b) Cardiac Function

(c) Overall Function

(1) Unplanned ATTR-CM related hospitalization, or

(2) Increased New York Heart Association (NYHA) class; and (II)(a) treating a patient with amyloid rebound with a full dose treatment of NI006/ALXN2220 for a duration of 32 weeks in the subsequent cycle and continue treatment of the patient with maintenance treatment of NI006/ALXN2220 thereafter ; or

(II)(b) treating a patient without amyloid rebound at baseline with maintenance treatment of NI006/ALXN2220; and

(IV)(a) treating a patient with amyloid rebound with a full dose treatment of

NI006/ALXN2220 for a duration of 32 weeks in the subsequent cycle and continue treatment of a patient with maintenance treatment of NI006/ALXN2220 thereafter; or

(IV)(b) continue treating a patient without amyloid rebound at baseline with maintenance treatment of NI006/ALXN2220, wherein the maintenance treatment is administered

(i) Q16W-Q26W, preferably Q16W and comprises 2400 mg of NI006/ALXN2220;

(ii) Q2W-Q6W, preferably Q4W and comprises 600 mg of NI006/ALXN2220; or

(iii) Q4W-Q12W, preferably Q8W and comprises 1200 mg of NI006/ALXN2220; and the full dose treatment is administered Q4W and comprises a weight-bracketed flat dose regimen comprising: (i) 2400 mg to a patient having body weight of < 60 kg; (ii) 3200 mg to a patient having body weight of > 60 kg and < 100 kg; and (iii) 4800 mg to a patient having a body weight of > 100 kg.

83. The method of claim 82, wherein the patient only receives full dose treatment for 32 weeks once during the treatment cycle.

84. A method of treating TTR amyloidosis in a human patient in need thereof, the method comprising:

(i) initial full dose treatment of the patient, which comprises administering a full dose of an anti-TTR antibody to the patient for at least 24 months, preferably for at least 48 months and/or until amyloid depletion has been achieved, preferably wherein the anti-TTR antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a patient weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion; and subsequently

(ii) maintenance treatment of the patient according to any one of claims 1 to 21, preferably wherein the maintenance treatment comprises administering antibody NI006/ALXN2220 at a concentration of

(i) 2400 mg every 16-26 weeks (Q16W-Q26W), preferably Q16W via IV infusion;

(ii) 600 mg every 2-6 weeks (Q2W-Q6W), preferably Q4W via IV infusion; or

(iii) 1200 mg every 5-12 weeks (Q4W-Q12W), preferably Q8W via IV infusion.

85. The method of claim 84, wherein the treatment comprises the following steps after step

(ii) of claim 84:

(iii) assessing amyloid rebound in the patient, and classifying the patient with amyloid rebound or without amyloid rebound, wherein the patient is classified as amyloid rebound if at least one criterion in each of the following three parameter (a) to (c) is fulfilled:

(a) Cardiac Structure

(b) Cardiac Function

(c) Overall Function

(1) Unplanned ATTR-CM related hospitalization, or (2) Increased New York Heart Association (NYHA) class; and

(iv)(a) secondary full dose treatment of a patient with amyloid rebound, which comprises administering a full dose of an anti-TTR antibody to the patient for a maximum of 32 weeks and/or until amyloid depletion has been achieved, preferably wherein the anti-TTR antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a patient weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion, and optionally continue treatment of the patient with the maintenance treatment thereafter; or

(iv)(b) continue maintenance treatment of a patient without amyloid rebound; optionally wherein steps (iii) and (iv) can be repeated.

86. A method of treating TTR amyloidosis in a human patient in need thereof, wherein the method comprises:

(i) initial full dose treatment of the patient, which comprises administering a full dose of an anti-TTR antibody to the patient for at least 24 months, preferably for at least 48 months and/or until amyloid depletion has been achieved, preferably wherein the anti-TTR antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a patient weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion;

(ii) pausing the treatment until amyloid rebound is detected in the patient, and

(iii) full dose treatment of the patient with amyloid rebound, which comprises administering a full dose of an anti-TTR antibody to the patient for a maximum of 32 weeks, preferably for 8 to 32 weeks and/or until amyloid depletion has been achieved, preferably wherein the anti-TTR antibody is antibody NI006/ALXN2200 and is administered at a dose of 2400 mg to a patient weighing equal or more than 40 kg (> 40 kg) to under 60 kg (< 60 kg); (b) 3200 mg to a patient weighing equal or more than 60 kg (> 60 kg) to under 100 kg (< 100 kg); or (c) 4800 mg to a patient weighing equal or more than 100 kg (> 100 kg) every four weeks (Q4W) via IV infusion; optionally

87. Use of an anti-TTR antibody for the manufacture of a medicament for TTR amyloidosis (ATTR) maintenance treatment, wherein the maintenance treatment is performed as defined in any one of the preceding claims.