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WO2025163008A1 - Compositions de fragments de liaison à la lymphopoïétine stromale thymique (tslp), et leurs méthodes d'utilisation - Google Patents

Compositions de fragments de liaison à la lymphopoïétine stromale thymique (tslp), et leurs méthodes d'utilisation

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Publication number
WO2025163008A1
WO2025163008A1 PCT/EP2025/052281 EP2025052281W WO2025163008A1 WO 2025163008 A1 WO2025163008 A1 WO 2025163008A1 EP 2025052281 W EP2025052281 W EP 2025052281W WO 2025163008 A1 WO2025163008 A1 WO 2025163008A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
antigen binding
binding fragment
leucine
histidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/052281
Other languages
English (en)
Inventor
Sarah Doffman
Maria Sorhede Winzell
Scott T. Manetz
Muhammad Waqas SADIQ
Simon Carter
Sara Asimus
David Lechuga
Charina LAMPA
Behzad Damadzadeh
Nicholas CARRIGY
Penny Lim Tan
Hitesh Champaklal Pandya
Mariam Ibrahim
Sajal Manubhai Patel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of WO2025163008A1 publication Critical patent/WO2025163008A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • compositions of thymic stromal lymphopoietin (TSLP) binding fragments and methods of use thereof are provided.
  • the present disclosure relates to pharmaceutical compositions comprising antigen binding fragments specific for thymic stromal lymphopoietin (TSLP) suitable for inhalation, as well as a process for preparing a pharmaceutical composition for inhalation comprising said antigen binding fragment specific for TSLP.
  • TSLP thymic stromal lymphopoietin
  • the present disclosure further relates to methods of treating TSLP-related conditions, such as asthma and COPD, using the pharmaceutical compositions.
  • the pharmaceutical compositions include a mixture of leucine, trileucine, and histidine that results in a formulation that is suitable for delivering antigen binding fragments derived from anti-TSLP antibodies via inhalation.
  • Asthma affects an estimated 300 million people worldwide, including all age groups, and poses a serious burden on the health care system, and on society, through loss of productivity at the workplace and disruption to the family. (“Pocket Guide for Asthma Management and Prevention,” Global Initiative for Asthma; 2019). Asthma causes symptoms such as wheezing, shortness of breath, chest tightness and cough that vary over time with their occurrence, frequency and intensity. Symptoms are often associated with bronchoconstriction, airway wall thickening and increased production of mucus. Asthma can have varying degrees of symptoms and be well controlled, or poorly controlled, based on number of attacks and severity.
  • Thymic stromal lymphopoietin an epithelial cell-derived cytokine produced in response to environmental and pro-inflammatory stimuli, leads to the activation of multiple inflammatory cells and downstream pathways.
  • TSLP Thymic stromal lymphopoietin
  • Th2 cytokine and chemokine expression leads to the activation of multiple inflammatory cells and downstream pathways.
  • TSLP is increased in the airways of patients with asthma and correlates with Th2 cytokine and chemokine expression, and disease severity. While TSLP is central to the regulation of Th2 immunity, it may also play a key role in other pathways of inflammation and therefore be relevant to multiple asthma phenotypes.
  • Dry powder formulations comprising anti-TSLP antibody fragments suitable for inhalation for the treatment of asthma have been described in WO 2021/083908.
  • An anti-TSLP Fab with improved stability is described in WO 2022/223514.
  • W02017/042701 and WO 2021/152488 describe methods for treating inflammatory or obstructive airway diseases, such as asthma, using an anti-TSLP antibody or an anti- TSLP antibody fragment.
  • the present disclosure provides a novel pharmaceutical composition
  • a novel pharmaceutical composition comprising an antibody fragment of an anti-TSLP antibody with notable beneficial characteristics, including high manufacturing yield, low levels of sub-visible particles and minimal throat and device powder retention.
  • a preclinical toxicity study further demonstrated that the novel composition exhibited a favourable toxicity profile, with minimal immune-related toxicity.
  • the described pharmaceutical composition is expected to be safe and achieve clinical benefit when administered to patients for the treatment of TSLP-related conditions.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising spray-dried particles, the spray-dried particles comprising: a. about 5% (w/w) to about 15% (w/w) leucine; b. about 1 % (w/w) to about 5% (w/w) trileucine; c. about 1 % (w/w) to about 10% (w/w) histidine buffer at a pH of between about pH 5 to pH 6; d. about 1 % (w/w) to about 80% (w/w) of an antigen binding fragment of an anti-thymic stromal lymphopoietin (TSLP) antibody; and e. a glass stabilisation agent.
  • TSLP anti-thymic stromal lymphopoietin
  • the pharmaceutical composition comprises about 1 % (w/w) to about 3% (w/w) trileucine.
  • the pharmaceutical composition comprises about 2% (w/w) trileucine.
  • the pharmaceutical composition comprises about 8% (w/w) to about 12% (w/w) leucine.
  • the pharmaceutical composition comprises about 10.5% (w/w) leucine.
  • the pharmaceutical composition comprises about 1 % (w/w) to about 5% (w/w) histidine buffer.
  • the pharmaceutical composition comprises about 2.5% (w/w) to about 3.5% (w/w) histidine buffer.
  • the pharmaceutical composition comprises about 3.14% (w/w) histidine buffer.
  • the pharmaceutical composition comprises about 0.55% (w/w) L-histidine and about 2.59% (w/w) histidine HCI.
  • the antigen binding fragment is present at a concentration of about 1 % (w/w).
  • the antigen binding fragment is present at a concentration of about 2% (w/w).
  • the antigen binding fragment is present at a concentration of about 3% (w/w).
  • the antigen binding fragment is present at a concentration of about 10% (w/w).
  • the antigen binding fragment is present at a concentration of about 30% (w/w).
  • the antigen binding fragment is present at a concentration of about 40% (w/w).
  • the antigen binding fragment is present at a concentration of about 80% (w/w). In some instances, the total mass solids content of the pharmaceutical composition is 20 mg, and the pharmaceutical composition comprises 0.2 mg, 0.4 mg, 0.6 mg, 2 mg, 6 mg, 8 mg or 16 mg of antigen binding fragment. In such instance, the pharmaceutical composition may comprise 0.4 mg, 2 mg or 8 mg of antigen binding fragment.
  • the antigen binding fragment comprises: a. a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1 ; b. a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2; c. a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; d. a LCDR1 comprising the amino acid sequence of SEQ ID NO: 5; e. a LCDR2 comprising the amino acid sequence of SEQ ID NO: 6; and f. a LCDR3 comprising the amino acid sequence of SEQ ID NO: 7.
  • the antigen binding fragment comprises: a. a HCDR1 having the amino acid sequence of SEQ ID NO: 1 ; b. a HCDR2 having the amino acid sequence of SEQ ID NO: 2; c. a HCDR3 having the amino acid sequence of SEQ ID NO: 3; d. a LCDR1 having the amino acid sequence of SEQ ID NO: 5; e. a LCDR2 having the amino acid sequence of SEQ ID NO: 6; and f. a LCDR3 having the amino acid sequence of SEQ ID NO: 7.
  • the antigen binding fragment comprises: a. a HCDR1 consisting of the amino acid sequence of SEQ ID NO: 1 ; b. a HCDR2 consisting of the amino acid sequence of SEQ ID NO: 2; c. a HCDR3 consisting of the amino acid sequence of SEQ ID NO: 3; d. a LCDR1 consisting of the amino acid sequence of SEQ ID NO: 5; e. a LCDR2 consisting of the amino acid sequence of SEQ ID NO: 6; and f. a LCDR3 consisting of the amino acid sequence of SEQ ID NO: 7.
  • the antigen binding fragment comprises a VH domain comprising a sequence at least 95%, 90%, 85% or 80% identical to, SEQ ID NO:4 and a VL domain comprising a sequence at least 95%, 90%, 85% or 80% identical to SEQ ID NO:8.
  • the antigen binding fragment comprises a VH domain comprising the sequence of SEQ ID NO: 4; and a VL domain comprising the sequence of SEQ ID NO: 8.
  • the antigen binding fragment is a Fab, Fab’, F(ab’)2, scFv, minibody or diabody.
  • the antigen binding fragment is a Fab.
  • the Fab is of an lgG1 antibody.
  • the antigen binding fragment comprises a first sub-unit having the sequence set forth in SEQ ID NO: 28 and a second sub-unit having the sequence set forth in SEQ ID NO: 29.
  • the glass stabilization agent is selected from trehalose, sucrose, raffinose, inulin, dextran, mannitol, and cyclodextrin. In some instances, the glass stabilization agent is trehalose.
  • the trehalose is at a percent (w/w) concentration to make up to about 100%.
  • the composition does not comprise a surfactant.
  • the pharmaceutical composition comprises: a. 2% (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 84.2% (w/w) trehalose ⁇ 10%, and 1.3% (w/w) histidine ⁇ 10%, at pH 5.5; b. 2% (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 82.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5; c.
  • the pharmaceutical composition comprises: a. 0.4 mg antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 84.2% (w/w) trehalose ⁇ 10%, and 1.3% (w/w) histidine ⁇ 10%, at pH 5.5; b. 0.4 mg antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 82.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5; c.
  • the pharmaceutical composition may comprise about 0.55% (w/w) L-histidine and about 2.59% (w/w) histidine HCI. In some instances, when the pharmaceutical composition comprises 3.14% (w/w)) histidine, the pharmaceutical composition may comprise 0.55% (w/w) L-histidine and 2.59% (w/w) histidine HCI.
  • the number of sub-visible particles between 5 pm to 200 pm is less than about 2.5x10 4 /ml.
  • the number of sub-visible particles between 5 pm to 200 pm is less than about 0.5x10 4 /ml.
  • the number of sub-visible particles between 10 pm to 200 pm is less than about 1x10 4 /ml.
  • the number of sub-visible particles between 10 pm to 200 pm is less than about 0.2x10 4 /ml.
  • the number of sub-visible particles between 25 pm to 200 pm is less than about 2x10 3 /ml.
  • the number of sub-visible particles between 25 pm to 200 pm is less than about 0.2x10 3 /ml.
  • the number of sub-visible particles is determined by dynamic flow imaging microscopy, optionally by microflow imaging (MFI).
  • MFI microflow imaging
  • the number of sub-visible particles is determined following reconstitution in water, to an antigen-binding fragment concentration of either 2.5 mg/ml or 30 mg/ml.
  • the disclosure provides a process for making a pharmaceutical composition for inhalation, comprising: a. Providing an aqueous solution of about pH 5 to about pH 6 comprising leucine, trileucine, histidine, a glass stabilization agent and an antigen binding fragment of an anti-thymic stromal lymphopoietin (TSLP) antibody; b. Spray drying the aqueous solution of (a) to produce dry powder particles; and c.
  • aqueous solution of about pH 5 to about pH 6 comprising leucine, trileucine, histidine, a glass stabilization agent and an antigen binding fragment of an anti-thymic stromal lymphopoietin (TSLP) antibody
  • TSLP anti-thymic stromal lymphopoietin
  • the aqueous solution comprises about 5% (w/w) to about 15% (w/w) leucine, about 1 % (w/w) to about 5% (w/w) trileucine, about 1 % (w/w) to about 10% (w/w) histidine, about 5% (w/w) to about 50% (w/w) antigen binding fragment and % (w/w) glass stabilization agent to 100% total solids content.
  • the aqueous solution has a pH of 5.5.
  • the glass stabilization agent is trehalose.
  • the aqueous solution comprises: a. 2% (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 84.2% (w/w) trehalose ⁇ 10%, and 1.3% (w/w) histidine ⁇ 10%, at pH 5.5; b. 2% (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 82.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5; c.
  • the present disclosure provides a dry powder formulation obtained by the process of the second aspect of the disclosure.
  • the present disclosure provides a method of treating a TSLP-related condition in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of the first aspect or the dry powder formulation of the third aspect of the present disclosure.
  • the present disclosure also provides a pharmaceutical composition of the first aspect or the dry powder formulation of the third aspect for use in treating a TSLP-related conditions.
  • the disclosure provides the use of the pharmaceutical composition of the first aspect or the dry powder formulation of the third aspect in the manufacture of a medicament for the treatment of a TSLP-related condition.
  • the TSLP-related condition is asthma, COPD, allergic rhinitis, allergic rhinosinusitis, allergic conjunctivitis, eosinophilic esophagitis, chronic spontaneous urticaria or chronic rhinosinusitis.
  • the TSLP-related condition is asthma.
  • the TSLP-related condition is COPD.
  • the present disclosure provides a method for improving lung function in a subject with asthma or COPD, the method comprising administering to the subject a pharmaceutical composition of the first aspect or the dry powder formulation of the third aspect of the present disclosure.
  • the present disclosure also provides a pharmaceutical composition of the first aspect or the dry powder formulation of the third aspect for use in a method of improving lung function in a patient with asthma or COPD.
  • the disclosure provides the use of the pharmaceutical composition of the first aspect or the dry powder formulation of the third aspect in the manufacture of a medicament for improving lung function in a patient with asthma or COPD.
  • improvement of lung function means one or more of the following parameters: improvement compared to baseline of (i) pre-bronchodilator (BD) FVC, (ii) post-BD-FVC, (iii) pre-BD-FEVi , (iv) post-BD FEVi, (v) mean morning PEF and/or (vi) mean evening PEF.
  • the present disclosure relates to a method for improving symptoms of asthma or COPD in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of the first aspect or the dry powder formulation of the third aspect of the present disclosure.
  • improving symptoms of asthma means one of the following parameters: improvement compared to baseline (i) mean asthma symptom diary score, (ii) Asthma Control Questionnaire 6 (ACQ-6) score, (iii) Asthma Quality of Life Questionnaire (AQLQ) score, and/or (iv) St. George’s Respiratory Questionnaire (SGRQ) score.
  • ACQ-6 Asthma Control Questionnaire 6
  • AQLQ Asthma Quality of Life Questionnaire
  • SGRQ Respiratory Questionnaire
  • the asthma is moderate to severe asthma.
  • the pharmaceutical composition or the dry powder formulation is administered by inhalation or intranasally. In some instances of any of the fourth, fifth and sixth aspects of the disclosure, the pharmaceutical composition is administered by dry powder inhaler.
  • the pharmaceutical composition or the dry powder formulation to be administered to the subject comprises a dose of about 0.2 mg to about 16 mg of the antigen binding fragment of the anti-TSLP antibody. In some instances of any of the fourth, fifth and sixth aspects of the disclosure, the pharmaceutical composition or the dry powder formulation to be administered to the subject comprises a dose of about 0.4 mg to about 8 mg of the antigen binding fragment of the anti-TSLP antibody. In some instances of any of the fourth, fifth and sixth aspects of the disclosure, the pharmaceutical composition or the dry powder formulation is administered or is to be administered to the subject comprises a dose of about 0.4 mg, about 2 mg or about 8 mg of the antigen binding fragment of the anti-TSLP antibody.
  • the asthma is uncontrolled moderate to severe asthma.
  • the pharmaceutical composition or the dry power formulation is administered or is to be administered to the subject once daily (Q1 D) by inhalation.
  • the disclosure includes the combination of the aspects and features described except where such a combination is clearly impermissible or expressly avoided.
  • Figure 1 shows Scanning Electron Microscope (SEM) images of formulations tested in study 1.
  • FIGS. 2A and 2B show the Micro Flow Imaging (MFI) results for 10% bulk powder reconstituted in water for injection to the (FIG. 2A) 2.5 mg/ml protein and to (FIG. 2B) feedstock concentration (7.5mg/ml protein). Results are expressed as particle counts per ml as an average of three replicates.
  • MFI Micro Flow Imaging
  • Figures 3A and 3B show the MFI results for 40% bulk powder (BP) reconstituted in water for injection to the (Fig. 3A) 2.5 mg/ml protein and to (Fig. 3B) feedstock concentration (30 mg/ml protein). Results are expressed as particle counts per ml as an average of three replicates.
  • BP bulk powder
  • Figures 4A, 4B, and 4C show the MFI results for (Fig. 4A) drug substance (DS) and (Fig. 4B) 10% and (Fig. 4C) 40% FAB1 reconstituted BP at feedstock protein concentration (7.5 mg/ml for 10% formulations and 30 mg/ml for 40% formulation).
  • Figures 5A, 5B, and 5C show the MFI results for 10% and 40% FAB1 BP at 2.5 mg/ml protein concentration across different formulations:(Fig. 5A) TLTC pH 5 at a concentration of 2.5 mg/ml; (Fig. 5B) TLTH pH 6 at a concentration of 2.5 mg/ml; (Fig. 5C) TLTH pH 5 at a concentration of 2.5 mg/ml.
  • FIG. 6A and 6B show (Fig. 6A) Next Generation Pharmaceutical Impactor (NGI) results for 10% FAB1 plotted by stage and (Fig. 6B) a summary of the results.
  • the Next Generation Pharmaceutical Impactor (NGI) is as described in United States Pharmacopeia (USP) ⁇ 601 > Apparatus 6.
  • FIGS 7A and 7B show (Fig. 7A) Next Generation Pharmaceutical Impactor (NGI) results for 10% FAB1 plotted by stage and (Fig. 7B) a summary of the results.
  • the Next Generation Pharmaceutical Impactor (NGI) is as described in USP ⁇ 601 > Apparatus 6.
  • Figure 8 shows study 2 40% FAB1 SEM images.
  • Figure 9 shows study 2 10% FAB1 SEM images.
  • Figures 10A and 10B show the study 2 subvisible particles (SVP) detected by MFI for 10% FAB1 formulations reconstituted to (Fig. 10A) 2.5mg/ml, or (Fig. 10B) the feedstock concentration of 7.5 mg/ml. Particle counts are expressed as particles/ml in BP for the listed sizes (no larger than (NLT) 2, 5, 10, 25 pm).
  • Figures 11 A and 11 B show the study 2 MFI results for 40% FAB1 formulations reconstituted to (Fig. 11 A) 2.5mg/ml, or (Fig. 11 B) 30 mg/ml (feedstock concentration). Particle counts are expressed as particles/ml in BP for the listed sizes (no larger than (NLT) 2, 5, 10, 25 pm).
  • FIGS 12A and 12B show (Fig. 12A) Next Generation Pharmaceutical Impactor (NGI) results for study 2 10% FAB1 plotted by stage; and (Fig. 12B) a summary of the results.
  • the Next Generation Pharmaceutical Impactor (NGI) is as described in United States Pharmacopeia (USP) ⁇ 601 > Apparatus 6.
  • FIGS 13A and 13B show (Fig. 13A) Next Generation Pharmaceutical Impactor (NGI) results for study 240% FAB1 plotted by stage, and (Fig. 13B) a summary of the results.
  • the Next Generation Pharmaceutical Impactor (NGI) is as described in United States Pharmacopeia (USP) ⁇ 601 > Apparatus 6.
  • Figure 14 shows study 3 SEM images.
  • Figures 15A and 15B shows study 3 MFI results 10% FAB1 reconstituted to (Fig. 15A) 2.5mg/ml, or (Fig. 15B) the feedstock concentration of 7.5 mg/ml. Particle counts are expressed as particles/ml in BP for the listed sizes (no larger than (NLT) 2, 5, 10, 25 pm). Results are shown as the average of triplicate samples.
  • Figures 16A and 16B show study 3 SVP detected by MFI for 40% FAB1 formulations reconstituted to (Fig. 16A) 2.5mg/ml, or (Fig. 16B) the feedstock concentration of 30 mg/ml. Particle counts are expressed as particles/ml in BP for the listed sizes (no larger than (NLT) 2, 5, 10, 25 pm). Results are shown as the average of triplicate samples.
  • Figures 17A and 17B show study 3 NGI results of (Fig. 17A) 10% FAB1 plotted by stage (Lot 21 -VMS- 055, 056 and 057), (Fig. 17B) 40% FAB1 plotted by stage (Lot 21-VVS-061 , 058 and 059), and (Fig. 17C) a summary of the results.
  • the Next Generation Pharmaceutical Impactor (NGI) is as described in United States Pharmacopeia (USP) ⁇ 601 > Apparatus 6.
  • Figure 18 shows study 4 stability (1 month accelerated conditions) SEM images.
  • Figures 19A and 19B shows study 4 NGI results of 10% FAB1 (Fig. 19A) TLTH 1.3% His; (Fig. 19B) TLTH 3.15% His, (Fig. 19C) TLTH 5% plotted by stage.
  • the Next Generation Pharmaceutical Impactor (NGI) is as described in United States Pharmacopeia (USP) ⁇ 601 > Apparatus 6.
  • Figures 20A and 20B shows study 4 NGI results of 40% FAB1 (Fig. 20A) TLTH 1.3% His; (Fig. 20B) TLTH 3.14% His, (Fig. 20C) TLTH 5% plotted by stage.
  • the Next Generation Pharmaceutical Impactor (NGI) is as described in United States Pharmacopeia (USP) ⁇ 601 > Apparatus 6.
  • Figure 21 shows perivascular/peribronchiolar mononuclear inflammatory cell infiltrates (arrows) with macrophage aggregates (triangles) in a mouse receiving 7.1 mg/kg/day FAB1 in TLTC, pH 6 with PS80 compared with a placebo control, labelled as “2M 2001 , placebo”.
  • Figure 22 shows visible particles in the reconstituted FAB1 TLTC, pH 6 with PS80 in water.
  • Figure 23 shows representative images FAB1 -related lung pathology for the second toxicity study, at the indicated dose levels (placebo, 4mg/kg, and 9.2 mg/kg). Arrows for the lung images point to mononuclear cell (MNC) infiltrates.
  • MNC mononuclear cell
  • Figure 24 lists the pathology results for the second toxicity study.
  • Figure 27 ACQ-6 Change from Baseline by Dose Over Time, least squares (LS) means (80% confidence interval (Cl)) - Results from the high dose arm (top - 8mg) or placebo (bottom) Part B of Study described in Example 7
  • Figure 29 FAB1 predicted serum (dashed line) and lung concentration (solid line) following inhaled 0.4, 2 and 8mg QD administration. Grey shaded area is a visualisation aid to separate serum and lung predictions. Horizontal dotted line is the predicted lung Cave concentration of tezepelumab following SC 210mg administration (Q4W)-
  • Figure 30 shows a Phase 2b protocol design for testing the efficacy of an anti-TSLP Fab fragment.
  • compositions are provided for the stabilization and delivery of pharmaceutical active agents.
  • the pharmaceutical compositions are formulated for pulmonary delivery, including via inhalation via a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • the pharmaceutical composition comprises a “dry powder formulation”.
  • compositions provided herein comprise spray-dried particles, the particles comprising: about 5% (w/w) to about 15% (w/w) leucine; about 1% (w/w) to about 5% (w/w) trileucine; about 1% (w/w) to about 10% (w/w) histidine buffer at a pH of between about pH 5 to pH 6; about 1% (w/w) to about 80% (w/w) of an antigen binding fragment of an anti-thymic stromal lymphopoietin (TSLP) antibody; and a glass stabilisation agent.
  • TSLP anti-thymic stromal lymphopoietin
  • “Pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of the active ingredient (e.g., an anti-TSLP Fab disclosed herein) to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered. Such composition can be sterile.
  • “spray dried particles” refers to particles manufactured in a process that uses an aerosol phase to spray dry particles to form the basis for dry dosage forms. The spray-dried particles thus refer to a plurality of solid microparticles in a powder composition that suitably contains less than about 20% moisture, more suitably less than 10% moisture, less than about 5-6% moisture, or less than about 3% moisture.
  • the pharmaceutical compositions can be utilized for delivery via inhalation to a patient.
  • the pharmaceutical compositions can be reconstituted and administered in a liquid form, either orally, intravenously, parenterally, etc.
  • An exemplary process of preparing spray- dried particles, in accordance with instances hereof may take place as follows.
  • a liquid feedstock containing the desired final components of the dry powder formulation are atomized using an atomizer, to a fine mist.
  • the mist is then dried as described herein.
  • the atomized droplets contain the dissolved components, initially as a liquid droplet. As the droplet dries, different components of the formulation begin to saturate and precipitate at varying rates.
  • a shell begins to form around an outer surface of the microparticles of the dry powder formulations.
  • This shell suitably includes the leucine and trileucine components at an outer surface of the shell.
  • leucine and trileucine become preferentially located at an outer surface of the microparticles, while smaller amounts of leucine and trileucine can also be found throughout the microparticles.
  • a higher concentration of leucine and trileucine are suitably found at or near the surface of the microparticles, rather than near the center of the microparticles.
  • the center of particles contains a substantial amount of the active agent, along with other excipient components as described herein, suitably in an amorphous form.
  • a “substantial amount” of the active agent means at least about 60% of the active agent (i.e., of the total active agent in the formulation) is located at or near the center of the microparticles, suitably at least about 70%, and more suitably at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, and in instances about 95%-100%, of the active agent is located at or near the center of the microparticles.
  • a “microparticle” as used herein refers to a solid particle having a size mass mean diameter (MMD) of less than 20 pm.
  • Mass mean diameter is a measure of the mean particle size of the microparticles, measured using a suitable method, including for example centrifugal sedimentation, electron microscopy, light scattering, laser diffraction, etc.
  • active agent refers to an antigen binding fragment derived of an anti-TSLP antibody, as defined herein.
  • the ratios described herein are expressed as ratios by weight % (w/w - also referred to as a “weight ratio”).
  • the amounts of leucine, trileucine, histidine buffer, and antigen -binding fragment of an anti-TSLP antibody provided herein, unless otherwise stated, are provided as weight percentages (wt %) of the formulations.
  • weight percentages wt % of the formulations.
  • the ratios are achieved by providing a desired mg/mL concentration of these components in a feedstock, and then spray drying to remove the feedstock solvent resulting in an atomized microparticle where the starting concentration ratio (expressed in mg/mL), is maintained as a final ratio by weight.
  • leucine refers to the amino acid leucine (C6H13NO2), which may be a racemic mixture or in either its D- or L-form, as well as modified forms of leucine (i.e., where one or more atoms of leucine have been substituted with another atom or functional group).
  • C6H13NO2 amino acid leucine
  • modified forms of leucine i.e., where one or more atoms of leucine have been substituted with another atom or functional group.
  • Trileucine refers to the chemical compound in which three leucine molecules are linked together in a peptide, as leucine-leucine-leucine (Leu-Leu-Leu), C18H35N3O4.
  • leucine-leucine-leucine Leu-Leu-Leu
  • C18H35N3O4 The chemical structure of trileucine is provided below:
  • the dry powder formulations comprise about 5% to about 15% leucine and about 1 % to about 5% trileucine.
  • compositions described herein comprise about 5% to about 15% leucine by weight, more suitably about 5% to about 14%, about 5% to about 13%, about 5% to about 12%, about 5% to about 11 %, about 5% to about 10%, about 5% to about 9%, about 5% to about 8%, about 5% to about 7%, about 5% to about 6%, about 6% to about 15%, about 7% to about 15%, about 8% to about 15%, about 9% to about 15%, about 10% to about 15%, about 11% to about 15%, about 12% to about 15%, about 13% to about 15%, about 14% to about 15%, about 5% to about 14%, about 6% to about 14%, about 7% to about 14%, about 8% to about 14%, about 9% to about 14%, about 10% to about 14%, about 11% to about 14%, about 12% to about 14%, about 8% to about 14%, about 9% to about 14%, about 10% to about 14%, about 11% to about 14%, about 12% to about
  • the pharmaceutical compositions described herein comprise about 10.5% leucine by weight. In some instances, the pharmaceutical compositions described herein comprise 10.5% leucine ⁇ 1%, 10.5% leucine ⁇ 2%, 10.5% leucine ⁇ 3%, 10.5% leucine ⁇ 4%, 10.5% leucine ⁇ 5%, 10.5% leucine ⁇ 10%, by weight.
  • the pharmaceutical compositions comprise about 1% to about 5 % trileucine by weight, more suitably about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 2% to about 4%, about 2% to about 3%, about 3% to about 5%, about 3% to about 4%, about 4% to about 5%, about 1 %, about 3%, about 4%, about 5% trileucine, by weight.
  • the pharmaceutical compositions described herein comprise about 2% leucine by weight.
  • the pharmaceutical compositions described herein comprise 2% leucine ⁇ 0.5%, 2% leucine ⁇ 1%, 2% leucine ⁇ 2%, 2% leucine ⁇ 3%, 2% leucine ⁇ 4%, 2% leucine ⁇ 5%, 2% leucine ⁇ 10%, by weight.
  • the pharmaceutical compositions comprise about 8% to about 12% leucine and about 1% to about 3% trileucine, and in some instances, the pharmaceutical compositions comprise about 10.5% leucine and about 2% trileucine.
  • the particles contain leucine and trileucine located substantially throughout the microparticles, but with higher amounts at or near the surface of the microparticles.
  • substantially throughout the microparticles means that the leucine and/or trileucine are located in a gradient from the outer surface of the microparticles toward the center of the microparticles, but suitably with decreasing amounts of the leucine and/or trileucine as you move toward the center, and in instances, no leucine or trileucine are found at the center of the microparticles where the active agent is located.
  • the amounts and leucine and trileucine can be substantially uniform throughout a crosssection of the microparticles.
  • substantially each of the particles of the pharmaceutical composition comprises leucine and trileucine. That is, suitably at least about 60% of the microparticles contain leucine and trileucine, or at least about 70%, and more suitably at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, and in instances about 95%-100%, of the microparticles comprise leucine and trileucine. In instances each of the microparticles of the dry powder formulations comprise leucine and trileucine.
  • leucine and/or trileucine can be found in pharmaceutical compositions, but not contained within or associated with a microparticle of the formulation.
  • free leucine and/or trileucine that is not associated with a microparticle can be found in the dry powder formulations.
  • the amount of free leucine and/or trileucine is on the order of less than about 10%, less than about 5%, less than about 1 %, and more suitably less than about 0.1 % of the total amount of leucine and/or trileucine in the formulations.
  • Hetidine whether present as a single amino acid or as an amino acid component of a peptide, refers to the amino acid histidine (C6H9N3O2), which may be a racemic mixture or in either its D- or L-form, as well as modified forms of histidine (i.e., where one or more atoms of leucine have been substituted with another atom or functional group).
  • the chemical structure of histidine is provided below.
  • a pharmaceutical composition comprising a histidine buffer significantly reduced protein aggregation and device and throat deposition, at least partly by reducing the level of subvisible particles, compared with a reference buffer. Accordingly, the pharmaceutical compositions described herein comprise a histidine buffer.
  • the histidine buffer is present at about 1 % to about 10%, for example the histidine buffer may be present at about 1 % to about 9%, about 1 % to about 8%, about 1 % to about 7%, about 1 % to about 6%, about 1 % to about 5%, about 1 % to about 4%, about 1 % to about 3%, about 1 % to about 2%, about 2% to about 10%, about 2% to about 9%, about 2% to about 8%, about 2% to about 7%, about 2% to about 6%, about 2% to about 5%, about 2% to about 4%, about 2% to about 3%, about 2.% to about 3.5%, or about 1 %, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, or about 6, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5% by weight.
  • the pharmaceutical composition comprises about 3.14% histidine buffer by weight.
  • the pharmaceutical compositions described herein comprise 3.14% histidine buffer ⁇ 0.5%, 3.14% histidine buffer ⁇ 1 %, 3.14% histidine buffer ⁇ 2%, 3.14% histidine buffer ⁇ 3%, 3.14% histidine buffer ⁇ 4%, 3.14% histidine buffer ⁇ 5%, 3.14% histidine buffer ⁇ 10%, by weight.
  • the pharmaceutical composition comprises about 3.14% histidine buffer ⁇ 10%, by weight (w/w).
  • the pharmaceutical composition comprises about 3.14% histidine buffer, by weight (w/w).
  • the pharmaceutical composition comprises about 0.55% (w/w) L-histidine and 2.59% (w/w) histidine HCI.
  • a “reference buffer” as used herein is a buffer that does not contain histidine at the ratios described herein, for example, a reference buffer may not comprise any histidine buffer.
  • the reference buffer comprises citrate.
  • the reference buffer comprises trehalose, leucine, trileucine and citrate (TLTC).
  • the reference buffer has a pH of about pH 6.
  • the reference buffer comprises a surfactant, for example polysorbate 80 (PS80).
  • the histidine buffers also provide control of the pH of the pharmaceutical composition, suitably maintaining a pH of about pH 5.5 to about pH 6, such as about pH 5.5, about pH 5.6, about pH 5.7, about pH 5.8, about pH 5.9. In certain instances, the pH of the histidine buffer is 5.5.
  • compositions described herein comprise an antigen binding fragment of an anti-thymic stromal lymphopoietin (anti-TSLP) antibody.
  • anti-TSLP anti-thymic stromal lymphopoietin
  • the formulations described herein enable delivery of the antigen binding fragment via inhalation directly into the lung. Delivery of a therapeutically active antigen binding fragment of an anti-TSLP antibody via inhalation allows for the use of biologic medicines for the treatment of asthma in a primary care setting.
  • the antigen binding fragment is present at about 1% to about 80%, for example the antigen binding fragment may be present at about 1% to about 50%, at about 1 % to about 45% about 1% to about 40%, about 2% to about 50%, 2% to about 45% or about 2% to about 40% by weight (w/w).
  • the antigen binding fragment is present in the pharmaceutical composition at a concentration of about 1% to about 10% by weight (w/w), about 1% to about 9% by weight (w/w), about 1% to about 8% by weight (w/w), about 1% to about 7% by weight (w/w), about 1 % to about 6% by weight (w/w), about 1% to about 5% by weight (w/w), of about 1% to about 4% by weight (w/w), about 1% to about 3% by weight (w/w), about 2% to about 10% by weight (w/w), about 2% to about 9% by weight (w/w), about 2% to about 8% by weight (w/w), about 2% to about 7% by weight (w/w), about 2% to about 6% by weight (w/w), about 2% to about 5% by weight (w/w), about 2% to about 4% by weight (w/w), about 2% to about 3% by weight (w/w), about 3% to about 10% by weight (w/w/w
  • the antigen binding fragment is present in the pharmaceutical composition at a concentration of about 1%, about 2% about 3% about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or about 80% by weight (w/w).ln certain instances, the antigen binding fragment is present in the pharmaceutical composition at a concentration of about 1 % (w/w) to about 80% (w/w), for example about 1 % (w/w) to about 40% (w/w).
  • the antigen binding fragment is present in the pharmaceutical composition at a concentration of about 1 % (w/w), about 2% (w/w), about 3% (w/w), about 10% (w/w), about 15% (w/w), about 20% (w/w), about 25% (w/w), about 30% (w/w), about 35% (w/w), about 40% (w/w), about 45% (w/w), about 50% (w/w), about 55% (w/w), about 60% (w/w), about 65% (w/w), about 70% (w/w), about 75% (w/w) or about 80% (w/w).
  • compositions described herein further comprise a glass stabilization agent to aid in stabilizing the formulation, and in particular, in stabilising the active agent.
  • a “glass stabilisation agent” refers to an excipient that stabilizes an active agent (suitably a polypeptide) in a dry powder formulation, suitably by substituting for water at the active agent surface during drying, or otherwise impeding the degradation process, and forms an amorphous solid that includes the active agent.
  • glass stabilization agents include amorphous saccharides, polymeric sugars, buffers, salts, or synthetic polymers (e.g., poly-L-glycolic acid), as well as mixtures of such components.
  • the glass stabilization agent is an amorphous saccharide.
  • the glass stabilization agent is a buffer.
  • the formulations described herein can include both an amorphous saccharide and a buffer, which together or separately may act as a glass stabilization agent.
  • Exemplary amorphous saccharides for use in the compositions described herein include, but are not limited to, trehalose, sucrose, raffinose, inulin, dextran, mannitol, and cyclodextrin.
  • the amorphous saccharide is present at about 30% to about 70% (weight percentage) of the dry powder formulation.
  • the amorphous saccharide is present at about 30% to about 65%, about 35% to about 65%, about 35% to about 60%, about 40% to about 60%, about 30% to about 50%, or about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60%.
  • the amorphous saccharide is trehalose, and is present in the formulations at about 30%-60%, more suitably about 35%-55%, or about 35%, about 40%, about 45% or about 50%, of the weight of the dry powder formulation.
  • compositions and formulations that “consist essentially” of the recited ingredients contain the recited components and those that do not materially affect the basic and novel characteristics of the claimed formulations.
  • Components that do not materially affect the basic and novel characteristics of the claimed compositions are those that do not limit the ability of the leucine and trileucine to stabilize the dry powder formulations.
  • compositions and formulations that consist essentially of the recited ingredients specifically exclude other amino acids or tripeptide amino acids, but can include additional sugars, buffers, etc.
  • a pharmaceutical composition comprises: a. 1 % (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 85.2% (w/w) trehalose ⁇ 10%, and 1.3% (w/w) histidine ⁇ 10%, at pH 5.5; b. 1 % (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 83.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5; c.
  • a pharmaceutical composition comprises: a. 1 % (w/w) antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 85.2% (w/w) trehalose, and 1 .3% (w/w) histidine, at pH 5.5; b. 1 % (w/w) antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 83.36% (w/w) trehalose, and 3.14% (w/w) histidine, at pH 5.5; c.
  • a pharmaceutical composition comprises 1 % (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 83.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5.
  • the pharmaceutical composition comprises 1 % (w/w) antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 83.36% (w/w) trehalose, and 3.14% (w/w) histidine, at pH 5.5.
  • a pharmaceutical composition comprises 10% (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 74.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5.
  • the pharmaceutical composition comprises 10% (w/w) antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 74.36% (w/w) trehalose, and 3.14% (w/w) histidine, at pH 5.5.
  • a pharmaceutical composition comprises 40% (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 44.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5.
  • the pharmaceutical composition comprises 40% (w/w) antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 42.5% (w/w) trehalose, and 5.0% (w/w) histidine, at pH 5.5.
  • the pharmaceutical composition comprises: a. 0.2 mg (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 85.2% (w/w) trehalose ⁇ 10%, and 1 .3% (w/w) histidine ⁇ 10%, at pH 5.5; b. 0.2 mg (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 83.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5; c.
  • the total mass solids content of the pharmaceutical composition is 20 mg.
  • the pharmaceutical composition comprises: a. 0.2 mg (w/w) antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 85.2% (w/w) trehalose, and 1.3% (w/w) histidine, at pH 5.5; b. 0.2 mg (w/w) antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 83.36% (w/w) trehalose, and 3.14% (w/w) histidine, at pH 5.5; c.
  • antigen binding fragment 2% (w/w) trileucine, 10.5% (w/w) leucine, 82.36% (w/w) trehalose, and 3.14% (w/w) histidine, at pH 5.5; f. 0.4 mg antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 80.5% (w/w) trehalose, and 5.0% (w/w) histidine, at pH 5.5; g.
  • the total mass solids content of the pharmaceutical composition is 20 mg.
  • a pharmaceutical composition comprises 0.4 mg ⁇ 20% antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 83.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5.
  • the pharmaceutical composition comprises 0.4 mg antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 83.36% (w/w) trehalose, and 3.14% (w/w) histidine, at pH 5.5.
  • the total mass solids content of the pharmaceutical composition is 20 mg.
  • a pharmaceutical composition comprises 2 mg ⁇ 20% antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 74.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5.
  • the pharmaceutical composition comprises 2 mg antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 74.36% (w/w) trehalose, and 3.14% (w/w) histidine, at pH 5.5.
  • the total mass solids content of the pharmaceutical composition is 20 mg.
  • a pharmaceutical composition that comprises 8 mg ⁇ 20% antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 44.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5.
  • the pharmaceutical composition comprises 8 mg antigen binding fragment, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 42.5% (w/w) trehalose ⁇ 10%, and 5.0% (w/w) histidine ⁇ 10%, at pH 5.5.
  • the total mass solids content of the pharmaceutical composition is 20 mg.
  • the pharmaceutical composition disclosed herein comprises about 3.14% (w/w) histidine
  • the pharmaceutical composition may comprise about 0.55% (w/w) L-histidine and about 2.59% (w/w) histidine HCI.
  • the pharmaceutical composition may comprise 0.55% (w/w) L-histidine and 2.59% (w/w) histidine HCI.
  • the particles that make up the pharmaceutical compositions described herein suitably have a specified mass median aerodynamic diameter (MMAD) when provided in aerosol form.
  • the microparticles may also have a specified equivalent optical volume mean diameter (oVMD).
  • oVMD may also be referred to as particle size distribution (PSD or pPSD).
  • MMAD mass median aerodynamic diameter
  • the aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior and is the diameter of a unit density sphere having the same settling velocity, in air, as the microparticle.
  • the aerodynamic diameter encompasses particle shape, density and physical size of a microparticle.
  • MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by cascade impaction, unless otherwise indicated.
  • the microparticles of the dry powder formulations provided herein have a mass median aerodynamic diameter (MMAD) of about 1 m to about 10 pm, more suitably about 2 pm to about 8 pm, about 2 pm to about 7 pm, about 2 pm to about 6 pm, about 2 pm to about 5 pm, about 2 pm to about 4 pm, about 3 pm to about 7 pm, about 4 pm to about 7 pm, about 3 pm to about 6 pm, or about 2 pm, about 3 pm, about 4 pm, about 5 pm, about 6 pm, or about 7 pm.
  • MMAD mass median aerodynamic diameter
  • the fine particle fraction (the fraction of particles emitted from an inhalation device having an aerodynamic particle diameter of less than 5 pm of the dry powder formulations described herein is > 50%, more suitably > 60%.
  • This fine particle fraction (FPF) may contribute to a low device retention of the dry powder formulations of less than 20%, suitably less than 15%, less than 10%, or less than 5%, remaining in a device following delivery to a patient.
  • the spray-dried particles suitably have an equivalent optical volume mean diameter (oVMD) of about 0.5 pm to about 7 pm.
  • Equivalent optical volume mean diameter (oVMD) refers the mean diameter of a sphere that best approximates a specific optical interaction of the particle with light, where half of the microparticles are best approximated by an equivalent sphere smaller, and half of the microparticles are best approximated by an equivalent sphere larger than the mean, when measured using a suitable optical technique.
  • the microparticles have an equivalent optical volume mean diameter (oVMD) of about 0.5 pm to about 6 pm, or about 1 pm to about 5 pm, or about 1 pm to about 4 pm, or about 2 pm to about 4.5 pm, or about 2.5 pm to about 4 pm, or about 2 pm to about 4 pm, or about 2 pm to about 3 pm, or about 2 pm to about 3.5 pm, or about 1 pm, about 1 .5 pm, about 2 pm, about 2.5 pm, about 3 pm, about 3.5 pm, about 4 pm, about 4.5 pm, or about 5 pm.
  • oVMD equivalent optical volume mean diameter
  • leucine and trileucine in the dry powder formulations also results in microparticles having the desired sizes (MMAD), as well as desirable specific surface area (SSA) and roughness, resulting in microparticles that can flow appropriately and be delivered to the lungs using various inhalation platforms.
  • MMAD desired sizes
  • SSA desirable specific surface area
  • Specific surface area (SSA) of the microparticles is defined as the total surface area of the microparticles per unit of mass (suitably with units of m 2 /g).
  • Methods of measuring SSA are known in the art, and include for example Brunauer-Emmett-Teller (BET) measurements using specific surface area evaluation of materials by nitrogen adsorption measured as a function of relative pressure. The surface area is determined by calculating the amount of adsorbate gas corresponding to a monomolecular layer on the surface of the microparticles. The technique measures external area and any pore area evaluations to determine the total specific surface area. Instruments for measuring BET are known in the art.
  • the specific surface area (SSA) of the microparticles of the dry powder formulations is about 3 m 2 /g to about 8 m 2 /g.
  • the SSA of the plurality of microparticles is about 3.5 m 2 /g-7.5 m 2 /g, or about 4 m 2 /g-7 m2/g, or about 4.5 m 2 /g-7 m 2 /g, or about 5 m 2 /g-7 m 2 /g, or about 4.5 m 2 /g-6 m 2 /g, or about 5 m 2 /g-6 m2/g, or about 4 m 2 /g, about 4.5 m 2 /g, about 5 m 2 /g, about 5.5 m 2 /g, about 6 m 2 /g, about 6.5 m 2 /g, or about 7 m 2 /g.
  • the dry powder formulation has a compressed bulk density of about 0.4-1 .0 g/cm 3 .
  • the compressed bulk density of the dry powder formulation is about 0.5-0.8 g/cm 3 .
  • the compressed bulk density of a dry powder formulation described herein is about 0.4-0.9 gm/cm3, about 0.4-0.8 gm/cm 3 , about 0.5-0.8 gm/cm 3 , about 0.6-0.8 gm/cm 3 , or about 0.4 gm/cm 3 , about 0.5 gm/cm 3 , about 0.6 gm/cm 3 , about 0.7 gm/cm 3 , or about 0.8 gm/cm 3 .
  • the compressed bulk density of a dry powder formulation described herein is from about 0.4 gm/cm 3 to about 0.9 gm/cm 3 . In certain instances, the compressed bulk density of a dry powder formulation described herein is from about 0.5 gm/cm 3 to about 0.8 gm/cm 3 .
  • the pharmaceutical compositions described herein do not comprise a surfactant, such as a polysorbate, e.g. polysorbate-80 or polysorbate-20. While addition of a surfactant minimises the formation of protein aggregates, it increases device deposition, thus reducing lung deposition, and reduces dry-spraying yield.
  • a surfactant minimises the formation of protein aggregates, it increases device deposition, thus reducing lung deposition, and reduces dry-spraying yield.
  • the present inventors optimised the composition described in such a way that omitting the surfactant had minimal effect on protein aggregation while, advantageously, minimising device deposition of the powder (Example 3).
  • a “sub-visible particle” (“SVP”) as referred to herein is a particle not visible to the naked eye of from about 1 pm to about 200 pm. Removing or reducing the formation of SVPs simplifies the analytical characterization of the formulation, as it removes the burden of tracking the formation of SVPs during manufacturing.
  • the analytical characterization of SVPs may involve the development of orthogonal techniques to identify and quantify SVPs for quality control purposes. Thus, removing SVPs or reducing them to acceptable levels removes the necessity of this characterization step from the manufacturing process, streamlining manufacturing. The removal of SVPs may also make dose ranging more predictable, since the kinetics of drug-release from SVPs is unknown.
  • removing SVPs is likely to increase the amount of active agent available to engage in pharmacological activity postreconstitution, which may mean not only that a higher delivered dose can be achieved, but a more accurate prediction of the delivered dose can be calculated.
  • a higher delivered dose may also benefit the patient, for example, by potentially reducing the number or frequency of doses that must be delivered for extracting a pharmacological benefit.
  • MFI microflow imaging
  • FIM flow imaging microscopy
  • DIA dynamic imaging analysis
  • Dynamic flow imaging microscopy combines microfluidic flow microscopy and high resolution imaging particle analysis to quantify SVP counts.
  • MFI can bin these counts across a particle size range, for example, by binning particles counts in a size range of about 1 to about 200 pm, about 2 pm to about 200 pm, about 5 pm to about 200 pm, about 10 pm to about 200 pm and about 25 pm to about 200 pm.
  • An alternative technique for the measurement of SVP is background membrane imaging (BMI). Briefly, SVPs from a liquid sample are isolated onto a filer surface for counting analysis by a microscope. The BMI software images the baseline prior to particle isolation and, and then subtracts that baseline pixel-by-pixel form the isolated particles so that only photographic information remains (Vargas et al., 2020). Optimisation of the formulation excipients and other aspects of the composition significantly lowered the formation of SVPs.
  • the number of SVPs of between 5 pm to 200 pm in size is less than about 30,000 particles per ml, such as 25,000 particles per ml, 20,000 particles per ml, 15,000 particles per ml, 10,000 particles per ml or 5,000 particles per ml. In certain instances, the number of SVPs of 5 pm to 200 pm in size are less than 1 ,000 particles per ml. In certain instances, the number of SVPs of between 5 pm to 200 pm in size are less than below 1 ,000 particles per ml. In certain instances, the number of SVPs of between 5 pm to about 200 pm in size are less than below 100 particles per ml.
  • the number of SVPs of 10 pm to 200 pm in size are less than about 100,000 particles per ml, such as 90,000 particles per ml, 80,000 particles per ml, 70,000 particles per ml, 60,000 particles per ml, 50,000 particles per ml, 40,000 particles per ml or 30,000 particles per ml. In certain instances, the number of SVPs of 10 pm to 200 pm in size are less than about 10,000 particles per ml. In certain instances, the number of SVPs of 10 pm to 200 pm in size are less than about 2,000 particles per ml. In certain instances, the number of SVPs of 10 pm to about 200 pm in size are less than 100 particles per ml.
  • the number of SVPs of 25 pm to 200 pm in size is less than about 200,000 particles per ml, such as 180,000 particles per ml, 170,000 particles per ml, 160,000 particles per ml, 150,000 particles per ml or 140,000 particles per ml.
  • the number of SVPs of about 5 pm to about 200 pm in size are less than about 50,000 particles per ml.
  • the number of SVPs of 5 pm to 200 pm in size are less than about 10,000 particles per ml.
  • the number of SVPs of about 5 pm to about 200 pm in size are less than about 2,000 particles per ml.
  • the number of SVPs of 10 pm to about 200 pm in size are less than about 200 particles per ml.
  • the number of SVPs is determined following reconstitution in water, to an antigenbinding fragment concentration of either 2.5 mg/ml or 30 mg/ml.
  • a process for making a pharmaceutical composition for inhalation comprising: providing an aqueous solution of about pH 5 to about pH 6 comprising leucine, trileucine, histidine, a glass stabilization agent as described herein and an antigen binding fragment of an anti- thymic stromal lymphopoietin (TSLP) antibody; spray drying the aqueous solution of (a) to produce dry powder particles; and collecting the dry powder particles wherein the aqueous solution comprises about 5% (w/w) to about 15% (w/w) leucine, about 1% (w/w) to about 5% (w/w) trileucine, about 1% (w/w) to about 10% (w/w) histidine, about 5% (w/w) to about 50% (w/w) antigen binding fragment and % (w/w) glass stabilization agent to 100% total solids content.
  • the aqueous solution has a pH of 5.5.
  • the aqueous solution comprises: a. 1% (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 85.2% (w/w) trehalose ⁇ 10%, and 1.3% (w/w) histidine ⁇ 10%, at pH 5.5; b. 1% (w/w) antigen binding fragment ⁇ 20%, 2% (w/w) trileucine ⁇ 10%, 10.5% (w/w) leucine ⁇ 10%, 83.36% (w/w) trehalose ⁇ 10%, and 3.14% (w/w) histidine ⁇ 10%, at pH 5.5; c.
  • the aqueous solution comprises: a. 1 % (w/w) antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 85.2% (w/w) trehalose, and 1 .3% (w/w) histidine, at pH 5.5; b. 1 % (w/w) antigen binding fragment, 2% (w/w) trileucine, 10.5% (w/w) leucine, 83.36% (w/w) trehalose, and 3.14% (w/w) histidine, at pH 5.5; c.
  • the pharmaceutical composition may comprise about 0.55% (w/w) L-histidine and about 2.59% (w/w) histidine HCI. In some instances, when the pharmaceutical composition comprises 3.14% (w/w)) histidine, the pharmaceutical composition may comprise 0.55% (w/w) L-histidine and 2.59% (w/w) histidine HCI.
  • the aqueous solution is prepared by combining these components in a liquid solvent, to create a feedstock in which each of the components is dissolved. Temperature control may be added as desired or required to increase the solubility of the various components to form the aqueous solution.
  • Exemplary liquid solvents include water, including deionized water, as well as dilute solutions of alcohols with water.
  • the active agent is suitably added to the aqueous solution after the addition and dissolution of the remaining components of the feedstock.
  • the aqueous solution may then be atomized.
  • the aqueous solution may be filtered prior to atomizing.
  • the liquid feedstock may be filtered through a 0.22 micron filter.
  • the aqueous solution comprising leucine, trileucine, and histidine is filtered prior to the addition of the active agent.
  • the aqueous solution is filtered after the addition of the active agent prior to atomizing.
  • Atomizing refers to converting the solution to fine droplets, suitably using a pressurized gas (such as an inert gas or compressed dry air).
  • a pressurized gas such as an inert gas or compressed dry air.
  • Exemplary devices for producing an atomized solution are known in the art and include the use of various atomizing nozzles have desired sizes and flow characteristics.
  • Exemplary parameters for the atomizing including an outlet temperature of about 50°C-90°C, suitably about 60°C- 80°C, or about 70°C; a feedstock feed rate of about 8-15 ml/min, suitably about 9-14 ml/min, about 10-13 ml/min, or about 12 ml/min; an atomizer gas flow rate of about 9-15 kg/hour (hr. or h), suitably about IQ- 14 kg/hr, about 12-14 kg/hr, or about 13 kg/hr; and drying gas flow rate of about 60-100 kg/hr, suitably about 60-90 kg/hr, about 70-90 kg/hr, or about 80 kg/hr.
  • the atomized solution may then be dried, suitably under heat and in combination with flowing air to aid in the drying.
  • the result of the drying yields a plurality of microparticles. Drying temperatures typically range from about 50°-100°C, or about 60°-100°C, or about 70°-90°C; air flow rate can be on the order of about 10-40 m 3 /hour.
  • Exemplary glass stabilization agents including amorphous saccharides and buffers are described herein, as are suitable amounts of the glass stabilization agents. Suitable amounts of leucine and trileucine are provided throughout as well. As the final, dry powder formulation should contain the recited amounts of leucine, trileucine, histidine (and other components), such amounts are also used in the liquid feedstock. The result of the drying process following atomization is that any liquid solvent is removed, and thus the full amount of the original dry weight of the components corresponds to the final dry weight of the compounds in the dry powder formulation. Exemplary active agents are also described herein.
  • Such containers can be produced with 10-200 mg of dry powder, suitably 10-100 mg, 15-25 mg, or 20-75 mg, 20 mg or 50 mg or dry powder formulation.
  • Such containers can suitably deliver 0.1-10 mg of a dry powder formulation to a patient’s lungs.
  • the use of the methods described herein provide pharmaceuticals that can reduce the total number of capsules required for use in an inhalation device.
  • the volume required to deliver 50-100 mg of active agent can be reduced from two larger 00 capsules to a single size 3 capsule.
  • Methods for producing an aerosol form of dry powder particles include for example, the use of inhaler devices such as a dry-powder inhaler (DPI) (e.g., a Monodose RS01 DPI by PLASTIAPE (Osnago, Italy)).
  • DPI dry-powder inhaler
  • the pharmaceutical compositions described herein can be dispensed into a gas stream by either a passive or an active inhalation device, and remain suspended in the gas for an amount of time sufficient for at least a portion of the microparticles to be inhaled by the patient, so that a portion of the microparticles reaches the lungs.
  • Anti-TSLP antibodies and antigen binding fragments thereof are known in the art and include for example, the use of inhaler devices such as a dry-powder inhaler (DPI) (e.g., a Monodose RS01 DPI by PLASTIAPE (Osnago, Italy)).
  • the pharmaceutical compositions described herein can be dispensed
  • the various methods, pharmaceutical compositions, unit doses disclosed herein utilize an antigen binding fragment of an anti-thymic stromal lymphopoietin (TSLP) antibody.
  • TSLP anti-thymic stromal lymphopoietin
  • the antigen binding fragment is a Fab.
  • Heavy Chains and Light Chains refer to substantially full-length canonical immunoglobulin light and heavy chains (see e.g., Immunobiology, 5th Edition (Janeway and Travers et al., Eds., 2001).
  • antibody includes naturally occurring antibodies as well as all recombinant forms of antibodies, e.g., humanized antibodies, fully human antibodies and chimeric antibodies.
  • antibody fragment refers to a portion of an intact antibody.
  • antigen-binding fragment refers to a portion of an intact antibody that binds to an antigen.
  • Antigen-binding fragments of antibodies include, inter alia, Fab, Fab', F(ab')2, Fv, domain antibody (dAb), complementarity determining region (CDR) fragments, CDR- grafted antibodies, single-chain antibodies (scFv), single chain antibody fragments, chimeric antibodies, diabodies, triabodies, tetrabodies, minibody, linear antibody; chelating recombinant antibody, a tribady or bibody, an intrabody, a nanobody, a small modular immunopharmaceutical (SMIP), an antigen-binding- domain immunoglobulin fusion protein, single domain antibodies (including camelized antibody), a VHH containing antibody, or a variant or a derivative thereof, and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide, such as one, two, three, four, five or six CDR sequences, as long as the antibody retains the desired biological activity.
  • dAb
  • the antigen-binding fragment of an antibody of the disclosure is selected from Fab, Fab', F(ab')2, scFv, minibody, or diabody.
  • the antigen-binding fragment is a Fab.
  • the antigen-binding fragment is of an IgG, IgM, IgA, IgD or IgE.
  • the anti- TSLP antibody fragment is of an IgG 1 .
  • Fab refers to an antibody fragment comprising the VH-CH1 and VL-CL pairing.
  • the term encompasses Fabs comprising non-canonical sequence variants such as amino acid substitutions, deletions, or insertions within the Fab outside of sequence regions typically associated with high sequence variability.
  • Fab variants include Fabs comprising non-canonical amino acid or sequence changes in VH or VL framework regions or in the CH1 or CL domains. Such changes may include the presence of non-canonical cysteines or other derivatizable amino acids, which may be used to conjugate said Fab variants to heterologous moieties.
  • Other such changes include the presence of non-canonical polypeptide linkers, which are polypeptide sequences that covalently bridge between two domains.
  • a Fab variant may comprise a linker polypeptide that covalently attaches the CH1 domain to the VL domain, or the CL domain to the VH domain, such that the Fab can be expressed as a single polypeptide chain.
  • LCDR Light chain CDR
  • VL light chain variable domain
  • HCDR heavy chain CDR
  • VH heavy chain variable domain
  • the antigen binding fragment within the composition comprises: a heavy chain variable domain comprising: a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:1 , a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:2, and a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:3, wherein either of heavy chain CDR1 , 2 or 3 optionally comprises a single amino acid substitution, and a light chain variable domain comprising: a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:5, a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:6, and a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:7; wherein either of light chain CDR 1 , 2 or 3 optionally comprises a single amino acid substitution.
  • the antigen binding fragment within the composition comprises a heavy chain variable domain comprising a light chain CDR1 sequence having the amino acid sequence set forth in SEQ ID NO:1 , a heavy chain CDR2 sequence having the amino acid sequence set forth in SEQ ID NO:2, and a heavy chain CDR3 sequence having the amino acid sequence set forth in SEQ ID NO:3, and a light chain CDR1 sequence having the amino acid sequence set forth in SEQ ID NO:5, a light chain CDR2 sequence having the amino acid sequence set forth in SEQ ID NO:6, and a light chain CDR3 sequence having the amino acid sequence set forth in SEQ ID NO:7.
  • the antigen binding fragment for use in the pharmaceutical composition comprises a heavy chain variable domain that is a sequence of amino acids that is at least 95%, 90%, 85% or 80% identical to SEQ ID NO: 4 and a light chain variable domain that is a sequence of amino acids that is at least 95%, 90%, 85% or 80% identical to, SEQ ID NO: 8.
  • the antigen binding fragment for use in the composition comprises (a) a heavy chain variable domain that is a sequence of amino acids that is at least 95%, 90%, 85% or 80% identical to, SEQ ID NO: 4; or a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 30, (b) a light chain variable domain that is a sequence of amino acids that is at least 95%, 90%, 85% or 80% identical to SEQ ID NO: 8; or a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 31 ; or a heavy chain variable domain of (a) and a light chain variable domain of (b).
  • the antigen binding fragment for use in the pharmaceutical composition comprises a heavy chain variable domain comprising SEQ ID NO:4; and a light chain variable domain comprising SEQ ID N0:8. In additional instances, the antigen binding fragment for use in the pharmaceutical composition comprises a heavy chain comprising the sequence set forth in SEQ ID NO:28; and a light chain comprising the sequence set forth in SEQ ID NO:29.
  • LCDR light chain CDR
  • VL light chain variable domain
  • HCDR heavy chain CDR
  • VH heavy chain variable domain
  • the heavy variable chain and the light variable chain domains of the antigen binding fragment of the disclosure comprise any of the combinations of CDR sequences set out in Table 3 below:
  • the antigen binding fragment for use in the pharmaceutical composition may be derived from one of those described WO2023098491A1 , WO2021155634A1 , WO2022166072A1 , WO2021043221 A1 , WO2022184074A1 , WO2021104053A1 , WO2023116925A1 , WO2021155861 A1 , WO20221 16858A1 , WO2022117079A1 , WO2020244544A1 , WO2021152488A1 , WO2022253147A1 , W02023070948A1 , WO2023142309A1 , WO2022095689A1 , WO2021115240A1 , WO2022166739A1 and W02019100111A1 , the disclosure of each of which is incorporated by reference herein.
  • the antigen binding fragment for use in the pharmaceutical composition may be derived from one of those set out in the Table 4 below (which includes sequence identifiers from the listed publications themselves): Table 4: alternative anti-TSLP antibodies that could be used in the formulations disclosed herein.
  • Also provided herein are methods of treatment comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition described herein.
  • the method is for the treatment of a TSLP-related condition.
  • Treating” or “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.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 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 condition or disorder is to be prevented.
  • “Therapeutically effective amount” refers to an amount of an antigen binding fragment of an anti-TSLP antibody disclosed herein or other drug effective to "treat” a disease or disorder in a subject or mammal.
  • Subject or “individual” or “animal” or “patient” or “mammal” is means any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired, except where the subject is defined as a ‘healthy subject’.
  • Mammalian subjects include humans; domestic animals; farm animals; such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and so on.
  • the subject is human.
  • the patient may be an adult, or a child or adolescent.
  • compositions for use in therapy are also provided herein.
  • the therapy is the treatment of a TSLP-related condition.
  • the disease is a TSLP-related condition.
  • the disclosure also provides for the use of the antigen binding fragment of an anti-TSLP antibody or pharmaceutical compositions comprising the same in therapy.
  • the therapy is the treatment of a TSLP-related condition.
  • the TSLP-related condition is a TSLP-related inflammatory condition.
  • the TSLP-related inflammatory condition is selected from asthma, sepsis, septic shock, atopic dermatitis, allergic rhinitis, allergic rhinosinusitis, allergic conjunctivitis, eosinophilic esophagitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, COPD overlap syndrome (ACOS), chronic bronchitis, emphysema, chronic rhinosinusitis with or without nasal polyps, vasculitis, GvHD, uveitis, chronic idiopathic urticaria, sinusitis or pancreatitis.
  • the TSLP-related condition is asthma.
  • the TSLP-related condition is COPD.
  • the asthma is moderate or severe asthma, or moderate-to-severe asthma.
  • the subject having moderate or severe asthma, or moderate-to-severe asthma may mean the subject has a diagnosis of moderate or severe asthma, or moderate-to-severe asthma.
  • the subject may have a documented history of moderate or severe asthma, or moderate-to- severe asthma for at least 1 year.
  • Asthma is a chronic inflammatory disease of the airways affecting 1-18% of the population in different countries and is characterized by bronchial hyperreactivity and reversible airflow limitation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough. The etiology of asthma is thought to be multi-factorial and there are recognizable clusters of demographic, clinical and/or pathophysiological phenotypes. In patients with more severe phenotypes, some phenotype-guided treatments are available. However, no strong relationship between pathological symptoms and clinical presentations and response to therapies have been established.
  • Asthma may be diagnosed or assessed by a number of different measures, including:
  • FeNO Exhaled Nitric Oxide
  • atopic status This can be identified by a skin prick test with common environmental alleges or by measuring the level of specific IgE in serum.
  • allergy tests do not rule in or rule out a diagnosis of asthma but the presence of atopy increases the probability that a patient with respiratory symptoms has allergic asthma.
  • Bronchial provocation testing These tests monitor variable airflow limitation to assess airway hyperresponsiveness (AHR).
  • Subjects can be challenged with chemical agents such as methacholine. Such tests are moderately sensitive to the diagnosis of asthma.
  • FENO refers to fractional exhaled nitric oxide, which is a biomarker for bronchial or airway inflammation.
  • FENO is produced by airway epithelial cells in response to inflammatory cytokines, such as TSLP, IL-4 and IL-13.
  • cytokines such as TSLP, IL-4 and IL-13.
  • FENO levels in healthy adults range from 2 to 30 parts per billion (ppb).
  • An exemplary assay for measuring FENO comprises subjects inhaling to total lung capacity through the NIOX MINO® Airway Inflammation Monitor and then exhaling for 10 seconds at 50 ml/sec (assisted by visual and auditory cues).
  • asthma subtypes include allergic asthma, non-allergic asthma, late-onset asthma (which typically tends to be non-allergic), asthma with persistent airflow limitation (which is linked to airway wall remodeling, leading to a long-standing, persistent, irreversible airflow limitation), and asthma with obesity (which is typically linked to a non/low eosinophilic mechanism of action).
  • subjects treated by the present disclosure may have any type or origin of asthma.
  • the severity index comprises three main groups: mild asthma, moderate asthma, and severe asthma. Severity of asthma is defined on the GINA scale by the level of treatment required to gain adequate control of symptoms.
  • the GINA scale is defined in the “Pocket Guide for Asthma Management and Prevention,” Global Initiative for Asthma; 2019. Unless otherwise stated herein, references to “moderate asthma” or “severe asthma” are in accordance with the definitions on the GINA scale. For instance, moderate asthma refers to asthma that has a Global Initiative for Asthma (GINA) scale of 3 or less, suitably a GINA scale of 2 or 3 (i.e.
  • GINA Global Initiative for Asthma
  • GINA step 2 or step 3 and severe asthma refers to asthma that requires high intensity treatment (e.g., GINA Step 4 and Step 5) to maintain good control, or where good control is not achieved despite high intensity treatment
  • GINA Step 4 and Step 5 high intensity treatment
  • the subject has a history of > 1 or > 2 severe exacerbation(s) within the last 12 months prior to the treatment. Severe exacerbations are defined as those episodes that lead to hospitalisation, emergency room visit, and/or treatment with oral glucocorticosteroid as detailed below:
  • Inpatient hospitalization an admission to an inpatient facility and/or evaluation and treatment in healthcare facility for > 24 hours due to asthma;
  • the asthma moderate asthma, severe asthma, or moderate-to-severe asthma.
  • the asthma is not well-controlled on controller or reliever standard of care therapies defined in steps 1 and 2 of the GINA scale. In some instances, therefore the asthma to be treated by the present disclosure may have uncontrolled asthma.
  • the asthma is moderate asthma uncontrolled on standard of care therapy, severe asthma uncontrolled on standard of care therapy, or moderate-to-severe asthma uncontrolled on standard of care therapy.
  • Standard of care (SOC) therapy is as defined in the GINA scale.
  • COPD chronic obstructive pulmonary disease
  • AECOPD Acute exacerbations of COPD
  • COPD COPD
  • AECOPDs are also responsible for much of the morbidity and mortality from COPD.
  • Patients with frequent AECOPD show associated increased airway inflammation and accelerated decline in lung function compared with patients with infrequent exacerbations.
  • the subject has a baseline blood eosinophil count of > 150 cells/pl or > 300 cells/pl.
  • baseline refers to the blood eosinophil count prior to commencement of the treatment, e.g. within one month of the commencement of treatment.
  • the methods disclosed herein improve lung function in a subject with asthma.
  • the improving lung function means one or more of the following: improvement compared to baseline of pre-bronchodilator (BD) FVC, post-BD-FVC, pre-BD-FEV1 , post-BD FEV1 , mean morning PEF or mean evening PEF.
  • BD pre-bronchodilator
  • the improvement means achieving the minimal clinical important difference (MCID) for each of pre-bronchodilator (BD) FVC, post-BD-FVC, pre-BD-FEV1 , post-BD FEV1 , mean morning PEF or mean evening PEF, respectively.
  • BD pre-bronchodilator
  • MCID minimal clinically important difference
  • pre-BD FEV1 refers to pre-bronchodilator forced expiratory volume 1 . This is a measurement of forced expiratory volume of a subject in 1 second before administration of bronchodilator. In some instances, the minimum clinical important difference for pre-BD-FEVi is 100 ml.
  • the increase in pre-BD-FEVi compared to baseline is at least 5 ml, at least 10 ml, at least 15 ml, at least 20 ml, at least 25 ml, at least 30 ml, at least 35 ml, at least 40 ml, at least 45 ml, at least 50 ml, at least 55 ml, at least 60 ml, at least 65 ml, at least 70 ml, at least 75 ml, at least 80 ml, at least 85 ml, at least 90 ml, at least 95 ml, at least 100 ml, at least 105 ml, at least 110 ml, at least 115 ml, at least 120 ml, at least 125 ml, at least 130 ml, at least 135 ml, at least 140 ml, at least 145 ml, at least 150 ml,
  • the increase in pre-BD-FEVi compared to baseline is at least 80 ml at day 2 after commencement of treatment, at least 45 ml or at least 100 ml at day 7 after commencement of treatment, at least 100 ml at day 14 after commencement of treatment, or at least 5 ml or at least 100 ml at day 28 after commencement of treatment.
  • postBD-FEV1 or “post-bronchodilator (BD)-FEVT’ refers to post-bronchodilator forced expiratory volume 1 . This is a measurement of forced expiratory volume of a subject in 1 second after administration of bronchodilator.
  • pre-BD-FVC pre-bronchodilator (BD) forced vital capacity (FVC) refers to bronchodilator Forced vital capacity. This is the total amount of air exhaled by a subject during a forced expiratory volume test or FVC test before administration of bronchodilator.
  • BD pre-bronchodilator
  • FVC forced vital capacity
  • post-BD-FVC post-bronchodilator (BD)-FVC refers to post-bronchodilator forced vital capacity. This is the total amount of air exhaled by a subject during a forced expiratory volume test or FVC test after administration of bronchodilator.
  • bronchodilator is a substance which dilates the bronchi and bronchioles, decreasing resistance in the respiratory airways and increasing airflow to the lungs.
  • Suitable bronchodilators include a short-acting beta agonist (SABA) such as albuterol (90 1-1 g metered dose) or salbutamol (1 00 1-1 g metered dose) or equivalent (Sorkness et al, J Appl Physiol. 1 04(2):394-403, 2008).
  • SABA short-acting beta agonist
  • peak expiratory flow rate indicates the fastest rate that a subject can force air out of the lungs during a forced expiratory volume test or FVC test, typically measured in Litres/minute.
  • FEV force expiratory volume
  • FVC forced vital capacity
  • pre-BD-FEVi, post-BD-FEVi, pre-BD-FVC, post-BD-FVC Spirometry is performed according to ATS/European Respiratory Society (ERS) guidelines (Miller et al, Eur Respir J. 26(1 ):153- 61 , 2005).
  • ERS European Respiratory Society
  • multiple forced expiratory efforts (at least 3 but no more than 8) is performed at each spirometry session and the 2 best efforts that meet ATS/ERS acceptability and reproducibility criteria are recorded.
  • the best efforts will be based on the highest FEV1 .
  • the maximum fluvial exhalation volume (FEV1) of the 2 best efforts will be used for the analysis.
  • Both the absolute measurement (for FEV1 and forced vital capacity (FVC)) and the percentage of predicted normal value will be recorded using appropriate reference values.
  • the highest FVC will be reported regardless of the effort in which it occurred (even if the effort did not result in the highest FEV1).
  • Post-bronchodilator (Post-BD) spirometry testing is assessed after the subject has performed pre-BD spirometry.
  • Pre-BD FEV1 is measured as defined above using spirometry before administration of a suitable bronchodilator to the subject.
  • SABA short-acting beta agonist
  • albuterol 90 1-1 g metered dose
  • salbutamol 1 00 1 - 1g metered dose
  • equivalent a spacer device for a maximum of 8 total puffs
  • the improvement in lung function is within 0.5 h of first dose with the composition disclosed herein. In some instances, the improvement in lung function is within 1 h of first dose with the composition disclosed herein. In some instances, the improvement in lung function is within 6 h of first dose with the composition disclosed herein. In some instances, the improvement in lung function is within 24 h of first dose with the composition disclosed herein. In some instances, the improvement in lung function is within 7 days of first dose with the composition disclosed herein. In some instances, the improvement in lung function is within 14 days of first dose with the composition disclosed herein. In some instances, the improvement in lung function is within 28 days of first dose with the composition disclosed herein.
  • Figure 26B shows that subjects in part B of NCT05110976 who were administered 8 mg FAB1 displayed a trend towards an improvement in pre-BD FEV1 in the high dose arm, with 105ml increase at day 28, and early effects seen at 6 hours after first dose.
  • improving symptoms of asthma means one or more of the following: improvement compared to baseline mean asthma symptom diary score, ACQ-6 score, AQLQ score, or SGRQ score.
  • the Asthma Control Questionnaire (ACQ) 6 is a patient-reported questionnaire assessing asthma symptoms (i.e., night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing) and daily rescue bronchodilator use and FEV1 (Juniper et al, Oct 1999).
  • the ACQ-6 is a shortened version of the ACQ that omits the FEV1 measurement from the original ACQ score. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled).
  • the mean ACQ score is the mean of the responses.
  • the disclosure provides methods for improving lung function, wherein the method results in a 0.5 point improvement in ACQ-6 score compared to baseline.
  • Standardised asthma quality of life questionnaire for 12 years and older (AQLQ(S)+12)
  • the AQLQ(S)+12 is a questionnaire that measures the health-related quality of life experienced by asthma subjects.
  • the questionnaire comprises 4 separate domains (symptoms, activity limitations, emotional function, and environmental stimuli). Subjects are asked to recall their experiences during the previous 2 weeks and to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The overall score is calculated as the mean response to all questions.
  • the 4 individual domain scores (symptoms, activity limitations, emotional function, and environmental stimuli) are the means of the responses to the questions in each of the domains.
  • the responder definition for AQLQ(s)+12 is 0.5-point improvement from baseline. Accordingly, in some instances, the minimum clinical important difference for AQLQ is 0.5.
  • the disclosure provides methods for improving lung function, wherein the method results in a 0.5 point improvement in AQLQ compared to baseline.
  • the SGRQ is a 50-item PRO instrument developed to measure the health status of patients with airway obstruction diseases (Jones et al 1991).
  • the questionnaire is divided into 2 parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual’s respiratory condition.
  • the SGRQ yields a total score and 3 domain scores (symptoms, activity, and impacts).
  • the total score indicates the impact of disease on overall health status. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible health status and 0 indicates the best possible health status. Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater impairment.
  • MCID clinically important difference
  • the disclosure provides methods for improving lung function, wherein the method results in a 4 point improvement in SGRQ score compared to baseline.
  • the improvement in asthma symptoms is within 7 days of first dose with the composition disclosed herein. In some instances, the improvement in asthma symptoms is within 14 days of first dose with the composition disclosed herein. In some instances, the improvement in asthma symptoms is within 28 days of first dose with the composition disclosed herein.
  • Figure 27 shows that subjects in part B of NCT05110976 who were administered 8 mg FAB1 displayed a trend towards an improvement in ACQ-6 score as evidenced by mean change from baseline over time in the high dose arm (8 mg).
  • CompEx Asthma is a composite endpoint that allows evaluation of treatment effect on exacerbation involving fewer participants compared with severe exacerbations.
  • CompEx Asthma events There are two main types of CompEx Asthma events:
  • the disclosure provides a method for improving time to first CompEx event in a subject with asthma.
  • the disclosure provides a method for improving lung function in a subject with asthma, wherein the improvement in lung function comprised an improved in time to first CompEx event compared to placebo.
  • the disclosure provides a method for improving lung function in a subject with asthma, wherein the improvement in lung function comprised an improved in time to first CompEx event.
  • the improved time is compared to placebo.
  • the improved time is compared to baseline.
  • baseline is the time to first CompEx event in a subject who has not received the treatment described herein.
  • the pharmaceutical composition described herein may be administered by inhalation or intranasally.
  • the pharmaceutical composition described herein may be an inhalable pharmaceutical composition.
  • the pharmaceutical composition is administered by dry powder inhaler.
  • the composition is administered frequently and at lower dosages than a systemically administered anti-TSLP medicine.
  • the formulation may be administered daily. Such instances may be more convenient for the subject or patient. Furthermore, such instances may reduce side effects that can occur via systemic administration.
  • the anti-drug antibody (ADA) prevalence in the subject following treatment with the pharmaceutical composition or the dry powder formulation disclosed herein is less than 6%, less than 5% or less than 4% and/or the ADA incidence is less than 4%, less than 3% or less than 2%.
  • ADA prevalence is the percentage of ADA-evaluable participants who were ADA+ at any time, while ADA incidence is the percentage of ADA-evaluable participants who had treatment emergent anti-drug antibodies (TE-ADA+).
  • the compositions provide for the possibility of treating patients with moderate-severe asthma who could be managed in a primary care setting, or for treating patients with moderate-severe asthma with poor access to treatment via specialist care.
  • the compositions may be useful for the treatment of moderate-severe asthma patients with a Global Initiative for Asthma (GINA) scale of 4-5.
  • the compositions provide for the possibility of treating moderate-severe asthma that is uncontrolled.
  • the compositions provide for the possibility of treating moderate-severe asthma that is uncontrolled on medium dose to high dose ICS:LABA with one or more exacerbations and frequent symptoms.
  • composition disclosed herein may be administered in combination with any known therapy for asthma and/or COPD, including any agent or combination of agents that are known to be useful, or which have been used or are currently in use, for treatment of inflammatory diseases, e.g. asthma or COPD.
  • any known therapy for asthma and/or COPD including any agent or combination of agents that are known to be useful, or which have been used or are currently in use, for treatment of inflammatory diseases, e.g. asthma or COPD.
  • Exemplary active agents that can be administered in combination with the composition described herein include, but are not limited to, inhaled corticosteroids (ICS), bronchodilators (including long-acting beta agonists (LABA), long-acting anti-muscarinic agonists (LAMA), short-acting beta agonist (SABA), and muscarinic p2-agonists (MABA)), antihistamines, antileukotrienes, PDE-4 inhibitors, janus kinase inhibitors and phosphoinositide 3-kinase inhibitors.
  • ICS inhaled corticosteroids
  • bronchodilators including long-acting beta agonists (LABA), long-acting anti-muscarinic agonists (LAMA), short-acting beta agonist (SABA), and muscarinic p2-agonists (MABA)
  • antihistamines antileukotrienes
  • PDE-4 inhibitors janus kinase inhibitors and phospho
  • the subject to be or being treated is co-administered a background therapy.
  • the subject is already receiving the background therapy prior to the treatment.
  • the background therapy is selected from: inhaled corticosteroids, Leukotriene modifiers, long- acting beta agonists (LABAs), long-acting muscarinic antagonists (LAMAs), combination therapies such as Fluticasone and salmeterol, budesonide and formoterol, mometasone and formoterol and fluticasone and vilanterol, theophylline, short-acting beta agonists (SABAs), ipratropium or a combination of ipratropium and albuterol or oral corticosteroids.
  • the background therapy comprises medium or high dose ICS (as per GINA 2023 report) in combination with LABA (GINA step 4 or 5 therapy).
  • combination refers to either a fixed combination in one dosage unit form, or a combined administration where a pharmaceutical composition as described herein and a combination partner (e.g. another drug, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • a pharmaceutical composition as described herein and a combination partner e.g. another drug, also referred to as “therapeutic agent” or “co-agent”
  • a combination partner e.g. another drug, also referred to as "therapeutic agent” or “co-agent”
  • the single components may be packaged in a kit or separately.
  • One or both of the components e.g., powders or liquids
  • co- administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents.
  • fixed combination means that the therapeutic agents, e.g. an anti-TSLP Fab and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the therapeutic agents, e.g., an anti-TSLP Fab and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more therapeutic agent.
  • combination therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients.
  • such administration encompasses coadministration in multiple, or in separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration.
  • such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • the pharmaceutical composition may be administered to a human or other animal in accordance with the aforementioned methods of treatment/medical uses in an amount sufficient to produce a therapeutic effect.
  • the pharmaceutical composition can be administered to such human or other animal in a conventional dosage form prepared by combining the anti-TSLP Fab with a conventional pharmaceutically acceptable carrier or diluent according to known techniques.
  • the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the pharmaceutical compositions are formulated to comprise a pharmaceutically acceptable, non-toxic, sterile carrier such as physiological saline, non-toxic buffers, preservatives and the like.
  • the pharmaceutical composition may include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Suitable formulations for use in the therapeutic methods disclosed herein are described in Remington's Pharmaceutical Sciences (Mack Publishing Co.) 16th ed. (1980).
  • the components as recited herein for preparing said pharmaceutical composition may be packaged and sold in the form of a kit.
  • a kit will in some instances have labels or package inserts indicating that the associated pharmaceutical compositions are useful for treating a subject suffering from, or predisposed to a disease or disorder.
  • the pharmaceutical composition is administered or is to be administered to a subject in need thereof at a dose comprising about 0.2 mg to about 16 mg of the anti-TSLP antigen binding fragment.
  • the pharmaceutical composition is administered or is to be administered to a subject in need thereof at a dose comprising about 0.2 mg, about 0.4 mg, about 0.6 mg, about 2 mg, about 6 mg, about 8 mg or about 16 mg of the anti-TSLP antigen binding fragment.
  • the pharmaceutical composition is administered or is to be administered to a subject in need thereof at a dose comprising about 0.4 mg to about 8 mg of the anti-TSLP antigen binding fragment.
  • the pharmaceutical composition is administered or is to be administered to a subject in need thereof at a dose comprising about 0.4 mg, about 2 mg, or about 8 mg of the anti-TSLP antigen binding fragment.
  • the pharmaceutical composition is administered or is to be administered to a subject in need thereof at a dose comprising about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, or about 16 mg of the anti-TSLP antigen binding fragment.
  • the pharmaceutical composition is administered or is to be administered to a subject in need thereof at a dose comprising 0.2 mg to 16 mg of the anti-TSLP antigen binding fragment.
  • the pharmaceutical composition is administered or is to be administered to a subject in need thereof at a dose comprising 0.2 mg, 0.4 mg, 0.6 mg, 2 mg, 6 mg, 8 mg or 16 mg of the anti-TSLP antigen binding fragment.
  • the pharmaceutical composition is administered or is to be administered to a subject in need thereof at a dose comprising 0.4 mg to 8 mg of the anti-TSLP antigen binding fragment.
  • the pharmaceutical composition is administered or is to be administered to a subject in need thereof at a dose comprising 0.4 mg, 2 mg, or 8 mg of the anti-TSLP antigen binding fragment.
  • the pharmaceutical composition is administered or is to be administered to a subject in need thereof at a dose comprising 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, or 16 mg of the anti-TSLP antigen binding fragment.
  • the dose of the anti-TSLP antigen binding fragment is administered or is to be administered to a subject in need thereof once per day. In some instances, the dose of the anti-TSLP antigen binding fragment administered to or to be administered to the subject in need thereof is a daily dose. In some instance, the dose of the anti-TSLP antigen binding fragment administered to or to be administered to the subject in need thereof is the total daily dose. In some instances, the dose of the TSLP antigen binding fragment is administered or is to be administered to the subject in need thereof every other day. In some instances, the dose of the anti-TSLP fragment is administered or is to be administered to the subject in need thereof daily.
  • the dose of the anti-TSLP antigen binding fragment is administered or is to be administered to a subject in need thereof twice a day or once a day. In some instances, the dose of the anti-TSLP antigen binding fragment is administered or is to be administered to a subject in need thereof once daily (Q1 D).
  • the pharmaceutical composition comprising the anti-TSLP antigen binding fragment is administered or is to be administered to a subject in need thereof for at least 2 weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.
  • the pharmaceutical composition comprising the anti-TSLP antigen binding fragment is administered or is to be administered to a subject in need thereof for at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, or at least 52 weeks.
  • the pharmaceutical composition comprising the anti-TSLP antigen binding fragment is administered or is to be administered to a subject in need thereof for about 12 to about 52 weeks, e.g. for 12 to 52 weeks.
  • the pharmaceutical composition comprising the anti-TSLP antigen binding fragment is administered or is to be administered to the subject orally or intranasally, e.g. in aerosolized form.
  • the pharmaceutical composition comprising the antigen binding fragment is administered or is to be administered to the subject by inhalation, e.g. by using a dry powder inhaler.
  • the pharmaceutical composition comprising the antigen binding fragment is administered or is to be administered to the subject by oral inhalation, e.g. by using a dry powder inhaler.
  • the dose of the anti-TSLP antigen binding fragment to be administered to or administered to the patient is the target amount of the anti-TSLP antigen binding fragment present in the pharmaceutical composition, e.g. a dry powder formulation, for administration to the patient.
  • the pharmaceutical composition e.g. a dry powder formulation
  • it may be the dose present in an inhalation device for administration the patient, e.g. the dose may be the nominal metered dose for addition to an inhalation device, such as a dry powder inhaler.
  • the dose may be the amount of the anti-TSLP antigen binding fragment present in a capsule comprising the pharmaceutical composition, e.g. as a dry powder formulation, for addition to an inhalation device, e.g. a dry powder inhaler.
  • ⁇ x% refers to a percentage of the value preceding it, rather than adding or subtracting the absolute percentage listed, e.g. “20% ⁇ 10%” means “18-22%”, rather than “10-30%”.
  • FAB1 is an antibody fragment directed against the cytokine TSLP and may be used for treatment of moderate to severe asthma patients.
  • the route of administration is inhalation of a dry powder formulation via a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • the selected phase 1 formulation comprised trehalose, leucine, trileucine and citrate (TLTC) at pH 6 with addition of polysorbate 80 (PS80) to mitigate protein aggregations and keep low counts of subvisible particles.
  • TLTC dry powder inhaler
  • PS80 polysorbate 80
  • the surfactant resulted in impaired powder properties mainly by reduced manufacturing yield and significant elevation of the powder retention in device and throat.
  • Selection criteria for drug product were based on aerosol performance, solid state characterisation, and protein aggregate formation upon reconstitution of dry powder.
  • Table 6 shows that all batches were at 10g batch size except for the 40% TLTH, pH 5, which was 20g. Despite the small batch sizes, the spray drying yield based on FS mass was high for all of them. The powders were produced at low throughput processing parameters.
  • Table 8 shows that the solid properties were similar between all formulations and that protein purity was very high in DS, FS and BP with low aggregation. Primary particle size distribution was similar across all formulations and moisture content was low, being below 1% for the histidine formulations. Glass transition was high and similar for all formulations. High glass transition and low residual moisture content suggest room temperature stable powder. Compressed bulk density was in a favourable range with slightly higher numbers for the TLTH formulations indicating a slightly more flowable powder also reflected in a slightly increased surface area.
  • a critical readout for the dry powder formulation is the protein aggregation following reconstitution.
  • MFI Mass Flow Imaging
  • Figure 2 shows the number of particles present in the tested powder formulations (TLTC pH 5 (21 -VMS- 016); TLTH pH 6 (21-VVS-018); and TLTH pH 5 (21-VVS-023)). Particle counts were significantly higher with the TLTC formulation compared with TLTH, having “low” particle counts at 2.5mg/ml and at feedstock concentration.
  • Figure 3 shows the number of particles in the tested powder formulations (TLTC pH 5 (21-VVS-017); TLTH pH 6 (21-VVS-019); and TLTH pH 5 (21-VVS-024)). Particle counts were higher with the TLTC formulation compared to TLTH at feedstock concentration but not at 2.5 mg/ml.
  • Figure 4 shows the number of particles in the tested formulations (Drug substance citrate pH 5; Drug substance histidine pH 6; Drug substance histidine pH 5). Notably, DS in TLTC had higher particle counts than DS in TLTH where pH 5 was lower than pH 6. The same trend was observed for FS ( Figures 4B and C).
  • Figure 5 compares reconstituted powder with 10% and 40% FAB1 across the different formulations, and the lowest particle counts were observed for TLTH, pH 5 (see Figure 5C). Together, Figures 2 to 5 show that particle counts in DS, FS and reconstituted BP all followed the same pattern with lowest counts in TLTH, pH 5, slightly higher in TLTH, pH 6, and significantly higher in TLTC, pH 5. Due to the significantly higher levels of protein aggregation in the citrate-containing buffers, the histidine buffer was considered superior.
  • the inhaler device is “actuated” when a vacuum pump imposes a given flow rate, simulating a patient inspiration through the device’s mouthpiece.
  • Active agent amounts left in the device, including capsule, as well on throat, and on each of the stages is determined with an appropriate analytical method after each actuation. Aerosol performance is comparable across the formulations, with a very high (>80%) fine particle fraction (FPF) ( ⁇ 5pm) and favourable median mass aerodynamic diameter (MMAD) of 2.5 microns ( ⁇ 0.5).
  • the device deposition was low for all formulations, and lowest for the TLTH formulations.
  • Study 2 was designed to explore the formulation space for histidine and the shell-forming excipients leucine and trileucine.
  • the first goal was to study the effect of reduced histidine on the particle surface by decreasing the total amount of histidine in the formulation (from 5% to 1 .3%) or by increasing the leucine/trileucine ratio. Addition of a small amount of PS80 was also explored.
  • Table 11 is summary of the study processing results, including actual processing parameters and yields.
  • Study 3 investigates the optimum histidine concentration for the TLTH formulation. Three levels of histidine were explored to select the optimal concentration. Six batches were produced as shown in Table 13. The composition of each batch is summarized in Table 14.
  • Table 15 shows a summary of the study 3 processing results, including actual processing parameters and yields. Solid state testing results are shown in Table 16 and SEM images are shown in Figure 14.
  • TLTH formulations show excellent solid-state properties based on the following criteria: D90 ⁇ 5pm (90% of the particles less than 5pm), %water ⁇ 5%, Tg >80°C at 2% water content.
  • histidine Three levels of histidine 1.3%, 3.14% and 5% were explored at 10% and 40% protein strength to establish optimal histidine concentration. There was no significant difference in solid-state or aerosol performance between the different formulations and protein aggregations were low with a small trend for lower numbers at the higher histidine levels.
  • Study 4 was added to gain insight in the stability of the TLTH formulation with optimized histidine and pH.
  • Powder and filled capsules previously manufactured in studies 1-3 were used for the stability testing, as shown in Table 17.
  • High (5%) and low (1 .3%) histidine formulations were set down at 40°C/75% RH (protected with foil overwrap and desiccant) to support TLTH as the proposed phase 2 formulation.
  • NLT 2g of powder for each lot was transferred into aluminum Tournaire containers and foil overwrapped with desiccant and a stability test was performed for 1 month at 40°C/75%RH. Capsules were filled and packed in foil pouches with desiccant and stored protected at 40°C/75%RH.
  • Table 22 shows the study results of a first 28-day toxicity study in which cynomolgus monkeys were treated with FAB1 reconstituted in TLTC at pH 6 with PS80. No adverse effects were seen on food consumption, body weights, clinical observations, clinical pathology, pulmonary function tests, ECGs, blood pressure, neurobehavioral assessments, or ophthalmology.
  • Table 23 shows the results of a second 28-day toxicity study in which cynomolgus monkeys were treated with TLTH, pH 5.5 with 3.14% histidine (w/w).
  • Figure 23 shows representative images of FAB1 -related lung pathology.
  • Mononuclear cell (MNC) infiltrates in the lungs were minimal, for all tested doses. Microscopic findings were suggestive of a localised low-grade immune response to an inhaled foreign protein and were considered non-adverse ( Figure 24).
  • the NOAEL is this study was 2.3 mg/kg deposited dose (as opposed to 1 mg/kg deposited dose for the first toxicity study).
  • Part A of the study was a randomised, single-blinded, placebo-controlled study in male and female healthy volunteers to evaluate the safety, tolerability, PK, and immunogenicity of FAB1 by DPI administration (1 cohort in Sub Part A1 received IV FAB1).
  • Part A consisted of 4 sub parts (A1 , A2, A3, and A4).
  • the overall design of Part A is presented in Table
  • MAD multiple ascending dose
  • SAD single ascending dose
  • the primary objectives for Part A were the safety and tolerability of inhaled FAB1 , and the PK and safety of IV FAB1 .
  • Secondary objectives were the PK of inhaled FAB1 (including participants of Japanese and Chinese ethnicity), and the immunogenicity of FAB1 following single and multiple dose administration.
  • Part B of the study was a randomised, double-blinded, placebo-controlled study in male and female adults with asthma on a combination of medium to high dose ICS plus LABA medications. Patients were randomised to one of 3 inhaled dose levels (0.4 mg, 2 mg, and 8 mg) of FAB1 or placebo, once daily by dry powder inhaler (DPI) administration, for 28 days in a parallel-group design.
  • DPI dry powder inhaler
  • the predicted dose to man following inhaled administration of FAB1 was based on two elements: First, the predicted human PK profile for FAB1 systemically and in the lung tissue, secondly, identification of a target lung concentration based on clinical efficacy data for tezepelumab.
  • the clinical PK profile for FAB1 was predicted using PK parameters which were allometrically scaled from cynomolgus monkeys.
  • the average partition of FAB1 from lung to systemic circulation was estimated to be 2500 based on bronchial-alveolar lavage data from cynomolgus monkeys.
  • a target Ctrough concentration in the lung was identified from a therapeutically efficacious systemic exposure of the systemic TSLP specific mAb (tezepelumab), with an assumed lung distribution coefficient from the serum.
  • a calculated lung deposited dose of 1 mg (once daily) resulted in a Ctrough concentration higher than the target concentration in lung tissue, corresponding to predicted average concentration (Cave) in lung with 210 mg dose every 4 weeks of TSLP inhibiting systemic mAb, which has been proven to be efficacious in a Phase 3 study (Corren et al. N Engl J Med 2017: 377: 936-946). Based on these assumptions, delivered doses of 0.4, 2 and 8 mg (once daily over 28 days) were proposed in Part B of the study, with a decrease in FeNO as the primary outcome.
  • the primary objective was the safety and tolerability of inhaled FAB1 in patients with asthma on medium/high dose ICS/LABA. Secondary objectives were the PK and immunogenicity of inhaled FAB1 , and the above mentioned effect on FeNO of inhaled FAB1 versus placebo, following once daily administration for 28 days.
  • Lung function measures were assessed by change from baseline in pre-bronchodilator (pre-BD) FEVi and FVC and post-bronchodilator (post-BD) FEVi and FVC.
  • Asthma symptom measures were assessed by change from baseline in weekly ACQ-6 score.
  • PEFR for 2 weeks during run-in: PEFR average daily variability > 10%.
  • Interparticipant variability was high as judged by geometric mean percent coefficient of variation (%CV) for maximum plasma (peak) drug concentration after a given number of doses (N) before steady state is reached (Cmax), area under the plasma concentration-time curve from time 0 to last quantifiable concentration (AUCIast), and area under plasma concentration-time curve from time 0 to infinity (AUCinf).
  • %CV geometric mean percent coefficient of variation
  • N number of doses
  • AUCIast area under the plasma concentration-time curve from time 0 to last quantifiable concentration
  • AUCinf area under plasma concentration-time curve from time 0 to infinity
  • DPI dry powder inhaler
  • N number of participants in treatment group
  • n number of participants included in analysis
  • NC not calculated.
  • %CV percent coefficient of variation
  • AUC(0-24) area under the plasma concentration-time curve from time 0 to 24 hours
  • AUCIast area under the plasma concentration-time curve from time 0 to last quantifiable concentration
  • Cmax maximum plasma (peak) drug concentration after a given number of doses (N) before steady state is reached
  • t1/2A terminal elimination half-life
  • tmax time to reach maximum concentration following drug administration of FAB1.
  • the PK of FAB1 has been characterised in both healthy volunteers (Part A) and in patients with asthma in Part B.
  • the observed Tmax of FAB1 was a median time of 5-7 hours (range 3-24 hours), with a geometric mean t1/2Az of 22-28 hours (range 14-45 hours) across the doses.
  • the observed Tmax of FAB1 was a median time of 6 to 8 hours (range 0.25-24 hours).
  • serum concentrations had not declined sufficiently within the sampling period in all subjects to characterise the t1/2Az using non-compartmental analysis, however in 4/24 subjects a geometric mean t1/2Az of 31 hrs in the 8 mg once daily dose regimen could be estimated (range 23-48 hours).
  • ADA-evaluable patients who were treatment-induced or treatment boosted ADA positive. Percentages are based on the number of ADA-evaluable patients (patients with at least 1 ADA assessment).
  • the change from baseline in FeNO level was analysed using MMRM with treatment group, baseline FeNO, visit, treatment-by-visit interaction as fixed effect and patient as random-effect. Analyses was performed on the log- transformed FeNO data (change from baseline and percentage change) to normalise the skewed distribution of this endpoint and result back-transformed to linear scale. The within-patient correlation was modeled using the unstructured covariance matrix. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. The analysis was performed using only the OC without imputation of missing values. A REML method was used for estimation.
  • Treatment effect was estimated using contrasts of the LS means on the correspondent treatment by-day interaction, along with 2-sided 80% Cl and 1 -sided test for the p-value corresponding to the between- treatment group difference.
  • One patient was excluded from due to incompatible FeNO data in CRF, and 2 patients were excluded due to important protocol deviation.
  • PSOI post-start of inhalation
  • n number of subjects (D28 figure); numbers in square brackets denote p- value
  • a population PK (popPK) model was developed to quantify the variability in observed clinical PK data and to understand any differences in population between those in Part 1A in healthy adult volunteers, and Part 1 B in asthmatic adult patients on medium/high doses of inhaled corticosteroids/long acting beta2 agonists (NCT05110976).
  • the popPK model had four compartments defined with a combined zero order and first order absorption of the administered dose in the lung, and observations defined by the dotted line in the serum of FAB1 ( Figure 28). Briefly, the IV and Part 1 A single ascending dose data were used to estimate bioavailabilities for each absorption type, which were then fixed in the subsequent multiple ascending dose popPK model which included the individuals from Part 1A and Part 1 B.
  • This example describes a Phase 2b, randomised, double-Blind, placebo controlled dose range finding study to assess efficacy and safety of 3 dose levels of inhaled FAB1 (8 mg, 2 mg, 0.4 mg) given once daily via inhalation for 12 to 52 weeks in adults.
  • the target population includes severe asthma, similar to the tezepelumab clinical program, but expands to include moderate disease. Approximately 30% will have had 1 exacerbation in the last 12 months (defined as: asthma worsening which results in OCS use for >3 days, hospitalization or ER visit which results in systemic CS use) and approximately 70% of patients will have had > 2 severe exacerbations within the last 12 months.
  • Eligible patients will be randomised 1 :1 :1 :1 to FAB1 8 mg once daily, 2 mg once daily, 0.4 mg once daily or placebo.
  • the range of doses in the Phase lib study is based on results from the Phase I, Part b study, where these same 3 doses (8 mg, 2 mg, and 0.4 mg) were explored against placebo.
  • the study is of variable length with a 12-week treatment period and an optional safety extension of up to 52 weeks of total dosing.
  • the safety extension component will end when the final patient enrolled to the study completes 12 weeks of treatment.
  • the study design is provided in Figure 30.
  • CompEx Asthma is a composite endpoint that allows evaluation of treatment effect on exacerbation involving fewer participants compared with severe exacerbations.
  • CompEx Asthma events There are two main types of CompEx Asthma events:
  • Severe exacerbations will be evaluated by the investigator at each visit. Severe exacerbations are defined as those episodes that lead to hospitalisation, emergency room visit, and/or treatment with oral glucocorticosteroid as detailed below:
  • Inpatient hospitalization an admission to an inpatient facility and/or evaluation and treatment in healthcare facility for > 24 hours due to asthma.
  • Diary-based CompEx events are based on patient-reported deteriorations in three e-Diary variables, captured twice daily (morning and evening). This combination results in 6 different e-Diary variables.
  • Diary-based CompEx events are defined by threshold and slope criteria using the following Morning/Evening e-Diary variables:
  • PEF (L/min) is a home spirometry measure. The capture of PEF follows standardized procedures. During data collection, all required attempts (usually three) are recorded. Only the best of the three attempts (max PEF) is included in the diary dataset and should be used in calculating CompEx events.
  • PEFm measurements are conducted at home by the patient, with the exception of site visit days. On a site visit day, the patient performs PEF assessment on-site, and the home PEFm data might not be available. PEFm cannot be imputed with site PEF measurements from on-site visit days (this is because PEFm is patient-reported data and site PEF is investigator-reported data and these two data sources cannot be used interchangeably in CompEx calculations).
  • Asthma symptom scores during night-time and day-time will be assessed by the patient each morning and evening according to the following scoring system:
  • the number of doses of rescue medication is defined as the number of puffs of inhaler recorded in the morning (for preceding night) and evening (for preceding day), respectively. If a nebulizer is used in a study, the number of doses of reliever medication use is defined as the number of puffs of inhaler plus twice the number of nebulizer applications. Determination of Diary-based (Objective Deterioration) CompEx events
  • the e-Diary events are based on deteriorations in the e-Diary variables PEFm, PEFe, Sm, Se, Rm and Re as defined above.
  • Diary-based CompEx Asthma events can be of two types based on:
  • a participant will be considered to have a CompEx event during the planned treatment period if the participant has one or both of the following:
  • An objective deterioration which is defined as either the threshold criterion or
  • “2 consecutive days” means strictly the same 2 consecutive days when assessing multiple requirements within those days.
  • one day will be defined by the morning/evening pairing for consistency with published precedent for the CompEx endpoint. (Note: other e-Diary endpoints in this study will use an evening/morning pairing to define one day.)
  • the morning e-Diary recordings captured on the first day of treatment will not be included in the calculation of the CompEx endpoint.
  • baseline values need to be calculated for each of the six diary-based variables: PEFm, PEFe, Sm, Se, Rm and Re. Baseline values will be calculated for each individual patient as the average of the variable during the last ten days of the Run-in Period (days -10 to -1 with day -1 denoting the day before randomisation). In the event that less than 10 days of data is available, at least 5 days of data is required to calculate the baseline values.
  • Threshold criteria CompEx Asthma event: a. PEFm or PEFe >15% decrease from baseline in either morning or evening home-based PEF, and at least one of the following: b. Rm or Re >1 .5 doses increase from baseline in rescue medication in either the morning (for preceding night) or evening (for preceding day) c. Sm or Se >1 score increase from baseline in symptom score or achieving the absolute maximal symptom score (3), in either the morning or evening. This means the criterion is also met when the value is at the highest on the symptom score 3.
  • the number of doses of rescue medication is defined as the number of puffs of inhaler recorded in the morning and evening, respectively.
  • Assessment of the threshold criteria in any rolling 2-day consecutive period will be based on the available data during that period.
  • the threshold criteria can be met with non-missing values for fewer than the six variables specified above, provided those non-missing values meet the criteria. In other words, this gives a total of eight variable combinations: PEFm-Rm, PEFm-Re, PEFe-Rm, PEFe-Re and PEFm-Sm, PEFm- Se, PEFe-Sm, and PEFe-Se, where the deterioration criteria need to be fulfilled for both variables in at least one combination for at least 2 consecutive days.
  • a threshold and slope criteria CompEx Asthma event is when: (a), (b) or (c) of the threshold criteria above is met for at least 2 consecutive days and the regression slope requirement over the preceding 5 days is also met. Note that a CompEx event is never based on slope criteria only.
  • the regression slope is the point estimate of the slope obtained from a linear regression of the absolute values of each of the six variables separately against day number, with no other variables included in the model.
  • the regression slope thus obtained will first also be divided by the baseline PEFm and PEFe value and multiplied by 100 respectively before applying the above criteria.
  • a regression slope will be calculated provided there are at least two non-missing values in the required 5 days. If one or more of the six variables above does not have at least two non-missing values in the required 5 days, then the slope requirement cannot be met.
  • the start date of a CompEx Asthma event is defined as the earliest of the exacerbation or objective deterioration start dates which meets the definition.
  • Objective deterioration start date is defined as the earliest Day 1 from any series of rolling 2 consecutive days which first qualifies using either the threshold or slope criteria.
  • the end date of a CompEx event is defined as the latest of the exacerbation or objective deterioration end dates which meets the definition.
  • Objective deterioration end date is defined as the latest from any series of rolling 2 consecutive days which last qualifies using either the threshold or slope criteria. Whether or not diary-based CompEx criteria are met, is evaluated by a rolling window, with each pair of two consecutive days evaluated for fulfilment of the criteria. This also applies if different consecutive days fulfil different types of criteria (threshold only or threshold and slope).

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Abstract

La présente divulgation concerne des compositions pharmaceutiques comprenant des fragments de liaison à l'antigène spécifiques à la lymphopoïétine stromale thymique (TSLP) appropriées pour l'inhalation, ainsi qu'un procédé de préparation d'une composition pharmaceutique pour inhalation comprenant ledit fragment de liaison à l'antigène spécifique à la TSLP. La présente divulgation concerne en outre des méthodes de traitement d'affections liées à la TSLP, telles que l'asthme et la BPCO, à l'aide des compositions pharmaceutiques. Les compositions pharmaceutiques comprennent un mélange de leucine, de trileucine et d'histidine qui donne une formulation qui est appropriée pour délivrer des fragments de liaison à l'antigène dérivés d'anticorps anti-TSLP par inhalation.
PCT/EP2025/052281 2024-01-29 2025-01-29 Compositions de fragments de liaison à la lymphopoïétine stromale thymique (tslp), et leurs méthodes d'utilisation Pending WO2025163008A1 (fr)

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