[go: up one dir, main page]

WO2025228863A1 - Régime posologique pour un dérivé de 7-phénoxy-n- (3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5 h-pyrrolo[1,2-b][1,2,4]triazol-2-amine - Google Patents

Régime posologique pour un dérivé de 7-phénoxy-n- (3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5 h-pyrrolo[1,2-b][1,2,4]triazol-2-amine

Info

Publication number
WO2025228863A1
WO2025228863A1 PCT/EP2025/061489 EP2025061489W WO2025228863A1 WO 2025228863 A1 WO2025228863 A1 WO 2025228863A1 EP 2025061489 W EP2025061489 W EP 2025061489W WO 2025228863 A1 WO2025228863 A1 WO 2025228863A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
disease
dose
use according
octan
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/EP2025/061489
Other languages
English (en)
Inventor
Carina Ann CANTRILL
Stefan Simonne Albert DE BUCK
Lothar Lindemann
Rosa Maria Rodriguez Sarmiento
Rosanna TORTELLI
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.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Publication of WO2025228863A1 publication Critical patent/WO2025228863A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Case P39070 DOSE REGIMEN Field of the invention relates to (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with amyloidosis, such as Alzheimer’s Disease, and its method of treatment thereof.
  • Alzheimer’s Disease is the most common form of dementia.
  • amyloid plaques Two major pathological hallmarks of AD are amyloid plaques, which result from extracellular accumulation and deposition of amyloid ⁇ -peptides (A ⁇ ), mostly A ⁇ 40 and A ⁇ 42 (Steiner et al. 2018), and neurofibrillary tangles containing the hyper-phosphorylated tau protein in neurons (Masters et al.2015; Knopman et al 2021).
  • a ⁇ plaques The formation of amyloid plaques (A ⁇ plaques) is predominantly driven by the longer forms of A ⁇ peptides, A ⁇ 42 and to a lesser extent A ⁇ 40; these longer forms of A ⁇ are therefore called amyloidogenic.
  • the shorter forms of A ⁇ are called non-amyloidogenic as they do not contribute to the formation of A ⁇ plaques.
  • a ⁇ peptides involved the proteolytic cleavage of amyloid precursor protein (APP) by two proteases, the BACE1 (Beta-secretase 1; beta-site amyloid precursor protein cleaving enzyme 1) and gamma secretase.
  • BACE1 Beta-secretase 1; beta-site amyloid precursor protein cleaving enzyme 1
  • Gamma secretase is an aspartate protease composed of four subunits named Nicastrin (NCT), anterior pharynx-defective 1 (APH), presenilin enhancer 2 (PEN2), and presenilin 1 or 2 (PS) ( Figure 1).
  • APP is initially cleaved by BACE1 followed by a first gamma secretase cleavage, producing long A ⁇ peptides of either 48 or 49 amino acids, respectively ( Figure 2).
  • These long A ⁇ precursor peptides remain bound to the gamma secretase complex where they subsequently undergo further proteolytic trimming by removal of di- or tri-peptides, leading to the mix of A ⁇ peptides with a length of 40 and 42, as well as 38 and 37 amino acids, respectively.
  • Gamma secretase has emerged as an attractive drug target as this enzyme is critical for the production of A ⁇ peptides and for defining the composition of A ⁇ in their different lengths. Modulating the activity of gamma secretase is a compelling approach to lower the levels of the neurotoxic A ⁇ 42 peptide in the brain while leaving the proteolytic processing of other gamma secretase substrates such as Notch unchanged (Luo and Li 2023; Hur 2022).
  • GSMs Gamma Secretase Modulators selectively change the processing of APP by gamma secretase such that the production of the amyloidogenic A ⁇ 42 and A ⁇ 40 peptide fragments are reduced while the production of the non-amyloidogenic shorter fragments A ⁇ 38 and A ⁇ 37 are concomitantly increased.
  • GSMs do not inhibit the gamma secretase enzyme, thus, the total amount of A ⁇ peptides remains unchanged.
  • the processing of other proteins by gamma secretase is not affected by GSMs.
  • BACE1 and gamma secretase inhibitors (GSIs) – which were initially tested as possible therapies for AD.
  • BACE1 inhibitors and GSIs block the entire enzyme activity and reduce the total amount of A ⁇ produced.
  • both BACE1 and gamma secretase are processing a large number of protein substrates other than APP, many of which play critical roles in the whole organism for e.g. the formation and maintenance of synapses and the differentiation of gastrointestinal stem cells (BACE1: Hampel et al. 2015; gamma secretase: Guener and Lichtenthaler 2020).
  • Gamma secretase is composed of four subunits named Nicastrin (NCT), anterior pharynx- defective 1 (APH), presenilin enhancer 2 (PEN2), and presenilin (PS); presenilin occurs in two isoforms, presenilin 1 and 2, respectively, which have essentially the same biological function in the presenilin complex.
  • the proteolytically active site of the gamma secretase complex is located within the presenilin subunit, the aspartate residues critical for the enzymatic activity are indicated by asterisks (Figure 1, with modifications Luo and Li, 2023).
  • APP undergoes an initial cleavage by BACE1, followed by the first cleavage by gamma secretase, termed epsilon ( ⁇ ) cut.
  • ⁇ gamma secretase
  • a ⁇ 48 and A ⁇ 49 peptides remain bound to the gamma secretase enzyme where they undergo trimming by sequential removal of di- and tri-peptides by ⁇ - and ⁇ -cuts leading to shorter A ⁇ peptides which are eventually released by the enzyme complex.
  • the length of the initially produced A ⁇ peptides determines the lengths of the final A ⁇ peptides released from the enzyme complex: A ⁇ 48 fragments lead to the production of predominantly A ⁇ 42 and A ⁇ 38 (‘A ⁇ 48 product line’), while A ⁇ 49 fragments lead to the production of predominantly A ⁇ 40 and A ⁇ 37 (‘A ⁇ 49 product line’).
  • newly produced A ⁇ peptides consist of ca.
  • AD Alzheimer's Disease
  • ADAD Autosomal-dominant Alzheimer's Disease
  • FAD Familial Alzheimer’s Disease – FAD
  • EOAD Early Onset Alzheimer’s Disease - EOAD
  • a ⁇ production and formation of A ⁇ deposits in the brain plays a causal role in AD.
  • a ⁇ 42 (and to a lesser extent A ⁇ 40) is amyloidogenic, i.e. causes the formation of A ⁇ aggregates and eventually A ⁇ deposits in the brain.
  • the shorter A ⁇ fragments A ⁇ 37 and A ⁇ 38 are not amyloidogenic, i.e.
  • AD therapy AChEi and NMDA receptor antagonists, addressing neurotransmitter deficits which arise as a consequence of synaptic and neuronal degeneration in the course of the disease.
  • a ⁇ -targeted therapies are being actively pursued in preclinical and clinical studies for the treatment of AD.
  • Two A ⁇ amyloid-directed antibodies, aducanumab [ADUHELMTM] and lecanemab (LEQEMBITM) received accelerated approval in the United States for the treatment of AD in June 2021 and January 2023.
  • Lecanemab a monoclonal antibody targeting aggregated forms of A ⁇ amyloid, achieved a lowering of amyloid plaques in the brain of early-stage AD patients, which was linked to a significant slowing of decline in cognition and function and downstream biomarkers of AD (van Dyck et al.2023).
  • Aducanumab another therapeutic antibody targeting aggregated A ⁇ amyloid, also achieved a reduction of A ⁇ amyloid load in AD patients and showed a trend towards the slowing of cognitive decline, along with positive effects on downstream biomarker (Budd Haeberlein et al.2022, Tampi et al.2021).
  • continued approval for both products may be contingent upon verification of clinical benefit in confirmatory trial(s) observed in treated patients.
  • ADUHELM USPI, LEQEMBI USPI; FDA 2021; FDA 2023 Other A ⁇ amyloid immunotherapies such as donanemab are currently in clinical development. Nevertheless, no drug can yet improve or halt the worsening of AD symptoms and declining of daily function, and there remains a high unmet medical need.
  • the present invention intends to respond to this unmet medical need.
  • a first aspect of the invention relates to the compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with amyloidosis, at a dose ranging from 5 to 480 mg per subject.
  • a second aspect of the invention relates to a method for the treatment of a disease associated with amyloidosis, comprising administering to a subject (in particular a subject in need thereof) (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, at a dose ranging from 5 to 480 mg.
  • a third aspect of the invention relates to the use of compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with amyloidosis, at a dose ranging from 5 to 480 mg per subject.
  • Figure 1 illustrates the composition of the gamma secretase complex (Luo and Li (2023), Turning the tide on Alzheimer’s disease: Modulation of ⁇ -secretase. Cell & Bioscience 12, 2. DOI: 10.1186/s13578-021-00738-7).
  • Figure 2 illustrates the biogenesis of amyloid beta (A ⁇ ) by proteolytic processing of amyloid precursor protein (APP) by BACE1 and gamma secretase (Luo and Li (2023), Turning the tide on Alzheimer’s disease: Modulation of ⁇ -secretase. Cell & Bioscience 12, 2. DOI: 10.1186/s13578-021-00738-7).
  • a ⁇ amyloid beta
  • APP amyloid precursor protein
  • the term "Active pharmaceutical ingredient” or “API” refers to the compound or molecule in a pharmaceutical composition that has a particular biological activity.
  • the term “Amyloidosis” refers to the accumulation of amyloid deposits in the brain caused by an elevated production or a reduction of clearance of amyloid beta peptides.
  • the term “Alzheimer’s Disease” or “Alzheimer’s disease” (AD) refers to a disease of the brain in which the progressive degeneration of brain cells causes symptoms of dementia such as memory loss, difficulty performing daily activities, and changes in judgement, reasoning, behavior and emotions.
  • Neuropathological hallmarks of AD are the occurrence of deposits of aggregated amyloid beta peptides, or amyloid plaques, as well as deposits of aggregated and hyperphosphorylated Tau protein, also known as neurofibrillary tangles.
  • the term “sporadic Alzheimer’s Disease” refers to the most common form of Alzheimer’s disease; it is not linked to any specific, identifiable genetic mutation and does not show a pattern of inheritance in family pedigrees. Sporadic Alzheimer’s disease is due to a complex combination of genes, environmental conditions and lifestyle. The single greatest risk factor for developing sporadic Alzheimer’s disease is aging. Most symptoms become noticeable after age 60-65 years.
  • the term “genetically caused Alzheimer’s disease” refers to a rare form of Alzheimer’s disease (accounts for less than 5% of all cases of Alzheimer’s disease) due to changes or alterations in specific genes that can be directly passed on from parent to child.
  • Synonyms of “genetically caused Alzheimer’s disease” are Autosomal-dominant Alzheimer's disease (ADAD), Familial Alzheimer’s Disease (FAD), or Early Onset Alzheimer’s Disease (EOAD).
  • ADAD Autosomal-dominant Alzheimer's disease
  • FAD Familial Alzheimer’s Disease
  • EOAD Early Onset Alzheimer’s Disease
  • the specific genes in which mutations have been identified that underlie “genetically caused Alzheimer’s disease” include: two presenilin genes (PSEN1 and PSEN2), and an amyloid precursor protein (APP) gene.
  • Familial Alzheimer’s disease symptoms are similar to those of sporadic Alzheimer’s disease which typically start at a younger age compared to sporadic Alzheimer’s Disease. Alterations in the PSEN1, PSEN2, and APP genes will almost certainly develop young onset Familial Alzheimer’s disease (before the age of 65). Familial Alzheimer’s disease is hereditary. If a subject has familial Alzheimer’s disease, each of their children has an increased chance of inheriting the disease-causing mutation and developing Alzheimer’s disease.
  • symptomatic Alzheimer’s disease refers to an individual with AD pathological changes and progressive cognitive and functional decline. It includes: 1- mild cognitive impairment due to Alzheimer's disease (pre-dementia) and 2- dementia due to Alzheimer's disease.
  • the term “preclinical Alzheimer’s disease” refers to a subject who has evidence of early AD pathological changes but does not meet clinical criteria for MCI or dementia (Sperling RA, et al. 2011).
  • the term “elderly person” refers to a person who is above 60 years of age.
  • the term "individual” or “subject” refers to, used interchangeably, a mammal. Mammals include, but are not limited to, domesticated animals (e.g. cows, sheep, cats, dogs, and horses), primates (e.g. humans and non-human primates such as monkeys), rabbits, and rodents (e.g. mice and rats). In certain embodiments, the individual or subject is a human.
  • mg/kg refers to the dose in milligram of (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)- 3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-amine being used per kilogram of body weight of the subject to be treated.
  • 0.25 mg/kg means a dose of 0.25 milligram of (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine per kilogram of body weight of the subject to be treated.
  • the term “mg” refers to the dose in milligram of (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3- (6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-amine being used in the subject to be treated.
  • the subject is a human.
  • patient refers to a human (such as a male or female human) who is in need of a treatment with RO7269162.
  • pharmaceutically acceptable excipient can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products.
  • pharmaceutical composition refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered.
  • pharmaceutically acceptable denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.
  • Cmax (expressed in units of ng/mL) means maximum observed plasma concentration.
  • Tmax (expressed in units of hours, or as a median number of hours for Tmax in the study population) means the observed time to reach Cmax following drug administration; if it occurs at more than one time point Tmax is defined as the first time point with this value.
  • AUC0-24h (expressed in units of ng ⁇ h/mL) means the cumulative area under the plasma time concentration curve (AUC) calculated using the trapezoidal method from time 0 to 24h.
  • NOAEL refers to No Observed Adverse Effect Level. In other words, the term NOAEL refers to the greatest concentration or amount of a substance, found by experiment or observation, which causes no detectable adverse alteration of morphology, functional capacity, growth, development, or life span of the patient under defined conditions of exposure.
  • the invention provides compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with amyloidosis, at a dose ranging from 5 to 480 mg per subject.
  • the invention provides compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in the treatment of Alzheimer’s disease, at a dose ranging from 5 to 480 mg per subject.
  • the invention provides compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in the treatment of sporadic Alzheimer’s disease or genetically caused Alzheimer’s disease, at a dose ranging from 5 to 480 mg per subject.
  • the invention provides compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in the treatment of symptomatic Alzheimer’s disease or pre-clinical Alzheimer’s disease, at a dose ranging from 5 to 480 mg per subject.
  • the invention provides compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in the treatment of dementia caused by amyloidosis occurring in the context of Down’s Syndrome (trisomy 21), at a dose ranging from 5 to 480 mg per subject.
  • the invention provides compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with amyloidosis, at a dose ranging from 5 to 480 mg per subject, wherein the disease is increased or accelerated by formation of amyloid deposits in the brain as consequence of traumatic brain injury, and neuro-psychiatric symptoms such as dementia associated with said formation of amyloid deposits.
  • the invention provides compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein said compound is orally administered.
  • the invention provides compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein said compound is administered once a day.
  • the invention provides compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein said compound is administered at a dose ranging from 30 to 230 mg.
  • the invention provides compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein said compound is administered at a dose ranging from 30 to 120 mg.
  • the invention provides compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein said compound is administered at a dose selected from 30, 60, 70, 100, 120 and 230 mg, particularly 30, 60, 70, 100 and 120 mg.
  • the invention provides compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein said compound is administered at a dose selected from 30, 60 and 120 mg.
  • the invention provides compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein the subject is a human.
  • the invention provides compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein the subject is an elderly person.
  • the invention provides compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein the subject is younger than 60 years of age and is at increased risk of developing a disease associated with amyloidosis.
  • the invention provides compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein the subject is a human, wherein said compound is being administered orally at a dose between 30 and 120 mg.
  • the invention provides compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, for use as described herein above, wherein the subject is a human, wherein the compound is being administered orally at a dose selected from 30, 60 and 120 mg.
  • the invention provides a method for the treatment of a disease associated with amyloidosis, comprising administering to a subject (in particular a patient, more particularly a patient in need thereof) (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4- yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, at a dose ranging from 5 to 480 mg per subject.
  • a subject in particular a patient, more particularly a patient in need thereof
  • the invention provides a method for the treatment of Alzheimer’s disease, comprising administering to a subject (in particular a patient, more particularly a patient in need thereof) (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, at a dose ranging from 5 to 480 mg per subject.
  • a subject in particular a patient, more particularly a patient in need thereof
  • the invention provides a method for the treatment of sporadic Alzheimer’s Disease or genetically caused Alzheimer’s disease, comprising administering to a subject (in particular a patient, more particularly a patient in need thereof) (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, at a dose ranging from 5 to 480 mg per subject.
  • the invention provides a method for the treatment of symptomatic Alzheimer’s disease or pre-clinical Alzheimer’s disease, comprising administering to a subject (in particular a patient, more particularly a patient in need thereof) (R)-7-(3,5-difluorophenoxy)- N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, at a dose ranging from 5 to 480 mg per subject.
  • a subject in particular a patient, more particularly a patient in need thereof
  • the invention provides a method for the treatment of dementia caused by amyloidosis occurring in the context of Down’s Syndrome (trisomy 21), comprising administering to a subject (in particular a patient, more particularly a patient in need thereof) (R)- 7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan- 8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, at a dose ranging from 5 to 480 mg per subject.
  • a subject in particular a patient, more particularly a patient in need thereof
  • the invention provides a method for the treatment of a disease caused by amyloidosis occurring in the context of Down’s Syndrome (trisomy 21), comprising administering to a subject (in particular a patient, more particularly a patient in need thereof) (R)- 7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan- 8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, at a dose ranging from 5 to 480 mg per subject, wherein the disease is increased or accelerated by formation of amyloid deposits in the brain as consequence of traumatic brain injury, and neuro-psychiatric symptoms such as dementia associated with said formation of amyloid deposits.
  • a subject in particular a patient, more particularly a patient in need thereof
  • the invention provides a method for the treatment of a disease as described herein above, wherein (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, is orally administered.
  • the invention provides a method for the treatment of a disease as described herein above, wherein (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, is administered once a day.
  • the invention provides a method for the treatment of a disease as described herein above, wherein (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, is administered at a dose ranging from 30 to 230 mg.
  • the invention provides a method for the treatment of a disease as described herein above, wherein (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, is administered at a dose ranging from 30 to 120 mg.
  • the invention provides a method for the treatment of a disease as described herein above, wherein (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, is administered at a dose selected from 30, 60, 70, 100, 120 and 230 mg. particularly 30, 60, 70, 100 and 120 mg.
  • the invention provides a method for the treatment of a disease as described herein above, wherein (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, is administered at a dose selected from 30, 60 and 120 mg.
  • the invention provides a method for the treatment of a disease as described herein above, wherein the subject is a human.
  • the invention provides a method for the treatment of a disease as described herein above, wherein the subject is an elderly person. In a more particular embodiment, the invention provides a method for the treatment of a disease as described herein above, wherein the subject is younger than 60 years of age and is at increased risk of developing a disease associated with amyloidosis. In a more particular embodiment, the invention provides a method for the treatment of a disease as described herein above, wherein the subject is a human, wherein the compound is being administered orally at a dose between 30 and 120 mg.
  • the invention provides a method for the treatment of a disease as described herein above, wherein the subject is a human, wherein the compound is being administered orally at a dose selected from 30, 60 and 120 mg.
  • the invention provides the use of compound (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease associated with amyloidosis at a dose ranging from 5 to 480 mg per subject.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of Alzheimer’s disease at a dose ranging from 5 to 480 mg per subject.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of sporadic Alzheimer’s disease or genetically caused Alzheimer’s disease at a dose ranging from 5 to 480 mg per subject.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of symptomatic Alzheimer’s disease or pre-clinical Alzheimer’s disease at a dose ranging from 5 to 480 mg per subject..
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of dementia caused by amyloidosis occurring in the context of Down’s Syndrome (trisomy 21) at a dose ranging from 5 to 480 mg per subject.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease associated with amyloidosis at a dose ranging from 5 to 480 mg per subject, wherein the disease is increased or accelerated by formation of amyloid deposits in the brain as consequence of traumatic brain injury, and neuro- psychiatric symptoms such as dementia associated with said formation of amyloid deposits.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein said compound is orally administered.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein said compound is administered once a day.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein said compound is administered at a dose ranging from 30 to 230 mg.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein said compound is administered at a dose ranging from 30 to 120 mg.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein said compound is administered at a dose selected from 30, 60, 70, 100, 120 and 230 mg, particularly 30, 60, 70, 100 and 120 mg.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein said compound is administered at a dose selected from 30, 60 and 120 mg.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein the subject is a human.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein the subject is an elderly person.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein the subject is younger than 60 years of age and is at increased risk of developing a disease associated with amyloidosis.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein the subject is a human, wherein the compound is being administered orally at a dose between 30 and 120 mg.
  • the invention provides the use of compound (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable thereof, in the manufacture of a medicament for the treatment of a disease as described herein above, wherein the subject is a human, wherein the compound is being administered orally at a dose selected from 30, 60 and 120 mg.
  • the patient according to the invention in particular is a human, more particularly a male or female human.
  • the human can be of any race (e.g. Caucasian or Oriental).
  • Pharmaceutical composition and administration Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable thereof, and a pharmaceutically acceptable excipient.
  • Compound of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories).
  • the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
  • the administration can also be effected topically, e.g. transdermal administration, or in form of eye drops or ear drops.
  • Compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations, such as tablets, coated tablets, dragées, hard gelatin capsules, injection solutions or topical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acids or salts thereof, and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules.
  • Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatin capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, alcohols, polyols, saccharose, glucose, invert sugar, vegetable oil, etc.
  • Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi- liquid or liquid polyols, etc.
  • Suitable carriers for topical ocular formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.
  • Medicaments containing compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula (I) and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable excipients.
  • Example 1 RO7269162 was studied in a randomized, adaptive, double-blind, single ascending dose (SAD) and multiple ascending dose (MAD), placebo-controlled, parallel-arm, Phase I study in healthy subjects.
  • SAD single ascending dose
  • MAD multiple ascending dose
  • the study investigated the safety, tolerability, pharmacokinetics (including food effect), and pharmacodynamics (PD) of orally administered RO7269162.
  • the interaction with caffeine and midazolam was also investigated; these results are not discussed here as they have no relevance for the dose selection.
  • Part 1a and Part 3a were the SAD and MAD parts, respectively, in healthy male and female participants aged 18 ⁇ 45 years (Part 1a) and 18 ⁇ 64 years (Part 3a).
  • Part 1b included the investigation of food effect (FE) on RO7269162 exposure in participants aged 18 ⁇ 45 years.
  • Part 3b included the investigation of multiple oral doses of RO7269162 in healthy elderly participants (aged 65 ⁇ 85 years).
  • Part 2 investigated the effect of single oral doses of RO7269162 on cerebrospinal fluid (CSF) and plasma PD related to amyloid beta (A ⁇ ) metabolism and their relationship to RO7269162 exposure in healthy participants aged 40 ⁇ 70 years.
  • CSF cerebrospinal fluid
  • a ⁇ amyloid beta
  • RO7269162 PK profiles showed systemic absorption after single and multiple oral administration with median time to reach peak plasma concentration (Cmax) ranging 1-3.5 h postdose across cohorts.
  • Cmax peak plasma concentration
  • RO7269162 plasma concentration declined in a bi-exponential manner with an estimated apparent terminal half-life (t 1/2 ) ranging from approximately 13 to 21 hours across the dose range tested.
  • RO7269162 exposures increased with increasing doses in a dose-proportional manner in terms of C max and area under the plasma concentration-time curve (AUC; area under the plasma concentration-time curve over a dosing interval [AUC ⁇ ] and area under the plasma concentration-time curve from Time 0 to infinity [AUCinf]).
  • Exposure in CSF represents approximately 1.5% to 3% of the total drug exposure in plasma, indicating CSF levels are similar to free (unbound) drug levels in plasma (free fraction of RO7269162 in human plasma was, on average, 2.3%).
  • the plasma PK profiles observed after once daily oral administration of 100 mg RO7269162 for 14 days in elderly participants in Part 3b were overall consistent with those of young participants observed in Part 3a.
  • the PK plasma profiles observed after daily oral administration of 150 mg RO7269162 for 6 days (Part 4) were consistent with the PK plasma profiles observed in Part 3a, and the concomitant administration of 2 mg midazolam and 200 mg caffeine had no effect on RO7269162 exposure.
  • a dose-dependent reduction in plasma A ⁇ 42 levels was observed following single and multiple oral administration of RO7269162.
  • the maximum mean percent change from baseline of A ⁇ 42 was -70% after administration of 480 mg RO7269162.
  • Plasma A ⁇ 42 levels returned to their baseline levels within 5 days after the administration of RO7269162.
  • the maximum mean percent change from baseline in plasma A ⁇ 42 on Day 14 was - 74% and remained at around -70% up to pre-dose (24h post last dose).
  • Steady-state PD effect was achieved within 7 days post onset of daily dose administration.
  • a dose-dependent decrease in A ⁇ 42 and A ⁇ 40 and a dose-dependent increase in A ⁇ 37 and A ⁇ 38 were observed in CSF following once daily administration of RO7269162 for 14 days at doses ranging 30-230 mg.
  • steady-state predose (trough) levels of A ⁇ 42 and A ⁇ 40 were decreased in CSF by approximately -70% and -60%, respectively, while corresponding A ⁇ 37 and A ⁇ 38 were increased by approximately 370% and 38%, respectively.
  • the maximum mean percent change from baseline of A ⁇ 42 in plasma was - 45.9% (at 2 h post dose on Day 14), - 51.8% (at 12 h post dose on Day 8), and - 74.2% (at 12 h post dose on Day 8), following daily oral administration of 30 mg, 70 mg, and 230 mg RO7269162, respectively.
  • Time to steady state pharmacodynamics appeared to be reached at approximately 7 days post onset of daily administration.
  • the maximum mean percent change from baseline of A ⁇ 42 was - 40.6%, - 45.2%, and - 70.5% following multiple administration of 30 mg, 70 mg, and 230 mg RO7269162, respectively.
  • Plasma A ⁇ 42 levels returned to their predose baseline levels within about 5 days after the last administration of RO7269162. Plasma and CSF levels of markers of amyloid deposition were measured using Elecsys immunoassays.
  • Plasma Elecsys® ⁇ -Amyloid (1-42) plasma; Elecsys® ⁇ -Amyloid (1-40) plasma immunoassay.
  • CSF Elecsys® ⁇ -Amyloid (1-42) CSF II; Elecsys® ⁇ -Amyloid (1-40) CSF; Elecsys® ⁇ -Amyloid (137) CSF; Elecsys® ⁇ -Amyloid (1-38) CSF.
  • Plasma A ⁇ 42 Pharmacodynamics after Multiple Dose Administration in Elderly Healthy Participants (Part 3b) Consistent with the data obtained in healthy volunteers, following daily oral administration of RO7269162 at 100 mg or placebo in fed conditions for 14 days in elderly healthy participants, the maximum mean percent change from baseline of A ⁇ 42 in plasma were - 42.2%, - 61.1%, and - 62.7% at around 12 h post dose on respectively Day 1, Day 8, and Day 14. Pharmacodynamics steady state was achieved within 7 days of daily administration. At predose on Day 14, the maximum mean percent change from baseline of A ⁇ 42 was - 59.0%.
  • a ⁇ monomers levels in CSF and percent change from baseline have been determined following daily oral administration of RO7269162 at 30 mg, 70 mg, and 230 mg RO7269162 or placebo in fed conditions for 14 days in young healthy participants.
  • a dose-dependent decrease in both A ⁇ 42 and A ⁇ 40 along with a concurrent dose-dependent increase in A ⁇ 37 and A ⁇ 38 were observed in CSF following multiple RO7269162 administration.
  • predose levels of A ⁇ 42 and A ⁇ 40 decreased by approximately - 70% and - 60%, respectively, at steady state; and A ⁇ 37 and A ⁇ 38 increased by approximately 370% and 38%, respectively.
  • Plasma and CSF levels of markers of amyloid deposition were measured using Elecsys immunoassays.
  • Plasma Elecsys® ⁇ -Amyloid (1-42) plasma; Elecsys® ⁇ -Amyloid (1-40) plasma immunoassay.
  • CSF Elecsys® ⁇ -Amyloid (1-42) CSF II; Elecsys® ⁇ -Amyloid (1-40) CSF; Elecsys® ⁇ - Amyloid (137) CSF; Elecsys® ⁇ -Amyloid (1-38) CSF.
  • a dose-dependent reduction in A ⁇ 42 was observed after single oral administration of doses up to 480 mg and multiple oral administration of doses up to 230 mg RO7269162 once daily for 14 days.
  • ⁇ A dose-dependent decrease in A ⁇ 42 and A ⁇ 40 along with a concurrent dose-dependent increase in A ⁇ 37 and A ⁇ 38 were observed in CSF following multiple oral dose administration of RO7269162 at doses ranging 30-230 mg.
  • Example 2 Study BP44745 is a randomized, double-blind, placebo-controlled, multiple-dose, multi-center, parallel-group Phase IIa study to investigate the safety, tolerability, and the effects of longer term oral dosing of RO7269162 on amyloid and non-amyloid disease-related biomarkers in cognitively unimpaired participants at risk of AD, and in participants with prodromal AD. Participants The planned number of participants for the study is approximately 245.
  • Participants aged 60 to 85 years will be selected to be: a) amyloid positive based on amyloid depositions of ⁇ 24 centiloids (CL) units measured by an amyloid positron emission tomography (PET) scan; note: a CL value > 100 will be allowed only for approximately 15% of the total sample size; b) either cognitively unimpaired, or with a diagnosis of mild cognitive impairment (MCI) due to AD according to the National Institute on Aging-Alzheimer’s Association (NIA – AA) workgroups on diagnostic guidelines for AD (Sperling et al 2011, Albert et al 2011), and/or according to the updated NIA-AA research framework (Jack et al 2018); c) with a value of CDR-GS of either 0 (for cognitively unimpaired participants), or 0.5 (for participants with MCI); d) participants must meet all the eligibility criteria outlined in ‘Study Population’ section of the protocol.
  • CCI mild cognitive impairment
  • Treatment Groups The study uses a parallel group study design, with participants randomized into one of four arms: three different dose arms of RO7269162 and one control arm of matching placebo.
  • the doses and the (approximate) number of participants in the four treatment arms, randomized according to ratio of 2:1:2:2, are as follows: Arm 1, Placebo: 70 participants Arm 2, 30 mg RO7269162: 35 participants Arm 3, 60 mg RO7269162: 70 participants Arm 4, 120 mg RO7269162: 70 participants
  • the Principal Investigators (PIs) and site personnel involved in the clinical conduct of the study will remain blinded to participants’ study treatment and dose level until the completion of the study. Study team members and Sponsor representatives will also remain blinded.
  • the total duration of Participation The total duration of the study will be approximately 90 weeks and it is divided as follows: Screening period: The overall screening period may last up to 12 weeks; Baseline period: Up to 2-week baseline period prior to first dose administration; Double-blind treatment period: From Day 1 to completion of Week 72; Safety follow-up period: 28 days (4 weeks) after End of Treatment (EoT). End of Study The end of the study is defined as the date when the last participant last observation (LPLO) occurs. LPLO is expected to occur 4 weeks after the last dose administration.
  • AD biomarkers Changes in AD biomarkers have been suggested to occur in a temporally ordered manner (Ingelsson et al 2004; Mormino et al 2009, Jack et al 2013) with A ⁇ abnormalities (measured by CSF A ⁇ 42 or amyloid PET) among the first to appear.
  • Fluid biomarkers of neuroinflammation like glial fibrillary acidic protein, GFAP), synaptic (neurogranin), and neuronal dysfunction (several plasma p-Tau species) have also been found to become abnormal in the course of AD (Wellington et al 2016, Barthélemy et al 2020, Benedet et al 2021).
  • Treatment randomization will be stratified by subjects’ cognitive level (measured by the CDR- GS), amyloid burden, APOE- ⁇ 4 status and CSF sampling. To avoid an excessive presence of participants with very high amyloid burden, the proportion of those with amyloid levels above 100 CL will be limited to approximately 15% of the entire study population. Rationale for Control Group Participants will be randomized to RO7269162 or placebo treatment. A placebo arm is considered necessary to generate an adequate within study comparator dataset that will allow proper evaluation of the magnitude of any effects related to safety, tolerability and PD. To eliminate potential bias, all participants, Investigators and other study personnel at the site and at the Sponsor will be blinded to individual treatment allocation.
  • RO7269162 gamma secretase modulation
  • BP42242 gamma secretase modulation
  • RO7269162 free (but not total) drug exposure of RO7269162 in plasma has shown close alignment between mice and monkeys at the Lowest-Observed-Adverse Effect Level (LOAEL) for CNS effects (250 mg/kg and 100 mg/kg in mouse and monkey, respectively), suggesting that free drug is the more relevant metric to evaluate exposure multiples (relative to human) for this type of toxicity.
  • LOAEL Lowest-Observed-Adverse Effect Level
  • the approach to compare exposure across species based on free rather than total drug is supported by the substantial inter-species differences in the average RO7269162 fraction unbound in plasma in mice, cynomolgus monkey and humans of 1.7%, 6.0%, and 2.3%, respectively.
  • Table 2 shows that the doses selected for this study are supported by an adequate exposure multiple established in the preclinical GLP (Good Laboratory Practice) toxicology studies:
  • the systemic exposure margin for chronic dosing in the monkey is ⁇ 1 when compared to the highest dose of 20 mg/kg/day used in the 39 week chronic toxicity study in monkeys (the corresponding margin for the mouse exceeds 10-fold and is not displayed).
  • Table 2 supports that human median steady-state free drug exposure at the highest dose proposed for this study (120 mg daily) will remain well below the free drug concentration observed at the NOEL dose in cynomolgus monkey, with large animal-to-human exposure multiples established in terms of both free Cmax (10-fold) and free AUC 0-24h (5-fold). The corresponding exposure multiples for the mouse are higher than those for monkey and are not displayed. In conclusion, the doses selected for this study are supported by adequate exposure multiples as established in preclinical GLP toxicology studies.
  • Cognitive status will be defined based on the CDR-GS of either 0 (cognitively unimpaired individuals) or 0.5 (mild cognitive impairment). Participants must meet all the eligibility criteria outlined in this section. Prospective approval of protocol deviations, also known as protocol waivers or exemptions, is not permitted. Inclusion criteria Participants are eligible to be included in the study only if all of the following criteria apply: 1. Ability to participate in all scheduled evaluations and willing to provide written informed consent and to comply with the study protocol according to ICH and local regulations (e.g., PET, MRI, LP). Also, the participant has to be fluent in the language of the tests used at the study site. 2. Agreement not to donate blood or blood products for transfusion for the duration of the study and for four weeks after final dose of study treatment. 3.
  • a positive PET scan using any amyloid PET tracer, acquired outside this study protocol is not permitted to confirm participant inclusion due to the longitudinal PET imaging requirements for all participants enrolled in this study. Furthermore, please note that a CL value > 100 will be allowed only for approximately 15% of the total sample size 11. In case of treatment with symptomatic AD medications, dosing regimen must be stable for at least eight weeks prior to baseline. 12. Biological Male and Female Participants The reliability of sexual abstinence for the eligibility and enrolment of male and/or female participants needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant.
  • Periodic abstinence e.g., calendar, ovulation, symptothermal, or post ovulation methods
  • withdrawal are not acceptable methods of preventing drug exposure.
  • a female participant is eligible to participate if she is not pregnant, is not breastfeeding, and at least one of the following conditions applies: ⁇ Participant of non-childbearing potential (PONCBP) or ⁇ Participant of childbearing potential (POCBP), who: - Have a negative serum ⁇ -hCG at screening, a negative ⁇ -hCG urine pregnancy test at baseline, and during the study - Agree to remain abstinent (refrain from heterosexual intercourse) or use of at least one highly effective contraceptive method that results in a failure of ⁇ 1% per year from the screening visit until 35 days after last study treatment administration.
  • PONCBP non-childbearing potential
  • POCBP Participant of childbearing potential
  • Any medical history or evidence of a condition other than AD that may affect cognition including, but not limited to, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, Parkinson’s disease, corticobasal syndrome, Creutzfeldt-Jakob disease, progressive supranuclear palsy, Huntington’s disease, normal pressure hydrocephalus (clinical diagnosis), seizure disorder, delirium, posterior reversible encephalopathy syndrome, intracranial mass (e.g., glioma, meningioma), mental retardation, or hypoxia. 2.
  • Presence of infections that affect brain function or history of infections that resulted in neurologic sequelae e.g., human immunodeficiency virus [HIV], syphilis, Lyme disease, neuroborreliosis, and viral or bacterial meningitis and encephalitis.
  • HAV human immunodeficiency virus
  • syphilis a progressive neurologic disease with associated cognitive deficits
  • cognitive deficits e.g., multiple sclerosis, lupus erythematosus, anti-phospholipid antibody syndrome, and Behçet disease.
  • Chronic kidney disease indicated by creatinine clearance ⁇ 30 mL/min to be calculated by the central laboratory using the Cockcroft-Gault formula at screening, which remains ⁇ 30 mL/min if retested.
  • Participants with active or uncontrolled infections should not be enrolled until complete resolution of signs and symptoms.
  • Abnormal thyroid function that is not adequately controlled by medication. Note: A participant may be rescreened if, in the opinion of the Investigator, cognition is not improved after 12 weeks of adequate treatment for thyroid function. 18.
  • Uncontrolled/poorly controlled diabetes Note: A participant may be rescreened after 12 weeks to allow optimization of diabetic control. 19. History of or active inflammatory bowel disease (e.g., Crohn disease or ulcerative colitis). 20. Medical history of malignancy, with the following exceptions: - If considered to be cured and, If not being actively treated with anti-cancer therapy or radiotherapy and, in the opinion of the Investigator, is not likely to require treatment in the ensuing five years and, For prostate cancer or basal cell carcinoma, no significant progression over the previous two years. - In-situ cervix carcinoma that has been successfully treated - Fully excised non-melanoma skin cancers or in-situ melanoma 21.
  • Any active immunotherapy (vaccine) that is being evaluated to prevent or postpone cognitive decline administered within 1 year prior to baseline. Note: participant may be eligible earlier for this study if it can be documented that he/she was randomized to placebo. 26. Any passive immunotherapy (immunoglobulin) or other long-acting biologic agent that is under evaluation or approved to prevent or postpone cognitive decline administered within 1 year prior to baseline. Note: participant may be eligible earlier for this study if it can be documented that he/she was randomized to placebo. 27.
  • any other investigational treatment including anti-amyloid small molecules (i.e., BACE and GSIs, other GSMs) within five half-lives or 16 weeks prior to screening (calculated from the last safety follow-up visit of the previous study), whichever is longer.
  • participant may be eligible for this study if it can be documented that he/she was randomized to placebo.
  • FLAIR fluid attenuated inversion recovery
  • Contraindication to LP including coagulopathy, concomitant anti-coagulation (except for monotherapy with a platelet inhibitor such as aspirin or clopidogrel), thrombocytopenia, or other factors such as history of clinically significant hypersensitivity to local anesthetics (e.g., xylocaine) that may preclude safe lumbar puncture in the opinion of the Investigator.
  • a platelet inhibitor such as aspirin or clopidogrel
  • thrombocytopenia or other factors such as history of clinically significant hypersensitivity to local anesthetics (e.g., xylocaine) that may preclude safe lumbar puncture in the opinion of the Investigator.
  • Prior lumbar surgery or deformity of the lumbosacral region of the spine, not interfering with safe LP may be allowed at the discretion of the Investigator. 31.
  • the first dose of IMP will be administered at the site on Study Day 1, once all Baseline pre-dose assessments have been conducted, including the confirmation of eligibility at baseline. For all subsequent visit days, study treatment administration will be at the study center (or home-based if it is a remote visit) after all the assessment scheduled for that visit have been performed and under supervision of site staff (or home nurse). Participants should be instructed to take the dose of RO7269162 or placebo at approximately the same time each day (preferentially in the morning), except on the visit days as described before. RO7269162/placebo should be taken with a glass of water regardless of food intake. Participants should be instructed to swallow the capsules whole and not to chew them. If vomiting occurs during the course of treatment, no re dosing is allowed before the next scheduled dose.
  • Table 6 Primary objectives and corresponding estimands Primary Objective Estimand Definition To assess the effect of Population: daily oral dosing of Participants aged 60 to 85 years, amyloid positive (amyloid RO7269162 on brain burden of ⁇ 24 centiloids (CL) units), either cognitively amyloid accumulation unimpaired or with a diagnosis of Mild Cognitive Impairment (MCI), with a value of Clinical Dementia Rating scale – Global Score (CDR-GS) of either 0 (for cognitively unimpaired participants), or 0.5 (for participants with MCI) and satisfying study inclusion and exclusion criteria
  • Endpoint Change from baseline in brain amyloid load at 72 weeks, as measured by amyloid PET scan
  • Treatment Experimental arms: daily oral administration of 30 mg, 60 mg or 120 mg doses of RO7269162 for up to 72 weeks
  • Control arm daily oral administration of placebo for up to 72 weeks
  • Intercurrent events and handling strategies Hypothetical strategy (see section on ‘Rationale for estimands’) Population-level summary: Difference between each treatment arm and placebo in change
  • the CDR (Morris 1993) is a clinician-reported outcomes measure used to stage the severity of AD dementia based on a semi-structured interview with the participant and a reliable informant (e.g., study partner).
  • CDR-GS CDR Global Score
  • CDR-SB CDR Sum of Boxes
  • the CDR-SB score is a detailed quantitative general index that provides more information than the CDR-GS in participants with mild dementia (Berg 1988, Morris et al 2001, O'Bryant et al 2010).
  • Aspects of the invention Aspect 1.
  • Aspect 2 The compound for use according to aspect 1, wherein the disease is Alzheimer’s disease.
  • Aspect 3 The compound for use according to aspect 1 or 2, wherein the compound is for use in the treatment of sporadic Alzheimer’s Disease or genetically caused Alzheimer’s disease.
  • Aspect 4. The compound for use according to aspect 1 or 2, wherein the compound is for use in the treatment of symptomatic Alzheimer’s disease or pre-clinical Alzheimer’s disease.
  • Aspect 5. The compound for use according to aspect 1, wherein the disease is dementia caused by amyloidosis occurring in the context of Down’s Syndrome (trisomy 21).
  • Aspect 7 The compound for use according to any one of aspects 1 to 6, wherein (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, is orally administered.
  • Aspect 8
  • Aspect 11 The compound for use according to any one of aspects 1 to 10, wherein the compound is administered at a dose selected from 30, 60 and 120 mg.
  • Aspect 12. The compound for use according to any one of aspects 1 to 11, wherein the subject is a human.
  • Aspect 13 The compound for use according to any one of aspects 1 to 12, wherein the subject is an elderly person.
  • Aspect 14 The compound for use according to any one of aspects 1 to 13, wherein the subject is younger than 60 years of age and is at increased risk of developing a disease associated with amyloidosis.
  • Aspect 15 The compound for use according to any one of aspects 1 to 9, wherein the compound is administered at a dose ranging from 30 to 120 mg.
  • Aspect 12 The compound for use according to any one of aspects 1 to 10, wherein the compound is administered at a dose selected from 30, 60 and 120 mg.
  • Aspect 12 The compound for use according to any one of
  • a method for the treatment of a disease associated with amyloidosis comprising administering to a subject (in particular in a patient, more particularly in a patient in need thereof) (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, at a dose ranging from 5 to 480 mg per subject.
  • Aspect 17 The method according to aspect 16, wherein the disease is Alzheimer’s disease.
  • Aspect 18 The method according to aspect 16 or 17, wherein the compound is for use in the treatment of sporadic Alzheimer’s Disease or genetically caused Alzheimer’s disease.
  • Aspect 19 The method according to aspect 16 or 17, wherein the compound is for use in the treatment of symptomatic Alzheimer’s disease or pre-clinical Alzheimer’s disease.
  • Aspect 20 The method according to aspect 16, wherein the disease is dementia caused by amyloidosis occurring in the context of Down’s Syndrome (trisomy 21).
  • Aspect 21 The method according to aspect 16, wherein the disease is dementia caused by amyloidosis occurring in the context of Down’s Syndrome.
  • Aspect 22 The method according to any one of aspects 16 to 21, wherein (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, is orally administered.
  • Aspect 23 The method according to aspect 16, wherein the disease is increased or accelerated by formation of amyloid deposits in the brain as consequence of traumatic brain injury, and neuro- psychiatric symptoms such as dementia associated with said formation of amyloid deposits.
  • Aspect 26 The method according to any one of aspects 16 to 24, wherein the compound is administered at a dose ranging from 30 to 120 mg.
  • Aspect 26 The method according to any one of aspects 16 to 25, wherein the compound is administered at a dose selected from 30, 60 and 120 mg.
  • Aspect 27 The method according to any one of aspects 16 to 26, wherein the subject is a human.
  • Aspect 28 The method according to any one of aspects 16 to 27, wherein the subject is an elderly person.
  • Aspect 29 The method according to any one of aspects 16 to 28, wherein the subject is younger than 60 years of age and is at increased risk of developing a disease associated with amyloidosis.
  • Aspect 30 The method according to any one of aspects 16 to 24, wherein the compound is administered at a dose ranging from 30 to 120 mg.
  • Aspect 27 The method according to any one of aspects 16 to 26, wherein the subject is a human.
  • Aspect 28 The method according to any one of aspects 16 to 27, wherein the subject is an elderly person.
  • Aspect 29 The method according
  • Aspect 32 The use according to aspect 31, for the manufacture of a medicament for the treatment of Alzheimer’s disease.
  • Aspect 33 The use according to aspect 31 or 32, for the manufacture of a medicament for the treatment of sporadic Alzheimer’s disease or genetically caused Alzheimer’s disease.
  • Aspect 34 The use according to aspect 31 or 32, for the manufacture of a medicament for the treatment of symptomatic Alzheimer’s disease or pre-clinical Alzheimer’s disease.
  • Aspect 35. The use according to aspect 31, for the manufacture of a medicament for the treatment of dementia caused by amyloidosis occurring in the context of Down’s Syndrome (trisomy 21).
  • Aspect 36 The use according to aspect 31, for the manufacture of a medicament for the treatment of dementia caused by amyloidosis occurring in the context of Down’s Syndrome (trisomy 21).
  • Aspect 37 The use according to any one of aspects 31 to 36, wherein (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, is orally administered.
  • Aspect 38 Aspect 38.
  • Aspect 41 The use according to any one of aspects 31 to 40, wherein the compound is administered at a dose selected from 30, 60 and 120 mg.
  • Aspect 42 The use according to any one of aspects 31 to 41, wherein the subject is a human.
  • Aspect 43 The use according to any one of aspects 31 to 42, wherein the subject is an elderly person.
  • Aspect 44 The use according to any one of aspects 31 to 43, wherein the subject is younger than 60 years of age and is at increased risk of developing a disease associated with amyloidosis.
  • Aspect 45 The use according to any one of aspects 31 to 39, wherein the compound is administered at a dose ranging from 30 to 120 mg.
  • Aspect 42 The use according to any one of aspects 31 to 41, wherein the subject is a human.
  • Aspect 43 The use according to any one of aspects 31 to 42, wherein the subject is an elderly person.
  • Aspect 44 The use according to any one of aspects 31 to 43, wherein the subject is younger than 60 years of age and is at increased risk of developing
  • Aspect 46 The compound for use, method or use according to any one of aspects 1 to 45, wherein the treatment (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)- 3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, leads to a decrease of A ⁇ 40 and A ⁇ 42 levels in CSF and/or A ⁇ 40 and A ⁇ 42 levels in plasma.
  • Aspect 47 The compound for use, method or use according to any one of aspects 1 to 45, wherein the treatment (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)- 3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof, leads to a dose-dependent decrease of A ⁇ 40 and A ⁇ 42 levels in CSF and/or A ⁇ 40 and A ⁇ 42 levels in plasma.
  • Aspect 48 Aspect 48.
  • the compound for use, method or use according to aspect 54 wherein the brain amyloid load is reduced by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 centiloids units, as measured by amyloid positron emission tomography (PET) scan.
  • PET amyloid positron emission tomography
  • Aspect 57 The compound for use, method or use according to any one of aspects 1 to 56, wherein the treated individual has a CDR-GS rating of 0 or 0.5 at baseline.
  • Aspect 58 The compound for use, method or use according to any one of aspects 1 to 57, wherein the treatment leads to a stabilization in CDR-SB score.
  • Aspect 59 The compound for use, method or use according to any one of aspects 1 to 58, wherein the treatment leads to a stabilization in the Cogstate Cognitive Test Battery.
  • Aspect 60 The compound for use, method or use according to any one of aspects 1 to 56, wherein the treated individual has a CDR-GS rating of 0 or 0.5 at baseline.
  • Aspect 58 The compound for use, method or use according to any one of aspects 1 to 57, wherein the treatment leads to a stabilization in CDR-SB score.
  • Aspect 59 The compound for use, method or use according to any one of aspects 1 to 58, wherein the treatment leads to a stabilization
  • the treatment includes daily administration of (R)-7-(3,5-difluorophenoxy)-N- ((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof.
  • the compound for use, method or use according to any one of aspects 1 to 59 wherein the treatment includes daily administration during 72 weeks of (R)-7-(3,5- difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, or a pharmaceutically acceptable salt thereof.
  • Aspect 62 The compound for use, method or use according to any one of aspects 1 to 61, wherein the CDR-GS score at baseline was 0 or 0.5.
  • Aspect 63 The compound for use, method or use according to any one of aspects 1 to 61, wherein the CDR-GS score at baseline was 0 or 0.5.
  • Aspect 64 The compound for use, method or use according to any one of aspects 1 to 62, wherein the CDR-GS score at baseline was 0.
  • Aspect 65 The compound for use, method or use according to any one of aspects 1 to 62, wherein the patients are and/or were previously on anticholinesterase therapy.
  • Aspect 66 The compound for use, method or use according to any one of aspects 1 to 65, wherein the brain amyloid load at baseline was ⁇ 24, ⁇ 30, ⁇ 40, ⁇ 50, ⁇ 60 or ⁇ 70 centiloids (CL) units measured by an amyloid positron emission tomography (PET) scan.
  • CL centiloids
  • Aspect 67 The compound for use, method or use according to any one of aspects 1 to 65, wherein the brain amyloid load at baseline was ⁇ 20 centiloads (CL) units and ⁇ 90 centiloids (CL) units measured by an amyloid positron emission tomography (PET) scan.
  • Aspect 68 The compound for use, method or use according to any one of aspects 1 to 67, wherein the brain amyloid load at baseline was ⁇ 24 centiloads (CL) units and ⁇ 90 centiloids (CL) units measured by an amyloid positron emission tomography (PET) scan.
  • Aspect 69 The compound for use, method or use according to any one of aspects 1 to 65, wherein the brain amyloid load at baseline was ⁇ 20 centiloads (CL) units and ⁇ 90 centiloids (CL) units measured by an amyloid positron emission tomography (PET) scan.
  • Aspect 71. The compound for use, method or use according to any one of aspects 1 to 67, wherein the brain amyloid load at baseline was ⁇ 60 centiloids (CL) units measured by an amyloid positron emission tomography (PET) scan.
  • Aspect 73. The compound for use, method or use according to any one of aspects 1 to 72, wherein the brain amyloid load at baseline was ⁇ 100 centiloids (CL) units measured by an amyloid positron emission tomography (PET) scan.
  • Aspect 74 The compound for use, method or use according to any one of aspects 1 to 73, wherein the brain amyloid load at baseline was ⁇ 90 centiloids (CL) units measured by an amyloid positron emission tomography (PET) scan.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne la (R)-7-(3,5-difluorophénoxy)-N-((1R,5S,8s)-3-(6-méthoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5 H-pyrrolo[1,2-b][1,2,4]triazol-2-amine, ou un sel pharmaceutiquement acceptable de celle-ci, destinée à être utilisée dans le traitement d'une maladie associée à l'amyloïdose, et son procédé de traitement.
PCT/EP2025/061489 2024-05-03 2025-04-28 Régime posologique pour un dérivé de 7-phénoxy-n- (3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5 h-pyrrolo[1,2-b][1,2,4]triazol-2-amine Pending WO2025228863A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP24174067.9 2024-05-03
EP24174067 2024-05-03

Publications (1)

Publication Number Publication Date
WO2025228863A1 true WO2025228863A1 (fr) 2025-11-06

Family

ID=91022890

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/061489 Pending WO2025228863A1 (fr) 2024-05-03 2025-04-28 Régime posologique pour un dérivé de 7-phénoxy-n- (3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5 h-pyrrolo[1,2-b][1,2,4]triazol-2-amine

Country Status (1)

Country Link
WO (1) WO2025228863A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020120521A1 (fr) 2018-12-13 2020-06-18 F. Hoffmann-La Roche Ag Dérivés de 7-phénoxy-n-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5h-pyrrolo[1,2-b][1,2,4]triazol-2-amine et composés apparentés en tant que modulateurs de gamma-sécrétase pour le traitement de la maladie d'alzheimer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020120521A1 (fr) 2018-12-13 2020-06-18 F. Hoffmann-La Roche Ag Dérivés de 7-phénoxy-n-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5h-pyrrolo[1,2-b][1,2,4]triazol-2-amine et composés apparentés en tant que modulateurs de gamma-sécrétase pour le traitement de la maladie d'alzheimer

Non-Patent Citations (21)

* Cited by examiner, † Cited by third party
Title
BATEMAN ET AL.: "Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease", ALZHEIMER'S RESEARCH & THERAPY, vol. 3, 2011, Retrieved from the Internet <URL:https://alzres.biomedcentral.com/articles/10.1186/alzrt59>
BLAIN ET AL.: "Characterization of FRM-36143 as a new γ-secretase modulator for the potential treatment of familial Alzheimer's disease", ALZHEIMER'S RESEARCH & THERAPY, vol. 8, 2016
CULLEN ET AL.: "Association of CSF Aβ38 Levels With Risk of Alzheimer Disease-Related Decline", NEUROLOGY, vol. 98, no. 9, 2022, pages e958 - e967
DE STROOPER BART ET AL: "New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of [gamma]-secretases", vol. 43, no. 6, 15 March 2024 (2024-03-15), Oxford, pages 887 - 903, XP093204864, ISSN: 0261-4189, Retrieved from the Internet <URL:https://www.embopress.org/doi/full/10.1038/s44318-024-00057-w> DOI: 10.1038/s44318-024-00057-w *
FILSER ET AL.: "Pharmacological Inhibition of BACE1 Impairs Synaptic Plasticity and Cognitive Functions", BIOLOGICAL PSYCHIATRY, vol. 77, 2015, pages 729 - 739, XP029150927, DOI: 10.1016/j.biopsych.2014.10.013
GUENERLICHTENTHALER: "The substrate repertoire of γ-secretase/presenilin", SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, vol. 105, 2020, pages 27 - 42
HAMPEL ET AL.: "The β-Secretase BACE1 in Alzheimer's Disease", BIOLOGICAL PSYCHIATRY, vol. 89, 2015, pages 745 - 756
HUR: "Secretase in Alzheimer's disease", EXPERIMENTAL & MOLECULAR MEDICINE, vol. 54, 2020, pages 433 - 446
JONSSON ET AL.: "A mutation in APP protects against Alzheimer's disease and age-related cognitive decline", NATURE, vol. 488, 2012, pages 96 - 99, XP055675990, DOI: 10.1038/nature11283
KNOPMAN ET AL.: "Alzheimer's disease", NATURE REVIEWS DISEASE PRIMERS, vol. 7, 2021
LOTT D ET AL, 27 October 2023 (2023-10-27), XP093204865, Retrieved from the Internet <URL:https://medically.gene.com/content/dam/pdmahub/restricted/neurology/ctad-2023/CTAD-2023-poster-portron-RG6289-a-new-[gamma]-secretase-modulator.pdf> *
LUOLI: "Turning the tide on Alzheimer's disease: Modulation of γ-secretase", CELL & BIOSCIENCE, vol. 12, 2023, pages 2
MASTERS ET AL.: "Alzheimer's disease", NATURE REVIEWS DISEASE PRIMERS, vol. 1, 2015
MOORE ET AL.: "Short A(3 peptides attenuate Aβ42 toxicity in vivo", JOURNAL OF EXPERIMENTAL MEDICINE, vol. 215, no. 1, 2018, pages 283 - 301
no. 2443487-67-8
QUARTEY MONYARKO JNKMALEY JMBARNES JRBOLANOS MACHEISTAD RMKNUDSEN KJPENNINGTON PRBUTTIGIEG JDE CARVALHO CE: "The Aβ(1-38) peptide is a negative regulator of the Aβ(1-42) peptide implicated in Alzheimer disease progression", SCI REP., vol. 11, no. 1, 11 January 2021 (2021-01-11), pages 431
RYNEARSON ET AL.: "Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention", J EXP MED., vol. 218, no. 4, 2021, pages 20202560
SIRKIS ET AL.: "Dissecting the clinical heterogeneity of early-onset Alzheimer's disease", MOLECULAR PSYCHIATRY, vol. 27, 2022, pages 2674 - 2688, Retrieved from the Internet <URL:https://www.nature.com/articles/s41380-022-01531-9>
STEINER ET AL.: "Making the final cut: pathogenic amyloid-β peptide generation by γ-secretase", CELL STRESS, vol. 2, no. 11, 2018, pages 292 - 310
VAN BROECK ET AL.: "Chronic treatment with a novel γ-secretase modulator, JNJ-40418677, inhibits amyloid plaque formation in a mouse model of Alzheimer's disease", BR J PHARMACOL, vol. 163, no. 2, 2011, pages 375 - 389
VARIOUS: "SYMPOSIA - 16th Conference Clinical Trials Alzheimer�??s Disease, October 24-27- 2023, Boston, MA, USA", vol. 10, 30 October 2023 (2023-10-30), pages S4 - S55, XP093200482, ISSN: 2274-5807, Retrieved from the Internet <URL:https://link.springer.com/article/10.14283/jpad.2022.129> DOI: 10.14283/jpad.2022.129 *

Similar Documents

Publication Publication Date Title
US20220152057A1 (en) Methods and compositions for treating various disorders
AU2024227357A1 (en) Ganaxolone For Use In Treating Genetic Epileptic Disorders
AU2013295370B2 (en) Use of biotin for the treatment of multiple sclerosis
KR20150002681A (ko) App 특이적 bace 억제제(asbi) 및 이의 용도
US20200113883A1 (en) Durable treatment with 4-aminopyridine in patients with demyelination
US20190381049A1 (en) Compositions and methods for treating dementia
WO2025228863A1 (fr) Régime posologique pour un dérivé de 7-phénoxy-n- (3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5 h-pyrrolo[1,2-b][1,2,4]triazol-2-amine
US20240148709A1 (en) Methods of treating eye pain and eye disorders
US20240100069A1 (en) Methods and Compositions for Treating Amyotrophic Lateral Sclerosis
CN120051284A (zh) 用于治疗早期阿尔茨海默病的方法
CA3268619A1 (fr) Méthodes de traitement de la maladie d&#39;alzheimer précoce
TW202519200A (zh) 用於各種疾病之治療的組成物及方法
HK40008598A (en) Use of biotin for the treatment of multiple sclerosis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25722193

Country of ref document: EP

Kind code of ref document: A1