Dose regimen for a 7-phenoxy-n-(3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5h-pyrrolo[1,2-b][1,2,4]triazol-2-amine derivative

Abstract

The present 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, and its method of treatment thereof.

Description

[0001] Case P39070 DOSE REGIMEN Field of the invention The present 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. Background of the invention Alzheimer’s Disease (AD) is the most common form of dementia. Two major pathological hallmarks of AD are amyloid plaques, which result from extracellular accumulation and deposition of amyloid β-peptides (Aβ), mostly Aβ40 and Aβ42 (Steiner et al. 2018), and neurofibrillary tangles containing the hyper-phosphorylated tau protein in neurons (Masters et al.2015; Knopman et al 2021). The formation of amyloid plaques (Aβ plaques) is predominantly driven by the longer forms of Aβ peptides, Aβ42 and to a lesser extent Aβ40; these longer forms of Aβ are therefore called amyloidogenic. The shorter forms of Aβ are called non-amyloidogenic as they do not contribute to the formation of Aβ plaques. The biogenesis of Aβ 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. 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 Aβ peptides of either 48 or 49 amino acids, respectively (Figure 2). These long Aβ 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 Aβ peptides with a length of 40 and 42, as well as 38 and 37 amino acids, respectively. Once the Aβ peptides have reached their final lengths they are released in the extracellular space. Gamma secretase has emerged as an attractive drug target as this enzyme is critical for the production of Aβ peptides and for defining the composition of Aβ in their different lengths. Modulating the activity of gamma secretase is a compelling approach to lower the levels of the neurotoxic Aβ42 peptide in the brain while leaving the proteolytic processing of other gamma secretase substrates such as Notch unchanged (Luo and Li 2023; Hur 2022). Gamma Secretase Modulators (GSMs) selectively change the processing of APP by gamma secretase such that the production of the amyloidogenic Aβ42 and Aβ40 peptide fragments are reduced while the production of the non-amyloidogenic shorter fragments Aβ38 and Aβ37 are concomitantly increased. Importantly, GSMs do not inhibit the gamma secretase enzyme, thus, the total amount of Aβ peptides remains unchanged. Furthermore, the processing of other proteins by gamma secretase is not affected by GSMs. The latter is a key differentiation of GSMs from secretase inhibitors – 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 Aβ produced. However, 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). The processing of these other substrates is also inhibited by BACE1 inhibitors and GSIs, respectively, leading to severe side effects when human subjects are treated with either of these two drug classes. The lack of clinical efficacy combined with the side effect profile prompted the discontinuation of clinical development of BACE1 inhibitors and GSIs for the treatment of AD (Hur 2020; Alzforum BACE inhibitor update from 16 Dec 2020). Taken together, these observations support the expectation that GSMs have the potential to serve as an effective and safe disease modifying treatment of AD. 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 (ε) cut. These two initial proteolytic cuts produces 1) the APP intracellular domain (AICD) fragment which is released intracellularly, and 2) a mix of Aβ48 and Aβ49, respectively, with either 48 or 49 amino acids, depending on the location of the gamma secretase cleavage site (gamma secretase produces a mix of both fragment lengths). The Aβ48 and Aβ49 peptides remain bound to the gamma secretase enzyme where they undergo trimming by sequential removal of di- and tri-peptides by ζ- and γ-cuts leading to shorter Aβ peptides which are eventually released by the enzyme complex. The length of the initially produced Aβ peptides determines the lengths of the final Aβ peptides released from the enzyme complex: Aβ48 fragments lead to the production of predominantly Aβ42 and Aβ38 (‘Aβ48 product line’), while Aβ49 fragments lead to the production of predominantly Aβ40 and Aβ37 (‘Aβ49 product line’). In healthy individuals and under normal conditions, newly produced Aβ peptides consist of ca. 90% Aβ40 and 10% Aβ42, with smaller amounts of shorter Aβ fragments such as Aβ37 and Aβ38 (Steiner et al.2018; Figure with modifications Luo and Li, 2023). The key factor for the efficacy of GSMs is the above-mentioned selective reduction of aggregation-prone toxic Aβ42 and Aβ40 fragments. The concomitantly and proportionally increased shorter peptides Aβ37 and Aβ38 on the other hand are significantly less prone to toxic aggregate formation and can even inhibit Aβ42 aggregation (Blain et al 2016, Moore et al 2018, Quartey et al 2021, Braun et al 2022). Moreover, higher levels of shorter Aβ fragments are linked to a later onset of AD in observational cohorts (Cullen et al.2022). Chronic GSM treatment of transgenic mice that show an age-dependent amyloid accumulation, effectively reduced Aβ42 and Aβ40 levels in brain tissue, CSF and plasma, and reduced the deposition of amyloid plaques in brain (van Broeck et al.2011; Rynearson et al.2021). The causal role for Aβ42 and amyloid depositions in AD is also strongly supported by the AD pathobiology and human genetics. In general, there is no AD without Aβ deposits in the brain – other factors known to play a role in AD such as Tau pathology alone are insufficient to cause AD (Masters et al.2015, Knopman et al.2021). Moreover, subjects with Autosomal-dominant Alzheimer's Disease (ADAD, also known as Familial Alzheimer’s Disease – FAD, or Early Onset Alzheimer’s Disease - EOAD) mutations representing an estimated 1% of all AD cases, carry mutations in the genes encoding Presenilin 1, Presenilin 2, or APP which cause elevated levels of Aβ production and Aβ deposits occurring in the brain early in life (mostly 2nd– 3rddecade) (Sirkis et al.2022). Thus, in ADAD carriers, the increased production of Aβ is causal for the early onset aggressive forms of AD observed in these individuals. On the other hand, mutations leading to reduced levels of Aβ such as the ‘Icelandic mutation’ (APP A673T) are protective against the occurrence of AD (Jonsson et al.2012). Taken together, Aβ production and formation of Aβ deposits in the brain plays a causal role in AD. Here, especially Aβ42 (and to a lesser extent Aβ40) is amyloidogenic, i.e. causes the formation of Aβ aggregates and eventually Aβ deposits in the brain. The shorter Aβ fragments Aβ37 and Aβ38 are not amyloidogenic, i.e. they do not cause the formation of Aβ aggregates and eventually Aβ deposits in the brain; on the contrary, the shorter Aβ fragment lengths can even inhibit the formation of Aβ aggregates comprised by the longer Aβ fragments. These data, combined with the preclinical evidence, strongly support that the reduction of amyloidogenic Aβ42 and Aβ40 by GSM treatment will translate into reduced levels of aggregated Aβ and Aβ deposits leading to a prevention of AD onset or a slowing of AD progression, depending on when treatment starts in the disease trajectory. References: Jonsson et al. (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature Vol.488, pp.96–99, doi:10.1038 / nature11283 Bateman et al. (2011) Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease. Alzheimer's Research & Therapy volume 3, Article number: Sirkis et al. (2022) Dissecting the clinical heterogeneity of early-onset Alzheimer’s disease. Molecular Psychiatry Vol.27, pp.2674–2688, https: / / www.nature.com / articles / s41380-022- 01531-9 Masters et al. (2015) Alzheimer's disease. Nature Reviews Disease Primers, Vol.1, Article number: 15056. DOI: 10.1038 / nrdp.2015.56 Knopman et al (2021) Alzheimer's disease. Nature Reviews Disease Primers, Vol.7, Article number: 34. DOI: 10.1038 / s41572-021-00269-y. Cited references: Hampel et al. (2015) The β-Secretase BACE1 in Alzheimer’s Disease. Biological Psychiatry Volume 89, Issue 8, pp.745-756. DOI: 10.1016 / j.biopsych.2020.02.001 Masters et al. (2015) Alzheimer's disease. Nature Reviews Disease Primers, Vol.1, Article number: 15056. DOI: 10.1038 / nrdp.2015.56 Knopman et al (2021) Alzheimer's disease. Nature Reviews Disease Primers, Vol.7, Article number: 34. DOI: 10.1038 / s41572-021-00269-y. Steiner et al. (2018) Making the final cut: pathogenic amyloid-β peptide generation by γ- secretase. Cell Stress 2 (11): pp.292–310. DOI: 10.15698 / cst2018.11.162. Guener and Lichtenthaler (2020) The substrate repertoire of γ-secretase / presenilin. Seminars in Cell & Developmental Biology, Vol 105, pp 27-42. DOI: https: / / doi.org / 10.1016 / j.semcdb.2020.05.019 Hur (2020) γ-Secretase in Alzheimer’s disease. Experimental & Molecular Medicine, 54, pp 433–446. DOI: https: / / doi.org / 10.1038 / s12276-022-00754-8 Blain et al. (2016) Characterization of FRM-36143 as a new γ-secretase modulator for the potential treatment of familial Alzheimer’s disease. Alzheimer’s Research & Therapy 8, article no.34. DOI: 10.1186 / s13195-016-0199-5 Moore et al. (2018) Short Aβ peptides attenuate Aβ42 toxicity in vivo. Journal of Experimental Medicine 215(1), pp 283–301. DOI: 10.1084 / jem.20170600 Cullen et al. (2022) Association of CSF Aβ38 Levels With Risk of Alzheimer Disease-Related Decline. Neurology 98(9):e958-e967. DOI: 10.1212 / WNL.0000000000013228 Luo and Li (2023) Turning the tide on Alzheimer’s disease: Modulation of γ-secretase. Cell & Bioscience 12, 2. DOI: 10.1186 / s13578-021-00738-7. Van Broeck et al. (2011) 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. 163(2): 375–389. doi: 10.1111 / j.1476-5381.2011.01207.x Rynearson et al. (2021) Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention. J Exp Med.218(4): e20202560. DOI: 10.1084 / jem.20202560 Quartey MO, Nyarko JNK, Maley JM, Barnes JR, Bolanos MAC, Heistad RM, Knudsen KJ, Pennington PR, Buttigieg J, De Carvalho CE, Leary SC, Parsons MP, Mousseau DD. The Aβ(1- 38) peptide is a negative regulator of the Aβ(1-42) peptide implicated in Alzheimer disease progression. Sci Rep.2021 Jan 11;11(1):431. doi: 10.1038 / s41598-020-80164-w. PMID: 33432101; PMCID: PMC7801637. Filser et al. (2015) Pharmacological Inhibition of BACE1 Impairs Synaptic Plasticity and Cognitive Functions. Biological Psychiatry Volume 77, Issue 8, pp 729-739. DOI: 10.1016 / j.biopsych.2014.10.013 Alzforum news update on BACE inhibitors from 16 Dec 2020: https: / / www.alzforum.org / news / research-news / new-data-past-bace-inhibitor-trials-shed-light- side-effects Current therapies and unmet medical need There is a high unmet medical need for an effective disease-modifying AD therapy (Gauthier et al.2016, Golde 2022). To date, only medications treating the symptoms of AD have received marketing approval, including acetylcholinesterase inhibitors (AChEi) and N-methyl-d-aspartate (NMDA) receptor antagonists. The mainstay of symptomatic 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. These treatments provide some benefits with respect to cognitive function, but these are only maintained for a short period of time after the start of therapy due to the disease progression. Aβ-targeted therapies are being actively pursued in preclinical and clinical studies for the treatment of AD. Two Aβ amyloid-directed antibodies, aducanumab [ADUHELM™] and lecanemab (LEQEMBI™), 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 Aβ 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 Aβ amyloid, also achieved a reduction of Aβ 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). Of note, 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 Aβ 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. 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, also known as RO7269162, is currently investigated in clinical trials. The Phase I Study BP42242, was the EIH study. This was a randomized, adaptive, double-blind, single ascending dose (SAD) and multiple ascending dose (MAD), placebo- controlled, parallel-arm, Phase I study to investigate the safety, tolerability, PK and PD of orally administered RO7269162 in healthy participants. In this EIH study (BP42242), RO7269162 was safe and well tolerated as a single dose up to 480 mg (SAD), and multiple doses up to 230 mg / day for up to 14 days both in young and elderly healthy participants (MAD). It was surprisingly found that a dose-dependent reduction in Aβ42 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. Moreover, a dose- dependent decrease in Aβ42 and Aβ40 along with a concurrent dose-dependent increase in Aβ37 and Aβ38 were observed in CSF following multiple oral dose administration of RO7269162 at doses ranging 30-230 mg. Summary of the invention 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. Brief description of the figures Figure 1 illustrates the composition of the gamma secretase complex (Luo and Li (2023), Turning the tide on Alzheimer’s disease: Modulation of γ-secretase. Cell & Bioscience 12, 2. DOI: 10.1186 / s13578-021-00738-7). Figure 2 illustrates the biogenesis of amyloid beta (Aβ) 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 γ-secretase. Cell & Bioscience 12, 2. DOI: 10.1186 / s13578-021-00738-7). Figure 3(a) (shown at the top) illustrates the Preliminary Mean (+ SD) Percent Change from Baseline of Aβ42 versus Time Profile in Plasma after Daily Oral Administration of 30 mg, 70 mg and 230 mg or Placebo for 14 Days (336 hours) under Fed Conditions in Young Healthy Participants (Part 3a) - Real Time Analysis Note: Arithmetic mean (+ SD) Percent Change from Baseline of Aβ42 in plasma is displayed for placebo (n = 8), 30 mg (n = 6), 70 mg (n = 9), and 230 mg (n = 9). Figure 3(b) (shown at the bottom) illustrates the Mean (95% CI) Percent Change from Baseline of A42 versus Time Profile in Plasma after Daily Oral Administration of 30 mg (n=6), 70 mg (n=9) and 230 mg (n=9) or Placebo (n=8) for 14 Days under Fed Conditions in Young Healthy Participants - Batch Analysis (Study Part 3a) Figure 4 illustrates the Mean (SD) Percent Change from Baseline of A42 versus Time Profile in Plasma after Daily Oral Administration of 100 mg (n= 6) or Placebo (n=2) for 14 Days (336 hours) under Fed Conditions in Elderly Healthy Participants – Batch Analysis (Study Part 3b) Detailed description of the invention All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The nomenclature used in the present application is based on IUPAC systematic nomenclature, unless indicated otherwise. Various features and embodiments of the present invention are disclosed herein, however other features of the invention, modifications and equivalents will be apparent to a person skilled in the relevant art, based on the teachings provided. The invention described is not limited to the examples and embodiments provided, various alternatives equivalents will be appreciated by those skilled in the art. As used herein, the singular forms "a", "an" and "the" include the plural unless the context clearly dictates otherwise. For example, "an" individual will also include "individuals". Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: 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). 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 The term “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. The term “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. For example, 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. In some embodiments, the subject is a human. The term "patient" refers to a human (such as a male or female human) who is in need of a treatment with RO7269162. The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert 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. The term "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. The term "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. The term “Cmax” (expressed in units of ng / mL) means maximum observed plasma concentration. The term “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. The term “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. The term “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. (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 according to the present invention refers to the compound of formula (I) also known as RG6289, RO7269162, CAS Number 2443487-67-8. Methods of making and using the compound are described in WO2020 / 120521. In one embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In one embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In a particular embodiment, the invention provides a method for the treatment of a disease as described herein above, wherein the subject is a human. In a more particular embodiment, 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. 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 selected from 30, 60 and 120 mg. In one embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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.. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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. In a more particular embodiment, 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). However, 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. Moreover, 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.

[0002] The following examples are intended merely to illustrate the practice of the present invention and is not provided by way of limitation. 1) 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. 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. The study was conducted in five parts (1a, 1b, 2, 3a, 3b, 4 – see also Table 1): 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 (Aβ) metabolism and their relationship to RO7269162 exposure in healthy participants aged 40−70 years. Proof of mechanism was established through assessment of changes in CSF of Aβ species as the best proxy for the expected effects of RO7269162 in the brain. Part 4 (drug-drug interaction [DDI]) investigated the effect of multiple oral doses of RO7269162 on the pharmacokinetics (PK) of a single oral dose of caffeine (sensitive CYP1A2 substrate) and midazolam (sensitive CYP3A substrate) in healthy participants aged 18−64 years. These results are not presented and discussed here as they have no relevance for the dose selection. The study has been completed, and the preliminary analyses have been conducted. Table 1: Phase study parts with study participants, drug doses, and objectives Study No. of Doses of RO7269162 / Objective part subjects Placebo (or other) per day Part 1a 52 5 – 480 mg, or Placebo; Single Ascending Dose (SAD) (single doses) study; young healthy subjects Part 1b 8 30 – 230 mg; Food effect (FE); multiple doses young healthy subjects Part 2 12 16, 60, 240 mg, or Continuous CSF sampling for Placebo; measuring of PD effects; young single doses healthy subjects Part 3a 32 30, 70, 230 mg, or Multiple Ascending dose (MAD) Placebo; study; multiple doses young healthy subjects Part 3b 8 100 mg, or Placebo Multiple Ascending dose (MAD) multiple doses study; elderly healthy subjects Part 4 14 150 mg, with / without Drug-Drug-Interaction (DDI) caffeine 200 mg and study; midazolam 2 mg young healthy subjects; 200 mg caffeine / midazolam 2 mg on day 1 + 7, 150 mg RO7269162 on days 3 - 8 The results of Part 4 are not presented here as the interaction of the study drug with caffeine had no relevance for the dose selection. i. 1.1) Clinical Pharmacology Preliminary 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. RO7269162 plasma concentration declined in a bi-exponential manner with an estimated apparent terminal half-life (t1 / 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 Cmaxand area under the plasma concentration-time curve (AUC; area under the plasma concentration-time curve over a dosing interval [AUCτ] and area under the plasma concentration-time curve from Time 0 to infinity [AUCinf]). After multiple oral administration with RO7269162, exposure accumulation ratios (for Cmax, AUCτ, and Ctrough) were approximately 1.5 to 1.8. Steady state was achieved at around 7 days post onset of dosing. When RO7269162 was administered with food, the median time to achieve peak plasma concentration (Tmax) was delayed to approximately 3 hours, and Cmax was reduced by about 20%. There was no relevant change in AUCinf. These results indicate that food may slightly decrease the rate but not the extent of RO7269162 oral drug absorption. Following single oral administration, RO7269162 appeared rapidly in the CSF. RO7269162 exposures in CSF after single oral administration in fasted conditions increased with increasing doses in a dose-proportional manner. 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 Aβ42 levels was observed following single and multiple oral administration of RO7269162. After single dose administration, the maximum mean percent change from baseline of Aβ42 was -70% after administration of 480 mg RO7269162. Plasma Aβ42 levels returned to their baseline levels within 5 days after the administration of RO7269162. Following once daily administration of 230 mg RO7269162 for 14 days, the maximum mean percent change from baseline in plasma Aβ42 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. Following administration of 60 mg RO7269162 in fed conditions, the maximum mean decrease in Aβ42 was delayed and observed at 12 hours post dose, but no significant difference in Aβ42 maximum reduction versus fasted conditions was observed. A dose-dependent decrease in Aβ42 and Aβ40 and a dose-dependent increase in Aβ37 and Aβ38 were observed in CSF following once daily administration of RO7269162 for 14 days at doses ranging 30-230 mg. Following daily administration of 230 mg RO7269162, steady-state predose (trough) levels of Aβ42 and Aβ40 were decreased in CSF by approximately -70% and -60%, respectively, while corresponding Aβ37 and Aβ38 were increased by approximately 370% and 38%, respectively. ii. 1.2) Safety Safety and tolerability were assessed by reviewing individual and aggregate data from the BP42242 study which included results available for 127 healthy participants. Overall, the data indicate that RO7269162 was safe and well-tolerated with single oral doses up to 480 mg and multiple oral doses up to 230 mg once daily for 14 days. No deaths or serious adverse events (SAEs) were reported. Two adverse events (AEs) leading to withdrawal from study were reported in Part 3a (MAD young participants) and Part 4 (DDI). These two AEs were considered not related to the study drug. All AEs reported in Part 1a (SAD), Part 1b (FE), and Parts 3a and 3b (MAD young participants and MAD elderly participants) were mild except for one moderate AE (preferred term [PT]: food poisoning) which was not related to RO7269162 as assessed by the investigator in the 240 mg cohort of Part 1a (SAD). In Part 2, where the effect of single doses of RO7269162 or placebo on the CSF PD were studied, the majority of AEs were mild to moderate, except three severe AEs in 3 participants (two post lumbar puncture syndrome and one procedural pain). All moderate AEs but one AE (pain in extremity in the 240-mg group,) and all severe AEs were considered related to the study procedure (CSF sampling), and all resolved. No other severe AEs were reported. In Part 4 (DDI), all AEs were mild and considered not related to RO7269162 by the investigator. There were no dose-dependent changes in vital signs, ECG or safety laboratory parameters, neurological examination, Columbia-Suicide Severity Rating Scale and neurocognitive tests monitored in this study. 2. 1.3) EFFECTS IN HUMANS a. Clinical Pharmacodynamics Plasma Pharmacodynamics after Multiple Oral Dose Administration of RO7269162 in Young Healthy Participants (Part 3a) Preliminary mean percent change from baseline of Aβ42 monomers versus time profiles in plasma following daily oral administration of RO7269162 at 30 mg, 70 mg, 230 mg RO7269162 or placebo in fed conditions for 14 days in Part 3a are displayed in Figure 3. A dose-dependent Aβ42 reduction was observed in plasma following daily administration of oral doses at 30 mg, 70 mg, and 230 mg RO7269162 for 14 days. The maximum mean percent change from baseline of Aβ42 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. At trough (24 hours post last dose on Day 14), the maximum mean percent change from baseline of Aβ42 was - 40.6%, - 45.2%, and - 70.5% following multiple administration of 30 mg, 70 mg, and 230 mg RO7269162, respectively. Plasma Aβ42 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. For plasma: Elecsys® β-Amyloid (1-42) plasma; Elecsys® β-Amyloid (1-40) plasma immunoassay. For CSF: Elecsys® β-Amyloid (1-42) CSF II; Elecsys® β-Amyloid (1-40) CSF; Elecsys® β-Amyloid (137) CSF; Elecsys® β-Amyloid (1-38) CSF. Table 2 summarizes the predose Monomers Concentrations (pg / mL) and Percent Change from Baseline in CSF after 14-Days Daily Oral Dose Administration of 30, 70, and 230 mg RO7269162 or Placebo under Fed Conditions in Young Healthy Participants (Part 3a) 30 mg 70 mg 230 mg Placebo RO7269162 RO7269162 RO7269162 (N=4) (N=3) (N=7) (N=6) Ab42 Day -2 Level 1420 1240 1190 1130 (pg / mL) (539) (46.1) (283) (388) Day 13 Level 1340 919 652 347 (pg / mL) (496) (26.8)a(173)b(188) Percent Change from -5.35 -25.3 -43.0 -70.1 Baseline (6.61) (1.60)a(10.3)b(7.04) Ab40 Day -2 Level 16000 15300 14200 13400 (pg / mL) (4060) (615) (3040) (3950) Day 13 Level 15500 12300 8380 5310 (pg / mL) (4130) (431)a(1500)b(2160) Percent Change from -2.93 -18.0 -38.7 -60.4 Baseline (8.43) (0.0234)a(11.4)b(7.76) Ab37 Day -2 Level 1320 1240 1120 1130 (pg / mL) (251) (68.0) (182) (353) Day 13 Level 1240 2430 3300 5110 (pg / mL) (289) (672)a(1040)b(1310) Percent Change from -6.16 99.7 199 357 Baseline (4.72) (47.1)a(67.3)b(45.3) Ab38 Day -2 Level 8240 7680 7010 6920 (pg / mL) (1550) (434) (1260) (2510) Day 13 Level 7740 7580 7240 9690 (pg / mL) (1870) (846) (1700)b(3850) Percent Change from -6.67 2.13 5.59 38.5 Baseline (4.70) (12.2)a(15.1)b(13.0) Arithmetic mean (SD) is reported. Source: t_lb_abeta_pcfb_MADYOUNG_SE. Plasma Aβ42 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 Aβ42 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 Aβ42 was - 59.0%. CSF Pharmacodynamics after Multiple Administration Preliminary mean Aβ 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 Aβ42 and Aβ40 along with a concurrent dose-dependent increase in Aβ37 and Aβ38 were observed in CSF following multiple RO7269162 administration. Following daily administration of 230 mg RO7269162, predose levels of Aβ42 and Aβ40 decreased by approximately - 70% and - 60%, respectively, at steady state; and Aβ37 and Aβ38 increased by approximately 370% and 38%, respectively. Plasma and CSF levels of markers of amyloid deposition were measured using Elecsys immunoassays. For plasma: Elecsys® β-Amyloid (1-42) plasma; Elecsys® β-Amyloid (1-40) plasma immunoassay. For CSF: Elecsys® β-Amyloid (1-42) CSF II; Elecsys® β-Amyloid (1-40) CSF; Elecsys® β- Amyloid (137) CSF; Elecsys® β-Amyloid (1-38) CSF.

[0003] Summary and Conclusion ● A dose-dependent reduction in Aβ42 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 Aβ42 and Aβ40 along with a concurrent dose-dependent increase in Aβ37 and Aβ38 were observed in CSF following multiple oral dose administration of RO7269162 at doses ranging 30-230 mg. 2) 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. 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. 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. 2.1) Rationale for study design Rationale for Study Population Cognitively unimpaired participants at risk of AD, or participants with MCI due to AD have been chosen to allow the assessment of the effects of RO7269162 on safety, PK, and PD markers in the target population. Evidence from observational cohorts and clinical-pathological correlation studies suggest that the AD neuropathological hallmarks and the in vivo biomarker changes typical of AD begin many years before the clinical symptoms. Furthermore, the rate of change of certain AD-related biomarkers is higher at the preclinical and prodromal stages of the disease, compared to the more advanced ones (Jack et al 2013). 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 Aβ abnormalities (measured by CSF Aβ42 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-ε4 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. 2.2) Justification for dose The dose range to be investigated in this study (30-120 mg / day) has been selected based on PK, pharmacodynamics, and safety data from administration of single and multiple doses of RO7269162 in the SAD and MAD study in healthy volunteers, as well as preclinical data (Investigator’s Brochure RO7269162). In the entry into human (EIH) study (BP42242), RO7269162 was safe and well tolerated as a single dose up to 480 mg (SAD), and multiple doses up to 230 mg / day for up to 14 days both in young and elderly healthy participants (MAD). The pharmacological activity of RO7269162 (gamma secretase modulation) was evaluated in the EIH SAD and MAD study (BP42242) by measuring the ability to decrease the relative production of Aβ42 (decrease from pre-dose baseline) in plasma and CSF. A clear dose- dependency was seen and the observed exposure effect relationship was characterized by population PK / PD to determine drug potency (IC50) and maximum modulatory capacity (Imax). The simulated (steady-state) maximum and minimum Aβ42modulation for each of the selected doses is shown in Table 3. In the population median patient, once daily dosing at the lowest dose of 30 mg is expected to achieve ~30% reduction from baseline in Aβ42 levels at pre-dose (trough), and a maximum reduction of 40% over the dosing interval . The highest dose of 120 mg is anticipated to achieve ~55% reduction from baseline in Aβ42levels at pre dose, and a maximum of about 70%, a value in proximity of the apparent maximum inhibition potential (Imax) of the molecule. The simulated (population PK [pop PK] model) population median steady-state drug exposure for each of the selected dose levels (30 mg, 60 mg and 120 mg once daily) is shown in Table 3. The highest mean observed single (SAD) and multiple dose (MAD) exposures in the phase 1 study (see example 1) in healthy volunteers (after single dose of 480 mg: mean Cmax= 3’920 ng / mL and AUC0-24h= 41’300 ng*hr / mL; after multiple dose of 230 mg: mean Cmax= 2’660 ng / mL and AUC0-24h = 32’400 ng*hr / mL) provide a respective exposure multiple relative to the simulated human steady-state exposure for the highest selected dose of 120 mg in this Phase IIa study of 2.6 and 1.8-fold for Cmaxand 2.1 and 1.6-fold for AUC (based on total drug concentration). No adverse toxicities were seen in the chronic toxicity studies in mice (26 weeks) and monkeys (39-week) up to the highest doses selected with daily oral dosing, 200 mg / kg and 20 mg / kg respectively. Two key toxicities were observed in animal studies at higher doses than those administered in chronic toxicity studies: 1) subacute central nervous system (CNS) toxicity at high doses in mice (250 mg / kg) and monkeys (100 mg / kg) and 2) Infiltration and inflammation in the small intestine only in monkeys (40 mg / kg). Because free (unbound) but not total (bound and unbound) drug in plasma can enter the CNS, this toxicity is most likely driven by the free drug concentration in plasma. In agreement to this, 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. 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). Thus, at the highest dose (120 mg), human steady-state total drug exposure (AUC0-24,ss) will, on average, not exceed the mean exposure seen in monkey at the No-Observed-Adverse Effect Level (NOAEL) dose of the chronic toxicity study (20 mg / kg / day), and peak drug levels (Cmax,ss) would remain, on average, about 1.6-fold lower than seen in monkey (Table 2). In the cynomolgus monkey, the No-Observed-Effect Level (NOEL) for CNS toxicity was established at 40 mg / kg / day. 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 AUC0-24h(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. Table 3: Simulated Human Exposure (elderly), PD Effect and Estimated animal-to-human exposure multiples for acute and chronic toxicity Human Simulated Simulated Human Animal-to-human Animal-to- Dose Aβ42 Systemic Exposure exposure multiple human (mg) reduction1(total drug based) (free drug based) to exposure after Multiple Doses1the NOEL for multiple (total subacute CNS drug based) toxicity2for chronic toxicity studies3Min Max Cmax AUC0-24h Cmax AUC0-24h Cmax AUC0- (ng / mL) (ng•hr / mL) (ng / mL) (ng•hr / (ng / 24h mL) mL) (ng•hr / mL) 30 mg 27% 41% 370 5’000 42.1 20.3 6.5 3.7 (220- (2’900- 570) 8’400) 60 mg 41% 54% 740 10’000 21.1 10.1 3.3 1.9 (440- (5’820- 1140) 16’700) 120 mg 55% 66% 1480 20’100 10.5 5.0 1.6 0.9 (880- (11’600- 2280) 33’455) 1. Simulated median human minimum (at trough) and maximum Aβ42 reduction and systemic exposure (median (90% prediction interval)) at steady-state based on a preliminary population PK / PD model developed on Study BP42242. 2. Mean animal-to-human exposure multiple (free drug based) was calculated from male and female cynomolgus monkey TK data (13 week, 40 mg / kg / day). In male monkey, mean total drug exposure at the CNS No-Observed-Effect Level (NOEL) was Cmax: 5460 ng / mL and AUC0-24h: 37’800 ng•hr / mL. In female monkey, mean total drug exposure at the NOEL was Cmax: 6510 ng / mL and AUC0-24h: 40’000 ng•hr / mL. Unbound (free drug) exposure was estimated as the observed total drug value multiplied with the mean fraction unbound (cynomolgus monkey: 6.0%; human 2.3%) 3. Mean animal-to-human exposure multiple calculated from male and female cynomolgus monkey TK data (39 week, 20 mg / kg / day). In male monkey, mean total drug exposure at the NOAEL was Cmax: 1650 ng / mL and AUC0-24h: 15’200 ng*hr / mL. In female monkey, mean total drug exposure at the NOAEL was Cmax: 3210 ng / mL and AUC0-24h: 21’800 ng*hr / mL. 2.3) Study population The participants in this study will be male and female participants between 60 and 85 years of age (inclusive) who are amyloid positive based on an amyloid burden of ≥ 24 CL units, and either cognitively unimpaired, or with a diagnosis of MCI due to AD according to the 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). 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. Agreement not to participate in other research studies for the duration of this study. 4. Agree to APOE-ε4 genotyping. 5. Availability of a person (referred as a “study partner” throughout the protocol) who: (a) has frequent and sufficient contact (e.g., minimum twice a week in-person, via telephone, video calls, by e-mail or other electronic means) with the participant, and is willing and able to provide accurate information regarding the participant’s cognitive and functional abilities, signs the necessary ICF(s), and has sufficient cognitive capacity to accurately report on the participant’s cognitive and functional abilities; (b) is in sufficient good general health to have a high likelihood of maintaining the same level of interaction with the participant and participation in study procedures throughout the duration of the study; and (c) is fluent in the language of the tests used at the study site. 6. Age 60 to 85 years (inclusive) at screening, at the time of the written informed consent. 7. Body Mass Index (BMI) between 18 to 35 kg / m2inclusive, at screening. 8. Participants must be either cognitively unimpaired or with a diagnosis of MCI due to AD, according to the 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). 9. Clinical Dementia Rating-Global Score (CDR-GS) of 0 or 0.5. 10. Positive amyloid PET scan based on a cut-off of ≥24 CL units. Note: 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) and 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 β-hCG at screening, a negative β-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. The Investigator should evaluate with the participant the best contraceptive method based on anatomy and physiology, - Examples of highly effective contraceptive methods with a failure rate of < 1% per year are included in Appendix 5. All contraceptive methods must be supplemented by a barrier method: Condom or occlusive cap (diaphragm or cervical / vault caps) with spermicidal foam / gel / film / cream / suppository. Note: Oral and implantable hormonal contraceptives methods that inhibit ovulation are not acceptable as an effective contraceptive method in female participants of this study as RO7269162 may possibly decrease their effectiveness (by decreasing their exposure). - Male participants (whether surgically sterilized or not) agree to remain abstinent (refrain from heterosexual intercourse) or use a barrier method, (i.e., condom) during the study and for 7 days after the last dose with a partner who is of childbearing potential or a pregnant partner to avoid exposing the embryo. The investigator should evaluate with the participant the best contraceptive method based on anatomy and physiology. - Must refrain from donating sperm for the duration of the study and for at least seven days after the last dose. Exclusion criteria Participants are excluded from the study if any of the following criteria apply: 1. 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. History or presence of clinically evident systemic or localized (“strategic”) vascular disease (e.g., clinically significant carotid / vertebral artery stenosis or plaque, aortic aneurysm), that in the opinion of the Investigator has the potential to affect cognitive function. Note: Participants with asymptomatic developmental venous anomalies may be eligible. The Medical Monitor is available to the Investigator to advise and answer any questions. 3. History or presence of any stroke with clinical symptoms within the past 12 months, or documented history within the last six months of an acute event that is consistent, in the opinion of the Investigator, with a transient ischemic attack. 4. History of severe, clinically significant (persistent neurologic deficit or structural brain damage) CNS trauma (e.g., cerebral contusion). 5. 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). 6. History or presence of systemic autoimmune disorders that potentially cause progressive neurologic disease with associated cognitive deficits (e.g., multiple sclerosis, lupus erythematosus, anti-phospholipid antibody syndrome, and Behçet disease). 7. Evidence of folic acid deficiency (as indicated by folic acid level below the lower limit of normal) or vitamin B-12 deficiency (as indicated by vitamin B-12 level below the lower limit of normal and / or methylmalonic acid levels above upper limit of normal [ULN]). Note: A participant may be rescreened if, in the opinion of the Investigator, cognition is not improved after 12 weeks of adequate treatment for folic acid or vitamin B-12 deficiency. 8. History of major psychiatric conditions, including but not limited to schizophrenia, schizoaffective disorder, or bipolar disorder. Note: History of major depression is acceptable, if participant has had no episode within the past year, or is considered in remission, or depression is controlled by treatment. 9. Alcohol and / or Substance Use Disorder (according to the criteria specified in the Diagnostic and Statistical Manual of Mental Disorders, Version 5 [DSM-5]; American Psychiatric Association 2013) within the past two years. 10. Participants who, in the investigator’s judgment, pose a suicidal or homicidal risk (e.g., history of suicidal or homicidal attempts or having a Yes to question number 4 or 5 of the Suicidal Ideation section of the Columbia-Suicide Severity Rating Scale [C-SSRS]). 11. History or presence of significant cardiovascular conditions, including but not limited to (A) clinically symptomatic atrial fibrillation requiring maintenance therapy. Note: Participants who experienced non-valvular atrial fibrillation that resolved more than 1 year ago and was not associated with prior stroke are eligible. (B) Unstable or clinically significant cardiovascular disease within the last year (e.g. myocardial infarction). Note: Heart failure classified as New York Heart Association (NYHA) Class I or II cardiac disease is not an exclusion criterion unless associated with hospitalization within the previous 12 months. (C) Uncontrolled hypertension (e.g., blood pressure generally > 160 mmHg systolic or > 95 mmHg diastolic). 12. History of any clinically significant hematological diseases 13. Confirmed and unexplained impaired hepatic function as indicated by screening AST or ALT ≥ 2x the upper limit of normal (ULN) or total bilirubin ≥ 1.5x ULN or alkaline phosphatase (ALP) ≥1.5xULN at screening. Note: Participants with total bilirubin ≥1.5 x ULN are not excluded if they meet all of the following criteria for Gilbert syndrome: ∙ Bilirubin is predominantly indirect (unconjugated) at screening (direct bilirubin within normal limits) ∙ Absence of liver disease ∙ ALT, AST, and ALP ≤1x ULN at screening ∙ Hemoglobin not significantly decreased at screening. 14. 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. 15. History or presence of HIV infection, hepatitis B or hepatitis C infection that has not been adequately treated in the opinion of the Investigator. 16. Participants with active or uncontrolled infections (including but not limited to gastrointestinal infections, SARS-CoV-2, influenza, respiratory syncytial virus) should not be enrolled until complete resolution of signs and symptoms. 17. 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 other severe or unstable medical condition that, in the opinion of the Investigator could be expected to progress, recur, or change to such an extent that it could put the participant at special risk, bias the assessment of the clinical or mental status of the participant to a significant degree, interfere with the participant’s ability to complete the study assessments, or would require the equivalent of institutional or hospital care. The Medical Monitor is available to the Investigator to advise and answer any questions. 22. Any surgery or hospitalization during the 4 weeks prior to screening or pre-planned / scheduled during the study period that, in the opinion of the investigator, may compromise eligibility to the study. The Medical Monitor is available to the Investigator to advise and answer any questions. 23. Use of any prohibited medications before study start or during the study 24. Any previous administration of RO7269162. 25. 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. Note: participant may be eligible for this study if it can be documented that he / she was randomized to placebo. 28. According to the central MRI reader, MRI evidence of any of the following: - Any white matter lesion that corresponds to an overall Fazekas score of 3 that requires at least one confluent hyperintense lesion on the fluid attenuated inversion recovery (FLAIR) sequence, which is ≥ 20 mm in any dimension. 29. Inability to tolerate MRI procedures or contraindication to MRI, including, but not limited to, presence of pacemakers not compatible with MRI, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body that would contraindicate an MRI scan, or any other clinical history or examination finding that, in the judgment of the Investigator, would pose a potential hazard in combination with MRI. 30. 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. Note: 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. Contraindication to have a PET scan (e.g., inability to lie flat or still for the duration of the scan) or intolerance to previous PET scans (i.e., previous hypersensitivity reactions to any PET ligand or imaging agent, failure to participate in and comply with previous PET scans). 32. Prior participation in other research study or clinical care within the last year such that the total radiation exposure would exceed the local or national annual limits. 2.4) Study treatments administered The treatments administered are summarized in Table 4. In countries where the PET radioligand is approved for marketing, the approved local product information will be provided as reference safety information, and in countries where they are not approved for marketing, the Investigator’s Brochure will be provided. 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 4: Summary of Treatments Administered Study RO7269162 RO7269162 Florbetaben Flutemetamol treatment Placebo (Neuraceq®)* (Vizamyl®)** name Use Experimental Placebo Radiopharmaceuti Radiopharmac comparator cal ligand for eutical ligand amyloid PET for amyloid imaging PET imaging Dose capsule capsule solution solution formulation Unit dose 30 / 60 / 120 mg Not applicable Single dose of 300 Approximately strength(s) ± 10% MBq (8.1 20 mL of mCi effective sterile solution radiation dose 5.8 for mSv), the approximately maximum of 30- 185 MBq mg mass dose, administered as single slow IV bolus within 40 seconds in a total volume of up to 10 mL prior to amyloid PET scans Dose and 30mg QD NA / QD Single dose of 300 Single dose of regimen 60mg QD ± 10% MBq 185 ± 10% 120mg QD MBq Route of Oral Oral Slow IV bolus Slow IV bolus administration injection injection QD = once a day 2.5) Objectives and endpoints The objectives and corresponding endpoints are provided in Table 5. Table 5: Objectives and endpoints Objectives Endpoints Primary Objectives ∙ To investigate the safety and tolerability ∙ Nature, incidence, severity, and of daily oral dosing of RO7269162 outcome of adverse events (AEs) ∙ Changes from baseline in vital signs, electrocardiogram (ECG) parameters, Columbia – Suicide Severity Rating Scale (C-SSRS) and safety laboratory findings ∙ To assess the effect of daily oral dosing ∙ Change from baseline in brain of RO7269162 on brain amyloid amyloid load, as measured by accumulation amyloid positron emission tomography (PET) scan Secondary Objectives ∙ To assess the effect of daily oral ∙ Change from baseline in Aβ37, Aβ38, dosing of RO7269162 on Aβ40 and Aβ42 in CSF and Aβ40 and pharmacodynamic (PD) biomarkers Aβ42 in plasma related to amyloid beta (Aβ) metabolism in cerebrospinal fluid (CSF) and plasma ∙ To investigate the pharmacokinetics ∙ Plasma concentrations of RO7269162 (PK) of daily oral dosing of (and its metabolite[s] as appropriate) RO7269162 (and its metabolite[s] as appropriate) in plasma and CSF ∙ CSF concentrations of RO7269162 (and its metabolite[s] as appropriate) ∙ To investigate the PK of daily oral ∙ Plasma concentrations of RO7269162 dosing of RO7269162 (and its (and its metabolite[s] as appropriate) metabolite[s] as appropriate) in plasma ∙ CSF concentrations of RO7269162 and CSF (and its metabolite[s] as appropriate) Exploratory Objectives ∙ To explore PK / safety relationships of ∙ Relationship between plasma exposure RO7269162 of RO7269162 and safety outcomes ∙ To explore PK / PD relationship of ∙ Relationship between plasma RO7269162 exposure of RO7269162 and key disease-related biomarkers,(mainly target engagement biomarkers) measured in CSF and / or plasma ∙ To explore the effect of daily oral ∙ Change from baseline in phospho-tau dosing of RO7269162 on additional species (e.g., p-tau217, p-tau181), BMs of disease-related fluid BMs neurodegeneration, neuroinflammation and BMs of synaptic dysfunction in CSF as well as other BMs related to Aβ metabolism in plasma and / or CSF ∙ To evaluate the effect of daily oral ∙ Change from baseline in MRI measures dosing of RO7269162 on MRI (volumetric-MRI and Diffusion Tensor neuroimaging biomarkers Imaging (DTI)-MRI) ∙ To evaluate the effect of daily oral ∙ Change from baseline in cerebral dosing of RO7269162 on cerebral perfusion as measured by the early frames perfusion of dynamically acquired amyloid PET images (in a subset of sites and participants, where available) ∙ To explore the effect of daily oral ∙ Change from baseline in the CDR dosing of RO7269162 on cognition Sum of Boxes (CDR-SB) score and function ∙ Changes from baseline in the Cogstate Cognitive Test Battery The primary biomarker study objective above described can be formulated using estimand language as summarized in Table 6. 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 from baseline of brain amyloid load, as measured by amyloid PET scan. Clinical Dementia Rating Scale (CDR) 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). The CDR characterizes the participant’s level of cognitive and functional impairment across six domains (i.e., memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care) on a 5-point rating scale in which 0 = “None”, 0.5 = “questionable”, 1 = “mild”, 2 = “moderate”, 3 = “severe” (with the exception of personal care, which is rated on a 4-point rating scale and excludes the questionable impairment level). Two scores can be generated: the CDR Global Score (CDR-GS) and the CDR Sum of Boxes (CDR-SB). The CDR-GS is calculated based on the Washington University CDR- assignment algorithm and characterizes a participant’s level of global impairment / stage of dementia according to the following categories: 0 (normal), 0.5 (very mild dementia), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia). The CDR-SB is calculated by summing the ratings across each of the six domains (total score: 0-18), with higher scores indicating greater impairment. 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. 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. 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 6. The compound for use according to aspect 1, 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 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. The compound for use according to any one of aspects 1 to 7, 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. Aspect 9. The compound for use according to any one of aspects 1 to 8, wherein the compound is administered at a dose ranging from 30 to 230 mg. Aspect 10. 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 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 15, wherein the subject is a human, wherein the compound is being administered orally at a dose between 30 and 120 mg. Aspect 16. 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 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 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 any one of aspects 16 to 22, 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. Aspect 24. The method according to any one of aspects 16 to 23, wherein the compound is administered at a dose ranging from 30 to 230 mg. Aspect 25. 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 29, wherein the subject is a human, wherein the compound is being administered orally at a dose between 30 and 120 mg. Aspect 31. 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. 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, 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 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. The use according to any one of aspects 31 to 37, 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. Aspect 39. The use according to any one of aspects 31 to 38, wherein the compound is administered at a dose ranging from 30 to 230 mg. Aspect 40. 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 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 44, wherein the subject is a human, wherein the compound is being administered orally at a dose between 30 and 120 mg. 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 Aβ40 and Aβ42 levels in CSF and / or Aβ40 and Aβ42 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 Aβ40 and Aβ42 levels in CSF and / or Aβ40 and Aβ42 levels in plasma. Aspect 48. The compound for use, method or use according to any one of aspects 1 to 47, 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 Aβ40 and Aβ42 levels in CSF and / or Aβ40 and Aβ42 levels in .plasma; and wherein the decrease of Aβ40 and Aβ42 levels is at least 20% compared to baseline. Aspect 49. The compound for use, method or use according to any one of aspects 1 to 48, 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 Aβ40 and Aβ42 levels in CSF and / or Aβ40 and Aβ42 levels in .plasma; and wherein the decrease of Aβ40 and Aβ42 levels is at least 30% compared to baseline. Aspect 50. The compound for use, method or use according to any one of aspects 1 to 49, 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 Aβ40 and Aβ42 levels in CSF and / or Aβ40 and Aβ42 levels in .plasma; and wherein the decrease of Aβ40 and Aβ42 levels is at least 40% compared to baseline. Aspect 51. The compound for use, method or use according to any one of aspects 1 to 50, 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 an increase of Aβ37 and Aβ38 levels in CSF and / or Aβ37 and Aβ38 levels in plasma. Aspect 52. The compound for use, method or use according to any one of aspects 1 to 50, 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 increase of Aβ37 and Aβ38 levels in CSF and / or Aβ37 and Aβ38 levels in plasma. Aspect 53. The compound for use, method or use according to any one of aspects 1 to 52, 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 an increase of Aβ37 levels in CSF and / or Aβ37 and plasma; and wherein the increase of Aβ37 levels is at least 100% compared to baseline. Aspect 54. The compound for use, method or use according to any one of aspects 1 to 53, 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 reduction from baseline in brain amyloid load, as measured by amyloid positron emission tomography (PET) scan. Aspect 55. 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. Aspect 56. The compound for use, method or use according to any one of aspects 1 to 55, 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, reduces the brain amyloid load from ≥ 24 centiloids (CL) units measured by an amyloid positron emission tomography (PET) scan at baseline to < 24 centiloids (CL) units measured by an amyloid positron emission tomography (PET). 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 59, wherein 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. Aspect 61. 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 62, wherein the CDR-GS score at baseline was 0. 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 0.5. 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. 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 67, wherein the brain amyloid load at baseline was ≥ 40 centiloids (CL) units measured by an amyloid positron emission tomography (PET) scan. Aspect 70. The compound for use, method or use according to any one of aspects 1 to 67, wherein the brain amyloid load at baseline was ≥ 50 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 72. The compound for use, method or use according to any one of aspects 1 to 67, wherein the brain amyloid load at baseline was ≥ 70 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.

Claims

Claims 1. 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.

2. The compound for use according to claim 1, wherein the disease is Alzheimer’s disease.

3. The compound for use according to claim 1 or 2, wherein the compound is for use in the treatment of sporadic Alzheimer’s disease or genetically caused Alzheimer’s disease.

4. The compound for use according to claim 1 or 2, wherein the compound is for use in the treatment of symptomatic Alzheimer’s disease or pre-clinical Alzheimer’s disease.

5. The compound for use according to claim 1, wherein the disease is dementia caused by amyloidosis occurring in the context of Down’s Syndrome (trisomy 21).

6. The compound for use according to claim 1, 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.

7. The compound for use according to any one of claims 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.

8. The compound for use according to any one of claims 1 to 7, 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.

9. The compound for use according to any one of claims 1 to 8, wherein the compound is administered at a dose ranging from 30 to 230 mg.

10. The compound for use according to any one of claims 1 to 9, wherein the compound is administered at a dose ranging from 30 to 120 mg.

11. The compound for use according to any one of claims 1 to 10, wherein the compound is administered at a dose selected from 30, 60 and 120 mg.

12. The compound for use according to any one of claims 1 to 11, wherein the subject is a human.

13. The compound for use according to any one of claims 1 to 12, wherein the subject is an elderly person.

14. The compound for use according to any one of claims 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.

15. The compound for use according to any one of claims 1 to 14, wherein the subject is a human, wherein the compound is being administered orally at a dose between 30 and 120 mg.

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