Use of TYK2 / JAK1 inhibitors to treat amyloid-related imaging abnormalities (ARIA)

Abstract

Provided for are compositions and methods for treating amyloid related imaging abnormalities (ARIA) with selective Janus kinase (JAK) inhibitors in Alzheimer's disease (AD) patients or patients with other with neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) undergoing anti-amyloid therapy, including anti- amyloid antibody therapies. Particularly useful are JAK inhibitors selective against JAK1 and tyrosine kinase 2 (TYK2).

Description

[0001] USE OF TYK2 / JAK1 INHIBITORS TO TREAT AMYLOID-RELATED IMAGING ABNORMALITIES (ARIA)

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This International Patent Application claims priority to United States Provisional Patent Application No. 63 / 652,309, filed May 28, 2024, United States Provisional Patent Application No. 63 / 709,501, filed October 20, 2024, United States Provisional Patent Application No. 63 / 723,263, filed November 21, 2024, and United States Provisional Patent Application No. 63 / 802,524, filed May 8, 2025, the contents of which applications are incorporated by reference herein in their entireties.

[0004] TECHNICAL FIELD

[0005] Provided for are compositions and methods for treating amyloid related imaging abnormalities (ARIA) with selective Janus kinase (JAK) inhibitors. Such compositions and methods are useful for treating ARIA in Alzheimer’s disease (AD) patients or patients with other with neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri), receiving anti-amyloid therapy including monoclonal antibody therapy. Particularly useful are JAK inhibitors selective against JAK1 and TYK2 (tyrosine kinase 2) kinases.

[0006] BACKGROUND

[0007] Alzheimer’s disease is a neurodegenerative disorder characterized by severe and progressive memory loss, leading to cognitive and behavioral changes. Currently, AD is the most common form of dementia, affecting over 6.9 million Americans aged 65 years or older. By 2060, this number is expected to triple. However, effective treatments are very limited with only few FDA approved therapies available in the US. Even for these approved therapies, there have been controversies surrounding their efficacy and safety measures in clinical trials. Both genetic and pathological studies have uncovered the pathophysiological role of neurotic plaques containing misfolded amyloid-P (amyloid-Beta or AP) peptides in AD. The dysregulation between Ap production and clearance leads to a wide distribution of amyloid plaques throughout the cerebral cortex. Neurons are especially vulnerable to the toxicity of amyloid plaques, which impairs synaptic function and neuronal viability. Notably, the emergence of amyloid plaques precedes major clinical symptoms and other pathological hallmarks, including neuroinflammation, neuronal loss, and the formation of tau-containing neurofibrillary tangles. The potential to target the emergence of these amyloid plaques presents a promising target for therapeutic interventions in AD and other neurodegenerative diseases or CAAri.

[0008] Various therapeutic approaches have been developed to target amyloid plaques, such as inhibitors of amyloid aggregation, inhibitors of proteases (e.g., P- and y- secretases responsible for Ap production), and immunotherapy aimed at reducing amyloid burden in the brain by targeting amyloid betai-42 (AP1-42) peptides. Among these, immunotherapy has undergone clinical testing based on evidence of reducing the neurotoxic effects of Ap. While the initiation of clinical trials employing various anti-Ap monoclonal antibodies, including aducanumab, donanemab, and lecanemab, instilled hope among affected individuals, early magnetic resonance imaging (MRI) brain examinations have revealed an elevated risk of edema and microhemorrhages associated with the administration of these antibodies. The observance of these plaque-based abnormalities by MRI has led to collectively referring to these abnormalities as amyloid-related imaging abnormalities (ARIA).

[0009] The exact molecular mechanisms underlying ARIA remain largely elusive, although emerging evidence suggests that ARIA arises from undesirable immune responses to increased vascular Ap deposition. Antibody-mediated breakdown of Ap leads to the mobilization of amyloid species within the parenchyma and vasculature, resulting in amyloid deposition within the arterial walls in the central nervous system (CNS). Subsequently, these vascular amyloid deposits recruit antibodies to the vessel walls, triggering an inflammatory response compromising vascular integrity and the blood-brain barrier. These effects exacerbate the clearance of amyloid plaques within vessel walls, culminating in the leakage of proteinaceous edema / effusion (ARIA-E) and / or iron-containing red blood cells in the form of hemorrhage or superficial siderosis (ARIA-H).

[0010] ARIA events predominantly manifest within the first three months of initiating anti-Ap monoclonal antibody therapy, with ARIA-E being the more prevalent adverse event, often preceding ARIA-H. Patients with ARIA-E typically experience parenchymal edema in the left parieto-occipital lobe and / or sulcal effusion in the right temporo-occipital lobe, with severity contingent upon the location and size of the MRI signal abnormality. ARIA-H refers to cerebral microhemorrhages, accompanied by superficial siderosis due to microvascular ruptures in cortical regions and subsequent leakage of red blood cells into the brain parenchyma. While most ARIA events are asymptomatic and resolve within 3-4 months upon dose-reduction or suspension of anti-Ap therapy, rare but severe neurological symptoms and life-threatening events have been reported. Several risk factors for ARIA have been identified, including the presence of microhemorrhage on baseline MRI, dose level of anti-Ap therapy, and AP0E-s4 (apolipoprotein E gene, s4 allele) carrier status, deterring those requiring medical attention from accessing necessary treatment. Given the unknown long-term clinical consequences of ARIA, the heightened risk linked to various monoclonal antibodies poses a significant obstacle in the advancement of effective AD therapeutics.

[0011] ARIA are immune-related events which generally occur shortly after initiation of effective anti-amyloid beta (AP) monoclonal antibody therapy for the treatment of Alzheimer’ s disease and may represent iatrogenic cerebral amyloid angiopathy with related inflammation (CAAri) (Piazza F, Caminiti SP, Zedde M, et al., Neurology 2022;99(12):el265-el277; Sperling RA, lack CR, Ir., Black SE, et al., Alzheimers Dement 2011;7(4):367-85; Cummings I, Apostolova L, Rabinovici GD, et al., I Prev Alzheimers Dis 2023;10(3):362-377; van Dyck CH, Swanson CI, Aisen P, et al., N Engl I Med 2023;388(l):9-21). While ARIA are a part of the natural history for individuals living with AD and / or CAA, there is an increased risk for ARIA associated with the administration of anti-amyloid antibody therapy (Sperling RA, lack CR, Ir., Black SE, et al., Alzheimers Dement 2011;7(4):367-85; Black RS, Sperling RA, Safirstein B, et al. Alzheimer Dis Assoc Disord 2010;24(2): 198-203). Recent research suggests ARIA may be the result of a mixed inflammatory response to the removal of vascular Ap or amyloid trafficking at the blood brain barrier (ALZFORUM Networking for a Cure. Alzheimer's Association International Conference (AAIC) - 2023. Part 6 of 14; Ketter N, Brashear HR, Bogert I, et al., I Alzheimers Dis 2017;57(2):557-573).

[0012] Individuals diagnosed with CAAri have a higher likelihood of developing AD. Recent studies have suggested that the complement cascade system may play a central role in ARIA pathogenesis. Upon detection of vascular amyloid deposition, anti-Ap monoclonal antibodies activate complement proteins, leading to glial and T-cell infiltration within the cerebral blood vessels. Although there are no approved medications for the prevention and / or treatment of ARIA, the use of immunosuppressants, such as glucocorticoids and their beneficial effects of alleviating acute clinical symptoms further support the neuroinflammation model underlying ARIA. These findings suggest the potential clinical application of selective lanus kinase ( AK) inhibitors to reduce the risk of ARIA by modulating the toxic immune response induced by the administration of anti-Ap monoclonal antibodies.

[0013] The IAK family of kinases (i.e., TYK2, IAK1, IAK2, and IAK3) are non-receptor tyrosine kinases that transduce cytokine-mediated signals via the anus kinases / signal transducer and activator of transcription (IAK-STAT) signaling pathway, which is implicated in the pathogenesis of various inflammatory and autoimmune diseases. The JAK-STAT signaling pathway is a molecular hub that regulates gene expression of various critical mediators of cellular inflammation. Recently, dysregulation of JAK-STAT signaling has been identified as a key driver of neuroinflammation that underlies the pathophysiology of neurodegenerative disorders. For instance, results of gene expression analysis on blood samples collected from individuals living with mild cognitive impairment (MCI) and AD demonstrated dysregulated signaling in 15 of 47 JAK-STAT genes relative to controls (p<0.05), with TYK2 identified as the most upregulated of the JAK-STAT genes (Nevado- Holgado AJ, Ribe E, Thei L, et al., Cells 2019;8(5)). Therefore, this signaling pathway represents a promising therapeutic target for diseases and / or conditions in which the innate and adaptive immune responses are compromised.

[0014] JAK inhibitors are a class of inhibitory compounds known to block JAK-STAT signaling in the periphery as well as the CNS via inhibition of any four members of mammalian JAK kinases. The promising effects of JAK-STAT inhibition have been demonstrated in in vivo models of neurodegenerative disease. For example, baricitinib, a dual JAK1 / 2 inhibitor, has been shown to reverse cognitive / behavioral abnormalities in a mouse model for HIV- associated neurocognitive disorder. To date, several JAK inhibitors have been approved by the FDA for the treatment of autoimmune disease including rheumatoid arthritis, inflammatory bowel disease, alopecia areata, and others. Similar to these aforementioned disorders, ARIA are a clinical consequence of a mixed inflammatory response from administration of anti-Ap monoclonal antibodies. It is found in the present invention that the use of JAK inhibitors in combination with AD immunotherapy may reduce and / or prevent its adverse effects by restoring unregulated complement activation and glial / T-cell infiltration caused by the removal of vascular Ap or amyloid trafficking at the blood brain barrier.

[0015] The compound, 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2-yl] acetonitrile, a brain-penetrant, inhibitor of JAK-STAT signaling, is described herein among related compounds as a therapeutic agent for pathophysiologic conditions that are driven by a broadbased inflammatory response within the CNS and in the periphery, such as ARIA. In vitro and ex vivo studies have shown that this compound is highly selective against IAK1 and TYK2, two key kinases in the IAK-STAT signaling pathway crucial for activating both the innate and adaptive immune systems. Signaling through IAK1 and TYK2 have been implicated in the activation of peripheral B and T cells, as well as glial cells within the CNS. See U.S. Patent No. 10,738,060 B2, to Congxin Liang, issued on August 11, 2020, and US Patent Application Publication No. 2022 / 0242873 Al, to Liang et al., published on August 4, 2022

[0016] For instance, 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2-yl] acetonitrile shows efficacy in preventing lipopolysaccharide (LPS)- induced inflammatory responses by inhibiting the production of IL-6, TNF, and MCP-1 in LPS- stimulated BV2 cells. IL-6: interleukin 6; LPS = lipopolysaccharide; MCP-1 = monocyte chemoattractant protein-1; TNF = tumor necrosis factor. Additionally, this compound successfully rescued ReN VM-derived human neurons from dsRNA-induced toxic innate immune responses in a dose-dependent manner. Previous in vivo pharmacological studies of this compound have confirmed its anti-inflammatory effects in various animal models, including the AIA Lewis rat model, the CIA DBA / 1 mouse model, and the MOG-EAE model. Combined, these findings offer great promise for the use of this compound as a preventive method of treatment for ARIA or for reducing the risk of developing ARIA, in individuals diagnosed with early AD, who are initiating anti-Ap monoclonal antibody therapy.

[0017] The present invention provides compositions and methods for reducing amyloid related imaging abnormalities (ARIA), with selective IAK inhibitors in Alzheimer’s disease (AD) patients receiving anti-amyloid monoclonal antibody therapy. More specifically, the present invention disclosure provides technical advantages, for example, methods to treat, ameliorate, and / or prevent ARIA with 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile and related compounds. Additionally, the methods and compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanisms of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

[0018] SUMMARY The present invention provides compositions and methods for treating amyloid related imaging abnormalities (ARIA) with selective Janus kinase (JAK) inhibitors.

[0019] In an embodiment, these compositions and methods are useful for treating ARIA in Alzheimer’s disease (AD) patients or patients with other with neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri), that are receiving anti-amyloid monoclonal antibody therapy.

[0020] In an embodiment, particularly useful are JAK inhibitors selective against JAK1 and TYK2 kinases.

[0021] In an embodiment is provided is provided a method for treating amyloid-related imaging abnormalities (ARIA) in a patient with a neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) receiving anti-amyloid therapy comprising administering a therapeutically effective amount of a Janus kinase (JAK) inhibitor to the patient.

[0022] In an embodiment is provided a method wherein the patient is a human patient.

[0023] In an embodiment is provided a method wherein the patient has an APOE-s4 mutation.

[0024] In an embodiment is provided a method wherein the patient has been diagnosed with Alzheimer’s disease (AD).

[0025] In an embodiment is provided a method wherein the anti-amyloid therapy is an antiamyloid antibody therapy, involving treating amyloid deposits with an anti-amyloid antibody or antigen-binding fragments thereof.

[0026] In some embodiments, the anti-amyloid antibody therapy is an anti-amyloid monoclonal antibody therapy.

[0027] In an embodiment is provided a method wherein the JAK inhibitor is selected from a JAK1 inhibitor, a tyrosine kinase 2 (TYK2) inhibitor, and combinations thereof.

[0028] In an embodiment is provided a method wherein the JAK inhibitor is a JAK1 inhibitor.

[0029] In an embodiment is provided a method wherein the JAK inhibitor is a TYK2 inhibitor.

[0030] In an embodiment is provided a method wherein the JAK inhibitor corresponds to the formula or a pharmaceutically acceptable salt, ester, prodrug, solvate, enantiomer, racemate, stereoisomer, or tautomer thereof, wherein:

[0031] R1is H, halogen, or C1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0032] R2is H, halogen, or C1-3 alkyl;

[0033] Cy is C3 -7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R3, oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR', wherein R3is Cl -3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; and

[0034] R and R' are each independently H, or C1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, and CN.

[0035] In an embodiment is provided a method wherein:

[0036] Cy is C5-7 cycloalkyl, or 5-7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R3, oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR', wherein R3is C1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2RR'.

[0037] In an embodiment is provided a method wherein: R2is hydrogen.

[0038] In some embodiments, Cy is pyran substituted with CN.

[0039] In some embodiments, R1is methyl.

[0040] In an embodiment is provided a method wherein the compound is selected from the group consisting of: trans-4-[2-[(R)-l-Hydroxyethyl]-lH-furo[3,2-b]imidazo[4,5-d]pyridin-l-yl] cyclohexanecarbonitrile, trans-4-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-l-yl] cyclohexanecarbonitrile, 2-[trans-4-[2-[(R)-l-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-l-yl]cyclohexyl] acetonitrile,

[0041] 2-[(2R,5S)-5-[2-[(R)-l-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-l-yl] tetrahydropyran-2-yl]acetonitrile,

[0042] 3-[2-[(R)-l-Hydroxyethyl]-lH-furo[3,2-b]imidazo[4,5-d]pyridin-l-yl]-N-(2,2,2- trifluoroethyl)pyrrolidine- 1 -carboxamide, (R)-4-[2-(l-Hydroxyethyl)-lH-furo[3,2-b]imidazo[4,5-d]pyridin-l-yl]-N-(2,2,2- trifluoroethyl)piperidine-l -carboxamide, 2-[(2R,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-l- y 1 ]tetrahy dropy ran-2-y 1 ] acetonitril e, 2-[(2S,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-l- y 1 ]tetrahy dropy ran-2-yl ] acetonitril e, 2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl] tetrahydropyran-2- yl]acetonitrile, 2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d] pyridin- 1 -yl] tetrahydropyran-2- yl]acetonitrile, and 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-1 -yl] tetrahydropyran-2- yl] acetonitrile. In an embodiment is provided a method wherein the compound is

[0043] 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2- yl] acetonitrile or a pharmaceutically acceptable salt of solvate thereof.

[0044] In an embodiment is provided a method wherein the anti-amyloid monoclonal antibody therapy is an anti-amyloid beta (A|3) Alzheimer Disease (AD) immunotherapy.

[0045] In an embodiment is provided a method wherein the immunotherapy comprises one or more monoclonal antibody therapies selected from aducanumab, donanemab, lecanemab, or antigen binding fragments thereof, and combinations thereof. In an embodiment is provided a method wherein the JAK inhibitor is administered, before, during, or after administration of the anti-amyloid monoclonal antibody therapy.

[0046] In an embodiment is provided a method wherein the ARIA is amyloid-related imaging abnormalities with edema or effusion (ARIA-E).

[0047] In an embodiment is provided a method wherein the ARIA is amyloid-related imaging abnormalities with hemorrhage (ARIA-H).

[0048] In an embodiment is provided a method wherein the JAK inhibitor is administered until a therapeutic benefit is achieved as quantified by a geometric reduction of at least 25% in the ARIA. Note that the reduction can be determined by comparison to a reference or baseline reference point for the ARIA observed. This reduction can be characterized by a geometric reduction of the ARIA which can be measured two dimensionally by a change in the cross section of the ARIA or volumetrically by a change determined from multiple cross-sections or other means of measurement.

[0049] In an embodiment is provided a method wherein the JAK inhibitor is administered until a therapeutic benefit is achieved as quantified by a reduction of at least 10% in the ARIA.

[0050] In an embodiment is provided a method wherein the JAK inhibitor is administered until a therapeutic benefit is achieved as quantified by a reduction of at least 5% in the ARIA.

[0051] In an embodiment is provided a method for treating amyloid-related imaging abnormalities (ARIA) in an Alzheimer’s disease patient receiving anti-amyloid monoclonal antibody therapy comprising administering a therapeutically effective amount of a Janus kinase (JAK) inhibitor to the patient.

[0052] In an embodiment is provided a method for treating amyloid-related imaging abnormalities (ARIA) in an Alzheimer’s disease patient receiving anti-amyloid monoclonal antibody therapy comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or solvate thereof

[0053] 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2- yl] acetonitrile. In an embodiment is provided a method wherein the compound is administered as a unit dose comprising from about 1 mg to about 100 mg of the compound.

[0054] In an embodiment is provided a method wherein the compound is administered as a unit dose comprising from about 10 mg to about 50 mg of the compound.

[0055] In an embodiment is provided a method wherein the compound is administered as a unit dose comprising from about 20 mg of the compound.

[0056] In an embodiment is provided a method wherein the compound is administered as a unit dose comprising from about 30 mg of the compound.

[0057] In an embodiment is provided a method wherein the compound is administered as a unit dose comprising from about 40 mg of the compound.

[0058] In an embodiment is provided a pharmaceutical composition for treating Alzheimer’s disease comprising a therapeutically effective amount of anti-amyloid beta (AP) Alzheimer’s Disease (AD) immunotherapy and a therapeutically effective amount of a Janus kinase (JAK) inhibitor. Note that these compositions can be such that the JAK inhibitor and the immunotherapy, e.g., the antibody therapy, comprises two agents are considered part of the overall therapy, but not necessarily administered concurrently together in a single combined dosage.

[0059] In an embodiment is provided a pharmaceutical composition for treating Alzheimer’s disease comprising a therapeutically effective amount of anti-amyloid beta (AP) Alzheimer’s Disease (AD) immunotherapy and a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or solvate thereof

[0060] 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2- yl] acetonitrile.

[0061] In an embodiment is provided a method for treating Alzheimer’s disease comprising administering to a patient in need thereof a therapeutically effective amount of anti-amyloid beta (AP) Alzheimer’s Disease (AD) immunotherapy and a therapeutically effective amount of a Janus kinase (JAK) inhibitor. In an embodiment is provided a method for treating Alzheimer’s disease comprising administering to a patient in need thereof a therapeutically effective amount of anti-amyloid beta (AP) Alzheimer’s Disease (AD) immunotherapy and a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or solvate thereof

[0062] 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2yl] acetonitrile.

[0063] In an embodiment is provided a method for preventing or reducing the risk of developing amyloid-related imaging abnormalities (ARIA) in a patient with a neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) receiving anti-amyloid therapy comprising administering a therapeutically effective amount of a Janus kinase (JAK) inhibitor to the patient.

[0064] In some embodiments, provided for are methods for treating vascular inflammation associated with (i.e., resultant from, including due to an immune response) intravascular amyloid deposits, comprising administering to a patient in need thereof a therapeutically effective amount of the compound:

[0065] 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2yl] acetonitrile, or a pharmaceutically acceptable salt or solvate thereof.

[0066] In some embodiments, the amyloid deposits are amyloid beta deposits.

[0067] In some embodiments, the amyloid beta deposits are pharmacologically-induced.

[0068] Pharmacologically-induced amyloid beta or other amyloid deposits are induced or caused by a medical treatment given to the patient. The medical treatment may be an anti-amyloid therapy as described herein, or may be any other therapy or medical treatment causing amyloid deposition in the vasculature and associated vascular inflammation.

[0069] In some embodiments, the amyloid beta deposits are induced by anti-amyloid therapy.

[0070] In some embodiments, the anti-amyloid therapy is an antibody therapy.

[0071] In an embodiment is provided the use of a Janus kinase (JAK) inhibitor for treating amyloid-related imaging abnormalities (ARIA) in a patient with a neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) receiving anti-amyloid therapy.

[0072] In an embodiment is provided the use of a Janus kinase (JAK) inhibitor for preventing or reducing the risk of developing amyloid-related imaging abnormalities (ARIA) in a patient with a neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) receiving anti-amyloid therapy.

[0073] In an embodiment is provided the use of a Janus kinase (JAK) inhibitor A in the manufacture of a medicament for treating amyloid-related imaging abnormalities (ARIA) in a patient with a neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) receiving anti-amyloid therapy.

[0074] In an embodiment is provided the use of a Janus kinase (JAK) inhibitor A in the manufacture of a medicament for preventing or reducing the risk of developing amyloid-related imaging abnormalities (ARIA) in a patient with a neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) receiving anti-amyloid therapy.

[0075] BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Aspects and advantages of the present disclosure will become apparent from the following exemplary embodiments taken in conjunction with the accompanying drawings, of which:

[0077] FIG. 1 shows the percent inhibition of cytokine (e.g., IL-6, MCP-1, and TNF) production in LPS-stimulated BV2 cells treated with 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2-yl] acetonitrile compared to DMSO treated control cells. Abbreviations: DMSO: dimethyl sulfoxide; IL-6: interleukin-6; LPS: lipopolysaccharides; MCP-1 : monocyte chemoattractant protein-1; TNF: tumor necrosis factor.

[0078] FIG. 2A-1 shows the percentage of cell survival of ReN VM-derived human neurons (a commercially available immortalized human neural progenitor cell line from ventral mesencephalic-derived human neurons) exposed to a double stranded RNA-induced (dsRNA) toxic innate immune response treated with varying concentrations of Baricitinib (EC50 = 35.6 nM) versus control.

[0079] FIG. 2A-2 shows an immunoblot analysis of phosphorylated STAT1 (signal transducer and activator of transcription 1, a transcription factor which in humans is encoded by the STAT1 gene) and P-actin (loading control) protein expression in control and dsRNA transfected [poly(I:C)] neurons before and after 10 uM Baricitinib treatment. Abbreviations: Ctrl: control; dsRNA: double-stranded ribonucleic acid

[0080] FIG. 2B-1 shows the percentage of cell survival of ReN VM-derived human neurons exposed to a double stranded RNA-induced (dsRNA) toxic innate immune response treated with varying concentrations of Ruxolitinib (EC50 = 47.7 nM) versus control.

[0081] FIG. 2B-2 shows an immunoblot analysis of phosphorylated STAT1 and P-actin (loading control) protein expression in control and dsRNA transfected [poly(EC)] neurons before and after 10 uM Ruxolitinib treatment. Abbreviations: Ctrl: control; dsRNA: doublestranded ribonucleic acid.

[0082] FIG. 2C-1 shows the percentage of cell survival of ReN VM-derived human neurons exposed to a dsRNA-induced (dsRNA) toxic innate immune response treated with varying concentrations of 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile (EC50 = 18.3 nM) versus control.

[0083] FIG. 2C-2 shows an immunoblot analysis of phosphorylated STAT1 and P-actin (loading control) protein expression in control and dsRNA transfected [poly(EC)] neurons before and after 10 uM 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile treatment. Abbreviations: Ctrl: control; dsRNA: doublestranded ribonucleic acid.

[0084] FIG. 3 A depicts reduction in IL-6 in IFNP-stimulated human microglial cells by 2- ((2A,55)-5-(2-methyl-l / 7-furo[3,2-Z>]imidazo[4,5- ]pyridin-l-yl)tetrahydro-2Z7-pyran-2- yl)acetonitrile.

[0085] FIG. 3B depicts reduction in IL-8 in IFNP-stimulated human microglial cells by 2- ((2A,55)-5-(2-methyl-l / 7-furo[3,2-Z>]imidazo[4,5- ]pyridin-l-yl)tetrahydro-2Z7-pyran-2- yl)acetonitrile.

[0086] FIGs. 4A-4C show results for a MOG35-55-induced MOG-EAE model. FIG. 4A depicts a neuroinflammatory disease score for2-((2A,55)-5-(2-methyl-l / 7-furo[3,2- Z>]imidazo[4,5-J]pyridin-l-yl)tetrahydro-2Z7-pyran-2-yl)acetonitrile treatment and controls FIG. 4B depicts counts of activated microglial cells in homogenized brain tissue. FIG. 4C depicts scoring of inflammation for hematoxylin and eosin stained cervical spinal cord.

[0087] FIG. 5A depicts representative single-dose pharmacokinetics for [(2R,5S)-5-[2- Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in humans.

[0088] FIG. 5B depicts representative multiple-dose pharmacokinetics for [(2R,5S)-5-[2- Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in humans.

[0089] FIG. 5C depicts representative CSF to plasma ratio for [(2R,5S)-5-[2-Methylfuro[3,2- b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in humans.

[0090] FIG. 5D depicts IFN-P reduction from [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile treatment in humans. In FIGs. 5D, 5E, and 5F, the bars for each day from left to right represent 6mg treatment, lOmg treatment, 20mg treatment, and placebo.

[0091] FIG. 5E depicts hsCRP reduction from [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile treatment in humans.

[0092] FIG. 5F IP-10 reduction from [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin- l-yl]tetrahydropyran-2-yl]acetonitrile treatment in humans.

[0093] FIG. 6A depicts simulated tissue concentrations of [(2R,5S)-5-[2-Methylfuro[3,2- b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile at 10 mg oral dosing.

[0094] FIG. 6B depicts simulated tissue concentrations of [(2R,5S)-5-[2-Methylfuro[3,2- b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile at 20 mg oral dosing.

[0095] DETAILED DESCRIPTION

[0096] The disclosure includes the surprising discovery that selective antagonists of the JAK family of kinases, specifically those inhibiting the kinase activity of JAK1 and TYK2 are effective in methods to prevent, reduce, and / or treat ARIA. Inhibition of JAK-STAT signaling with one or more JAK1 / TYK2 kinase antagonists may reduce the risk for ARIA in AD and other neurological disease patients receiving anti-Ap monoclonal antibody therapy.

[0097] JAK Kinases and Selective Inhibitors The Janus family of kinases is comprised of four members: JAK1, JAK2, JAK3, and Tyrosine kinases 2 (TYK2). Unlike other kinases, these kinases are non-receptor tyrosine kinases localized in the cytoplasm that interact with transmembrane cytokine receptors. JAK kinases transduce cytokine signaling from these receptors to signal transducers and activators of transcription, also known as JAK-STAT signaling. JAK -induced activation / phosphorylation of STAT facilitates its translocation to the nucleus altering the gene expression of numerous survival factors, cytokines, and chemokines. This rapid membrane to nucleus signaling cascade plays a central role in regulating the innate and adaptive immune response in the brain, affecting the function and viability of neuronal cells. Dysregulation of JAK-STAT signaling is a key driver of chronic neuroinflammation underlying many neurodegenerative disorders (e.g., Alzheimer’s disease, Parkinson’s disease, etc.), thereby representing a viable therapeutic target in the field.

[0098] JAK kinase inhibitors useful for the methods of the present invention may be brainpenetrant, small molecules that selectively inhibits one or more JAK family of kinases. In particular, the present disclosure is drawn to methods of treating, ameliorating the progression of, and preventing risk for ARIA comprising administering to a human subject initiating anti- Ap monoclonal antibody therapy, a selective JAK kinase inhibitor. Such selective JAK1 / TYK2 kinase inhibitors may be described by various generic or specific chemical formulas. In the exemplary chemical formulas shown herein, the general structure broadly describes a number of chemical structures in the alternative, and it can be appreciated that each alternative structure is contemplated.

[0099] Immunotherapy in Treating Neurological Diseases

[0100] The hallmark features of Alzheimer’s disease include aggregation of extracellular Ap plaques and hyperphosphorylated tau-containing neurofibrillary tangles as well as chronic neuroinflammation. Over the years, researchers have developed several therapeutic approaches based on the Ap cascade hypothesis, largely in the form of active (i.e., vaccines) and passive (i.e., AP-specific antibodies) immunotherapies. While active immunization may promote long- lasting generation of endogenous antibodies against Ap buildup, its reliance on the host immune response was deemed inadequate for elderly individuals vulnerable to and / or diagnosed with Alzheimer’s disease. On the other hand, passive immunotherapy utilizing anti- Ap monoclonal antibodies is regarded more suitable and have shown some effectiveness in promoting Ap clearance. However, the clinical use of such anti-Ap monoclonal antibodies has been deterred due to an increased risk for ARIA in patients initiating passive immunotherapy. Currently available immunotherapies include the following, such as:

[0101] Aducanumab

[0102] Developed by Biogen and Eisai, aducanumab is a high affinity, fully human IgGl monoclonal antibody that binds to the N-terminus of extended Ap peptides, designed to target Ap aggregates in soluble oligomeric and insoluble fibril forms. In clinical trials, aducanumab was effective in reducing the brain amyloid burden in a dose- and time-dependent manner. Patients with prodromal or mild Alzheimer’s disease receiving a high-dose of aducanumab have shown improved cognitive functions, such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and MMSE scores. Although EMERGE and ENGAGE, two Phase 3 clinical trials, were halted based on futility analysis of the preliminary data, an expanded analysis suggested that the primary endpoint of EMERGE was met and significant clinical improvements observed from the high dose group in ENGAGE allowed for a US FDA approval, making aducanumab the first drug for Alzheimer’s disease therapy. Nevertheless, safety monitoring analysis revealed an alarmingly high risk of ARIA-E associated with aducanumab treatment (Budd Haeberlein S, Aisen PS, BarkhofF, et al., JPrev Alzheimers Dis 2022;9(2): 197-210), as ARIA- E occurred dose-dependently in 35.2% of recipients and more commonly in 43.0% of APOE- s4 carriers (See Table 1).

[0103] Donanemab

[0104] Donanemab is a humanized monoclonal IgG antibody developed by Eli Lilly that specifically targets pyroglutamate-modified, N-terminally truncated Ap peptides found only in amyloid plaques in the brain. In the Phase 2 TRAILBLAZER-ALZ trial of donanemab, the primary outcome was met by significantly reducing integrated Alzheimer’s disease rating scale score in patients with early-stage AD, indicating slower cognitive and functional decline. Further, the Phase 3 TRAILBLZER-ALZ 2 study showed that participants receiving donanemab experienced slower disease progression at 76 weeks, accompanied by reduced amyloid plaque pathology and decreased plasma levels of phosphorylated tau. The efficacy of donanemab observed in participants with early symptomatic Alzheimer’s disease and preexisting amyloid and tau pathology suggested that the use of donanemab may even be effective for patients at a more advanced stage of Alzheimer’s disease who are typically more challenging to treat. Although the efficacy and safety of donanemab are being further evaluated, 24.0% of all participants receiving donanemab therapy developed ARIA-E, with 6% of recipients exhibiting adverse symptoms, and 1.6% of participants in the treatment group requiring hospitalization, supportive medical care, corticosteroid use, and / or experiencing death (Sims JR, Zimmer JA, Evans CD, et al., Jama 2023;330(6):512-527). The likelihood of developing edema / effusion was again higher among participants with the AP0E-s4 mutation, as 40.6% of APOE-s4 homozygous carriers experienced ARIA-E (See Table 1).

[0105] Lecanemab

[0106] Lecanemab, also known as Leqembi, is a humanized IgGl monoclonal antibody, jointly developed by the companies Eisai and Biogen. The antibody primarily targets soluble Ap aggregates but also has selectivity against oligomer, protofibril and insoluble fibril forms of Ap peptides. Its effectiveness at reducing brain amyloid plaques and other clinical benefits observed in the Phase 2 clinical trial allowed for enrollment of lecanemab into an accelerated approval pathway from the US FDA. In the Phase 3 clinical trial, CLARITY-AD, involving participants diagnosed with mild Alzheimer’s disease (mild cognitive impairment or mild dementia) and having verified amyloid pathology, lecanemab reduced markers of amyloid and resulted in less decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months. Although the efficacy of lecanemab was confirmed, the immunotherapy was once again associated with adverse events (van Dyck CH, Swanson CJ, Aisen P, et al., N Engl J Med 2023;388(l):9-21). The ARIA-E incidence was 12.6% at 10 mg / kg dosage in the overall population, with the frequency reaching 39.0% among APOE-s4 homozygous carriers (See Table 1).

[0107] Table 1 Incidence of ARIA-E by APOE-s4 Status in Anti-amyloid Monoclonal Antibody Phase

[0108] 3 Studies

[0109] Sample ARIA-E ARIA-E in APOE-E4 ARIA-E in APOE-E4 ARIA-E in Timing of size (Overall) Carriers Carriers Noncarriers Occurrence of

[0110] (Heterozygous) (Homozygous) APOE-E4 ARIA

[0111] EMERGE and

[0112] ENGAGE

[0113] Aducanumab 1,029 35.2% 43.0% 20.3% < 14 weeks

[0114] Placebo 1,076 2.7% 2.2%a3.9%

[0115] TRAILBLAZER-

[0116] ALZ2

[0117] Donanemab 853 24.0% 22.8% 40.6% 15.7% < 10 weeks

[0118] Placebo 874 1.9% 1.9% 3.4% 0.8%

[0119] CLARITY-AD

[0120] Lecanemab 898 12.6% 14% 39% 11.9% < 3 months

[0121] Placebo 897 1.7% 8.6% 21% 4.2% Data source summarized rates of ARIA across the EMERGE and ENGAGE trials by APOE- s4 carrier vs. noncarrier status; did not further distinguish between APOE-s4 heterozygous vs homozygous.

[0122] Abbreviations: APOE-s4 = apolipoprotein E s4 allele; ARIA-E = amyloid-related imaging abnormality-edema; ARIA-H = amyloid-related imaging abnormality -microhemorrhage

[0123] The general consensus in the field recommends earlier clinical detection followed by initiation of effective therapies in order to provide the greatest benefit for people living with Alzheimer’s disease. However, as therapeutic interventions are designed for application earlier in the disease course, and even into the pre-clinical stage, the tolerance for risk is minimal among vulnerable populations. For instance, individuals who are homozygous for APOE-s4 possess the greatest probability of AD progression, more rapid cognitive decline, and a higher burden of AD pathology, but also face the greatest risk for ARIA events associated with the initiation of a few FDA-approved anti-Ap immunotherapies. Adverse events, such as ARIA-E and / or ARIA-H, should be managed by either dose-reduction or immediate suspension of anti- Ap therapy. Ironically, individuals with AD who are homozygous carriers of the APOE-s4 mutation have been commonly marginalized in the abovementioned anti-Ap monoclonal antibody therapies due to concerns over heightened ARIA risk, signifying an urgent medical need for ARIA prevention. With the further administration of JAK inhibitors, such as 2- [(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2-yl] acetonitrile, anti-Ap monoclonal antibody therapy may finally achieve the fullest clinical potential as a disease modifying therapy with little to no risk for developing ARIA events in AD patients.

[0124] The term “composition” as used herein with respect to the compositions and methods, in addition to composition, is also intended to include the two or more agents are part of the overall therapy, but not necessarily administered concurrently in a combined dosage to treat the disease state or condition, which in this case is ARIA.

[0125] The term “treating” as used herein with respect to the compositions and methods for reducing ARIA in AD and other patients receiving antibody therapy, is also intended to encompass the terms ameliorating, alleviating, relieving, providing for prophylaxis of or prevention of, halting the progression of, and / or reducing the risk of ARIA. The term “treating” does not necessarily indicate a clinical result but is instead intended to encompass any meaningful patient benefit obtained by administering a therapeutically effective amount of a JAK inhibitor to a patient or subject in need thereof. The term “receiving” as used herein with respect to patients already undergoing antiamyloid monoclonal antibody therapy for AD and other neurological diseases is also intended to include patients that have not yet begun but will be initiating therapy the antibody therapy, patients that are about to complete the antibody therapy, and those patients that have completed the antibody therapy or patients having previously received an antibody therapy. It is recognized that ARIA might not be immediately observable in a patient undergoing or that has already undergone antibody therapy because of a lag time or latency period until manifestation of detectable ARIA, such that a lack of manifestation of ARIA should not necessarily preclude the patient from receiving the Janus inhibitor therapy, which should be determined in the professional judgment of the healthcare provider for the patient. Receiving of the JAK inhibitor is intended to also include administration, prior to, during, or after completion of treatment with the antibody therapy. When the JAK inhibitor is administered during therapy with the antibody, the administration of the JAK inhibitor can be simultaneously with or at some appropriate interval or separation from the time of administration of the antibody therapy, as determined by the judgment of the healthcare professional of the patient.

[0126] Candidate patients

[0127] Although the candidate patients (alternatively referred to as subjects) contemplated herein for receiving the JAK inhibitor therapy are generally those diagnosed with AD or at risk for AD, it will be recognized by healthcare professionals that patients with other neurodegenerative diseases or cerebral amyloid angiopathy-related inflammation (CAAri) that are candidates for antibody therapy or other therapies resulting in or associated with ARIA and similar conditions can also be candidates for the JAK inhibitor therapy. Additionally, patients that have been identified with an AP0E-s4 mutation are expected to be good candidates for the JAK inhibitor therapy if they are receiving the anti-amyloid immunotherapy. Patients do not necessarily require a clinical diagnosis or risk of ARIA for being a candidate under sound medical judgement of healthcare professionals. Patients are generally human subjects, but in alternative embodiments are other mammalian subjects.

[0128] Inhibitors of JAK for Treating ARIA

[0129] In some embodiments, a method of treating or preventing the development of ARIA, may comprise administering to a human subject in need thereof a therapeutically effective amount of a JAK inhibitor, such as a JAK1 / TYK2 kinase inhibitor according to Formula I: wherein:

[0130] R1is H, halogen, or C1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';

[0131] R2is H, halogen, or C1-3 alkyl;

[0132] Cy is C3 -7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R3, oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR', wherein R3is Cl -3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; and

[0133] R and R' are each independently H, or C1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, and CN.

[0134] With the JAK inhibitors exemplified herein, it is recognized that pharmaceutically acceptable salts, esters, prodrugs, solvates, enantiomers, racemates, stereoisomers, tautomers, and other forms of the compounds can be administered, as appropriate, particularly if these other forms of the compounds are tailored for provide specific physical and / or chemical properties, such as to facilitate formulation, administration, or provide enhanced stability, etc.

[0135] In some embodiments, the JAK kinase inhibitors described by general Formula I are selected from the following compounds, including pharmaceutically acceptable salts thereof: trans-4-[2-[(R)-l-Hydroxyethyl]-lH-furo[3,2-b]imidazo[4,5-d]pyridin-l-yl] cyclohexanecarbonitrile trans-4-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-l-yl] cyclohexanecarbonitrile,

[0136] 2-[trans-4-[2-[(R)-l-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-l-yl]cyclohexyl] acetonitrile,

[0137] 2-[(2R,5S)-5-[2-[(R)-l-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-l-yl] tetrahydropyran-2-yl]acetonitrile, 3-[2-[(R)-l-Hydroxyethyl]-lH-furo[3,2-b]imidazo[4,5-d]pyridin-l-yl]-N-(2,2,2- trifluoroethyl)pyrrolidine- 1 -carboxamide

[0138] (R)-4-[2-(l-Hydroxyethyl)-lH-furo[3,2-b]imidazo[4,5-d]pyridin-l-yl]-N-(2,2,2- trifluoroethyl)piperidine-l -carboxamide 2-[(2R,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-l- y 1 ]tetrahy dropy ran-2-y 1 ] acetonitril e and 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-1 -yl] tetrahydropyran- 2-yl] acetonitrile

[0139] In some embodiments, the selective dual inhibitor of JAK1 and TYK2 is 2-[(2R,5S)-5- [2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2-yl] acetonitrile, having the following structure:

[0140] Exemplary JAK1 inhibitors are disclosed in US Patent No. 10,738,060 B2, issued August 11, 2020 and which is incorporated by reference herein in its entirety, and particularly for its teachings on JAK1 inhibitor compounds, including compounds of Formula I therein and synthetic and definitional teachings related thereto. Further, methods for synthesizing certain JAK1 / TYK2 kinase inhibitor are disclosed in US Patent Application No. 17 / 615,437, filed April 30, 2020 and published as US 2022 / 0242873 Al on August 4, 2022, which is incorporated by reference herein in its entirety, and particularly for its teachings on methods of synthesis and salt form preparation.

[0141] Methods of Treating ARIA

[0142] JAK inhibitors, such as 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-1- yl] tetrahydropyran-2-yl] acetonitrile, are effective, selective dual inhibitors of JAK1 and TYK2, which are key non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT signaling pathway involved in the pathogenesis of various inflammatory and autoimmune diseases. JAK-STAT signaling influences both the innate and adaptive immune response, dysregulation of which has been identified as a key driver of neuroinflammation that promotes and increases risk for ARIA in a human subject, who is initiating the anti-Ap monoclonal antibody therapy. As a brain-penetrant compound and a selective inhibitor of TYK2 and JAK1 kinases, the compound, 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2-yl] acetonitrile, has the unique potential to favorably impact pathological processes that are driven by a broad-based inflammatory response, within the CNS and in the periphery, that involves the activation of both the innate and adaptive immune systems underlying the pathogenesis of ARIA.

[0143] In vitro, ex vivo, and in vivo nonclinical data collected to date demonstrate that 2- [(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile is highly potent and selective against TYK2 and JAK1, and capable of generating statistically significant reductions in inflammatory biomarkers associated with ARIA pathophysiology. See Examples 1-6, below. In a Phase 1 clinical study in healthy adults, 2- [(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile has been validated to be safe and well-tolerated at single doses up to 30 mg and once daily dosing for 14 days up to 20 mg. See Examples 7 and 8, below.

[0144] One aspect of the disclosure is a method for preventing risk for ARIA comprising the administration of a therapeutically effective amount of one or more compounds of Formula I in addition to standard of care anti-Ap monoclonal antibody therapy representative of the standard of care in the treatment of early AD (e.g., aducanumab, donanemab, lecanemab, or other anti-amyloid agent dosed in accordance with standard practice and in alignment with available FDA labeling) in a human patient.

[0145] Another aspect of the disclosure is a method for preventing risk for ARIA comprising the administration of a therapeutically effective amount of 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile to standard of care anti-Ap monoclonal antibody therapy representative of the standard of care in the treatment of early AD (e.g., aducanumab, donanemab, lecanemab, or other anti-amyloid agent dosed in accordance with standard practice and in alignment with available FDA labeling) in a human patient.

[0146] In some embodiments, the route of administration of JAK inhibitors may be oral. In some embodiments, a dose is daily, twice daily, three times daily, or four times daily. In some embodiments, a dose is once every other day, once every two days, once every three days, once every four days, once five days, once every six days, weekly, bi-weekly, or monthly. Typically, a dose may be from 0.01-30 mg / kg body weight, or from 0.15-20 mg / kg body weight, or from 0.2-10 mg / kg body weight, or from 0.5-5 mg / kg body weight, or from 1-2 mg / kg body weight. In other embodiments, the JAK inhibitors can be administered by other means, including but not limited to intravenous, intramuscular, intraperitoneal, subcutaneous, intranasal, inhalant, suppository, other parenteral, or any other appropriate administration route.

[0147] In some embodiments, the dosage is adjusted based upon MRI surveillance examination, rate of ARIA, and anti-Ap monoclonal antibody. -associated infusion reactions observed in the patient receiving standard of care anti-Ap monoclonal antibody therapy.

[0148] Pharmaceutically-acceptable salts of compounds of the present teachings can be formed using organic and inorganic bases, or organic and inorganic acids. Both mono and polyanionic salts are contemplated, depending on the number of charges available on the compound. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl -tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCC , Na2CO3, KHCO3, K2CO3, CsCO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, trifluoroacetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, di chloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.

[0149] In some embodiments, the unit dosage range is from 1 mg to 1000 mg of the JAK inhibitor. In some embodiments, the unit dosage range is from 1 mg to 100 mg of the JAK inhibitor. In some embodiments, the unit dosage range is from 5 mg to 50 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 10 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 20 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 30 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 40 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 50 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 60 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 70 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 80 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 90 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 100 mg of the JAK inhibitor. In some embodiments, the unit dosage is about 150 mg. In some embodiments, the unit dosage is about 200 mg. In some embodiments, the unit dosage is about 300 mg. In various embodiments, the term “about” in the context of unit dosage means within a reasonable range of the given value, for example, ±20% of the given value (in mg), or ± 5 mg, whichever is larger.

[0150] It is recognized that the dosage of the JAK inhibitor can be varied depending upon the compound chosen and consideration of patient factors such as age, weight, disease severity, other medications the patient is receiving, route of administration, etc.

[0151] Duration of administration of the JAK inhibitor

[0152] The JAK inhibitor can be administered for the duration of the antibody therapy. Generally, the JAK inhibitor would be administered on a daily base, with one or more doses given per day. The JAK inhibitor can be administered for some period prior to the commencement of the antibody therapy and administration can continue for some period after completion of the antibody therapy. The prior and subsequent administration periods of the JAK inhibitor can be tailored depending upon the specifics of the antibody treatment regimen for the patient. However, suitable pretreatment and post treatment periods with the JAK inhibitor can range from one day to about two weeks, with a period of about three days to about a week being some examples.

[0153] EXAMPLES

[0154] The following examples further describe and demonstrate embodiments within the scope of the present invention. The Examples are given solely for purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

[0155] Example 1: JAK1, TYK2 and JAK2 pharmacological assays.

[0156] In vitro pharmacology studies were performed, demonstrating that 2-[(2R,5S)-5-[2- Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile is a highly potent and selective inhibitor of TYK2 and JAK1 in biochemical enzyme assays of JAK family kinases (Table 2). Table 2 - Potency (IC50) of 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile Against Enzymatic Activity of JAK Family Kinases

[0157] JAK1 TYK2 JAK2 JAK3

[0158] 4 nM 4 nM 118 nM > 500 nM

[0159] ATP concentrations used in JAK1, TYK2 and JAK2 enzyme assays are 45 pM, 15 pM and 45 pM, respectively corresponding to the estimated Km of individual kinases.

[0160] Because plasma protein binding of kinase inhibitors can sometimes significantly impact their in vivo activity, the human whole blood cell-based assays were used to better characterize in vivo pharmacodynamic activity of 2-[(2R,5S)-5-[2-Methylfuro[3,2- b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in animal models and patients (equivalent to protein binding-adjusted potency). Specifically, the IL-6 induced pSTAT3 (regulated mainly by JAK1), TPO induced pSTAT3 (regulated mainly by JAK2), and IL- 12 / IL-18 induced IFNy production (regulated by TYK2) assays were performed and the results are reported in Table 3.

[0161] Table 3 Potency (IC50 ) of 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile against TYK2 / JAK1 Immune Cell Function

[0162] IL-6 Induced p-STAT3aTPO Induced p-STAT3aIL-12 / IL-18 Induced IFNy productionb

[0163] 1.29 / 0.39 pM 25.6 / 16.2 pM 0.091 pM

[0164] Values for IL-6-pSTAT3 and TPO-pSTAT3 represent 2 individual donors a Human whole blood b Human NK cell line NK92

[0165] The further in vitro assay was performed: The selectivity of 2-[(2R,5S)-5-[2- Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile for TYK2 / JAK1 was confirmed by profiling against a large panel of 358 human kinases. The data suggest that 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile is not only a J AK2 / JAK3 -sparing TYK2 / JAK1 inhibitor, but also exhibits excellent selectivity against all other human kinases tested. A highly selective dual TYK2 / JAK1 inhibitor may reduce some reported severe toxi cities associated with JAK2 and / or JAK3 inhibition.

[0166] Example 2: LPS-induced cytokine production in mouse microglial BV-2 cells.

[0167] The following in vitro assay was performed: Pre-treatment of LPS-treated BV2 cells with 2-[(2R,5S)-5-[2-Methylfuro [3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2- yl]acetonitrile dose-dependently reduced IL-6, TNF and MCP-1 cytokine production. 2- [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile at 1.7, 5 and 15pM inhibited IL-6 production by 49.1%, 72.4% and 83.6%. The inhibitions on TNF production at three doses were 39.9%, 81.2% and 118.5%, and were 56.9%, 83.3% and 110.6% on MCP-1 production. See Figure 1.

[0168] Abbreviations: IL-6: interleukin 6; LPS = lipopolysaccharide; MCP-1 = monocyte chemoattractant protein- 1; TNF = tumor necrosis factor

[0169] Example 3: Differentiated ReN VM human neural cells transfected with the dsRNA mimetic poly(I:C).

[0170] The following in vitro assay was performed to evaluate the neuroprotective effect of 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2- yl]acetonitrile in differentiated ReN VM human neural cells that are transfected with the dsRNA mimetic poly(LC), a model system established by Rodriguez et al., Genome-encoded cytoplasmic double-stranted RNAs, found in C9ORF72 ALS-FTD brain, propagate neuronal loss, Sci. Transl. Med. 2021; 13(601). dsRNA transfection induced cell death of differentiated ReN VM human neural cells. 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile efficiently rescued neurons from a dsRNA- induced toxic innate immune response in a dose-dependent manner, with the EC50 at 18.3nM. The EC50s of positive control drugs baricitinib and ruxolitinib were 35.6nM and 47.7nM, respectively. dsRNA transfection induced IFN-I response represented by increased phosphorylation level of STAT1, an IFN-I stimulated gene downstream of TYK2 / JAK1. 2- [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile at lOuM effectively blocked STAT1 phosphorylation, consistent with its action to reduce non-cell-autonomous IFN-I signaling. See FIGs2A-l, 2A-2, 2B-1, 2B-2, 2C-1, and 2C-2.

[0171] Abbreviations: EC50 = half maximal effective concentration; IFN-I = Interferon Type 1; MCP-1 = monocyte chemoattractant protein-1; TNF = tumor necrosis factor; STAT1 = signal transducer and activator of transcription 1; dsRNA= double-stranded ribonucleic acid; poly(LC) = polyriboinosinic-polyribocytidylic acid.

[0172] Example 4: Suppression of IFNP-induced Cytokine Production by Human Microglial Cells

[0173] This assay was performed to evaluate the anti-neuroinflammatory properties of 2- [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in an in vitro human cell model. In IFNP-treated human microglial HMC3 cells, there was a marked increase in IL-6 and IL-8 secretion with stimulation (see horizontal lines of FIGs. 3 A and 3B). At the highest level of IFN0 stimulation (represented by the highest horizontal line in FIGs. 3A and 3B), pre-treatment with 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile was performed and the results are indicated in FIG. 3A for IL-6 and FIG. 3B for IL-8. 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile decreased the concentration of each of these pro-inflammatory cytokines in a dose-dependent manner, with IC50 values of 2.1 and 1.1 pM, respectively.

[0174] Example 5: Mice / Female C57BL / 6, Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model of inflammation.

[0175] The following in vivo efficacy assay was performed to evaluate the therapeutic effect of 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2- yl]acetonitrile in inhibiting neuroinflammatory disease activity using an established MOG35-55 induced MOG-EAE mouse model.

[0176] EAE was induced in female C57BL / 6 mice by subcutaneous injection of MOG peptide on Day 1, and two intraperitoneal injections of pertussis toxin on Days 1 and 3, to increase disease incidence and severity. All MOG induced mice were randomized into 6 groups and treatments were started on Day 1. Mice were dosed orally, BID, on Days 1-31 with vehicle (0.5% HPMC in water) or 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile (10 or 30 mg / kg) (referred to in this Example as the “Treatment” groups G4 and G5, respectively). Due to the relatively short half-life of 2- [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in mice, the metabolic inhibitor 1 -Aminobenzotriazole (ABT1) was administered to treatment groups, at 100 mg / kg PO, QD, 2h prior to 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile dosing.

[0177] FTY-720 (fmgolimod) (1 mg / kg) was dosed orally QD as the positive control. Body weight was measured every other day from days 1-10, then daily to day 31. Clinical disease severity was measured daily from days 1-31. Disease severity was scored according to the criteria of 0 = Normal; 1 = Loss of tail tone; 2 = Loss of tail tone and hind limb weakness; 3 = Partial hind limb paralysis; 4 = Complete hind limb paralysis; 5 = Moribund state, death by EAE / humane sacrifice. Disease severity score across the study is shown in FIG. 4A. To measure CNS inflammation, brain tissue was homogenized and analyzed by FACS for CD45+CD1 lb+CD68+microglia (FIG. 4B), and sections of cervical spinal cord were stained by H&E. Spinal cord H&E stains were quantified as follows: 0 = no infiltration; 1 = infiltration of inflammatory cells in spinal membrane; 2 = inflammatory cell aggregation and infiltration in 1-2 blood vessels; 3 = inflammatory cell aggregation in 3-4 blood vessels and / or large range of parenchymal involvement; 4 = cell infiltration involving >20% of stained region (FIG. 4C).

[0178] All animals survived to study termination. No acute, gross toxicities were observed over the course of the study. Treatment with 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile (30 mg / kg) showed significant beneficial effects as determined by the discussed evaluations of disease activity. Moreover, 2-[(2R,5S)- 5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile decreased the number of activated microglia in brain and total inflammatory infiltrates in the spinal cord. PK analysis of brain homogenates showed brain penetration of 2-[(2R,5S)-5-[2- Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile with average concentrations ~50 ng / mL in the 10 mg / kg cohort and -350 ng / mL in the 30 mg / kg cohort 2 hours post-dosing (Table 4). These results indicate that 2-[(2R,5S)-5-[2-Methylfuro[3,2- b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile is brain penetrant and neuroprotective in an in vivo assay.

[0179] Table 4 - Brain Homogenate Concentrations (ng / mL) of 2-[(2R,5S)-5-[2-Methylfuro[3,2- b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in EAE Mice

[0180] Mouse #

[0181] DC P

[0182] Day

[0183] J" , Time 13 14 15 16 17 18 19 20 21 Mean ± SD Level

[0184] 10 mg / kg 2 28.1 95.7 28.8 50.9 ± 38.8

[0185] Day 18

[0186] 30 mg / kg 2 368 563 78.0 336 ± 244

[0187] 2 46.7 57.6 36.3 46.9 ± 10.7

[0188] 10 mg / kg

[0189] 12 BLOQ 0.31 0.38 0.35 ± N / A

[0190] Day 31 -

[0191] 2 395 400 355 383 ± 24.7

[0192] 30 mg / kg

[0193] 12 1.67 BLOQ BLOQ N / A ± N / A

[0194] Abbreviations: BLOQ = Below lower limit of quantification (0.3 ng / mL); N / A = Not available Example 6: Blood-brain barrier (BBB) Penetration of [(2R,5S)-5-[2- Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile

[0195] Brain penetrance of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile was further investigated in C57BL / 6J mice and SD rats. In these experiments, [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile was administered via oral gavage at the indicated dosages.

[0196] In C57BL / 6J mice, [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile was administered orally at 30 mg / kg. Following a single oral administration to mice (n=3), brain and CSF (cerebrospinal fluid) to plasma ratios were determined at 4 hours post-administration. The brain to plasma ratio was 0.394 ± 0.0313. The CSF to plasma ratio was 0.242 ± 0.0318.

[0197] In male SD rats, [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile was administered orally at 10 mg / kg. Following a single oral administration to rats (n=3), the brain and CSF to plasma ratios were determined at 8 hours post-administration. The brain to plasma ratio was 0.413 ± 0.101. The CSF to plasma ratio was 0.266 ± 0.0175. The unbound brain-to-plasma partition coefficient (Kpuu, brain) of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in rats was determined to be 0.22 at 8 hrs post dosing. These results demonstrate significant brain penetrance of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- y 1 ]tetrahy dropy ran-2-y 1 ] acetonitril e .

[0198] Example 7: Extended Release and Immediate Release Formulations of 2- [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2- yl] acetonitrile

[0199] Two extended release formulations were prepared. A first extended release formulation was prepared in 10 mg and 20 mg unit dosage tablets. The first extended release formulation included the drug and microcrystalline cellulose, mannitol, Hypromellose, colloidal silicon dioxide, magnesium stearate, and gastric-soluble film-coated premix (Opadry®). A second extended release formulation was prepared in 2 mg and 10 mg unit dosages. The second extended release formulation included the drug and mannitol, L(+)- tartaric acid, microcrystalline cellulose, hydroxypropyl methylcellulose, colloidal silicone dioxide, magnesium stearate and gastric-soluble film-coated premix (Opadry®). In immediate release formulation was prepared as a drug-in-capsule. The drug was placed in a two-piece white, opaque, size #0 HPMC capsule containing only the drug substance with no other excipient. For immediate release controls, the drug was replaced with microcrystalline cellulose.

[0200] Example 8: Phase I randomized, double-blind, placebo-controlled, sequential, parallel group, single or multiple ascending-dose (SAD / MAD) study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of an extended release (ER) formulation of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile acetonitrile following oral administration.

[0201] This is a completed Phase I study. Healthy adult male or non-childbearing potential female subjects were enrolled in the following ongoing Phase I clinical study. Up to four single ascending dose cohorts are planned in this study, with starting dose set at 10 mg, administered orally after at least a 10 hour fast. Doses for subsequent cohorts may be adjusted based on PK from previous cohort(s) to ensure that the projected exposure at the highest dose would not exceed AUCiast of 7,500 hr»ng / mL and Cmax of 1,200 ng / mL (based on nonclinical data of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2- yl]acetonitrile safety pharmacology and toxicology). The primary objectives of the study are to (1) evaluate the safety and tolerability, and (2) characterize the PK of [(2R,5S)-5-[2- Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile following oral single ascending dose administration. The secondary objective is to explore preliminary evidence of the PD activity of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile following oral single ascending dose administration. This is the first clinical study of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile to gather safety, tolerability, and PK information to support subsequent clinical studies with the compound.

[0202] A summary of the PK descriptive statistics following a single dose of [(2R,5S)-5-[2- Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile is provided in Table 5. A representative pharmacokinetic trace is provided in FIG. 5 A. An overview of results is as follows: Increasing the single dose of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin- l-yl]tetrahydropyran-2-yl]acetonitrile from 10 mg to 30 mg resulted in a general trend of increased exposure.

[0203] - Following the 10 mg dose of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin- l-yl]tetrahydropyran-2-yl]acetonitrile resulted in the geometric mean Cmax and AUCiast of 51.1 ng / mL and 1192 ng*h / mL, respectively. At the highest single dose of 30 mg, the geometric mean Cmax and AUCiast increased to 149 ng / mL and 4,100 ng h / mL, respectively.

[0204] - Following a single dose administration of ER formulation of [(2R,5S)-5-[2- Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile, the median Tmax ranged from 5 to 6 hours across the 10 mg to 30 mg doses.

[0205] The geometric mean ti / 2 for [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile ranged from 11.1 to 13.8 hours across all doses.

[0206] - Low PK variability in 20 mg and 30 mg dose groups (CV% ranged from 15 to 21%), whereas moderate PK variability in 10 mg (%CV ranged from 23 to 53%)

[0207] The AUC extrapolation for [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile was less than 5% at all doses indicating that a sampling period of 72 hours was sufficient to characterize the PK profile of [(2R,5S)- 5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile.

[0208] Table 5 Preliminary Results after Oral Administration of a Single Dose of Extended Release Formulation of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile - Pharmacokinetic Parameters

[0209] Pharmacokinetic Parameters 10 mg 20 mg 30 mg

[0210] Cmax(ng / mL) GMf 51.1 143 149

[0211] (geo CV%) (23.3) (15.9) (15.2)

[0212] T ax (h) Median 6 6 5

[0213] (Min, Max) (3, 6) (4, 12) (3, 8)

[0214] AUCiast (ng’h / mL) GMf 1192 4246 4100

[0215] (geo CV%) (52.6) (17.7) (16.3)

[0216] AUC[o-inf] (ng’h / mL) GMf 1232 4443 4189

[0217] (geo CV%) (51.6) (21) (17.3) ti / 2(h) GMf 11.3 13.8 11.1

[0218] (geo CV%) (24.8) (24.7) (23.3) Pharmacokinetic Parameters 10 mg 20 mg 30 mg

[0219] Kel (l / h) GMf 0.061 0.05 0.062

[0220] (geo CV%) (24.8) (24.6) (23.3)

[0221] Abbreviations: AUCiast = area under the concentration-time curve from time 0 last concentration; AUC[o-infj = area under the concentration-time curve from time 0 to infinity; C = maximum observed concentration; geo CV% = geometric coefficient of variation; GM = Geometric mean; h = hours; ti / 2 ei = apparent elimination halflife; Kei= elimination rate; Tmax= time of peak plasma concentration f Geometric mean

[0222] An overview of the results observed following multiple doses of [(2R,5S)-5-[2- Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile is provided below, and representative PK traces are shown in FIG. 5B.

[0223] Increasing the dose of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile from 6 mg to 20 mg resulted in a general trend of increased exposure. For the highest daily dose of 20 mg, the steady-state exposures resulted in a geometric mean Cmax of 210 ng / mL and an AUCo-tau of 3,694 ng h / mL.

[0224] - Median Tmax ranged from 4 to 6 hours across the 6 mg to 20 mg doses at steady state.

[0225] After multiple doses, the accumulation ratio at steady state increased by approximately 1.8-fold for both AUC and Cmax.

[0226] - Based on the ex-vivo protein binding, the average mean unbound fraction of [(2R,5S)-5- [2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in plasma after a 20 mg dose was 67% (33% bound), which is consistent with protein binding observed at 6 mg and 10 mg doses, showing 68% and 67% unbound, respectively. The average recovery of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile following dialysis was >83.7% in all three cohorts, indicating the compound was not subject to significant non-specific binding and / or degradation.

[0227] Additionally, the CSF to plasma ratio was determined in study patients to evaluate brain penetrance of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2- yl]acetonitrile in human subjects. Results at 6 and 24 hours post-dose are shown in FIG. 5C. The mean (CV%) CSF:plasma ratio at 6- and 24-hours post dose was 0.43(10.1) and 0.50 (13.3), respectively. Mean exposures in the CSF remained at therapeutic levels through 24 hours post dose. This result indicates that [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile is highly brain penetrant.

[0228] Pharmacodynamics were assessed from multiple dose data via serum biomarkers for neuroinflammation. The monitored biomarkers were IFN-P, hsCRP, and IP-10, and results are depicted in FIG. 5D, 5E, and 5F. Reductions from baseline interferon -gamma inducible protein 10 (IP- 10), high sensitivity c-reactive protein (hsCRP) and interferon-beta (IFN-P) were observed compared to placebo. In FIGs. 5D, 5E, and 5F, the bars for each day from left to right represent 6mg treatment (i.e., [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin- l-yl]tetrahydropyran-2-yl]acetonitrile), lOmg treatment, 20mg treatment, and placebo. [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile reduced neuroinflammatory markers in human subjects suggesting potential efficacy in neurologic and neurodegenerative diseases.

[0229] Example 9: Phase I, open-label, single-dose study to evaluate the pharmacokinetics of an immediate-release (IR) formulation of 2-[(2R,5S)-5-[2- Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile.

[0230] This is a completed Phase I study. Healthy adult male or non-childbearing potential female subjects were enrolled in the following ongoing Phase I clinical study, which aims to evaluate the PK, safety, and tolerability after single oral administration of an IR capsule formulation of 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile. Eight participants received a single oral 10 mg dose of an IR 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile formulation under fasting conditions. The primary objective of the study is to characterize the PK of 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile after a single oral administration of an IR capsule in healthy adult participants. The secondary objective is to evaluate the safety and tolerability 2- [(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile following a single oral administration of an IR capsule in healthy adult participants.

[0231] Based on the preliminary data, an overview of the initial results follows: 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2- yl] acetonitrile was rapidly absorbed with median peak 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile concentrations observed at 1.25 hours following administration of a single dose of IR formulation. The geometric mean ti / 2 for 2-[(2R,5S)-5-[2-Methylfuro [3 ,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile was 10.5 hours.

[0232] The AUC extrapolation for 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile was less than 5% indicating that a sampling period of 72 hours was sufficient to characterize the PK profile of 2- [(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile.

[0233] Table 6 - Results after Oral Administration of Immediate Release Formulation

[0234] Pharmacokinetic Parameters 10 mg IR Dose

[0235] Cmax (ng / mL) GMf 128

[0236] (geo CV%) (20.7)

[0237] Tmax (h) Median 1.25

[0238] (Min, Max) (0.67, 2.5)

[0239] AUCiast (ng-h / mL) GMf 1667

[0240] (geo CV%) (38)

[0241] AUC[o-inf] (ng-h / mL) GMf 1705

[0242] (geo CV%) (38.6) ti / 2 (h) GMf 10.5

[0243] (geo CV%) (27.8)

[0244] Kel (1 / h) GMf 0.066

[0245] (geo CV%) (27.8)

[0246] Abbreviations: AUCiast = area under the concentration-time curve from time 0 last concentration; AUC[o-infj = area under the concentration-time curve from time 0 to infinity; Cmax = maximum observed concentration; geo CV = geometric coefficient of variation; GM = Geometric mean; h = hours; ti / 2 ei = apparent elimination halflife;

[0247] Kei= elimination rate; Tmax = time of peak plasma concentration f Geometric mean

[0248] Example 10: Physiological-Based Pharmacokinetic Modeling

[0249] A PBPK model based on in vitro and in vivo data on the metabolism and PK of 2- [(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile was constructed. Physicochemical and in vitro data for 2-[(2R,5S)-5-[2- Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile, including the fraction unbound in plasma as well as in rat brain, permeability in cell lines, and solubility, were used as input. Clinical concentration-time profiles were used to refine the volume of distribution concordant with that observed in preclinical species; observed oral clearance was used to back-calculate hepatic intrinsic clearance. Measurements of efflux transporter kinetics in transfected MDCK cell lines were optimized to capture observed brain concentrations of 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l- yl]tetrahydropyran-2-yl]acetonitrile in rat then adjusted with a relative-activity factor for use in the human model. In addition, the PBPK model for humans was developed using a subset of clinical data and validated against the remaining data, including a cohort with CSF concentrations. This model was then employed to predict systemic and brain exposures of 2- [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in humans following 10 mg and 20 mg once daily dosing in healthy subjects.

[0250] As a part of model verification, simulated PK profiles, AUCinf and Cmax of 2-[(2R,5S)- 5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile following single and repeat oral doses of 6 mg to 30 mg in healthy subjects demonstrated reasonable agreement with observed data. All predictions were within 1.6-fold of the observed values, with the majority within 1.25-fold of clinical results (see Example 8). Additionally, predicted spinal CSF concentrations aligned well with observed clinical measurements (see Example 8).

[0251] Based on the PBPK model simulations, the predicted mean unbound-plasma-to-unbound- brain partitioning coefficient (Kp,uu, brain) was approximately 0.53, whereas the measurements of CSF were predicted to be similar to unbound brain concentrations. At steady state, following QD dosing of 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5- d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile, the simulated geometric mean (90% CI) unbound brain concentrations were as follows:

[0252] • 10 mg QD: Cmax was 35 ng / mL (32-39), and AUCT was 603 ng hr / mL (546-667).

[0253] • 20 mg QD: Cmax was 71 ng / mL (65-78), and AUCT was 1221 ng hr / mL (1105-1350).

[0254] As 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2- yl] acetonitrile is a TYK2 / JAK1 inhibitor, predicted concentration-time profiles for plasma, CSF, and brain tissues (total and unbound brain concentrations) following doses from 10 to 20 mg QD dosing were compared to a target concentration for achieving half maximal effect (EC50 value for TYK2-mediated pharmacology inhibition in NK92 cells and VM human neural cells. The simulated tissue concentrations of [(2R,5S)-5-[2-Methylfuro[3,2- b]imidazo[4,5-d]pyridin-l-yl]tetrahydropyran-2-yl]acetonitrile in plasma, total brain, spinal CSF, and unbound brain are shown in FIGs. 6A and 6B for 10 and 20 mg dosages, respectively. The plasma and total brain traces are essentially overlapping as indicated in the figures. The dotted line represents the EC50 for TYK2 inhibition (90.7 nM; 26.9 ng / mL) in NK92 cells. The dashed line represents the EC50 for JAK1 inhibition (18.3 nM; 5.42 ng / mL) in ReN VM human neural cells. The amounts of time arithmetic mean unbound brain concentrations were predicted to be above the EC50 values for TYK2 and JAK1 are listed in Table 7.

[0255] Table 7 - Mean Unbound Brain Concentration Exceeded EC50 Target (Unbound EC50 (ng / mL) = 26.9)

[0256] ECso Type OD Dose At steady state, time per 24-hour dosing interval that the arithmetic mean unbound brain concentration > unbound

[0257] ECso

[0258] TYK2 pharmacology-inhibition in NK92 10 mg 13.8 h (58%) cells: 90.7 nM (considered as unbound)2Q mg 24 0 h (100o / o)

[0259] JAK1 pharmacology -inhibition in ReN 10 mg 24. 0 h (100%)

[0260] VM human neural cells: 18.3 nM20 mg24.0 h (100%)

[0261] (considered as unbound)

[0262] Based on the PBPK modeling, mean steady-state unbound human brain concentrations were predicted to exceed the TYK2 EC50 (~27 ng / mL / 91 nM) for the entire dosing interval at a dose level of 20 mg ER tablet QD, and 58% of the dosing interval at 10 mg ER QD, and none at 5 mg ER QD dosing. In conclusion, doses of 10 mg and 20 mg ER QD are expected to produce adequate free brain concentrations for target engagement supporting continued development of [(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin- l-yl]tetrahydropyran-2-yl]acetonitrile for the management of neuroinflammatory conditions including Alzheimer’s disease and, more particularly, ARIA.

[0263] Example 11: Phase lb proof-of-concept study of 2-[(2R,5S)-5-[2-Methylfuro [3,2- b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile.

[0264] The following Phase lb clinical study is a two-part (Part A and Part B), single-arm, open-label study to assess the PD, safety, tolerability, and preliminary effectiveness of 2- [(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile administered in addition to standard of care anti -amyloid monoclonal antibody therapy representative of the standard of care in the treatment of early AD (e.g., donanemab, lecanemab, or other anti-amyloid agent dosed in accordance with standard practice and in alignment with available FDA labeling) in preventing ARIA in a population of adults with a diagnosis of early AD (MCI or mild Alzheimer’s dementia) who are homozygous for the APOE-84 allele. The study intends to enroll up to 35 participants enriched for APOE-s4 homozygotes for 12 weeks of treatment with the investigational agent in addition to the standard of care.

[0265] Part A consists of an open-label treatment phase that begins with 1 week of 2- [(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile monotherapy prior to the initiation of anti-amyloid monoclonal antibody therapy. This short “priming” period is intended to abate the chronic inflammatory environment within the CNS and in the periphery prior to the introduction of an amyloid-lowering agent, that 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile will be dosed once daily in this study, although the final dose will be based on the results of the ongoing Phase 1 SAD / MAD study (Example 7). Part B consists of an open label phase during which participants will receive anti-amyloid monotherapy therapy for 24 weeks.

[0266] At the conclusion of the 1-week priming period in Part A, dosing with an antiamyloid monoclonal antibody will commence. An anti-amyloid agent that is representative of the standard of care for the treatment of early will be utilized, preferably donanemab. Antiamyloid therapy will begin dosing after 1 week of priming with 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile, and continue repeat dosing, in strict accordance with the study protocol, consistent with standard practice, and in alignment with available FDA labeling, through the Week 12 primary endpoint (e.g., after 12 weeks of dosing with 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile and 11 weeks of anti-amyloid therapy).

[0267] The recruited population will be very consistent with the early AD cohort recruited to donanemab Phase 3 clinical studies, including TRAILBLAZER-ALZ2 with one notable exception being the requirement that all treated participants be homozygous for the APOE-s4 allele. The decision to target this particular subgroup is based on the fact that APOE-s4 carriers, and homozygotes in particular, carry a heightened risk for ARIA and represent a subpopulation that could most benefit from ARIA preventative interventions.

[0268] The primary objectives sought in Part A of the Phase lb study are to assess the 1) PD and 2) safety and tolerability of 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- l-yl] tetrahydropyran-2-yl] acetonitrile in addition to the standard of care (preferably donanemab or another FDA-approved anti-amyloid monoclonal antibody therapy). The key secondary objective in Part A is the preliminary assessment of whether 2-[(2R,5S)-5-[2- Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile prevents ARIA-E in the target population.

[0269] Beyond the Week 12 visit, all participants who complete Part A will be eligible to continue dosing with anti-amyloid treatment (e.g., donanemab or another anti-amyloid agent dosed in accordance with the study protocol, consistent with standard practice and in alignment with available FDA labeling) for an additional 24 weeks of open-label monotherapy. The Part B open label phase serves multiple key functions including: 1) the opportunity for participants to extend their exposure to anti -amyloid treatment and 2) the opportunity to assess the possibility of an ARIA rebound effect following the cessation of 2- [(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile at Week 12. Key exploratory objectives to be assessed over time, throughout the study include: 1) changes from Baseline in blood and CSF inflammatory biomarkers, 2) changes from Baseline in AD-specific fluid biomarkers; and 3) changes in Baseline amyloid- PET scan results. In addition, this study plans to evaluate participants for evidence of early improvements in cognitive and functional endpoints, and in quality of life (QoL) scales.

[0270] Example 12: Phase 2b / 3 registrational studies of 2-[(2R,5S)-5-[2-Methylfuro [3,2- b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile.

[0271] Beyond the Phase lb study (Example 11), a Phase 2b / 3, randomized, double-blind, placebo-controlled, dose-ranging study and a Phase 3 study are being planned. These clinical studies will target a population consistent with that recruited into the Phase lb study (Example 11) and that enrolled into the lecanemab and donanemab Phase 3 clinical studies. One notable exception is that the current studies will prioritize the enrollment of an enriched population that skews toward higher representation of s4 / s4 (approximately 25%) and s4 / - (approximately 55%) participants relative to the natural epidemiology.

[0272] In the planned Phase 2b / 3 study, eligible participants will be randomized 2:2: 1 to receive yet-to-be determined “high” and “low” doses of 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile or matching placebo once daily for 12 weeks of blinded treatment in addition to the FDA-approved standard of care anti-amyloid monoclonal antibody therapy for the treatment of early AD. Selected doses of the investigational agent will explore the breadth of the available dose range. Stratification will be based on ARIA risk factors including APOE-s4 genotype and the degree of cerebral amyloid angiopathy on baseline imaging. The estimated enrollment for this study will be approximately 530 randomized participants assuming a 15% dropout rate (212 per active arm and 106 in placebo). The 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2-yl] acetonitrile doses will be tested hierarchically, starting with the highest 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile dose. After a short priming period of 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile monotherapy, anti-amyloid therapy will be initiated (FDA-approved anti-amyloid mAb dosed in accordance standard practice and in alignment with FDA labeling) as a concomitant medication through the Week 12 study visit. The primary efficacy endpoint will be assessed at Week 12. The primary endpoint will compare the proportion of participants in each arm who experience ARIA-E. Other key endpoints to be assessed at the Week 12 timepoint include incidence of all ARIA, changes from Baseline in inflammatory and AD-specific fluid biomarkers, and a comparison in the rate of infusion reactions between those randomized to blinded 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile vs blinded placebo, in addition to anti-amyloid treatment

[0273] In the Phase 2b / 3 study, eligible participants who have completed the Week 12 visit will be provided the opportunity to receive anti-amyloid antibody monotherapy as part of an open-label extension (OLE) phase. In the Phase 2b / 3 study, participants will receive antiamyloid therapy, in strict accordance with the protocol, consistent with standard practice, and in alignment with FDA labeling, for an additional 36 weeks (to complete a total of 48 total weeks of amyloid-lowering therapy). The OLE phase is important to assess the potential for an ARIA rebound effect to occur after the discontinuation of 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile. Notably, during the OLE phase, participants who experience ARIA-E requiring medical intervention will be, in consultation with their PI, provided with the opportunity to use open-label 2-[(2R,5S)-5-[2- Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile or another immunosuppressant in the management of the ARIA event. One of the key secondary analyses from the Week 48 end-of-treatment visit will include a comparison of changes in baseline amyloid PET between participants who were originally randomized to 2-[(2R,5S)-5- [2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile or matching placebo during the 12-week double-blind treatment phase. This comparison will help inform the potential for 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-1- yl] tetrahydropyran-2-yl] acetonitrile to adversely impact the amyloid-lowering effects of standard of care treatment. Finally, other important endpoints to be assessed over time in the Phase 2b / 3 study include changes in cognitive and functional endpoints, and in QoL scales, between participants randomized to 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2-yl] acetonitrile or placebo during the 12-week double-blind phase.

[0274] The 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile for the prevention of ARIA general investigational plan also intends to include a randomized, double-blind, placebo-controlled Phase 3 study. This study will target the same population and generally match the design of the preceding ARIA prevention studies described above (Phase lb and Phase 2b / 3 ARIA prevention study of 2- [(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile). Eligible participants in the Phase 3 study will be randomized 2: 1 to receive blinded 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2- yl] acetonitrile or matching placebo in addition to FDA-approved anti-amyloid mAb therapy. It is anticipated the estimated enrollment for the Phase 3 study will be approximately 300 participants (approximately 200 randomized to receive blinded 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile and approximately 100 to receive blinded placebo); the sample size will be confirmed after the Phase 2b / 3 study. The conduct of this registrational study will generally match that of the Phase 2b / 3 study, including inclusion / exclusion criteria, major endpoints, and important safety measures.

[0275] Primary and key secondary endpoints proposed for the 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile for the prevention of ARIA registrational studies are detailed below.

[0276] Primary Endpoint:

[0277] - Rate of ARIA-E by MRI in participants randomized to receive blinded 2-[(2R,5S)-5- [2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile (either the “high” or “low” dose arm) vs. blinded placebo in addition to the standard of care through Week 12.

[0278] Key Secondary Endpoints:

[0279] Safety and tolerability of 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- l-yl] tetrahydropyran-2-yl] acetonitrile (“high” and “low” dose arms alone and cumulative) in addition to the standard of care through Week 12. Rate of ARIA (ARIA-H and ARIA-E) by MRI in participants randomized to receive blinded 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1-yl] tetrahydropyran-2-yl] acetonitrile (either the “high” or “low” dose arm) vs. blinded placebo in addition to the standard of care through Week 12.

[0280] - Rate of anti-amyloid monoclonal antibody-associated infusion reactions through Week 12 in participants randomized to receive blinded 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile (either the “high” or “low” dose arm) vs blinded placebo in addition to the standard of care.

[0281] - Rate of anti-amyloid monoclonal antibody dose interruption or dose reduction through Week 12 between participants randomized to receive blinded 2-[(2R,5S)-5-[2- Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile (either the “high” or “low” dose arm) or blinded placebo in addition to the standard of care.

[0282] Rate of ARIA (ARIA-E, ARIA-H, and Total) by MRI during the anti-amyloid monoclonal antibody open-label extension phase (Week 12 through Week 48) between participants randomized to receive blinded 2-[(2R,5S)-5-[2-Methylfuro [3,2- b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile (either the “high” or “low” dose arm) or blinded placebo in addition to the standard of care during the double-blind treatment phase.

[0283] Change in baseline brain amyloid plaque deposition through Week 48 (end-of- treatment visit) in participants randomized to receive blinded 2-[(2R,5S)-5-[2- Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2-yl] acetonitrile (either the “high” or “low” dose arm) vs blinded placebo in addition to the standard of care during the double-blind treatment phase.

[0284] Incorporation by Reference

[0285] The entire disclosure of each of the patent documents, including certificates of correction, patent application documents, scientific articles, governmental reports, websites, and other references referred to herein is incorporated by reference herein in its entirety for all purposes. In case of a conflict in terminology, the present specification controls.

[0286] Equivalents

[0287] The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are to be considered in all respects illustrative rather than limiting on the invention described herein. In the various embodiments of the compositions and methods of the present invention, where the term comprises is used with respect to the recited components of the compositions or steps of the methods, it is also contemplated that the compositions and methods consist essentially of, or consist of, the recited steps or components. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0288] In the specification, the singular forms also include the plural forms, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification will control.

[0289] Furthermore, it should be recognized that in certain instances a composition can be described as being composed of the components prior to mixing, because upon mixing certain components can further react or be transformed into additional materials.

[0290] All percentages and ratios used herein, unless otherwise indicated, are by weight.

Claims

CLAIMSWhat is claimed is:

1. A method for treating amyloid-related imaging abnormalities (ARIA) in a patient with a neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) receiving anti-amyloid therapy comprising administering a therapeutically effective amount of a Janus kinase (JAK) inhibitor to the patient.

2. The method according to claim 1, wherein the patient is a human patient.

3. The method according to claim 1 or 2, wherein the patient has an APOE-s4 mutation.

4. The method according to any one of claims 1 to 3, wherein the patient has been diagnosed with Alzheimer’s disease (AD).

5. The method according to any one of claims 1 to 4, wherein the anti-amyloid therapy is an anti-amyloid antibody therapy employing anti-amyloid antibodies or antigen-binding fragments thereof.

6. The method according to claim 5, wherein the anti-amyloid antibody therapy is antiamyloid monoclonal antibody therapy.

7. The method of claim 5 or claim 6, wherein the JAK inhibitor is selected from a JAK1 inhibitor, a tyrosine kinase 2 (TYK2) inhibitor, and combinations thereof.

8. The method of claim 7, wherein the JAK inhibitor is a JAK1 inhibitor.

9. The method of claim 7, wherein the JAK inhibitor is a TYK2 inhibitor.

10. The method of claim 5 or claim 6, wherein the JAK inhibitor corresponds to the formulaor a pharmaceutically acceptable salt, ester, prodrug, solvate, enantiomer, racemate, stereoisomer, or tautomer thereof, wherein:R1is H, halogen, or C1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR';R2is H, halogen, or C1-3 alkyl;Cy is C3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R3, oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR', wherein R3is Cl -3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR'; andR and R' are each independently H, or C1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, and CN.

11. The method of claim 10, wherein:Cy is C5-7 cycloalkyl, or 5-7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R3, oxo, halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2NRR', wherein R3is C1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R, and S(O)2RR'.

12. The method of claim 10 or 11, wherein Cy is pyran substituted with CN.

13. The method of any one of claims 10 to 12, wherein:R2is hydrogen.

14. The method of any one of claims 10 to 13, wherein R1is methyl.

15. The method of claim 10, wherein the compound is selected from the group consisting of: trans-4-[2-[(R)-l-Hydroxyethyl]-lH-furo[3,2-b]imidazo[4,5-d]pyridin-l-yl] cyclohexanecarbonitrile, trans-4-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-l-yl] cyclohexanecarbonitrile, 2-[trans-4-[2-[(R)-l-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-l-yl]cyclohexyl] acetonitrile,2-[(2R,5S)-5-[2-[(R)-l-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-l-yl] tetrahydropyran-2-yl]acetonitrile,3-[2-[(R)-l-Hydroxyethyl]-lH-furo[3,2-b]imidazo[4,5-d]pyridin-l-yl]-N-(2,2,2- trifluoroethyl)pyrrolidine- 1 -carboxamide, (R)-4-[2-(l-Hydroxyethyl)-lH-furo[3,2-b]imidazo[4,5-d]pyridin-l-yl]-N-(2,2,2- trifluoroethyl)piperidine-l -carboxamide, 2-[(2R,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-l- y 1 ]tetrahy dropy ran-2-y 1 ] acetonitril e, 2-[(2S,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-l- y 1 ]tetrahy dropy ran-2-yl ] acetonitril e, 2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d]pyridin-l-yl] tetrahydropyran-2- yl]acetonitrile, 2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d] pyridin-l-yl] tetrahydropyran-2- yl]acetonitrile, and 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2- yl] acetonitrile.

16. The method of claim 10, wherein the compound is2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2- yl] acetonitrile.

17. The method of any one of claims 5 to 16, wherein the anti-amyloid antibody therapy is an anti-amyloid beta (AP) Alzheimer Disease (AD) immunotherapy.

18. The method of claim 17, wherein the immunotherapy comprises one or more monoclonal antibody therapies selected from aducanumab, donanemab, lecanemab, or antigen binding fragments thereof, and combinations thereof.

19. The method of any one of claims 5 to 18, wherein the JAK inhibitor is administered, before, during, or after completion of administration of the anti-amyloid antibody therapy.

20. The method according to any one of claims 5 to 18, wherein the ARIA is amyloid-related imaging abnormalities with edema or effusion (ARIA-E).

21. The method according to any one of claims 5 to 18, wherein the ARIA is amyloid-related imaging abnormalities with hemorrhage (ARIA-H).

22. The method according to any one of claims 5 to 21 wherein the JAK inhibitor is administered until a therapeutic benefit is achieved as quantified by a reduction of at least 25% in the ARIA.

23. The method according to any one of claims 5 to 21 wherein the JAK inhibitor is administered until a therapeutic benefit is achieved as quantified by a reduction of at least 10% in the ARIA.

24. The method according to any one of claims 5 to 21 wherein the JAK inhibitor is administered until a therapeutic benefit is achieved as quantified by a reduction of at least 5% in the ARIA.

25. A method for treating amyloid-related imaging abnormalities (ARIA) in an Alzheimer’s disease patient receiving anti-amyloid monoclonal antibody therapy comprising administering a therapeutically effective amount of a Janus kinase (JAK) inhibitor to the patient.

26. A method for treating amyloid-related imaging abnormalities (ARIA) in an Alzheimer’s disease patient receiving anti-amyloid monoclonal antibody therapy comprising administering a therapeutically effective amount of the compound:2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2- yl] acetonitrile, or a pharmaceutically acceptable salt or solvate thereof.

27. The method of claim 26, wherein the compound is administered as a unit dose comprising from about 1 mg to about 100 mg of the compound.

28. The method of claim 26, wherein the compound is administered as a unit dose comprising from about 10 mg to about 50 mg of the compound.

29. The method of claim 26, wherein the compound is administered as a unit dose comprising from about 20 mg of the compound.

30. The method of claim 26, wherein the compound is administered as a unit dose comprising from about 30 mg of the compound.

31. The method of claim 26, wherein the compound is administered as a unit dose comprising from about 40 mg of the compound.

32. A pharmaceutical composition for treating Alzheimer’s disease comprising a therapeutically effective amount of anti-amyloid beta (AP) Alzheimer’s Disease (AD) immunotherapy and a therapeutically effective amount of a Janus kinase (JAK) inhibitor.

33. A pharmaceutical composition for treating Alzheimer’s disease comprising a therapeutically effective amount of anti-amyloid beta (AP) Alzheimer’s Disease (AD) immunotherapy and a therapeutically effective amount of the compound:2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2- yl] acetonitrile, or a pharmaceutically acceptable salt or solvate thereof.

34. A method for treating Alzheimer’s disease comprising administering to a patient in need thereof a therapeutically effective amount of anti-amyloid beta (AP) Alzheimer’s Disease (AD) immunotherapy and a therapeutically effective amount of a Janus kinase (JAK) inhibitor.

35. A method for treating Alzheimer’s disease comprising administering to a patient in need thereof a therapeutically effective amount of anti-amyloid beta (AP) Alzheimer’s Disease (AD) immunotherapy and a therapeutically effective amount of the compound:2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin- 1 -yl] tetrahydropyran-2yl] acetonitrile, or a pharmaceutically acceptable salt or solvate thereof.

36. A method for treating vascular inflammation associated with intravascular amyloid deposits, comprising administering to a patient in need thereof a therapeutically effective amount of the compound:2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-l-yl] tetrahydropyran-2yl] acetonitrile, or a pharmaceutically acceptable salt or solvate thereof.

37. The method of claim 36, wherein the amyloid deposits are amyloid beta deposits.

38. The method of claim 37, where in the amyloid beta deposits are pharmacologically- induced.

39. The method of claim 38, wherein the amyloid beta deposits are induced by anti-amyloid therapy.

40. The method of claim 39, wherein the anti-amyloid therapy is an antibody therapy.

41. A method for preventing or reducing the risk of developing amyloid-related imaging abnormalities (ARIA) in a patient with a neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) receiving anti-amyloid therapy comprising administering a therapeutically effective amount of a Janus kinase (JAK) inhibitor to the patient.

42. The use of a Janus kinase (JAK) inhibitor for treating amyloid-related imaging abnormalities (ARIA) in a patient with a neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) receiving anti-amyloid therapy.

43. The use of a Janus kinase (JAK) inhibitor A in the manufacture of a medicament for treating amyloid-related imaging abnormalities (ARIA) in a patient with a neurodegenerative disease or cerebral amyloid angiopathy-related inflammation (CAAri) receiving anti-amyloid therapy.

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