VAV1-targeting degraders for treatment of psoriatic arthritis

Abstract

The present invention relates to a method of treating psoriatic arthritis (PsA) using a VAV1-targeting degrader, in particular, 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione, a stereoisomer, or a pharmaceutically acceptable salt thereof.

Description

[0001] PAT059986-PCT-SEC01 -1- USE OF VAV1 -TARGETING DEGRADERS FOR TREATMENT OF PSORIATIC ARTHRITIS FIELD OF THE INVENTION

[0002] The present invention relates to a method of treating psoriatic arthritis (PsA) using a VAV1 -targeting degrader, in particular, 3-(2-chloro-4’-(2-oxopyridin-1(2H)-yl)-[1,1’-biphenyl]-3-yl)piperidine-2, 6-dione, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0003] BACKGROUND OF THE INVENTION

[0004] Psoriatic arthritis (PsA) is a chronic immune-mediated disorder involving both the musculoskeletal and dermatologic systems, often marked by peripheral and axial arthritis, enthesitis, dactylitis, and psoriatic lesions of the skin and nails. In order to be classified as having PsA, the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria require that a patient have inflammatory articular disease affecting joints, spine, or entheses in addition to a combination of other clinical features such as current psoriasis , a personal or family history of psoriasis, psoriatic nail changes, negative rheumatoid factor, dactylitis, and radiographic evidence of juxta-articular new bone formation (Taylor W, Gladman D, Helliwell P, et al (2006) Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum; 54(8):2665-73). Approximately 40% of patients with psoriasis develop PsA (Mease PJ, Palmer JB, Hur P, et al (2019) Utilization of the validated Psoriasis Epidemiology Screening Tool to identify signs and symptoms of psoriatic arthritis among those with psoriasis: a cross-sectional analysis from the US-based Corrona Psoriasis Registry. J Eur Acad Dermatol Venereol; 33(5):886-92) and the overall disease affects approximately 0.1-1.0% of the adult population worldwide (Karmacharya P, Crowson CS, Bekele D, et al (2021b) The Epidemiology of Psoriatic Arthritis Over Five Decades: A Population-Based Study. Arthritis Rheumatol; 73(10):1878-85). It shows similar incidence in men and women and exhibits geographic variability, being more frequently reported in Europe and North America compared with Asian and African regions (Lembke S, Macfarlane GJ, Jones GT (2024) The worldwide prevalence of psoriatic arthritis-a systematic review and meta-analysis. Rheumatology (Oxford); 63(12):3211-20). The condition is most prevalent in patients between 30 and 60 years of age (FitzGerald O, Ogdie A, Chandran V, et al (2021) Psoriatic arthritis. Nat Rev Dis Primers; 7(1):59).

[0005] The pathophysiology of PsA is multifactorial and involves a complex interplay between genetic predisposition and immune dysregulation. Strong familial aggregation has been demonstrated in patients with PsA, with HLA class I alleles and immune / inflammation-related genes as I L23 / Th17, nuclearfactor kappa-light-chain-enhancer of activated B cells (NF-KB), janus kinase (JAK) / signal transducers and activators of transcription (STAT), and mitogen-activated protein kinase (MAPK) implicated (Chen J, Yuan F, Fan X, et al (2020) Psoriatic arthritis: A systematic review of non-HLA genetic studies and important signaling pathways. I nt J Rheum Dis; 23(10): 1288-96). The immune system dysfunction is likely to involve both the innate and adaptive immune pathways, with central roles for tumor necrosis factor (TNF), interleukin-17 (IL-PAT059986-PCT-SEC01 -2- 17), and interleukin-23 (IL-23) (Lee HJ and Kim M (2023) Challenges and Future Trends in the Treatment of Psoriasis. Int J Mol Sci; 24(17)).

[0006] The initial management of PsA may include administration of non-steroidal antiinflammatory drugs (NSAIDs) and local corticosteroid injections for symptom relief; however, in patients with arthritis and inadequate response to these measures, systemic treatment with a disease-modifying antirheumatic drugs (DMARD) is recommended as per the European Alliance of Associations for Rheumatology (EULAR) (Gossec L, Kerschbaumer A, Ferreira RJO, et al (2024) EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update. Ann Rheum Dis; 83(6):706-19) and Group for Research and Assessment of Psoriasis and Psoriatic (GRAPPA) (Gossec et al 2024; Coates LC, Soriano ER, Corp N, et al (2022) Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA): updated treatment recommendations for psoriatic arthritis 2021. Nat Rev Rheumatol; 18(8):465-79). Systemic therapy typically begins with a conventional synthetic DMARD (csDMARD), with escalation to biologic DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) in patients who do not achieve treatment targets on csDMARD therapy.

[0007] Patients with active PsA have synovial inflammation, enthesitis, bone remodeling, and frequently experience irreversible structural damage. Despite the availability of different treatment modalities, a substantial proportion of PsA patients have active disease, with approximately 40-50% failing to achieve remission or low disease activity (Lopez-Medina C, Kalyoncu U, Gossec L (2024) Unmet needs in psoriatic arthritis, a narrative review. Arch Rheumatol; 39(2):159-71; Alten R, Conaghan PG, Strand V, et al (2019) Unmet needs in psoriatic arthritis patients receiving immunomodulatory therapy: results from a large multinational real-world study. Clin Rheumatol; 38(6): 1615-26). Between 13-44% of patients switch biologic or targeted synthetic DMARDs within 1-2 years, most commonly due to lack of efficacy or adverse events. Persistence at one-year ranges from 31-59%, with discontinuation rates of 35-56% depending on treatment and population (Bhushan V, Lester S, Briggs L, et al (2021) Real-Life Retention Rates and Reasons for Switching of Biological DMARDs in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis. Front Med (Lausanne), 8:708168; Lorenzin M, Ortolan A, Cozzi G, et al (2021) Predictive factors for switching in patients with psoriatic arthritis undergoing anti-TNFa, anti-IL12 / 23, or anti-IL17 drugs: a 15-year monocentric real-life study. Clin Rheumatol; 40(11):4569-80; Glintborg B, Ostergaard M, Krogh NS, et al (2013) Clinical response, drug survival, and predictors thereof among 548 patients with psoriatic arthritis who switched tumor necrosis factor a inhibitor therapy: results from the Danish Nationwide DANBIO Registry. Arthritis Rheum; 65(5):1213-23; Murage MJ, Princic N, Park J, et al (2022) Treatment patterns and health care costs among patients with psoriatic arthritis treated with biologic or targeted synthetic diseasemodifying antirheumatic drugs. J Manag Care Spec Pharm; 28(2):206-17; Sewerin P, Borchert K, Meise D, et al (2021) Real-World Treatment Persistence with Biologic Disease-Modifying Antirheumatic Drugs Among German Patients with Psoriatic Arthritis-A Retrospective DatabasePAT059986-PCT-SEC01 -3- Study. Rheumatol Ther; 8(1):483-97; Scholz GA, Papagiannoulis E, Blapp C, etal (2025) Longer Drug Retention of Interleukin-12 / 23 or Interleukin-17 Inhibitors Compared With TNF Inhibitors in Female Patients With TNF Inhibitor-Experienced Psoriatic Arthritis. Mayo Clin Proc Innov Qual Outcomes; 9(3): 100622; Soardo F, Spini A, Pellegrini G, et al (2025) Frequency of Biological Drug Use in Older Patients with Immune-Mediated Inflammatory Diseases: Results from the Large-Scale Italian VALORE Distributed Database Network. BioDrugs; 39(3):499-512). Thus, in the current treatment paradigm, many patients with PsA experience pain, fatigue, and reduced physical function. This symptomatic burden can negatively affect mental health, daily activities, sleep, work and leisure activities, and social participation, resulting in reduced health-related quality of life (Coates et al., 2022), underscoring the need for additional therapeutic options that can address persistent disease activity and overcome limitations of current treatments.

[0008] Compound A, i.e., 3-(2-chloro-4’-(2-oxopyridin-1(2H)-yl)-[1,1’-biphenyl]-3-yl)piperidine-2, 6-dione, is a highly potent and selective first-in-class compound that utilizes the natural cellular degradation pathway to target VAV1, a critical regulator of T- and B-cell receptor activity predominantly expressed in immune cells. VAV1 serves as a principal signal transduction protein operating downstream of immune receptors, particularly the T-cell receptor (TCR) and B-cell receptor (BCR). Upon activation mediated by these receptors, VAV1 -dependent signaling facilitates the activation and functional response of both T and B cells. Studies indicate that loss ofVAVI function correlates with diminished T- and / or B-cell activity (Betzler AC, KieserS, Fiedler K, et al (2022) Differential Requirement of Vav Proteins for Btk-dependent and -Independent Signaling During B Cell Development. Front Cell Dev Biol; 10:654181; Schmidt R, Steinhart Z, Layeghi M, et al (2022) CRISPR activation and interference screens decode stimulation responses in primary human T cells. Science; 375(6580):eabj4008; Turner M and Billadeau DD (2002) VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nat Rev Immunol; 2(7):476-86) and enhanced protection against immune-mediated diseases (Haubert D, Li J, Saveliev A, et al (2012) Vav1 GEF activity is required for T cell mediated allograft rejection. Transpl Immunol; 26(4):212-9; Korn T, Fischer KD, Girkontaite I, et al (2003) Vav1-deficient mice are resistant to MOG-induced experimental autoimmune encephalomyelitis due to impaired antigen priming. J Neuroimmunol; 139(1 -2): 17-26). Through the targeted degradation of VAV1 and subsequent suppression of its activity, Compound A offers a novel strategy for modulating dysregulated immune responses from both T and B cells in a non-depleting manner. This mechanism of action may provide therapeutic benefits for individuals with PsA.

[0009]

[0010] Compound APAT059986-PCT-SEC01 -4- The preparation of the compound of Formula I was first disclosed in WO2024 / 151547 as Example 24.

[0011] SUMMARY OF THE INVENTION

[0012] The present invention provides a method of treating psoriatic arthritis, comprising administering Compound A in a racemic or chiral form, or a pharmaceutically acceptable salt thereof to a patient in need.

[0013] BRIEF DESCRIPTON OF THE FIGURES FIG. 1. Effect of Compound A on TCR-mediated CD69 activation (Left), IL-2 secretion (Center), and proliferation (Right).

[0014] FIG. 2. Effect of Compound A on BCR-mediated CD69 activation (Left), IL-6 secretion (Center), soluble IgG secretion (Right), and Proliferation (Bottom).

[0015] FIG. 3. Compound A inhibits disease progression and incidence in a CIA Model.

[0016] FIG. 4. Plasma concentration of Compound A after single dose administration.

[0017] FIG. 5. VAV1 degradation >90% in peripheral blood T cells after single dose (FIG. 5a) or multiple dose (FIG. 5b) administration.

[0018] FIG. 6. VAV1 degradation by Compound A resulted in significant functional inhibition of T and B cells following a single dose administration.

[0019] FIG. 7. Suppression of CD69 upregulation (>90%) in peripheral blood T and B cells following TCR stimulation after single dose (FIG. 7a) or multiple dose (FIG. 7b) administration.

[0020] FIG. 8. Significant and sustained suppression of IL-2, IL-17A and IFN-y secretion from whole blood following ex vivo stimulation of TCR after single dose (FIG. 8a) or multiple dose (FIG. 8b) administration.

[0021] DETAILED DESCRIPTION OF THE INVENTION

[0022] Compound A, i.e., 3-(2-chloro-4’-(2-oxopyridin-1(2H)-yl)-[1,1’-biphenyl]-3-yl)piperidine-2, 6-dione, in a racemic or chiral form is a first-in-class molecular glue degrader that specifically targets VAV1 for proteasomal-mediated degradation. Preclinical studies of Compound A have demonstrated deep degradation of VAV1, resulting in a significant decrease in cytokines linked to immune-mediated conditions, with no detectable effects on other proteins. Compound A has shown promising activity in preclinical models of multiple immune-mediated conditions, and is currently under clinical development for PsA.

[0023] The present invention is described in the following embodiments.

[0024] In one embodiment, the invention provides a method of treating psoriatic arthritis in a patient, comprising administering 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-PAT059986-PCT-SEC01 -5-yl)piperidine-2, 6-dione ( Compound A), or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0025]

[0026] Compound A

[0027] In another embodiment, the invention provides a method of treating psoriatic arthritis in a patient, comprising administering orally 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A), or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0028] In another embodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1 , 1 '-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A), or a pharmaceutically acceptable salt thereof, for use in ingtreating psoriatic arthritis.

[0029] In another embodiment, the invention provides use of 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1 , 1 '-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A), or a pharmaceutically acceptable salt thereof for preparing a medicament for treating psoriatic arthritis.

[0030] In another embodiment, the invention provides use of 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1 , 1 '-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A), or a pharmaceutically acceptable salt thereof for preparing a medicament formulated for oral administration for treating psoriatic arthritis.

[0031] In anotherembodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A) of any of the preceding embodiments, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,T-biphenyl]-3-yl)piperidine-2, 6-dione (Formula I) is in a racemic or chiral form.

[0032] In anotherembodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Formula I) of any of the preceding embodiments, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,T-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A) comprises (F?)-3-(2-chloro-4'-(2-oxopyridin-1 (2 H)-y l)-[1 , 1 '- bipheny l]-3-y I) pi perid i ne-2 , 6-dione (Formula la) and (S)-3-(2-chloro-4'-(2-oxopyridin-1 (2 H)-y l)-[ 1 , 1 '- bi pheny l]-3-y I) pi peridi ne-2 , 6-dione (Formula lb).

[0033]

[0034] PAT059986-PCT-SEC01 -6- Compound A1 Compound A1

[0035] In anotherembodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-bipheny l]-3-y I) pi perid i ne-2 , 6-dione ( Compound A) of any of the preceding embodiments, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,T-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A) is (R)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A1).

[0036] In anotherembodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A) of any of the preceding embodiments, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,T-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A) is (S)-3-(2-chloro-4'-(2-oxopyridin-1 (2 H)-y l)-[ 1 , 1 '-bi pheny l]-3-y I) pi perid i ne-2 , 6-dione ( Compound A2).

[0037] In anotherembodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A), (R)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1 , 1 '-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A1), or (S)-3-(2-chloro-4'-(2-oxopyridin-1 (2H)-yl)-[1 , 1 '-biphenyl]-3-yl)piperidine-2, 6-dione ( Compound A2) of any of the preceding embodiments, in a therapeutically effective amount.

[0038] In anotherembodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of Compound A, Compound A1, or Compound A2, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, for use in treating psoriatic arthritis.

[0039] In anotherembodiment, the invention provides a method of treating psoriatic arthritis in a patient, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of Compound A, Compound A1, or Compound A2, or a pharmaceutically acceptable salt thereof of any of the preceding embodiments and one or more pharmaceutically acceptable carriers.

[0040] DEFINITIONS

[0041] The phrase “pharmaceutically acceptable” as employed herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0042] The term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.PAT059986-PCT-SEC01 -7- 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0043] The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and / or ameliorating a condition, or a disorder, or a disease or biological process (e.g., tissue regeneration and reproduction) (i) mediated by VAV1, or (ii) associated with VAV1 activity, or (iii) characterized by activity (normal or abnormal) of VAV1; or (2) reducing or inhibiting the activity of VAV1 ; or (3) reducing or inhibiting the expression of VAV1 ; or (4) reducing or inhibiting activation ofVAVI. In another non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit the activity of VAV1 ; or at least partially reduce or inhibit the expression of VAV1.

[0044] The term "treatment" or “treat” is herein defined as the application or administration of a compound according to the disclosure, to a subject or to an isolated tissue or cell line from a subject, where the subject has a particular disease (e.g., PsA), a symptom associated with the disease (e.g., PsA), or a predisposition towards development of the disease (e.g., PsA) (if applicable), where the purpose is to cure (if applicable), delay the onset of, reduce the severity of, alleviate, ameliorate one or more symptoms of the disease, improve the disease, reduce or improve any associated symptoms of the disease or the predisposition toward the development of the disease. The term “treatment” or “treat” includes treating a patient suspected to have the disease as well as patients who are ill or who have been diagnosed as suffering from the disease or medical condition, and includes suppression of clinical relapse.

[0045] Method of Treating Psoriatic Arthritis

[0046] In one embodiment, the invention provides a method of treating psoriatic arthritis in a patient, comprising administering 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione ( Compound A), or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0047]

[0048] PAT059986-PCT-SEC01 -8-

[0049] Compound A

[0050] In another embodiment, the invention provides a method of treating psoriatic arthritis in a patient, comprising administering orally 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A), or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0051] In anotherembodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A), or a pharmaceutically acceptable salt thereof, for use in ingtreating psoriatic arthritis.

[0052] In another embodiment, the invention provides use of 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1 , 1 '-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A), or a pharmaceutically acceptable salt thereof for preparing a medicament for treating psoriatic arthritis.

[0053] In another embodiment, the invention provides use of 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1 , 1 '-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A), or a pharmaceutically acceptable salt thereof for preparing a medicament formulated for oral administration for treating psoriatic arthritis.

[0054] In anotherembodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A) of any of the preceding embodiments, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,T-biphenyl]-3-yl)piperidine-2, 6-dione (Formula I) is in a racemic or chiral form.

[0055] In another embodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1 , 1'-biphenyl]-3-yl)piperidine-2, 6-dione (Formula I) of any of the preceding embodiments, wherein the 3-(2-chloro-4'-(2-oxopyridin-1 (2 H)-y l)-[1 , 1 '- bipheny l]-3-y I) pi perid i ne-2 , 6-dione (Compound A) comprises (F?)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Formula la) and (S)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]- 3-yl)piperidine-2, 6-dione (Formula lb).

[0056]

[0057] In anotherembodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-bipheny l]-3-y I) pi perid i ne-2 , 6-dione ( Compound A) of any of the preceding embodiments, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A) is (F?)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A1).PAT059986-PCT-SEC01 -9- In anotherembodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A) of any of the preceding embodiments, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A) is (S)-3-(2-chloro-4'-(2-oxopyridin-1 (2 H)-y l)-[ 1 , 1 '-bi pheny l]-3-y I) pi perid i ne-2 , 6-dione ( Compound A2).

[0058] In anotherembodiment, the invention provides 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A), (R)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1 , 1'-biphenyl]-3-yl)piperidine-2, 6-dione (Compound A1), or (S)-3-(2-chloro-4'-(2-oxopyridin-1 (2H)-yl)-[1 , 1'-biphenyl]-3-yl)piperidine-2, 6-dione ( Compound A2) of any of the preceding embodiments, in a therapeutically effective amount.

[0059] In anotherembodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of Compound A, Compound A1, or Compound A2, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, for use in treating psoriatic arthritis.

[0060] In anotherembodiment, the invention provides a method of treating psoriatic arthritis in a patient, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of Compound A, Compound A1, or Compound A2, or a pharmaceutically acceptable salt thereof of any of the preceding embodiments and one or more pharmaceutically acceptable carriers.

[0061] Psoriatic Arthritis and Effectiveness of Treatment according to the Invention

[0062] The disclosed VAV1 degrader, i.e., Compound A, or a pharmaceutically acceptable salt thereof, may be used in vitro, ex vivo, or incorporated into pharmaceutical compositions and administered in vivo to treat PsA patients (e.g., human patients).

[0063] The effectiveness of a PsA treatment may be assessed using various known methods and tools that measure PsA state and / or PsA clinical response as described below. Some examples include, e.g., achieving ACR50.

[0064] Efficacy

[0065] Clinical efficacy measurements related to primary and secondary objectives are outlined below.

[0066] American College of Rheumatology Response (ACR)

[0067] The American College of Rheumatology 50% improvement criteria (ACR50) from baseline is a well-established, clinically meaningful measure of response in psoriatic arthritis (PsA). Achievement of ACR50 indicates substantial disease control across multiple domains, including tender and swollen joint counts, patient-reported outcomes, and functional status. A participant will be considered as improved according to the ACR50 criteria if he / she has at least 50% improvement in the three following measures:

[0068] • Tender joint count (based on 78 joints);PAT059986-PCT-SEC01 -10- • Swollen joint count (based on 76 joints);

[0069] • and at least 3 of the following 5 domains:

[0070] a. Patient's assessment of pain (NRS);

[0071] b. Patient's global assessment of disease activity (NRS);

[0072] c. Physician's global assessment of disease activity (NRS);

[0073] d. Health Assessment Questionnaire - Disability Index (HAQ-DI©) score; and e. Acute phase reactant (hsCRP or ESR).

[0074] Similarly, efficacy can be measured by 70% improvement (ACR70), or 20% improvement (ACR20).

[0075] In one embodiment, the efficacy of the PsA treatment is achievement of ACR50.

[0076] In another embodiment, the efficacy of the PsA treatment is achievement of ACR70.

[0077] Psoriasis Area and Severity Index (PASI)

[0078] The PASI score (0-72) is a combination of the intensity of psoriasis, assessed by erythema (redness), induration (plaque thickness) and desquamation (scaling) scored on a scale from 0 (none) to 4 (very severe), together with the percentage of the area affected, rated on a scale from 0 (no involvement) to 6 (90% to 100% involvement). Four anatomic sites are assessed with the corresponding weights of head 10%, upper extremities 20%, trunk 30% and lower extremities 40%. The PASI score is calculated using this formula:

[0079] PASI = 0.1 (Eh + Ih + Dh)Ah + 0.2(Eu + lu + Du)Au + 0.3(Et + It + Dt)At + 0.4(EI + II + DI)AI

[0080] Where E = erythema, I = induration, D = desquamation, and A = area; and h, u, t, and / represent head, upper extremities, trunk, and lower extremities, respectively. A PASI 75, 90 or 100 response translates to at least 75, at least 90 or 100 percent improvement from baseline on the PASI score post-treatment.

[0081] In one embodiment, the efficacy of the PsA treatment is achievement of PASI 75.

[0082] In another embodiment, the efficacy of the PsA treatment is achievement of PASI 90. In another embodiment, the efficacy of the PsA treatment is achievement of PASI 100.

[0083] Minimal Disease Activity (MPA)

[0084] Minimal Disease Activity (MDA) in Psoriatic Arthritis (PsA) is a state of low disease activity that serves as a treatment target. It's defined by meeting at least 5 out of 7 specific criteria, reflecting a meaningful improvement in the patient's condition. To be classified as having MDA, a patient with PsA must meet at least 5 out of the following 7 criteria:

[0085] 1. < 1 tender joint count,

[0086] 2. < 1 swollen joint count,

[0087] 3. PASI < 1 or IGA < 1,

[0088] 4. participant pain VAS < 15,

[0089] 5. patient global VAS < 20,

[0090] 6. HAQ-DI < 0.5, andPAT059986-PCT-SEC01 -11- 7. tender entheseal points < 1

[0091] Pharmaceutical Composition

[0092] Compound A, or a pharmaceutically acceptable salt thereof, may be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition may contain, in addition to Compound A, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art. The characteristics of the carrier depend on the route of administration. The pharmaceutical compositions for use in the disclosed methods may also contain additional therapeutic agents for treatment of the particular targeted disorder. For example, a pharmaceutical composition may also include antiinflammatory or anti-itch agents. Such additional factors and / or agents may be included in the pharmaceutical composition to produce a synergistic effect with Compound A, or to minimize side effects caused by Compound A.

[0093] In some embodiments, the pharmaceutical composition is a tablet.

[0094] In some embodiments, the pharmaceutical composition is a capsule.

[0095] Kits of the Invention

[0096] The disclosure also encompasses kits for treating PsA. Such kits comprise Compound A, i.e., 3-(2-chloro-4'-(2-oxopyridin-1(2 / 7)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione, or a pharmaceutical composition thereof. Additionally, such kits may comprise instructions for use.

[0097] In one embodiment, the kit comprises two or more separate pharmaceutical compositions, at least one of which contains Compound A or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.

[0098] The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.

[0099] Example 1: Preclinical Studies

[0100] Example 1a: Compound A-mediated ternary complex formation with human CRBN and VAV1

[0101] Formation of a ternary complex between Compound A, CRBN, and VAV1 is expected to precede subsequent degradation of VAV1 by the proteosome. Both biochemical and cellular in vitro assays were utilized to evaluate Compound A-mediated ternary complex formation with VAV1 and CRBN. An in vitro homogenous time-resolved fluorescence assay was performed with increasing concentrations of Compound A to evaluate ternary complex formation withPAT059986-PCT-SEC01 -12-recombinant human CRBN / DDB1 and human VAV1. Compound A promoted complex formation in a concentration-dependent manner, with a mean half-maximal effective concentration (EC50) of 7.0 nM. In a species-adapted version of the assay for cynomolgus monkey, Compound A promoted in vitro ternary complex formation with an EC50 of 7.2 nM. EC50 values for mouse, rat, and rabbit were 9.7, 12.4, and 17.1 nM, respectively. A cellular NanoBRET™ assay was performed to evaluate Compound A-mediated cellular VAV1:CRBN protein interaction with increasing concentrations of Compound A. In the presence of exogenously expressed full-length VAV1 NanoLuc® and full-length CRBN-HaloTag in HEK293 cells, Compound A induced VAV1 :CRBN complex formation, with an EC50 of 6 nM.

[0102] Example 1b: Compound A-mediated VAV1 degradation in cells is CRBN dependent Compound A-mediated ternary complex formation of VAV1:CRBN is expected to lead to VAV1 degradation in cells in a CRBN-dependent manner. The Cullin RING E3 ligase (CRL) component of CRBN requires neural-precursor-cell-expressed developmentally down-regulated 8 (NEDD8) for neosubstrate binding and proteasomal degradation. To demonstrate this mechanism, Compound A-mediated degradation was assessed in Jurkat cells, a human T-cell acute lymphoblastic leukemia malignant cell line. A CRBN-knockout derivative of the Jurkat cell line was generated and characterized for CRBN loss to probe the CRBN dependency of Compound A-mediated degradation. Dose-dependent degradation of VAV1 was observed in wildtype Jurkat cells, with a concentration that results in 50% VAV1 degradation (DCso) of 5.2 nM. Both the genetic loss of CRBN or pre-treatment with MLN4924 (2 pM), a ubiquitin-like protein NEDD8-activating enzyme inhibitor, rescued VAV1 from degradation by Compound A, demonstrating that VAV1 degradation is mediated by neosubstrate formation between VAV1 and the CRL component of CRBN.

[0103] Example 1c: Compound A on TCR- and BCR-mediated functional activity

[0104] VAV1 is a dominant signal transduction protein downstream of both the TCR and BCR. Compound A was evaluated for its potential to attenuate both TCR- and BCR-mediated proximal PD effects and subsequent measures of activity in primary human lymphocytes. As shown in FIG.

[0105] 1 in primary human T cells, Compound A dose dependently attenuated TCR-mediated CD69 activation, IL-2 secretion, and proliferation in primary human T cells, with EC50 values of 0.2, 0.09, and 0.3 nM, respectively (average of 5 donors).

[0106] As shown in FIG. 2 in primary human B cells, Compound A dose dependently attenuated BCR-mediated CD69 activation, IL-6 and soluble IgG secretion, and proliferation with EC50 values of 0.62, 0.53, 1.3, and 2.8 nM, respectively.

[0107] Example 1d: Efficacy in a mouse model of collagen-induced arthritisPAT059986-PCT-SEC01 -13- Compound A was tested in a T / B-cell-mediated CIA model to evaluate its activity in attenuating disease progression.

[0108] Mice were immunized with bovine CH emulsified in complete Freund’s adjuvant twice, 21 days apart. After the second immunization, mice were monitored every 3 days for clinical signs of disease (comprising progressive erythematosus, redness, and swelling of paws) and enrolled into treatment groups upon a clinical score of 1 to 2 (maximum score per paw: 4; maximum total score: 16). Once enrolled, mice were orally administered vehicle (10% Captisol in water) or 1 mg / kg Compound A QD for 21 days. Following treatment initiation, mouse body weight and clinical signs of disease were monitored daily. At study termination, serum was collected for ex vivo analysis of anti-CII lgG1 antibodies by enzyme-linked immunosorbent assay and pro-inflammatory cytokines by Meso Scale Discovery immunoassay. Compound A inhibited disease progression as evidenced by significantly lower clinical scores in Compound A-treated mice compared to the vehicle group (1.7±0.6 versus 5.4±0.9, respectively) at study endpoint (FIG. 3). Analysis of clinical score area under the curve in Compound A-treated mice demonstrated significantly reduced disease severity of 67% compared to the vehicle group.

[0109] Example 2: Phase 1 Clinical Trial

[0110] A first-in-human study was conducted to assess the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple doses of Compound A in healthy volunteers, to support further clinical development of Compound A in autoimmune diseases. This study also explored the effect of food intake.

[0111] First-in-human study in approximately 108 healthy volunteers (HVs). Part 1 evaluated the safety and tolerability of single ascending oral doses of Compound A in healthy adult subjects. Part 2 evaluated the safety and tolerability of multiple ascending oral doses of Compound A in healthy adult subjects.

[0112] Part 1 (SAD):

[0113] Subjects in each cohort will receive a single oral dose of Compound A or placebo on Day 1, under fasting conditions.

[0114] Six cohorts were enrolled. In each cohort, subjects received a single oral dose of Compound A or a placebo under fasting conditions, with one cohort crossing over to receive the same dose of Compound A or placebo for the second time under fed conditions. Subjects were given the compound of Formula (I) at a pre-determined dose, depending on their cohort.

[0115] Plasma samples were collected predose through 168 hours following administration of Compound A to study its pharmacokinetics. Whole blood samples were collected predose through 168 hours following administration for the pharmacodynamics / biomarker assessments.

[0116] Part 2 (MAD):

[0117] Five cohorts were enrolled. Subjects were given one of five dose levels of Compound A, depending on their cohort. In each cohort, subjects received multiple oral doses of Compound APAT059986-PCT-SEC01 -14-or placebo once a day for 7 days under fasting conditions, with the last dose on the morning of Day 7. Safety was assessed throughout the study. Plasma samples were collected predose and through 24 hours following administration on Day 1. They were also collected predose and through 168 hours following the last administration of Compound A on Day 7. Plasma samples were also collected prior to morning doses for the assessment of trough PK concentrations. Urine samples were collected predose on Day 1 and for 24 hours on Day 7 following the last administration for the pharmacokinetics of Compound A.

[0118] Whole blood samples were collected prior to selected Compound A morning administration on Day 1 through Day 5 as appropriate, and predose through 168 hours following the last administration on Day 7 for the pharmacodynamics / biomarker assessments.

[0119]

[0120]

[0121] PAT059986-PCT-SEC01 -15-

[0122] Results Summary

[0123] Safety:

[0124] Compound A was well tolerated with no serious adverse events (SAE).

[0125] Pharmacokinetics:

[0126] Compound A displayed a dose-dependent human pharmacokinetic profile (Table 1 and FIG. 4).

[0127] Table 1. Compound A pharmacokinetic data

[0128]

[0129] Pharmacodynamics:

[0130] • Compound A achieved dose-dependent VAV1 degradation >90% in peripheral blood T cells after single (FIG. 5a) and multiple dose (FIG. 5b) administration.

[0131] • Similar results observed in peripheral blood B cells

[0132] • VAV1 protein reduction is sustained, with dose-dependent recovery post treatment • Pharmacodynamic studies suggest robust functional effects on cytokine production can be achieved with >80% degradation of VAV1 (FIG. 6):

[0133] o Significantly attenuated CD69 upregulation on T and B cells following TCR stimulation, reflecting functional inhibition

[0134] o Significantly (up to 99%) inhibited IL-2, IFN-y and IL-17A secretion from whole blood derived T cells following ex vivo TCR stimulationPAT059986-PCT-SEC01 -16- o Attenuated IL-6 production by 60-90% across dose levels following B-cell stimulation

[0135] • Compound A resulted in sustained suppression of TCR-mediated CD69 activation following single or multiple dose administration

[0136] o Marked suppression of CD69 upregulation (>90%) in peripheral blood T and B cells following TCR stimulation (data for selected SAD and MAD dose shown as example in FIG. 7a and FIG. 7b)

[0137] o Similar results observed in peripheral blood B cells following BCR stimulation • Compound A resulted in sustained suppression of TCR-mediated cytokine production following single or multiple dose administration

[0138] o Significant and sustained suppression of IL-2, IL-17A and IFN-y secretion from whole blood following ex vivo stimulation of TCR (data for selected SAD and MAD dose shown as example in FIG. 8a and FIG. 8b)

[0139] Conclusions

[0140] • Pharmacodynamic and functional ex vivo studies suggest significant effects on cytokine production can be achieved following marked and sustained degradation of VAV1 • Demonstrated levels of VAV1 degradation consistent with levels of degradation required to induce efficacy in preclinical models

[0141] • Functional impact on cytokine production consistent with levels predicted to be required to achieve efficacy in humans (based on benchmark clinical data)

[0142] • Highly favorable safety profile in humans

[0143] • Support potential application in treating psoriatic arthritis

Claims

PAT059986-PCT-SEC01 -17- CLAIMS1. A method of treating psoriatic arthritis in a patient, comprising administering a therapeutically effective amount of 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof to a patient in need thereof.

2. The method of claim 1, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione is in a racemic or chiral form.

3. The method of claim 1 or 2, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione comprises (R)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,T-biphenyl]-3-yl)piperidine-2, 6-dione and (S)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione.

4. The method of claim 1 or 2, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-bipheny l]-3-y I) pi perid i ne-2 , 6-dione is (R)-3-(2-chloro-4'-(2-oxopyridin-1 (2 H)-y l)-[ 1 , 1 '- bi pheny l]-3-yl)piperidine-2, 6-dione.

5. The method of claim 1 or 2, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-bipheny l]-3-y I) pi perid i ne-2 , 6-dione is (S)-3-(2-chloro-4'-(2-oxopyridin-1 (2 H)-y l)-[ 1 , 1 '- bi pheny l]-3-yl)piperidine-2, 6-dione.

6. A compound for use in the treatment of psoriatic arthritis, wherein the compound is 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein the 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2, 6-dione is in a racemic or chiral form.

8. The compound of claim 6 or 7, wherein the compound is (R)-3-(2-chloro-4'-(2-oxopyridin-1 (2H)-yl)-[1 , 1'-biphenyl]-3-yl)piperidine-2, 6-dione and (S)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1 , 1 '-biphenyl]-3-yl)piperidine-2, 6-dione.

9. The compound of claim 6 or 7, wherein the compound is (R)-3-(2-chloro-4'-(2-oxopyridin-1 (2H)-yl)-[1 , 1'-biphenyl]-3-yl)piperidine-2, 6-dione or (S)-3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1 , 1 '-biphenyl]-3-yl)piperidine-2, 6-dione.

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