Introduction: Although BTK inhibitors (BTKi) are effective therapeutics in the treatment of B cell malignancies, emerging BTK resistance mutations in chronic lymphocytic leukemia (CLL), as well as potential growth-promoting kinase-independent scaffolding function of BTK, present a need for improved or new approaches. NX-5948 is a novel, orally administered small molecule that induces specific BTK protein degradation by the cereblon E3 ligase complex without degradation of other cereblon neo-substrates. Importantly, NX-5948 induces degradation of wild-type and mutant forms of BTK in B-cells [Noviski et al. 2023] at sub-nanomolar potencies and exhibits potent tumor growth inhibition in TMD8 xenograft models that contain either wild-type BTK or BTKi-resistant mutations [Robbins 2021]. Here we provide the first disclosure of preliminary safety and efficacy findings from a Phase 1a trial of NX-5948 in patients with relapsed/refractory B cell malignancies.

Methods: NX-5948-301 is a Phase 1, first-in-human, dose-escalation and cohort-expansion trial evaluating the safety, tolerability, and clinical activity of NX-5948 in relapsed/refractory CLL and various subtypes of non-Hodgkin's lymphoma (NHL). Key eligibility criteria: ≥2 prior lines of therapy; measurable or other evaluable disease per indication-specific response criteria; Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1. Phase 1a (dose escalation) evaluates safety and tolerability of NX-5948 via a standard 3+3 dose escalation in patients with relapsed/refractory B cell malignancies. Approximately 110 patients (30 in Phase 1a, 80 in Phase 1b) may be enrolled and treated until confirmed disease progression or unacceptable toxicity. Endpoints include dose-limiting toxicities (DLTs); treatment-emergent adverse events (TEAEs); deaths; changes in safety parameters; objective response rate per disease-specific response criteria. Phase 1b (dose expansion) will include up to four expansion cohorts.

Results: As of June 9, 2023, 14 patients were enrolled in Phase 1a and received NX-5948 at 50 mg (n=7), 100 mg (n=4), or 200 mg (n=3) orally once daily. Median age was 65 (range 46-79) years; female/male ratio 28.6%/71.4%; white 92.9%; ECOG PS 0/1 21.4%/78.6%; primary diagnoses were CLL (n=4), diffuse large B cell lymphoma (DLBCL, n=4), mantle cell lymphoma (MCL, n=3), marginal zone lymphoma (MZL, n=2), and follicular lymphoma (FL, n=1). Median number of prior therapies was 4.5 (range 2-10), which included: for CLL - BTKi (n=4/4) and BCL2 inhibitor (n=3/4); for NHL - BTKi (n=5/10), bispecific antibody (n=3/10), and CAR-T (n=2/10). NX-5948 was well tolerated with no DLTs and no TEAEs resulting in drug discontinuation or dose reduction. In addition, there were no NX-5948-related grade ≥3 TEAEs or related serious adverse events. The most common TEAEs were purpura/contusion (57.1%, all below grade 3), nausea (35.7%), and thrombocytopenia (35.7%). No atrial fibrillation/flutter or hypertension was reported. Median duration of treatment was 2.8 (range 0.5-9.6) months with 9/14 patients remaining on treatment. Current data indicate that NX-5948 exhibits dose-dependent pharmacokinetics (PK) and a half-life of ~24 hours, supporting once daily dosing (Figure a). Rapid, robust and sustained BTK degradation was observed in all patients, regardless of absolute BTK starting level, tumor type, or NX-5948 dose (Figure b). Of three evaluable patients with CLL receiving the lowest dose of 50 mg, early signs of clinical activity were observed including one confirmed partial response (PR; at 8 and 16 weeks) and 2 patients with stable disease (SD; at 8 weeks). Further treatment responses will be reported at the time of presentation.

Summary/conclusion: Current findings in this heavily pre-treated population of patients with CLL and NHL are encouraging and indicate that NX-5948 is safe and well tolerated and has clinical activity, supporting continuation of its development in CLL and NHL. NX-5948 also exhibits dose-proportional PK, resulting in rapid, robust and sustained BTK degradation. Additional data with higher dose levels and longer treatment duration will be presented at the meeting.

Searle:Janssen: Honoraria, Other: Conference travel; Abbvie: Honoraria, Other: Conference travel; Sanofi: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Forconi:Abbvie: Honoraria, Other: Travel and accommodation, Speakers Bureau; Janssen-cilag: Honoraria, Other: Travel and accommodation, Speakers Bureau; beigene: Honoraria, Other: Travel and accommodation, Speakers Bureau; Astra-Zeneca: Honoraria, Speakers Bureau. Linton:Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hoffman-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Danilov:Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Research Funding; Nurix: Consultancy, Research Funding; MEI: Consultancy, Research Funding; Lilly Oncology: Consultancy, Research Funding; Merck: Consultancy; Cyclacel: Research Funding; Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Genentech: Consultancy; GenMab: Consultancy, Research Funding. McKay:Takeda: Consultancy, Other: Travel to scientific conferences; Roche: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel to scientific conferences; Incyte: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria, Other: Travel to scientific conferences; Celgene/BMS: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy. Lewis:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees. El-Sharkawi:Abbvie, ASTEX, AstraZeneca, BeiGene, Janssen, Kyowa Kiirin: Consultancy; Abbvie, AstraZeneca, BeiGene; Gilead, Janssen, Lily, Novartis, F. Hoffman-La Roche, Takeda: Honoraria; Royal Marsden NHS Foundation trust: Current Employment; Abbvie: Speakers Bureau. Gleeson:Incyte: Other: Speaker Fees. Riches:Janssen: Speakers Bureau. Injac:Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Shih:Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Nandakumar:Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Tan:Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Cherala:Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Gilead Sciences: Current equity holder in private company, Ended employment in the past 24 months; BioMarin: Current equity holder in private company. Meredith:Nurix Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins:Daiichi Sankyo: Consultancy, Honoraria; BMS: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau.

NX-5948 is a novel, orally administered, small molecule that induces specific BTK protein degradation by the cereblon E3 ligase complex, but not of other cereblon neo-substrates.

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2023
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