The Anti-BCMA Antibody-Drug Conjugate Hdp-101 with a Novel Amanitin Payload Shows Promising Initial First in Human Results in Relapsed Multiple Myeloma

Background: HDP-101 is a novel antibody-drug conjugate (ADC) that targets B-cell maturation antigen (BCMA) with a synthetic amanitin payload, which inhibits RNA polymerase II. This action effectively halts transcription and induces apoptosis in tumor cells, regardless of their proliferation status. HDP-101 has demonstrated cytotoxicity in vitro against BCMA-positive myeloma cell lines and non-proliferating primary CD138+ cells from refractory myeloma patients, even those with low BCMA density.

Clinical Study: HDP-101-01 is a first-in-human, open-label, non-randomized, multicenter phase 1/2a clinical trial conducted in patients with progressive or refractory multiple myeloma. The aim in Phase 1 is to determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D). Dose escalation is guided by an adaptive Bayesian logistic regression model (BLRM) with overdose control. The primary objective in Phase 2 is to assess the anti-tumor activity of HDP-101.

Study Progress: As of July 2024, the study had enrolled 19 patients (7 females, 12 males) across six consecutive dose cohorts: 20, 30, 60, 80, and 100 µg/kg and the latest cohort which is a dose-optimization cohort including three different treatment arms at a dose of 90 µg/kg in various settings including premedication or split dosing. The median age of these patients was 70 years (range 48-82). They were heavily pre-treated and multidrug-refractory, with a median of 6 prior treatment regimens (range 2-15).

Study Results: Preliminary data indicate that the pharmacokinetics of HDP-101 are consistent with non-clinical data and pharmacometric simulations, showing dose-proportional exposure. The free amanitin payload was not detected in serum at the detection limit of 30 ng/mL, and there were no occurrences of anti-drug antibodies or immunogenic reactions. Seventeen of the eighteen patients were evaluable for dose-limiting toxicities (DLTs) by July 2024 in the first 5 cohorts. The initial four dose cohorts were well tolerated, with no observed DLTs, including the absence of hepatic and renal toxicities, infusion reactions, or ocular disorders. Mild elevations in Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) were observed in Cohort 5 during Cycle 1, which resolved spontaneously, returned to baseline and did not recur in subsequent cycles. All patients in Cohort 5 experienced transient thrombocytopenia, characterized by platelet reductions starting on Cycle 1 Day 2 (C1D2), reaching a nadir on Cycle 1 Day 5 (C1D5), and fully recovering by Cycle 1 Day 15 (C1D15) without clinical sequelae or interventions. Subsequent dosing did not result in similarly profound thrombocytopenia episodes, suggesting this effect was not due to direct cytotoxicity against megakaryocytes. DLTs were observed in three patients in Cohort 5. Consequently, based on Safety Review Committee (SRC) recommendations after Cohort 5, the DLT criteria were revised for thrombocytopenia, and dose optimization strategies were developed, including resetting the BLRM statistics. Cohort 6 is currently ongoing with one patient enrolled.

Efficacy: In Cohort 3 (60 µg/kg), one patient achieved stable disease (SD) over 17 cycles. In Cohort 5 (100 µg/kg), two patients achieved partial response (PR), one patient is currently in very good partial response (VGPR) after 12 cycles of treatment, while three exhibited progressive disease, one of whom required a dose reduction after Cycle 1. The patient who is in VGPR had a prior BCMA-targeting CAR-T cell therapy and a GPRC5D/CD3 bispecific antibody therapy. These promising findings support the continuation and further optimization of dosing strategies. Updated data and further analysis will be presented at the ASH 2024 meeting.

Orlowski:Bristol Myers Squibb, CARsgen Therapeutics, Exelixis Inc, Heidelberg Pharma, Janssen Biotech Inc, Sanofi, Takeda Pharmaceuticals USA Inc; Laboratory Research Funding: Asylia Therapeutics Inc, BioTheryX Inc, Heidelberg Pharma: Research Funding; AbbVie Inc, Adaptive Biotechnologies Corporation, Asylia Therapeutics Inc, BioTheryX Inc, Bristol Myers Squibb, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Nanjing IASO Biotherapeutics, Neoleukin Therapeutics, Oncopeptides, Pf: Membership on an entity's Board of Directors or advisory committees; Asylia Therapeutics Inc.: Current equity holder in private company, Patents & Royalties; BioTheryX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; DEM BioPharma, Inc., Karyopharm Therapeutics, Lytica Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Myeloma 360, Nanjing IASO Biotherapeutics, Neoleukin Corporation, Oncopeptides AB, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sporos Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi, Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Richard:Heidelberg Pharma: Research Funding; C4 Therapeutics: Research Funding; Gracell Therapeutics: Other: Steering Committee, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kaufman:Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Ascentage: Consultancy, Honoraria; Genentech: Consultancy; Sebia: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Strassz:Heidelberg Pharma AG: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Pahl:Heidelberg Pharma AG: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Kulke:Heidelberg Pharma AG: Current Employment. Michael:Heidelberg Pharma AG: Current Employment. Last:Heidelberg Pharma AG: Current Employment. Szaboki:Heidelberg Pharma AG: Consultancy. Richard:Heidelberg Pharma AG: Current Employment. Schönborn-Kellenberger:Molecular Partners AG: Consultancy; Heidelberg Pharma AG: Consultancy. Raab:Heidelberg Pharma: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Other: travel expenses; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses, Research Funding.