OA – 60: The Anti-BCMA Antibody-Drug Conjugate HDP-101 with a Novel Amanitin Payload Shows Promising Initial First in Human Results in Relapsed Multiple Myeloma

Introduction:

Background: HDP-101 is a new antibody-drug conjugate targeting B-cell maturation antigen (BCMA) with a synthetic amanitin payload that inhibits RNA polymerase II, effectively stopping transcription and inducing apoptosis in tumor cells, regardless of their proliferation status. It's shown cytotoxicity in vitro against BCMA-positive myeloma cell lines and non-proliferating primary CD138+ cells from refractory myeloma patients, even with low BCMA density.



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

Study Progress: As of November 2023, 18 patients (7 females, 11 males) were enrolled in 5 consecutive dose cohorts of 20, 30, 60, 80, and 100 µg/kg. Patients had a median age of 70 years (48-82), were heavily pre-treated and multidrug-resistant, and had a median of 6.5 prior treatments (2-15).


Results: Study

Results: Preliminary data shows pharmacokinetics of HDP-101 aligns with expectations, and exposure is dose-proportional. Free payload was not detected in serum at a limit of detection of 30 ng/mL, and no anti-drug antibodies or immunogenic reactions were noted. 17 of 18 patients were evaluable for dose-limiting toxicities (DLT). Initial cohorts were well tolerated, without DLTs, including no hepatic and renal toxicities, infusion reactions, or ocular disorders. Mild ALT and AST elevations were detected in Cohort 5 at Cycle 1, which returned to baseline spontaneously and were not detected in later cycles. All patients in Cohort 5 had transient thrombocytopenia, with platelet reductions starting on Cycle 1/Day 2 (C1D2), a nadir on C1D5, and full recovery by C1D15 without clinical sequelae or interventions. Subsequent dosing did not produce similarly deep episodes of thrombocytopenia, suggesting it's not due to a direct cytotoxic effect against megakaryocytes. DLTs were observed in 3 patients in Cohort 5. Based on SRC recommendations, DLT rules were modified for thrombocytopenia and dose optimization strategies were developed with resetting the BLRM statistics.

Conclusions:
Efficacy: In cohort 3 (60µg/kg), one patient had 17 cycles with stable disease (SD). In Cohort 5 (100µg/kg), 3 patients achieved partial response (PR), 2 patients showed progressive disease, one with dose reduced after C1, one patient had stable disease as best response. One patient is ongoing in partial remission after 9 cycles with a decreasing trend in M-protein levels. These encouraging results support continuation of dose optimization. Updated data will be presented at the IMS 2024 meeting.