(OA-59) The Anti-BCMA Antibody-Drug Conjugate HDP-101 with a Novel Amanitin Payload Shows Promising Data in Relapsed/Refractory Multiple Myeloma in a Phase 1/2a Clinical Trial as it Advances into Cohort 7

HDP-101 is a novel antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA) with a synthetic amanitin payload. It exhibits cytotoxicity in vitro against BCMA-positive myeloma cells, even those with low BCMA density.

Methods:

HDP-101-01 is a first-in-human, open-label, non-randomized, multicenter phase 1/2a clinical trial in Relapsed/Refractory Multiple Myeloma (RRMM). Phase 1 aims to determine the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), using an adaptive Bayesian logistic regression model (BLRM).  As of April 15, 2025, 34 patients (11 female, 23 male; median age 68.5, range 43–82) were enrolled in seven dose cohorts (20–112.5 µg/kg). Patients were heavily pretreated (median 7 prior regimens, range 2-15). Cohort 7 is fully enrolled, DLT period completed; Cohort 8 (140 µg/kg) is enrolling. Dose escalation was initially performed with dosing every 3 weeks (Q3W) up to Cohort 5 (100 µg/kg). From Cohort 6 (90 µg/kg), based on PKPD modeling, dose optimization strategies were introduced including split dosing and/or premedication with corticosteroids and antihistamines, to mitigate the risk of adverse events like thrombocytopenia and liver enzyme elevations. These strategies were evaluated in three arms and further tested in Cohort 7 (112.5 µg/kg). Escalation continues with these new strategies.

Results:

Safety
Treatment was generally well tolerated. No drug-related deaths, infusion reaction, lung, or ocular toxicity were observed. Q3W dosing caused transient liver enzyme elevations and asymptomatic thrombocytopenia (Grade 1-4). No bleeding was associated with thrombocytopenia and platelet count recovered quickly and spontaneously.
Weekly or split dosing with premedication significantly reduced these effects, leading to discontinuation of Q3W dosing.

Efficacy

No responses were observed below 90 µg/kg. From 90 µg/kg/cycle, multiple responses emerged. At 100 µg/kg, three of six patients had partial responses (PR), including one stringent complete response (sCR) lasting 19 months to date. This patient had prior BCMA CAR-T and GPRC5D/CD3 bispecific antibody therapy. In Cohort 6 (90 µg/kg/cycle), two of ten patients showed PR. In Cohort 7 (112.5 µg/kg), 3 patients are ongoing; two have PR. Cohort 8 (140 µg/kg) is actively enrolling.

PKPD

Noncompartmental analysis revealed dose-proportional pharmacokinetics (Cmax, AUC) for all analytes, with a ~10-day half-life. A two-compartment model with linear clearance best described the PK of the total antibody, with minimal free payload observed in serum. PKPD modeling and simulation analyses confirmed that split dosing and/or premedication reduced the impact of HDP-101 on thrombocytes and LFTs.

Conclusions: HDP-101 showed a favorable safety profile up to 112.5 µg/ kg/cycle, with MTD not reached. Dose escalation continues at 140 µg/kg. Responses observed from 90 µg/kg suggest that optimized dosing maintains antitumor efficacy while enhancing tolerability.