Paper Details

ABSTRACT

Patients with heavily pretreated RRMM remain in need of novel therapies with differentiated mechanisms of action. HDP-101 is a novel BCMA-targeting ADC carrying a synthetic amanitin payload. By inhibiting RNA polymerase II, amanitin provides a mechanistically differentiated cytotoxic approach compared with commonly used ADC payloads. In preclinical studies, HDP-101 demonstrated potent antimyeloma activity, including in myeloma cells with low BCMA expression, non-proliferating/quiescent plasma cells, and models harboring high-risk cytogenetic features such as del(17p). HDP-101-01 is an ongoing first-in-human Phase 1/2a study evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of HDP-101 monotherapy in patients with heavily pretreated RRMM.

Eligible patients were adults with active RRMM previously treated with several lines of therapy, and who were relapsed, refractory, or intolerant to available standard therapies. In Phase 1, dose escalation was guided by an adaptive Bayesian logistic regression model. Dosing optimization strategies, including premedication and split dosing, were introduced from Cohort 6 onward to improve tolerability. The Phase 2a expansion evaluates HDP-101 at the RP2D of 175 µg/kg/cycle, administered as split dosing on Days 1 and 8 during Cycle 1, followed by full-dose administration on Day 1 of each subsequent 21-day cycle. Efficacy is assessed according to IMWG criteria.

As of June 2026, 60 patients had received HDP-101, including 53 patients treated in the completed Phase 1 dose-escalation part across 10 dose levels (20-218 µg/kg/cycle) and 3 dosing schedules, and 7 patients in the ongoing Phase 2a expansion at RP2D. The overall population was heavily pretreated, with a median of 5 prior lines of therapy (range, 2-15), at a median age of 69.5 years (range, 43-90), 25 female and 35 male patients, and. Prior BCMA-targeted therapy had been received by 28% of patients.

Across the 10 dose levels in Phase 1, HDP-101 demonstrated a manageable safety profile. Seven DLTs occurred in 6/52 DLT-evaluable patients. Grade ≥3 TEAEs were reported in 38/60 patients (63.3%), most commonly thrombocytopenia/platelet count decreased (17/60, 28.3%), anemia (6/60, 10%), neutropenia (4/60, 6.7%), and proteinuria (4/60, 6.7%). Cytopenias were transient. No treatment-emergent SAE leading to death occurred, and no drug-related deaths, infusion reactions, or drug-related lung, liver or ocular toxicity signals were observed. In the ongoing Phase 2a expansion, no TEAE led to permanent treatment discontinuation was observed.

Preliminary antitumor activity was observed at dose levels ≥90 µg/kg/cycle. Across Phase 1 cohorts 5-10, the DCR was 77.8% (28/36), the ORR was 44.4% among response-evaluable patients (16/36), including 8 PRs, 5 VGPRs, and 3 sCRs with MRD negativity. Responses were also observed in patients with prior BCMA-targeted therapy exposure (5/11, 45.5%). Median time to response was 1.4 months (range, 0.7-5.7).

Cohorts 8 and 9 showed DCRs of 100% and 80%, and ORRs of 57.1% and 60%, respectively. Although the maximum tolerated dose (MTD) was not reached, recurrent Grade 4 events at the highest tested dose of 218

Noncompartmental analysis demonstrated dose-proportional PK (Cmax, AUC) across doses up to 218 µg/kg/cycle, with a geometric mean half-life of approximately 9 days. At the RP2D (175 µg/kg/cycle), exposure was consistent with the predicted PK profile, the ADC remained stable in circulation without evidence of drug accumulation, free payload was not detected in the circulation, and no anti-drug antibodies were observed. PK/PD modeling supported the use of split dosing and premedication to improve tolerability while maintaining biologically active exposure.

HDP-101 demonstrates a favorable safety profile and encouraging preliminary anti-myeloma activity in heavily pretreated RRMM patients, including patients previously exposed to BCMA-targeted therapy. Selection of 175 µg/kg/cycle as the RP2D was supported by integrated safety, efficacy, PK/PD, and immunogenicity data, therefore supporting the ongoing Phase 2a expansion and further clinical development of HDP-101 as a mechanistically differentiated, amanitin-based BCMA-targeting ADC for RRMM.