HDP-101, an investigational B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate (ADC), is demonstrating promising efficacy in patients with relapsed or refractory multiple myeloma. These findings come from the phase 1/2a HDP-101-01 trial (NCT04879043), with updated results presented at the International Myeloma Society (IMS) 21st Annual Meeting. The study is a first-in-human, open-label, non-randomized, multicenter trial.
Novel Mechanism of Action
HDP-101 utilizes a synthetic amanitin payload, which inhibits RNA polymerase II, effectively halting transcription and inducing apoptosis in tumor cells, regardless of their proliferation status. This mechanism differs from other payloads and has 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. Preclinical studies suggest that HDP-101 can overcome preexisting drug resistance, even in cells with low BCMA expression.
Phase 1/2a Trial Design and Patient Population
The phase 1 portion of the study aimed to determine the maximum tolerated dose and/or the recommended phase 2 dose of HDP-101, using an adaptive Bayesian logistic regression model (BLRM) for dose escalation. The phase 2 portion is designed to assess the agent’s antitumor activity.
As of November 2023, 18 patients were enrolled across 5 dose cohorts (20, 30, 60, 80, and 100 μg/kg). The median patient age was 70 years (range 48-82), and patients were heavily pretreated, with a median of 6.5 prior lines of therapy (range 2-15). A significant portion of patients were multidrug resistant.
Pharmacokinetics and Safety
The pharmacokinetics of HDP-101 aligned with preclinical expectations, showing dose-proportionate exposure. No antidrug antibodies or immunogenic reactions were reported, and free payload was not detected in serum. Dose-limiting toxicities were observed in cohort 5 (100 μg/kg), including transient thrombocytopenia, which resolved without intervention. The dose-limiting toxicity rules were adjusted for thrombocytopenia based on recommendations from a scientific review committee, and the BLRM statistics were reset with dose optimization strategies.
Efficacy Results
Preliminary efficacy results are promising. One patient in cohort 3 achieved stable disease for 17 cycles, and 3 patients in cohort 5 experienced partial responses. Two patients in cohort 5 experienced disease progression, with one reducing the dose after cycle 1, and one additional patient experienced stable disease. Another patient is in partial remission after 9 cycles of therapy and is showing a decreasing trend in M-protein.
In cohort 5, 5 out of 6 patients experienced decreasing paraprotein percent changes from screening. One patient achieved a complete response after previously receiving 9 prior lines of therapy, including transplant, immunomodulatory drugs, proteasome inhibitors, daratumumab, and ADCs. After initiating treatment with HDP-101, this patient had a partial response in cycle 2 before experiencing a complete response in cycle 11.
Ongoing Development
The phase 1 trial will proceed with additional schedule-modified dose-escalation cohorts, with a dose-expansion portion anticipated to launch in 2025. These findings support continued research into dose optimization for HDP-101 in relapsed/refractory multiple myeloma.
