Novel antibody-drug conjugate HDP-101 shows promise in relapsed multiple myeloma

HDP-101, a novel investigational B-cell maturation antigen (BCMA) and targeted antibody-drug conjugate (ADC), demonstrated encouraging efficacy in patients in the Phase 1/2a study HDP-101-01 (NCT04879043). with progressive or refractory multiple myeloma). Updated results from the first-in-human, open-label, non-randomized, multicenter study were presented at the 21st Annual Meeting of the International Myeloma Society, held September 25-28, 2024 in Rio de Janeiro, Brazil.¹

“HDP-101 is a novel antibody-drug conjugate against BCMA with a synthetic amanitin payload that inhibits RNA polymerase II, effectively halts transcription, and induces apoptosis in tumor cells, regardless of their proliferation status,” the authors write. “It demonstrated in vitro cytotoxicity against BCMA-positive myeloma cell lines and non-proliferating primary CD138+ cells from patients with refractory myeloma, even at low BCMA density.”

In Phase 1, the study aimed to determine the maximum tolerated dose and/or the recommended Phase 2 dose of HDP-101, with dose escalation controlled by an adaptive Bayesian logistic regression model (BLRM). In phase 2, the researchers want to measure the anti-tumor activity of the active ingredient.

As of November 2023, a total of 18 patients were enrolled in 5 dose cohorts (20, 30, 60, 80 and 100 µg/kg in cohorts 1, 2, 3, 4 and 5). The median patient age was approximately 70 (48-82) years old and the patient population was heavily pretreated, with a median of 6.5 (2-15) prior lines of therapy. The patients were also multi-resistant.

To date, the pharmacokinetics of HDP-101 have been consistent with study expectations and exposure is proportional to dose. No anti-drug antibodies or immunogenic reactions were reported, and free payload, a mechanism of toxicity in ADCs,² was not detected in serum at a detection limit of 30 ng/ml.¹

Of the total 18 patients, 17 were included in an assessment of dose-limiting toxicities. No dose-limiting toxicities were noted in the initial cohorts—including liver or kidney toxicities, infusion reactions, or ocular disorders—but three dose-limiting toxicities were observed in cohort 5. In addition, Cohort 5 demonstrated mildly elevated alanine aminotransferase and aspartate aminotransferase levels in cycle 1, this level decreased to baseline without intervention and did not recur in subsequent cycles. Transient thrombocytopenia occurred in all patients in cohort 5, but all recovered without intervention.

The dose-limiting toxicity rules were adjusted for thrombocytopenia based on recommendations from a scientific review board and the BLRM statistics were reset with dose optimization strategies.

Efficacy results were promising: 1 patient in Cohort 3 underwent 17 cycles with stable disease and 3 patients in Cohort 5 had a partial response. Two patients in Cohort 5 experienced disease progression, with one reducing the dose after Cycle 1 and another patient experiencing stable disease. Another patient is in partial remission after 9 cycles of therapy and shows a decreasing trend in M ​​protein produced by myeloma cells.

Overall, the results are promising and support further research into dose optimization, according to the authors.

References

1. Raab MS. The anti-BCMA antibody-drug conjugate HDP-101 with a novel amanitin payload shows promising early human results in relapsed multiple myeloma. Presented at: 21st Annual Meeting and Exhibition of the International Myeloma Society; 25-28 September 2024; Rio de Janeiro, Brazil. Summary OA – 60.

2. Nguyen TD, Bordeau BM, Balthasar JP. Mechanisms of ADC toxicity and strategies to increase ADC tolerance. Cancer diseases (Basel). 2023;15(3):713. doi:10.3390/cancers15030713