Study Progress: As of July 2024, the study had enrolled 19 patients (7 females, 12 males) across six consecutive dose cohorts: 20, 30, 60, 80, and 100 µg/kg and the latest cohort which is a dose-optimization cohort including three different treatment arms at a dose of 90 µg/kg in various settings including premedication or split dosing. The median age of these patients was 70 years (range 48-82). They were heavily pre-treated and multidrug-refractory, with a median of 6 prior treatment regimens (range 2-15).

Study Results: Preliminary data indicate that the pharmacokinetics of HDP-101 are consistent with non-clinical data and pharmacometric simulations, showing dose-proportional exposure. The free amanitin payload was not detected in serum at the detection limit of 30 ng/mL, and there were no occurrences of anti-drug antibodies or immunogenic reactions. Seventeen of the eighteen patients were evaluable for dose-limiting toxicities (DLTs) by July 2024 in the first 5 cohorts. The initial four dose cohorts were well tolerated, with no observed DLTs, including the absence of hepatic and renal toxicities, infusion reactions, or ocular disorders. Mild elevations in Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) were observed in Cohort 5 during Cycle 1, which resolved spontaneously, returned to baseline and did not recur in subsequent cycles. All patients in Cohort 5 experienced transient thrombocytopenia, characterized by platelet reductions starting on Cycle 1 Day 2 (C1D2), reaching a nadir on Cycle 1 Day 5 (C1D5), and fully recovering by Cycle 1 Day 15 (C1D15) without clinical sequelae or interventions. Subsequent dosing did not result in similarly profound thrombocytopenia episodes, suggesting this effect was not due to direct cytotoxicity against megakaryocytes. DLTs were observed in three patients in Cohort 5. Consequently, based on Safety Review Committee (SRC) recommendations after Cohort 5, the DLT criteria were revised for thrombocytopenia, and dose optimization strategies were developed, including resetting the BLRM statistics. Cohort 6 is currently ongoing with one patient enrolled.

Efficacy: In Cohort 3 (60 µg/kg), one patient achieved stable disease (SD) over 17 cycles. In Cohort 5 (100 µg/kg), two patients achieved partial response (PR), one patient is currently in very good partial response (VGPR) after 12 cycles of treatment, while three exhibited progressive disease, one of whom required a dose reduction after Cycle 1. The patient who is in VGPR had a prior BCMA-targeting CAR-T cell therapy and a GPRC5D/CD3 bispecific antibody therapy. These promising findings support the continuation and further optimization of dosing strategies. Updated data and further analysis will be presented at the ASH 2024 meeting.

HDP-101-01 Clinical study: HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial with HDP-101 in patients with myeloma whose disease has progressed. The aim of the Phase 1 dose escalation part is to determine the Maximum Tolerated Dose and/or establish the Recommended Phase 2 Dose. The primary objective of the phase 2 dose expansion phase is to assess the preliminary anti-tumor activity of HDP-101. An adaptive Bayesian logistic regression model with overdose control principle is used to guide the dose escalation steps. An Interim Analysis is planned after each cohort is completed. The design of the study ensures a safe and adaptive dose escalation to reach a potential clinical benefit in a patient who have limited or no therapeutic options.

HDP-101-01 Study progress: The study started enrollment in February, 2022. As of 10th of July, 2023, eight (2 female and 6 male) patients were dosed in 3 consecutive dose cohorts. The median age of the patients was 70 years, ranging between 50 and 80. All 8 patients were heavily pre-treated and multidrug-resistant. The median previous lines of treatment were 7 (5 to 15).

Results: Seven of 8 patients were evaluable for dose limiting toxicities (DLTs) in the first 3 treatment cohorts. The initial 3 cohorts were well tolerated, without any DLTs, there were no signs of liver and kidney toxicity, no infusion reaction was detected. No reports of keratopathy or visual acuity loss were observed. Free payload was not detected in any of the available pharmacokinetic samples. Based on the limited data, the PK of HDP-101 was in line with our expectation based on the preclinical observations, exposure to HDP-101 is dose proportional. Anti-drug antibody (ADA) was not detected and there’s no sign of immunogenicity. Objective responses were not reported in these initial cohorts however in Cohort #3 (60μg/Kg) there was one patient ongoing after 8 cycles of treatment with SD. This patient had a slow decrease in M-protein levels.