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3334 Hdp-101, an Anti-BCMA Antibody-Drug Conjugate with a Novel Payload Amanitin in Patients with Relapsed Multiple Myeloma, Initial Findings of the First in Human Study

Program: Oral and Poster Abstracts
Session: 652. Multiple Myeloma: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Marc S. Raab1*, Jonathan L. Kaufman, MD2, Shambavi Richard, MD3, Sebastian Grosicki, MD, PhD4*, Istvan Takacs5*, Andras Strassz, MD, MBA6, Andreas Martin Pahl, PhD7, Thorsten Michael6*, Anette Last8*, Hajnalka Szaboki6*, Garrit Jentsch9*, Oliver Schönborn-Kellenberger10* and Robert Z. Orlowski, MD, PhD11

1Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
2Winship Cancer Institute, Emory University, Atlanta, GA
3Department of Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York
4Department of Hematology and Cancer Prevention, Faculty of Health Sciences, Medical University of Silesia, Katowice, Poland
5Ist Department of Medicine, Semmelweis University, Budapest, Hungary
6Heidelberg Pharma AG, Ladenburg, Germany
7Heidelberg Pharma, Ladenburg, Bw, DEU
8Gregor-Mendel-Straße 22, Heidelberg Pharma AG, Ladenbuerg, Germany
9BAST GmbH, Heidelberg, Germany
10Cogitars GmbH, Heidelberg, Germany
11Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX


Several antibody-drug conjugates (ADCs) are currently being evaluated in clinical trials in a variety of malignancies. The vast majority of these are based on a few toxic compounds, largely limited to microtubule- or DNA-targeting toxins which impact proliferating cells and have limited efficacy in diseases with a low proliferative fraction such as multiple myeloma. Thus, new compounds with alternative modes of action and the ability to actively induce cell death in non-proliferating tumor cells could enhance the therapeutic potential of ADCs. We are currently developing amanitin based ADCs. Amanitin specifically inhibits RNA polymerase II thereby inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell. Subsequently tumor cells enter apoptosis and are eliminated.

HDP-101 an Amanitin based antibody drug conjugate

HDP-101 is a new ADC targeting BCMA carrying a synthetic version of amanitin as a payload. In vitro cytotoxic potency of HDP-101 was demonstrated on BCMA-positive myeloma cell lines, as well as on non-proliferating primary CD138+ cells isolated from patients with refractory myeloma The cytotoxic effects of HDP-101 were seen even in non-proliferating myeloma cells with low BCMA density. Toxicity was observed neither in non-BCMA expressing control cells nor in myeloma cells exposed to an amanitin-loaded non-target control antibody. In murine xenograft models of human myeloma, HDP-101 caused dose-dependent tumor regression including complete remissions after a single dose in subcutaneous and as well as in disseminated models. Safety profiling in Cynomolgus monkeys revealed a good therapeutic index after repeated dosing.

Our non-clinical studies concluded that this amanitin-based ADC is a novel promising approach in the therapy of multiple myeloma to overcome drug resistance and improve patient outcome.

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).

Table 1

HDP-101-01 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.

Image 1

The initial dose cohorts showed good tolerability in late stage relapsed and/or refractory multiple myeloma patients. The study continues to enroll patients to higher dose cohorts at selected sites in the US, Germany, Poland and Hungary. Currently the study is enrolling patients in Cohort #4 at the dose of 80μg/Kg.

Additional updates will be provided at the 2023 ASH Annual Meeting.

Disclosures: Raab: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Heidelberg Pharma: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Heidelberg University Hospital: Current Employment. Kaufman: Abbvie: Consultancy; Incyte: Consultancy; BMS: Consultancy; Sanofi: Consultancy. Richard: C4 Therapeutics: Research Funding; Heidelberg Pharma: Research Funding; Janssen: Honoraria; Bristol Myers Squibb: Honoraria. Strassz: Heidelberg Pharma AG: Consultancy, Current equity holder in publicly-traded company. Pahl: Heidelberg Pharma: Current Employment, Current equity holder in publicly-traded company. Michael: Heidelberg Pharma AG: Current Employment. Last: Heidelberg Pharma AG: Current Employment. Szaboki: Heidelberg Pharma AG: Consultancy. Jentsch: Heidelberg Pharma AG: Consultancy. Schönborn-Kellenberger: Heidelberg Pharma AG: Consultancy. Orlowski: Asylia Therapeutics, BioTheryX Inc., Heidelberg Pharma: Other: Laboratory Research Funding, Research Funding; Asylia Therapeutics: Current equity holder in private company, Patents & Royalties; BMS/Celgene Corporation, CARsgen Therapeutics, Exelixis Inc., Heidelberg Pharma, Janssen Biotech Inc., Sanofi/Genzyme, Takeda Pharmaceuticals USA Inc.: Other: Clinical Research Funding, Research Funding; AbbVie, Adaptive Biotech, Asylia Therapeutics, Inc., BioTheryX, Bristol-Myers Squibb Pharmaceuticals, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Nanjing IASO Biotherapeutics, Neoleukin Corporation, Oncopeptides AB, Pfizer, In: Consultancy, Honoraria.

*signifies non-member of ASH