Novel ADC Pamlectabart Tismanitin Earns FDA Fast Track for Myeloma Treatment

The US FDA has granted fast track designation to the novel amanitin-based antibody-drug conjugate (ADC) pamlectabart tismanitin (HDP-101) for treatment of patients with relapsed or refractory (R/R) multiple myeloma (MM).¹

The FDA fast track program aims to facilitate the development and expedite the review of drugs that treat serious conditions and address unmet medical needs.² With this designation, Heidelberg Pharma, the sponsor, will be eligible for increased interaction with the FDA for guidance on drug development plans and clinical trial design, accelerated approval and priority review pending fulfillment of criteria, as well as rolling review of the biologics license application, all of which aim to streamline the regulatory process and accelerate delivery of pamlectabart tismanitin to patients.

“The FDA’s granting of [f]ast [t]rack [d]esignation … underscores the potential of [pamlectabart tismanitin] for the treatment of severely ill and heavily pretreated patients,” said Andreas Pahl, chief executive officer of Heidelberg Pharma, in a press release.¹ “This designation will support our efforts to advance our lead ADC candidate efficiently toward patients with [MM] who continue to face significant unmet medical needs.”

Pamlectabart tismanitin is an investigational ADC candidate targeting B-cell maturation antigen (BCMA) designed with a synthetic amanitin payload that inhibits RNA polymerase II, thereby stopping transcription and inducing tumor cell apoptosis.^3,4 Prior nonclinical studies have confirmed the agent’s in vitro cytotoxic potency and tumor regression on myeloma cell lines and models with a favorable toxicity profile,⁴ setting the stage for potential promising clinical activity.

What clinical studies have investigated this agent?

Pamlectabart tismanitin is currently being investigated in the first-in-human, ongoing, recruiting phase 1/2a trial HDP-101-01 (NCT04879043), which began in February 2022. This open-label, nonrandomized, multicenter study is evaluating the agent’s safety, tolerability, pharmacokinetics, and preliminary efficacy in patients with R/R MM whose disease has progressed.^3–5 As of an initial study report published in Blood in November 2024, 19 adult patients were enrolled across 6 consecutive dose cohorts: 20, 30, 60, 80, 100 µg/kg, and a dose-optimization cohort with 3 treatment arms receiving a 90-µg/kg dosage (cohorts 1–6, respectively). Enrolled patients were heavily pretreated, having received between 2 and 15 prior lines of therapy. Patients received the agent intravenously every 3 weeks at varying dose levels until disease progression or toxicities were intolerable.

The objective of the phase 1 dose-escalation portion is to determine the maximum tolerated dose and/or the recommended phase 2 dose of pamlectabart tismanitin. Initial phase 1 data were presented by Marc Raab, MD, PhD, professor of medicine at University Hospital Heidelberg in Germany, at the 21st Annual International Myeloma Society Meeting and Exposition in 2024. Here, pamlectabart tismanitin was well tolerated by patients, with manageable toxicities and no dose-limiting toxicities (DLTs) observed in the first 4 cohorts. Three DLTs occurred exclusively in cohort 5, associated with transient thrombocytopenia during the first cycle, fully resolving by day 15 of cycle 1. These events resulted in the revision of DLT criteria and dose-optimization strategy development.

Furthermore, pamlectabart tismanitin demonstrated notable preliminary efficacy in several patients, with 1 patient achieving stable disease over 17 cycles, 2 patients achieving partial response, and 1 patient in very good partial response (VGPR) after 12 treatment cycles.³ Three patients experienced disease progression.

The objective of the phase 2a dose-expansion portion is to assess the agent’s preliminary antitumor activity. In his presentation, Raab anticipated the launch of the phase 2a dose-expansion study in 2025.

REFERENCES:

1. PR: Heidelberg Pharma’s Lead ADC Candidate HDP-101 Granted Fast Track Designation by US FDA for the Treatment of Multiple Myeloma. News release. Heidelberg Pharma. October 23, 2025. Accessed October 23, 2025. https://tinyurl.com/k26c6psk

2. Fast Track. US Food & Drug Administration. Updated August 13, 2024. Accessed October 23, 2025. https://tinyurl.com/ms2695jn

3. Orlowski RZ, Richard S, Kaufman JL, et al. The Anti-BCMA Antibody-Drug Conjugate Hdp-101 with a Novel Amanitin Payload Shows Promising Initial First in Human Results in Relapsed Multiple Myeloma. Blood. 2024;144(Supplement 1):3381-3381. doi:https://doi.org/10.1182/blood-2024-210088

4. Raab MS, Kaufman JL, Richard S, et al. 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. Blood. 2023;142(Supplement 1):3334-3334. doi:https://doi.org/10.1182/blood-2023-182480

5. Study to Assess Safety of HDP-101 in Patients With Relapsed Refractory Multiple Myeloma. ClinicalTrials.gov. Updated July 24, 2024. Accessed October 23, 2025. https://www.clinicaltrials.gov/study/NCT04879043