A Phase 1/2a, First-in-human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of HDP-101 in Patients With Plasma Cell Disorders Including Multiple Myeloma

This study will assess the safety, tolerability, pharmacokinetics (PK) and the therapeutic potential of HDP-101 in patients with plasma cell disorders including multiple myeloma.

Start Date07 Feb 2022

Sponsor / Collaborator

Heidelberg Pharma AG

EUCTR2020-003414-12-DE / Unknown statusPhase 1/2

A Phase 1/2a, First-in-human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of HDP-101 in Patients with Plasma Cell Disorders Including Multiple Myeloma

Start Date09 Sep 2021

Sponsor / Collaborator

Heidelberg Pharma AG

100 Clinical Results associated with HDP-101

100 Translational Medicine associated with HDP-101

100 Patents (Medical) associated with HDP-101

Literatures (Medical) associated with HDP-101

01 Feb 2021·Molecular cancer therapeuticsQ2 · MEDICINE

HDP-101, an Anti-BCMA Antibody–Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells

Q2 · MEDICINE

Article

Author: Müller, Christoph ; Baumann, Anja ; Breunig, Christian ; Pahl, Andreas ; Raab, Marc S. ; Lutz, Christian ; Pálfi, Anikó ; Giesen, Nicola ; Figueroa-Vazquez, Vianihuini ; Hechler, Torsten ; Goldschmidt, Hartmut ; Müller-Tidow, Carsten ; Kulke, Michael ; Krämer, Alwin ; Ko, Jonathan

Abstract:

Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target in both proliferating and dormant cancer cells. Alpha-amanitin, a toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti–B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative. HDP-101 displayed high efficacy against both proliferating and resting myeloma cells in vitro, sparing BCMA-negative cells. In subcutaneous and disseminated murine xenograft models, HDP-101 induced tumor regression at low doses, including durable complete remissions after a single intravenous dose. In cynomolgus monkeys, HDP-101 was well tolerated with a promising therapeutic index. In conclusion, HDP-101 safely and selectively delivers amanitin to myeloma cells and provides a novel therapeutic approach to overcome drug resistance in this disease.

01 Dec 2018·Drug discovery today. Technologies

Amanitins and their development as a payload for antibody-drug conjugates

Review

Author: Pahl, Andreas ; Lutz, Christian ; Hechler, Torsten

Amanitin-based ADCs represent a new class of ADCs using a novel mode of action. This payload introduces a novel mode of action into oncology therapy, the inhibition of RNA Polymerase II. The high potency of the toxin leads to highly efficacious ADCs. The development of the technology around this toxin will be described. These developments support the clinical development of amanitin-based ADCs by using a toxin with a new mode of action and with a favorable therapeutic index. HDP-101 is an Amanitin based ADC directed against BCMA and will be advancing to the clinical phase in 2019.

Research square

Novel Anti-B-cell Maturation Antigen Alpha-Amanitin Antibody-drug Conjugate HDP-101 Shows Superior Activity to Belantamab Mafodotin and Enhanced Efficacy in Deletion 17p Myeloma Models

Author: Shirazi, Fazal ; Patel, Krina K ; Pahl, Andreas ; Kuiatse, Isere ; Singh, Ram Kumar ; Qin, Li ; Orlowski, Robert Z ; Lee, Hans C ; Jones, Richard J ; Zou, Jianxuan ; Hong, Samuel ; Wang, Hua ; Wan, Jie ; Choudhary, Rajan Kumar

Abstract:

B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior in patients with molecularly-defined high-risk disease, including those with deletion 17p (del17p) involving the tumor suppressor TP53, supporting the need for further drug development. Del17p has been associated with reduced copy number and gene expression of RNA polymerase II subunit alpha (POLR2A) in other tumor types. We therefore studied the possibility that HDP-101, an anti-BCMA antibody drug conjugate (ADC) with the POLR2A poison α-amanitin could be an attractive agent in myeloma, especially with del17p. HDP-101 reduced viability in myeloma cell lines representing different molecular disease subtypes, and overcame adhesion-mediated and both conventional and novel drug resistance. After confirming that del17p is associated with reduced POLR2A levels in publicly available myeloma patient databases, we engineered TP53 wild-type cells with a TP53 knockout (KO), POLR2A knockdown (KD), or both, the latter to mimic del17p. HDP-101 showed potent anti-myeloma activity against all tested cell lines, and exerted enhanced efficacy against POLR2A KD and dual TP53 KO/POLR2A KD cells. Mechanistic studies showed HDP-101 up-regulated the unfolded protein response, activated apoptosis, and induced immunogenic cell death. Notably, HDP-101 impacted CD138-positive but not -negative primary cells, showed potent efficacy against aldehyde dehydrogenase-positive clonogenic cells, and eradicated myeloma in an in vivo cell line-derived xenograft (CDX). Interestingly, in the CDX model, prior treatment with HDP-101 precluded subsequent engraftment on tumor cell line rechallenge in a manner that appeared to be dependent in part on natural killer cells and macrophages. Finally, HDP-101 was superior to the BCMA-targeted ADC belantamab mafodotin against cell lines and primary myeloma cells in vitro, and in an in vivo CDX. Together, the data support the rationale for translation of HDP-101 to the clinic, where it is now undergoing Phase I trials, and suggest that it could emerge as a more potent ADC for myeloma with especially interesting activity against the high-risk del17p myeloma subtype.

News (Medical) associated with HDP-101

19 Sep 2023

·pipelinereview.com

Heidelberg Pharma Provides Update on Phase I/IIa Clinical Trial with Lead Candidate HDP-101

LADENBURG, Germany I September 19, 2023 I Heidelberg Pharma AG (FSE: HPHA) announced today that the clinical Phase I/IIa study with the lead development candidate HDP-101 has already started to recruit patients for the fifth patient cohort with a dosing of 100 µg/kg. The Safety Review Committee's (SRC) evaluation of patient data concluded that no dose-limiting toxicities have occurred to date. The first four dose levels have shown to be safe and well tolerated. So far 12 patients have been treated in the trial. With the expansion of study sites this summer, patient enrollment has significantly accelerated. One patient from the third cohort has now been on HDP-101 monotherapy for over nine months and has been treated with eleven doses. Dr. András Strassz, Chief Medical Officer of Heidelberg Pharma, commented: “We are delighted that our first Amanitin-based antibody drug conjugate HDP-101 is well tolerated and does not show any dose-limiting toxicities to date. The dose escalation will continue as planned with the fifth cohort.” The BCMA antibody Amanitin conjugate HDP-101 is being tested in an open-label, multicenter study for the treatment of relapsed or refractory multiple myeloma, a cancer of the bone marrow. About the Phase I/IIa study with HDP-101 The first part of the study is a Phase I dose escalation study to determine the maximum tolerated dose of HDP-101. These findings will be used to determine the dose for the Phase IIa part, the primary objective of which is to initially evaluate the anti-tumor activity of HDP-101. The open-label, multicenter Phase I/IIa trial is expected to enroll up to 36 patients in the first part and up to 30 patients in the second part. Patients in Phase IIa will be stratified based on 17p deletion status. Preclinical data show that Amanitin has the potential to work particularly well on those tumors that have been genetically altered by a so-called 17p deletion to bypass a particular protective mechanism of cells. Patients with such a deletion generally respond less well to standard therapies and have a significantly poorer prognosis. Phase IIa will not only validate the efficacy of HDP-101 in patients with multiple myeloma, but also the clinical relevance of the 17p deletion. SOURCE: Heidelberg Pharma

Phase 1Phase 2ADC

16 Dec 2022

·pipelinereview.com

Encouraging Clinical Data from Two Antibody Drug Conjugates Based on Heidelberg Pharma’s ATAC Technology Presented at the ASH Annual Meeting 2022

LADENBURG, Germany I December 14, 2022 I Heidelberg Pharma AG (FSE: HPHA) today announced that initial clinical data from two Antibody Drug Conjugates (ADCs) based on the Company’s proprietary ATAC technology was presented at the ASH Annual Meeting 2022. Heidelberg Pharma showed preliminary safety data from the clinical trial with its candidate HDP-101 and partner Magenta Therapeutics, Cambridge, MA, USA, (Magenta) (NASDAQ: MGTA) presented in an oral session preliminary positive safety and initial efficacy data from its clinical trial with the ATAC candidate MGTA-117. HDP-101, an ATAC targeting BCMA, is currently being evaluated in an open-label, multi-center Phase I/IIa trial in patients with multiple myeloma, a bone marrow cancer with high unmet medical need. The first part of the trial is a Phase I dose escalation study to determine an optimal and safe dose of HDP-101 for the Phase II part of the study. Preliminary results from the first two patient cohorts showed good tolerability. Currently, the trial is enrolling patients in cohort 3. MGTA-117 is being tested in a Phase I/II dose-escalation trial in relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Patients with these conditions are deemed ineligible for transplant due to active disease characterized by high numbers of cancer blast cells present in the bone marrow and in the bloodstream. MGTA-117 is designed to deplete these cancer cells prior to a stem cell transplant or to receiving an ex vivo gene therapy product. Preliminary results from 15 patients across three dose-escalation cohorts showed target cell depletion in the blood and bone marrow, providing evidence of an active dose. Two transplant-ineligible patients became transplant-eligible due to the successful depletion of bone marrow cancer cells. MGTA-117 was well-tolerated in all participants. No serious adverse events were deemed to be related to MGTA-117; it cleared quickly as designed and no dose-limiting toxicities were observed. Currently, the trial is enrolling patients in cohort 4; further data is expected in Q1 2023. Prof. Andreas Pahl, Chief Scientic Officer of Heidelberg Pharma, commented: “We congratulate Magenta on their great progress with the development candidate MGTA‑117 and the preliminary but promising data from this clinical trial. We are very pleased that an ADC based on our proprietary ATAC technology has shown positive efficacy data in humans without unexpected or serious treatment-related adverse events. The presented data confirms our view that cancer therapies with ATACs can provide highly effective and well-tolerated treatment.” MGTA-117 is an Amanitin-based ADC consisting of a CD117 antibody and Amanitin as payload. It was developed under a partnership with Heidelberg Pharma that grants Magenta exclusive worldwide development and marketing rights for antibody-drug conjugates using an Amanitin payload and targeting CD117. About Heidelberg Pharma’s proprietary ATAC technology Antibody drug conjugates (ADCs) combine the high affinity and specificity of antibodies with the potency of cytotoxic small molecules for the treatment of cancer. ATACs are ADCs whose active ingredient is the mushroom toxin Amanitin. Amanitin inhibits mRNA transcription by binding to RNA polymerase II, a mechanism that is crucial for the survival of eukaryotic cells. In preclinical testing, ATACs have been shown to be highly efficacious, overcoming frequently encountered resistance mechanisms and combating even quiescent tumor cells. About Heidelberg Pharma Heidelberg Pharma is an oncology specialist and the first company to develop the toxin Amanitin into cancer therapies using its innovative ATAC technology and to advance the biological mode of action of the toxin as a novel therapeutic principle. The proprietary technology platform is being applied to develop the Company’s own therapeutic ATACs as well as in third-party collaborations. The lead candidate HDP-101 is a BCMA ATAC in clinical development for multiple myeloma. Further ATAC candidates are being developed against different targets such as CD37, PSMA or GCC each in the indications non-Hodgkin’s lymphoma, metastatic castration-resistant prostate cancer or gastrointestinal tumors such as colorectal cancer. Heidelberg Pharma AG is based in Ladenburg, Germany, and is listed on the Frankfurt Stock Exchange: ISIN DE000A11QVV0 / WKN A11QVV / Symbol HPHA. More information is available at http://www.heidelberg-pharma.com/. SOURCE: Heidelberg Pharma

Phase 1Clinical ResultADC

19 May 2021

·www.globenewswire.com

Multiple Myeloma Pipeline Analysis Demonstrates Stunning Growth With A Gamut of Pharma Companies Involved Worldwide

Los Angeles, USA, May 18, 2021 (GLOBE NEWSWIRE) -- Multiple Myeloma Pipeline Analysis Demonstrates Stunning Growth with a Gamut of Pharma Companies Involved Worldwide The Multiple Myeloma pipeline is majorly thriving owing to the several different companies developing novel and sophisticated blockbuster drugs, increasing R&D, increasing global prevalence, better awareness and appropriate diagnosis in patients. DelveInsight’s ‘Multiple Myeloma Pipeline Insights’ report provides a holistic view of the pipeline therapies that are under development in preclinical as well as clinical stages of development, and growth prospects across the Multiple Myeloma domain. Some of the key takeaways from the Multiple Myeloma Pipeline report: Got queries? Want to know more? Request for Sample @ Multiple Myeloma Pipeline Insights Multiple Myeloma is a malignant disorder characterized by uncontrolled proliferation of clonal plasma cells causing a wide variety of complications leading to organ dysfunction and eventually death. It is the second most prevalent hematological malignancy worldwide, with a median onset of 60 years. This incurable malignancy develops from an accumulation of terminally differentiated monoclonal plasma cells (PC) in the bone marrow. Reach out @ Multiple Myeloma Pipeline: Novel therapies and emerging technologies The Multiple Myeloma pipeline report proffers a holistic view of the business opportunities, threats, prospective collaborations and agreements, strong competitors, growth strategies, failed as well as discontinued drugs. Multiple Myeloma Pipeline: Drug Portfolio The report lays down a complete coverage of the therapeutics by development stage, product type, route of administration, molecule type, and MOA type for Multiple Myeloma across the complete product development cycle, including all clinical and non-clinical stages. Multiple Myeloma Therapeutic Assessment By Product Type By Stage By Molecule Type By Route of Administration By Mechanism of Action By Targets By Stage and Route of AdministrationBy Stage and Product Type Scope of the Report Coverage: GlobalKey Players: Kiadis Pharma, CASI Pharmaceuticals, NOXXON Pharma, MorphoSys), Sana Biotechnology, Ayala Pharmaceuticals, Cellectar Biosciences, Bristol-Myers Squibb, Poseida Therapeutics, AbbVie/Genentech, Janssen Research and Development, Nanjing Legend Biotech, Genenta Science, Biotest AG, Teneobio, iCell Gene Therapeutics, Juno Therapeutics, Arch Oncology, Regeneron Pharmaceuticals, Incyte Corporation, NexImmune Inc., Chongqing Precision Biotech, Novartis, CASI Pharmaceuticals, Ionis Pharmaceuticals, AgenTus Therapeutics, Biohaven Pharmaceuticals, CRISPR Therapeutics, Pfizer, GlaxoSmithKline, Seagen Inc., Heidelberg Pharma, Bluebird Bio, C4 Therapeutics, Inc., Hoffmann-La Roche, Phosplatin Therapeutics, Arcellx, Inc., HitGen Inc., Boehringer Ingelheim, I-Mab Biopharma, Celyad Oncology, Amgen and othersKey Multiple Myeloma Pipeline Therapies: TNB-383B, ONC201, AO-176, JCARH125, REGN5458, INCB001158, TAK-573, NEXI-002 T Cells, PHE885, CID-103, ION251, EMB-06, agenT-797, CTX120, PF-06863135, SEA-BCMA, AEVI-007, HDP-101, bb21217, CFT7455, RO7425781, PT-112, HG146, CYAD-211, AMG 701, Nivolumab, ventoclax, RAPA-201 autologous T cells, K NK004, CID 103, NOX-A12, TJ202, APG-2575, AL 102, CLR 131 and others. Reach out @ Multiple Myeloma Pipeline: Novel therapies and emerging technologies Table of Contents Visit to know more of what’s covered @ Multiple Myeloma Emerging Therapies Related Reports Multiple Myeloma MarketDelveInsight’s ‘Multiple Myeloma (MM)-Market Insights, Epidemiology and Market Forecast—2030’ report. Multiple Myeloma Epidemiology ForecastDelveInsight’s ‘Multiple Myeloma (MM)- Epidemiology Forecast to 2030’ report. Car T Cell Therapy For Multiple Myeloma MarketDelveInsight’s ‘CAR T-Cell Therapy for Multiple Myeloma-Market Insights and Market Forecast-2030’ report. Refractory Multiple Myeloma MarketDelveInsight's "Refractory Multiple Myeloma - Market Insights, Epidemiology, and Market Forecast-2030" report. Relapsed Refractory Multiple Myeloma MarketDelveInsight's "Relapsed/Refractory Multiple Myeloma (RRMM) - Market Insights, Epidemiology, and Market Forecast-2030" report. Triple Refractory Multiple Myeloma MarketDelveInsight's "Triple-refractory Multiple Myeloma - Market Insights, Epidemiology, and Market Forecast-2030" report. Higher Risk Chronic Myelomonocytic Leukemia MarketDelveInsight's "Higher-Risk Chronic Myelomonocytic Leukemia Market Insights, Epidemiology, and Market Forecast-2030" report. Related Posts Multiple Myeloma Market Insights Multiple Myeloma Therapies MarketRare Cancer Market Outlook About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports Pharma companies by providing end-to-end comprehensive solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve. For more insights, visit Pharma, Healthcare, and Biotech News

Small molecular drugCell TherapyCollaborate

100 Deals associated with HDP-101

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Myeloma	Phase 2	US	Heidelberg Pharma AG	01 May 2021
Paraproteinemias	Phase 2	DE	Heidelberg Pharma AG	01 May 2021
Chronic Lymphocytic Leukemia	Phase 1	DE	Heidelberg Pharma Research GmbH	30 Jan 2022
Diffuse Large B-Cell Lymphoma	Phase 1	DE	Heidelberg Pharma Research GmbH	30 Jan 2022

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04879043 (HDP-101-01, PipelineReview) Manual	Phase 1/2	Plasma cell myeloma refractory	12	HDP-101	fsgjvkpidn(oyuzzjfgrk) = The Safety Review Committee's (SRC) evaluation of patient data concluded that no dose-limiting toxicities have occurred to date. jmupskavth (wauzyzxyvm )	Positive	19 Sep 2023
NCT04879043 (HDP-101-01, ASH2022) Manual	Phase 1/2	Relapse multiple myeloma	4	HDP-101	xonehorplv(qyhepfsyal) = ezrludqvsv eazishlsrp (fvijkhhhxg )	Positive	15 Nov 2022

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