HDP-101 / BCMA-ATAC Project
In September 2016, Heidelberg Pharma had signed an exclusive option agreement with the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin covering various B-cell maturation antigen (BCMA) antibodies. In January 2017, the option was exercised and a license agreement was signed.
BCMA is a surface protein that is highly expressed in multiple myeloma cells and in approximately 50% of Chronic Lymphocytic Lymphoma and Diffuse Large B-Cell Lymphoma cells to which the selected antibodies specifically bind. Scientists at the MDC developed these BCMA-specific antibodies. Heidelberg Pharma has synthesized several proprietary ATAC® molecules with these antibodies and generated comprehensive preclinical data. Based on these data, Heidelberg Pharma has selected a lead candidate for later clinical development, HDP-101, which consists of a BCMA antibody, a specific linker and the Amanitin toxin.
Preclinical data showed that HDP-101 had strong in vitro anti-tumor activity and led to complete tumor remission in mouse models for multiple myeloma even at very low doses.
In addition, tolerability studies conducted in different in vivo models identified a very favorable therapeutic window. Multiple myeloma is a cancer affecting bone marrow and the third most common hematologic cancer; it represents a major unmet medical need where new, more effective therapies are urgently needed. HDP-101 also has potential in other hematologic indications.
A number of steps were necessary before the study could be approved by the FDA in the USA and by the Paul-Ehrlich-Institut in Germany: compatibility tests were carried out, the study protocol was drafted, clinical trial centers were selected, the logistics of the study were planned and the trial medication was manufactured, such that by January 2021 the data package for an IND application could be submitted with the FDA. The American regulatory authorities approved Heidelberg Pharma’s application to proceed with a Phase I/IIa study with HDP-101 in February 2021. This was followed by German authorities who approved the trial in July.
The first planned trial center which was to be initiated in the second quarter had to be changed due to the coronavirus pandemic. Stability tests had to be carried out for the new trial center to verify that the special closed system transfer device (CSTD) for the infusions was compatible with the trial center. Although these tests were completed successfully, they delayed the initiation of the first trial centers and the logistics of the trial medication by about three months. During the last quarter, two trial centers in the USA were opened: Winship Cancer Institute of Emory University in Atlanta, Georgia, and MD Anderson Cancer Center in Houston, Texas. The first German trial center in Heidelberg University Hospital was initiated soon after. Inclusion and dosage of the first patients followed in February 2022.
Further ATAC® Partnerships
HDP-102 / CD37-ATAC
HDP-102 is an ATAC® targeting CD37 that is overexpressed on B-cell lymphoma cells. HDP-102 will be developed for specific indications of non-Hodgkin lymphoma (NHL).
The production of antibody material (non-GMP and GMP) to be used in HDP-102 was completed. Production of toxin linker according to GMP standards for CD37 ATAC continued at the same time. This material is to be used for Good Laboratory Practice (GLP) studies and for the planned clinical Phase I study (1st half of 2023 at the earliest). Apart from conjugate production, further preclinical and toxicology studies with the candidate were carried out.
HDP-103 / PSMA-ATAC
PSMA is overexpressed in prostate cancer and is a promising target for ATAC® technology, as it shows very low expression in normal tissues.
Heidelberg Pharma has licensed several PSMA (prostate-specific membrane antigens) specific antibodies from Freiburg University. In pilot studies, Heidelberg Pharma investigated the anti-tumor efficacy of several monoclonal antibodies targeting PSMA conjugated to amatoxin. After humanization and de-immunization of the chosen anti-PSMA antibody, this was used to produce various ATACs®, which will be tested in preclinical studies for safety, tolerability and efficacy.
A lead candidate, HDP-103, was selected for the PSMA project and metastatic castration-resistant prostate cancer (mCRPC), an oncology disease with high unmet medical need, was selected as the clinical indication. Preclinical studies on in vitro and in vivo efficacy, tolerability and pharmacokinetics have shown that HDP-103 has a promising therapeutic window. This is confirmed by the fact that at 60 % there is a very high prevalence of a 17p deletion in mCRPC. The increased sensitivity of prostate cancer cells with a 17p deletion has already been preclinically validated. Since tumor cells with a 17p deletion are particularly sensitive to Amanitin, PSMA-ATACs might be particularly suitable for treating mCRPC.
The antibody material of HDP-103 to be used for the toxicological tests and for the planned clinical trials as well as the non-GMP toxin linker material were both manufactured successfully. Production of the ATACs® in non-GMP quality has already started and is expected to be completed by the third quarter of 2022. The production of toxin linker in GMP quality started at the same time.
Apart from work on conjugate production, further preclinical and toxicology studies with HDP-103 were carried out.