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ADC Portfolio

HDP-101/BCMA-ATAC Project

HDP-101 is a BCMA-ATAC that is being tested in multiple myeloma. BCMA (B-cell maturation antigen) is a surface protein that is highly expressed in multiple myeloma cells. BCMA antibodies specifically bind to this protein, thereby delivering the toxin Amanitin to the cancer cell. Multiple myeloma is a cancer affecting bone marrow and the second most common hematologic cancer; it represents a major unmet medical need where new, more effective therapies are urgently required. HDP-101 also has potential in further hematologic indications.

The candidate is being evaluated in a Phase I/IIa clinical trial for treatment of relapsed or refractory multiple myeloma. The first part of this trial is a Phase I dose escalation study to determine a safe and optimal dosage of HDP-101 for the Phase IIa part of the study.

Currently advancing in its sixth cohort, the study has shown encouraging results, including complete remission in one patient from the fifth cohort who had been previously treated multiple times and had received several courses of HDP-101. In addition, several patients showed promising biological activity and objective improvements, underscoring the potential of HDP-101 as a treatment option for patients with this disease.

In the Phase IIa dose expansion phase, at least 30 patients are to be treated with the recommended dose of HDP-101. The primary objective of the Phase IIa part of the trial is to assess the preliminary anti-tumor activity of HDP-101 along with further evaluation of the safety of the drug.

In spring 2024, the US Food and Drug Administration (FDA) had granted orphan drug designation (ODD) to the ATAC candidate HDP-101. Orphan drug designation is granted to a drug or biological product intended for the prevention, diagnosis or treatment of rare diseases affecting fewer than 200,000 people in the United States. The status provides significant incentives to encourage development of the drug.

HDP-102/CD37-ATAC Project

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). In preclinical trials, this development candidate has shown to have a comparatively broad therapeutic window. This means that the difference between its therapeutic dose and a dose that causes unacceptable toxicity is as great as possible.

Production of the clinical trial medication according to Good Manufacturing Practice (GMP) standards is proceeding according to plan and has largely been completed. Apart from conjugate production, the past months saw the completion of further preclinical and toxicology studies. The data package required for the clinical trial application will be finalized in Q4 of this year and submitted to the regulatory authorities.

HDP-103/PSMA-ATAC Project

HDP-103 will be developed for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The antibody used binds to PSMA, a surface antigen that is overexpressed on prostate cancer cells. This is a promising target for ATAC technology because PSMA shows only very limited expression in normal tissue.

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 Amanitin 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.

Production of HDP-103 under GMP conditions was completed. The preclinical and toxicology studies with HDP-103 have now been largely completed. Heidelberg Pharma plans to submit a trial application for HDP-103 to the regulatory authorities in 2025.

HDP-201/GCC-ADC Project

Heidelberg Pharma has been developing further ADC projects with other payloads since fall 2023. The first candidate is HDP-201, an exatecan-based ADC. Exatecan is a topoisomerase I inhibitor that has proven itself in cancer therapy and is used in two already approved ADCs. Its mode of action differs from that of Amanitin, and thus expands the company’s range of active ingredients.

HDP-201 targets guanylyl cyclase-C (GCC), a receptor that is expressed on the surface of intestinal cells and cancer cells in various gastrointestinal tumors. The target protein to which the antibody used binds is overexpressed in over 95% of colorectal cancers and around 65% of esophageal and gastric tumors as well as pancreatic tumors.

In vitro/in vivo tests and initial preclinical trials have now been completed. Preclinical results show that the tolerability and efficacy of HDP-201 is at least comparable to already approved exatecan ADCs.

Based on extensive preclinical efficacy and tolerability testing, the final development candidate for HDP-201 was selected and the indication determined in fall 2024. HDP-201 is to be developed for the treatment of colorectal cancer.

Prognostic Biomarker p 53 / 17p deletion

The tumor suppressor gene p53 and the gene for RNA polymerase II are located on chromosome 17. The product of the p53 gene is intended to prevent tumor formation in healthy cells. Cancer cells have changes in their genetic material in such a way that this protective function can no longer be fully exercised. This protein thus represents one of the most important control substances for cell growth and thus also a focus of oncological research. Tumors frequently loose or have mutations in the p53 gene in the tumor cells in order to weaken the cells' natural defenses. The deletion of p53 gene is almost always accompanied by the deletion of POLR2A gene as those genes are in close proximity on the short arm chromosome 17. This is known as 17p deletion. The POLR2A gene encodes the largest and essential subunit of RNA polymerase II, and the loss of POLR2A results in decreased copy number of this essential protein. Since the mode of action of Amanitin is to inhibit RNA polymerase II and eventually trigger a programmed cell death, the tumor cells with 17p deletion is particularly sensitive to Amanitin. This genetic alteration is found in many types of cancer and usually linked with more aggressive and treatment resistant forms of malignancies.

In collaboration with various research groups in Germany and the US, including Heidelberg University Hospital, the MD Anderson Cancer Center at the University of Texas, and the School of Medicine at Indiana University, preclinical studies have demonstrated that Amanitin has the potential to be particularly effective against tumors with a 17p deletion which are difficult to treat.

Heidelberg Pharma intends to explore the importance of 17p status clinically, i.e. to stratify the patient population according to their 17p status in the planned clinical trials. The presence of a 17p deletion could serve as a potential biomarker for Amanitin-based therapeutics. Heidelberg Pharma assumes that patients with a 17p deleted tumor could particularly benefit from treatment with Amanitin-based therapies.

ATACs thus represent a promising therapeutic strategy for patients suffering from highly resistant tumor diseases. In a clinical setting, the selection of patient based on TP53 and POLR2A gene status could allow the expansion of the therapeutic window, and ensure high efficacy while reduced side effects.