Despite recent breakthroughs with immuno-oncology agents in cancer treatment, patients with certain types of solid tumors still have few or no options and are in need of treatments to extend life. These patients have significant unmet medical needs.
Birinapant is being developed to enhance responses, and extend survival, of patients with solid tumors where existing treatments do not provide sufficient survival benefit, or where patients no longer have treatment options. Based on its unique design and mechanism, birinapant has the potential to enhance patients’ responses in combination with other treatments. Medivir’s initial focus is on developing birinapant in combination with an immuno-oncology agent.
Birinapant is a SMAC mimetic that in an efficient way binds to and degrades Inhibitors of Apoptosis Proteins (IAPs), causing their degradation which enables cell death (apoptosis) in tumor cells. At the same time, the immune system’s response is augmented, enhancing its attack on the tumor. Through its double action, on both tumor cells and cells of the immune system, birinapant has the potential to improve the treatment of several types of cancer when used in combination with other drugs.
In August 2017, Medivir initiated a clinical phase I/II study of birinapant in combination with MSD’s anti-PD-1 therapy Keytruda® (pembroluzimab) to clinically demonstrate birinapant’s effect as a combination treatment for patients with treatment-resistant solid tumors.
The multicenter, single arm, open label study, which is primarily being run in the US, is conducted in two parts. The objective of the initial dose escalation (phase I) study, is to identify the recommended phase II dose of birinapant for use in combination with Keytruda® . The second part of the study will evaluate the preliminary efficacy as well as the safety and tolerability of birinapant in combination with Keytruda® in several cohorts.
The initial dose escalation portion of the study (phase I) showed a positive safety profile and identified the recommended phase II dose of birinapant in combination with Keytruda® at 22 mg/m2, corresponding to the highest of the four dose levels studied.
In an interim analysis of patients treated with birinapant up to and including the dose of 17 mg/m2, one of the patients with microsatellite-stable colorectal cancer showed a confirmed partial response and the treatment continued for more than a year after it was initiated. In addition three patients achieved stable disease lasting up to 18 weeks after initiation of treatment.
The phase II part of the study was initiated in December 2018 to evaluate preliminary efficacy, as well as safety and tolerability, for birinapant in combination with Keytruda® in a patient group with colorectal cancer.
Medivir has an agreement with Merck & Co. under which Merck provides Keytruda® for the ongoing study at no cost. Merck participates on a Joint Development Committee bringing their considerable immuno-oncology expertise.
Medivir retains all rights to birinapant as well as the data generated in the study. In order for birinapant to be further developed in combination with an immunotherapy-based treatment, we intend to seek a partner who owns the rights to such a therapy.
In October 2019, the first patient was enrolled in a phase I study to investigate the safety and tolerability of a combination treatment of birinapant and radiation therapy in patients with recurrent Head and Neck Squamous Cell Carcinoma.
The study is sponsored and financed as part of the US National Cancer Institute (NCI)’s Cancer Therapy Evaluation Program (CTEP). Medivir provides birinapant and will be afforded full access to all reports from the study
The primary goals are to evaluate the safety of the combination treatment and to establish a maximum tolerated dose for further studies
Medivir’s decision to support this study was based on preclinical data from NCI showing good effects from birinapant in combination with radiotherapy in models of various types of cancer of the head and neck region1).
1) DF Eytan et al., SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2. Cancer Research (2016) 76, 5442-5454.