Despite recent breakthroughs with immuno-oncology agents in cancer treatment, patients with certain types of solid tumors 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 highly potent molecule that binds to and degrades cellular Inhibitor of Apoptosis Proteins (cIAPs), causing their degradation. Degradation of the cIAPs enables cell death in tumor cells, and augments the immune system response, enhancing its attack on the tumor. Through its actions on 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, including checkpoint inhibitors and DNA damaging agents.
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.
Positive interim data were announced following an analysis of phase I data from the ongoing phase I/II safety and efficacy study. No dose-limiting toxicity was observed in the first three groups of patients, and the dose escalation has been continued to the highest planned dose level in the study. One of the 12 patients in this interim analysis has had a confirmed partial response to treatment, which means a reduction in tumor dimensions of 30% or more on two consecutive assessments approximately two months apart when compared to the size of the tumor when treatment started. Three groups of 3-6 patients with advanced solid tumors have been fully recruited so far. The interim analysis is based on the safety and response data from the 12 patients in these three groups. The data from the current interim analysis show that the safety profile of birinapant in combination with Keytruda® is consistent with the published clinical safety profiles of Keytruda® and birinapant when used as single agents at equivalent doses.
The patient that responded to treatment with the combination of birinapant and Keytruda® had received four prior anti-cancer drug regimens to treat microsatellite stable (MSS) colorectal cancer, a cancer type in which responses to treatment with Keytruda® alone are very rare. This patient has had a confirmed partial response (by RECIST 1.1) to treatment with birinapant and Keytruda®, maintained this response at the last assessment in this interim analysis, and remains on treatment 45 weeks after starting therapy. Three additional patients in the study, with appendiceal cancer, esophageal cancer and sarcoma respectively, have had periods of stable disease lasting for at least 18 weeks following the start of treatment.
Medivir has an agreement with Merck & Co. under which Merck provides Keytruda® for this trial at no cost to Medivir and participates on a Joint Development Committee bringing their considerable immuno-oncology expertise.
Medivir retains all rights to birinapant as well as the data generated. It is likely that after demonstrating clinical efficacy, Medivir would out-license birinapant to a partner with global development and commercialization capabilities within oncology, potentially prior to phase III. In order for birinapant to be further developed in combination with an immunotherapy-based treatment, a partner owning the rights to such treatments would be desirable.
Unmet medical need
To enhance responses and extend survival of patients with solid tumors.
Birinapant is a SMAC mimetic. Preclinical studies have established its potential to be combined with immunooncology drugs, and other classes of cancer drugs, to enhance responses in patients.
Once the recommended phase II dose of birinapant has been selected, the second (phase II) part of the study can begin.