Birinapant for the treatment of solid tumours and for ovarian cancers
Birinapant is a bivalent peptidomimetic of the SMAC protein (Secondary Mitochondrial Activator of Caspase) and is therefore known as a SMAC mimetic compound. To date birinapant has been dosed in approximately 450 patients across 9 studies. The majority of studies was in oncology (one in HBV) and primarily recruited patients with refractory solid tumors & hematological malignancies (dominated by ovarian, colorectal, acute myeloid leukemia and Myelodysplastic syndromes). Overall birinapant has shown acceptable safety and tolerability for further development in oncology indications. The current plans are to study birinapant clinically in combination with Keytruda® for the treatment solid tumors and in an Investigator-Initiated study at UCLA for high-grade serous carcinoma (HGSC) in combination with platinum-based chemotherapy.
Mechanism of Action
Birinapant is a targeted cancer therapeutic belonging to the class of small molecule, peptidomimetic IAP antagonists known as SMAC mimetics. SMAC mimetics act to antagonize the activity of a group of proteins known Inhibitor of Apoptosis Proteins (IAPs). Birinapant is a particularly potent antagonist of two members of the IAP family, cIAP-1 and cIAP-2. cIAP-1 and -2 are ubiquitin ligases whose expression can protects cells from apoptosis and cause pro-survival effects of TNF-α and related ligands. When birinapant binds to cIAP-1 or -2 it causes the protein to ubiquitinate itself, which in turn drives the degradation of the protein. In this way birinapant suppresses the levels of cIAP-1 and cIAP-2, and therefore switches cell signaling to drive tumour cell apoptosis in the presence of TNF-α. Birinapant has been shown to give rise to sustained and substantial reductions of cIAP1 levels in Peripheral Blood Mononuclear Cells (PBMCs) and tumour tissue at doses of >11 mg/m2.
Combination study with Keytruda® for the treatment of solid tumours
Keytruda® is a PD-1 antagonist and a key part of the immuno-oncology (IO) revolution that’s transforming care for cancer patients. Revenues from the sale of PD-1 antagonists currently total $3.2B (1) annually and the market is growing with additional treatments in late-stage trials. Keytruda® is approved for the treatment of melanoma, NSCLC (non-small-cell lung carcinoma) and HNSCC (head and neck squamous cell carcinoma). However, while some patients derive enormous benefits from the use of a PD-1 antagonist, the benefits can be limited in many patients. The identification of combination regimens to enhance the proportion of patients benefitting from IO therapy is a major trend in cancer research.
One way that immune cells attack cancer is by releasing TNF within the tumour. By reducing cIAP levels, birinapant enhances the pro-apoptoic effects of TNF-α, while reducing the pre-survival effects. Furthermore birinapant has been shown to have direct effect on T-cell co-stimulation, leading to an enhanced anti-tumour immune response. Combining birinapant with a PD-1 antagonist such as pembrolizumab (Keytruda®), which acts to release the brakes on the immune system, is therefore expected to lead to an enhanced anti-tumour response. There are a number of publications on combinations of SMAC mimetics and other immunotherapies that support this hypothesis, showing superiority of the combination compared with either agent alone. This includes recently published preclinical data that show that birinapant in combination with a PD-1 antagonist has superior anti-tumour activity compared to either drug alone in a preclinical model of glioblastoma.
In august 2017, the first patient was enrolled in the company’s phase I/II study of birinapant in combination with the anti-PD-1 therapy KEYTRUDA® (pembrolizumab), which is marketed by MSD (known as Merck & Co., Inc, Kenilworth, NJ, USA in the US and Canada). The objectives of the study are to evaluate the safety, tolerability and preliminary efficacy of this combination in patients with treatment-resistant solid tumours.
The multicentre, single arm, open label study, which is primarily being run in the US, will be conducted in two parts. In the initial dose escalation (phase I) part of the study, the objective is to identify the recommended phase II dose of birinapant for use in combination with KEYTRUDA®. This is to be achieved by administering increasing doses of birinapant in combination with the approved dose of KEYTRUDA® to cohorts of up to 6 patients with refractory solid tumours.
Once the recommended phase II dose has been identified, the second part of the study will begin. The primary objective of the phase II part is to evaluate the safety and tolerability of birinapant in combination with KEYTRUDA® in several cohorts. Each cohort will be made up of patients with the same treatment refractory tumour type. An important secondary objective in the phase II part is the preliminary evaluation of the efficacy of the combination in each of the cohorts.
Birinapant for the treatment of high-grade serous carcinomas
High-grade serous carcinomas (HGSC) are a group of cancers believed to be derived from cells from the fallopian tube that may present as ovarian, endometrial, tubal or peritoneal cancer. HGSC is ~70% of ovarian carcinoma, and ~90% of advanced (stage III/IV) ovarian carcinomas. Treatment with platinum drugs is standard of care, but most patients relapse within 6-18 months. There are today few options available for patients who relapse, and chemotherapy remains the standard of care even for platinum-resistant carcinomas. The ovarian cancer market size overall is USD 840 million(2) and expected to reach > USD 1,500 million by 2024. Sales in the second-line platinum-resistant and -refractory treatable segments totaled approximately USD 75 million in 2014 and are expected to grow to approximately USD 210 million in 2024(2).
Some tumours have high levels of expression and activity of cIAPs, and may be dependent on them for survival. A tumour-initiating, CA125- subset of cells resistant to platinum in HGSCs has been identified by UCLA researchers(3), and it appears that expression of cIAPs, the molecular targets of birinapant, correlates with birinapant susceptibility. These stem-like cells are highly susceptible to the combination of platinum drugs and birinapant in ~50% of patients. The UCLA team has developed a bioassay that will allow selection of patients expected to benefit from this combination therapy. Medivir intends to support an investigator-initiated Phase I/II study at UCLA. This will evaluate the combination of birinapant with platinum-based chemotherapy in patients with newly diagnosed or recurrent HGSCs with evidence of susceptibility to birinapant. Medivir will provide birinapant, with full rights to generated data.
Facts and figures
- cIAP1 and cIAP2 are ubiquitin E3 ligases that target substrate proteins for destruction by the proteasome. Medivir is targeting the Ubiquitin-Proteasome System in complementary ways through birinapant and through inhibition of Deubiquitinases (DUBs).
1) Source: Merck and Bristol Myers Squibb financial reports
2) Source: Decision Resources
3) DM Janen et al, Nature Commun. (2015) 6:7956