Birinapant is a bivalent investigational SMAC‑mimetic. It was selected from our chemical library of over 3,000 SMAC‑mimetic compounds designed to bind to a greater or lesser extent with multiple IAPs. IAPs, including cIAP1, cIAP2, XIAP, and ML‑IAP, are a group of structurally‑related proteins that can suppress apoptosis. Based on our pre‑clinical studies and clinical trials, we believe that birinapant’s potential ability to inhibit the IAPs will block this suppression across multiple cancers and virally infected cells.
Over 300 study participants with cancer have been treated with birinapant alone or administered with standard chemotherapies. In clinical trials, birinapant was generally well tolerated, meaning that treatment‑related side effects were mild or moderate in severity in the majority of treated subjects, and showed signs of activity in subjects with cancer. In pre‑clinical cancer studies, birinapant was synergistic (or super‑additive) with agents that induce TNF, including established anti‑cancer chemotherapies (such as azacitidine, gemcitabine and irinotecan), other anti‑cancer therapies (such as radiotherapy), biological agents (such as GM‑CSF and IFN), and with TNF and other members of the TNF superfamily including TNF‑related apoptosis‑inducing ligand, or TRAIL and TRAIL‑Receptor 2 (also known as Death‑Receptor 5, or DR5) agonists.
As shown in the figure below, the principal target of birinapant is the IAP, cIAP1. A secondary target is the IAP, cIAP2 (not shown in figure below). Both are critical components of the TNF receptor 1 complex. It is this TNF receptor 1 complex that receives the TNF signal and then transmits it inside the cell, triggering a cascade of events that includes activation of NF‑κB which delivers the pro‑survival signal to a cancer (or virally infected) cell.
Birinapant is designed to mimic SMAC and enable TNF‑activated apoptosis.
In pre‑clinical studies, a significant number of tumor types resistant to single agent treatment with either TNF or TRAIL became sensitive in the presence of low concentrations of birinapant. The requirement for TNF underpins our clinical program: while birinapant is anticipated to have some activity when administered as the sole therapy, we believe its maximum anti‑cancer activity will occur when administered with chemotherapies that further induce TNF.
We believe that birinapant has the potential to be superior to other IAP inhibitors for two reasons. First, birinapant is a bivalent molecule similar to endogenous SMAC and allows for direct engagement of two IAP molecules. Our pre‑clinical studies suggest that bivalent SMAC‑mimetics are more potent inhibitors of TNF induced NF‑κB activation than monovalent IAP inhibitors. To our knowledge, birinapant is the only bivalent SMAC‑mimetic in clinical development in the United States. Second, based on our pre‑clinical studies, birinapant inhibits cIAP1 more than cIAP2. Complete degradation of cIAP2 is associated with increased toxicities. We believe that this is the basis for the pre‑clinical data suggesting that birinapant will be better tolerated than SMAC‑mimetics that are less selective. Consistent with these pre‑clinical studies, birinapant was generally well tolerated in our clinical trials.
Activity in Clinical Trials
Over 300 study participants with cancer have been treated with birinapant alone or administered with standard chemotherapies. In clinical trials, birinapant was generally well tolerated, meaning that treatment‑related side effects were mild or moderate in severity in the majority of treated subjects. Birinapant has also shown favorable pharmacokinetic, or PK properties, meaning how the subject’s body handles birinapant, including the length of time birinapant remains in a subject’s blood or tumor, with similar and predictable behavior among treated subjects. In addition, our clinical trials show evidence that birinapant is interacting with its intended target and that the activation of NF‑ κB was inhibited in subject tumor cells. Birinapant has thus far shown clinical activity in both hematological malignancies and solid tumors, including acute myelogenous leukemia, or AML and CRC. Phase 1 and Phase 2 clinical trials have been completed or are ongoing with birinapant.