Science

Evorpacept Development

We are pursuing a dual development path based on two differentiated mechanisms of action while at the same time evaluating the contribution of chemotherapy on top of them. The potential mechanism of action of evorpacept is dependent on the class of combination agent.

The distinct mechanism of actions and examples of the combinations are:

1. Anti-cancer antibodies (the “don’t eat me” signal): Combining with anti-cancer targeted antibodies with an active Fc domain, where evorpacept enables the Fc-mediated antibody dependent phagocytosis that is impaired by the expression of CD47 on cancer cells.
   An example of this mechanism is in our clinical trial, ASPEN-06, a randomized study evaluating the contribution of evorpacept to Herceptin® (traztuzumab) plus standard of care versus standard of care (CYRAMZA® + paclitaxel) in second line or later HER2-positive gastric/gastroesophageal junction cancer. We believe this mechanism is clinically validated by our Phase 1 data in combination with Herceptin in gastric cancer and in combination with rituximab in non-Hodgkin lymphoma where in both settings we saw improvement on overall response rate with respect to historical data. Positive data in ASPEN-06 will represent proof of concept for this mechanism and could lead to combinations with other anti-cancer antibodies. We have already initiated multiple clinical studies based on this mechanism (see Company pipeline) to rapidly expand the use of evorpacept in combination with this class of agents in multiple indications. This same mechanism of action also applies to antibody-drug conjugates which we are currently developing in two separate Phase 1 trials: one in combination with PADCEV® (enfortumab vedotin-ejfv) in patients with urothelial cancer, and the other in combination with ENHERTU® (fam-trastuzumab deruxtecan-nxki) in patients with unresectable or metastatic HER2-positive and HER2-low breast cancer.
2. PD-1/PD-L1 immune checkpoint inhibitors (the “don’t activate T-cell” signal): Combining with PD-1/PD-L1 checkpoint inhibitor, where evorpacept activates dendritic cells that are constitutively inhibited by the CD47/ SIRP alpha pathway.
   Activated dendritic cells present neoantigens to T-cells that once activated will kill cancer cells when the PD-1/PD-L1 inhibitory interaction is blocked by T-cell checkpoint inhibitors. The combination with a PD-1/PD-L1 checkpoint inhibitor allows the maximum activity of these newly activated T-cells. Examples of this mechanism are our clinical trials, ASPEN-03 and ASPEN-04, two randomized studies in combination with KEYTRUDA® (pembrolizumab), without or with chemotherapy respectively, comparing to the same treatments without evorpacept, in first line head and neck squamous cell carcinoma. This mechanism is validated by our Phase 1 data in the same indications and combinations where we saw an improvement in overall survival at 12 months with respect to historical data.

Based on our preliminary clinical results to date in multiple oncology indications showing encouraging anti-tumor activity and tolerability and our clinical development plans, our strategy is to pursue evorpacept as a potentially critical component of future oncology combination treatments.