A patient has died in a clinical trial that is testing Alpine Immune Sciences’ davoceticept in combination with Merck’s Keytruda. The death in the study of adults with advanced malignancies triggered a partial clinical hold—and raised the specter of an earlier tragedy.
Davoceticept is part of a wave of candidates that have renewed interest in CD28, a target previously best known in oncology in relation to TGN1412. The administration of CD28 superagonist TGN1412 to healthy volunteers caused critical illnesses linked to cytokine storms in a phase 1 trial, temporarily dampening interest in stimulating the T-cell-expressed protein to treat cancer.
ALPN-202 is designed to limit the risk of systemic immune activation and toxicity. Alpine’s molecule is a conditional costimulator of CD28 and a dual PD-L1/CTLA-4 inhibitor. CD28 costimulation should require T-cell receptor signaling and expression of PD-L1 on the antigen-presenting cell.
Details of what happened in the trial of ALPN-202 and Keytruda are limited. A choroidal melanoma patient previously treated with Bristol Myers Squibb’s Opdivo and Yervoy received a single dose each of davoceticept and Keytruda. The participant’s death was attributed to the inability of their heart to pump enough blood and oxygen to vital organs, a condition known as cardiogenic shock.
RELATED: ASCO: Alpine reports 61% response in trial of CD28 I-O drug
The treating physicians think the cardiogenic shock was likely related to immune-mediated myocarditis, or possibly infection. Work is now underway to better understand what happened and what precautions Alpine can take to prevent it from happening again. In a statement, Alpine CEO Mitchell Gold, M.D., expressed hope that “the study will soon be resumed after appropriate safety review.”
In the meantime, Alpine can continue to dose patients who are already enrolled in its NEON-2 trial but cannot enroll new participants. A clinical trial testing davoceticept as a monotherapy is unaffected by the partial clinical hold.
ALPN-202 is one of a clutch of candidates designed to target CD28 to treat cancer. Regeneron is testing a trio of bispecifics that target CD28, Sanofi is studying a trispecific against the target and Johnson & Johnson bought a spot in the race last year through a tie-up with Xencor.