Businessman showing stop sign
Credit: turk_stock_photographer/Getty Images

Alpine Immune Sciences has terminated two clinical trials for its anti-cancer candidate davoceticept after a second patient death attributed to cardiogenic shock. Davoceticept (ALPN-202) is a CD28 costimulator and dual checkpoint inhibitor immunotherapy that was been tested in concurrent clinical trials: NEON-1 with the candidate being evaluated as a monotherapy; and NEON-2 a study of a combination therapy of davoceticept and pembrolizumab (KEYTRUDA).

Both studies were voluntarily terminated by Alpine, though the two patient deaths occurred in the NEON-2 combination therapy trial. The second patient with metastatic colorectal cancer had been treated previously with a colectomy and other chemotherapeutic agents, and died after the administration of a single dose of davoceticept and pembrolizumab.

NEON-2 had previously been placed on a partial clinical hold in March—which allows a company to continue running a trial, but bars it from recruiting new patients—after the first reported death in the trial. At the time, the NEON-1 trial of davoceticept was unaffected, but after this second death, Alpine decided to shutter both studies.

“Patient safety remains our highest priority,” said Mitchell H. Gold, MD, executive chairman and CEO of Alpine in a press release. “We have determined it is in the best interest of all patients to terminate enrollment in the davoceticept studies and we will continue to work with the U.S. Food and Drug Administration, Merck, the study Safety Monitoring Committee, and the study investigators to further understand this important safety issue. Davoceticept has shown encouraging signs of clinical activity and it is unfortunate we have not yet been able to identify a safe dose regimen for the combination with pembrolizumab.”

The company now will turn its attention to advancing its lead program ALPN-303, a dual B cell cytokine (BAFF/APRIL) antagonist, which has shown potential against multiple autoimmune and inflammatory indications. In September, the company reported data from it Phase 1 RUBY study of ALPN-303 in healthy volunteers and non-clinical studies.

The RUBY study showed the candidate was well tolerated in both intravenous or subcutaneous at doses up to 960 mg. It also showed improved potency against BAFF and APRIL, and demonstrated superiority against BAFF- or APRIL-only inhibitors, as well as wild-type TACI, in preclinical disease models.

“The initial healthy volunteer data with ALPN-303 suggest a differentiated and potentially best-in-class development profile, which we anticipate could have a meaningful impact on clinical outcomes in SLE (systemic lupus erythematosus) and also potentially a wide range of autoantibody-related inflammatory diseases,” noted Stanford Peng, MD, PhD, Alpine’s president and head of R&D, in a statement released at the company’s RD day.

Based on this, the company now plans a Phase II randomized, placebo-controlled proof-of-concept study in SLE as well as open-label basket studies in renal, hematologic, and dermatologic autoimmune diseases, which it expects to initiate in late 2023.

In addition to ALPN-303, Alpine also has a collaboration with AbbVie for acazicolcept in SLE and has additional preclinical and clinical collaborations with Horizon Discovery and Adaptimmune.

Also of Interest