The FDA clinical hold comes after Alpine reported a patient died during the NEON-2 trial.
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Alpine Immune Sciences announced that the U.S. Food and Drug Administration has placed a partial clinical hold on its NEON-2 trial, which is evaluating davoceticept (ALPN-202) in combination with pembrolizumab in adults with cancer. The clinical hold comes after Alpine reported that a patient died during the trial.
Davoceticept is a CD28 costimulator and dual checkpoint inhibitor intended for cancer treatment. It is engineered to enable the immune system to mount a robust anti-tumor response to eliminate malignancies in a patient’s body by releasing the inhibition of and stimulating CD28, a protein expressed on T-cells that helps activate them to fight against abnormal cells in the body.
In early preclinical studies, davoceticept demonstrated superior efficacy in tumor models in comparison to other checkpoint inhibitor drugs. Emerging results from NEON-1, a Phase I study of the monotherapy in patients with advanced malignancies, showed that the drug was well-tolerated, and most enrolled patients derived clinical benefits including stable or non-progressing disease or even a decrease in tumor size. The patients enrolled were those whose tumors were considered nonresponsive to other immunotherapies.
NEON-2 was born in collaboration with Merck to evaluate the effectiveness of pairing davoceticept with pembrolizumab, an immunotherapy that is used to treat a variety of cancers by blocking the PD-1 pathway, which can “hide” cancer cells. Prior preclinical studies demonstrated that the combination of therapeutics was advantageous for patients.
Enrollment and dosing for the study began in June 2021. Now, NEON-2 faces uncertain waters after a serious adverse event occurred.
Alpine reported that one participant who had received a single dose of each davoceticept and pembrolizumab died. The patient had choroidal melanoma, a cancer of the eye that impacts the sponge-like membrane between the white of the eye and the retina.
The death is being attributed to cardiogenic shock, a rare condition in which the heart suddenly is unable to pump enough blood to meet the body’s needs. Treating physicians involved in the study believe that immune-mediated myocarditis, or inflammation of the heart, could be what caused the condition or possibly infection.
“Patient safety remains, as always, our top priority,” said Mitchell H. Gold, executive chairman and CEO of Alpine. “We appreciate the dialogue with FDA and look forward to working diligently with FDA, Merck, the study Safety Monitoring Committee, and the study investigators to further understand this unfortunate event. Given the strong scientific rationale for the combination of davoceticept and pembrolizumab to benefit treatment-refractory patients, we are hopeful that the study will soon be resumed after appropriate safety review, and with appropriate safety precautions in place.”
The partial clinical hold will allow time for the companies to adequately address the adverse event, and during the hold, no new patients will be enrolled in the study. However, patients currently enrolled in the study may continue to receive the combination of therapeutics.
The clinical hold does not impact the ongoing NEON-1 study, which is evaluating davoceticept as monotherapy and anticipates an expansion in the first half of 2022.
