A patient has died in a clinical trial testing an experimental Alpine Immune Sciences cancer immunotherapy, the second death in the study this year. The safety issue has prompted the company to stop enrollment in studies of the experimental drug. Meanwhile, Alpine said it will turn its focus to two immunology programs, including one partnered with AbbVie.
The Alpine drug, davoceticept, was being tested as a treatment for advanced cancers. The fatality reported Monday comes seven months after the first death prompted the FDA to place a partial clinical hold on a Phase 1 study that was seeking to find the appropriate dose to use in combination with pembrolizumab (marketed as Keytruda), a blockbuster cancer immunotherapy from Merck. Alpine was also testing its drug in a separate Phase 1 test as a monotherapy. Both deaths occurred in the combination study.
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“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,” Alpine CEO Mitchell Gold said in a prepared statement. “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 first death was reported in a patient who had choroidal melanoma, a cancer that affects the eye. The second fatality was in a patient with metastatic colorectal cancer. In both cases, the patient had received a single dose each of the Alpine drug and the Merck drug. Alpine said the cause of death for both patients was cardiogenic shock, a condition in which the heart is unable to pump enough blood to vital organs. When the first patient death was announced in March, Alpine said treating physicians considered the complication to be likely related to inflammation of the heart muscle or infection. The FDA cleared the company to resume the clinical trial in May after a review of safety data and revisions to the clinical trial protocol. Alpine said Monday that it is conducting an assessment of all davoceticept clinical trial participants.
Davoceticept is Alpine’s most advanced cancer program. The drug is a fusion protein designed to block PD-L1 and CTLA-4, two proteins found on the surface of cancer cells that keep immune cells from recognizing the cells. In addition to blocking those checkpoint proteins, the Alpine drug is also designed to target CD28, a protein on T cells that activates a response from these immune cells.
The decision to stop enrollment in the davoceticept studies shifts Alpine’s focus to ALPN-303, a fusion protein in development for treating autoimmune and inflammatory disorders. The drug targets the immune system’s B cells, whose overactivation is associated with several autoimmune diseases. ALPN-303 is designed to block two proteins, the inflammatory cytokines BAFF and APRIL. While drugs are already available that address B cells, Alpine says these drugs haven’t led to long-term or complete remission from disease. The company has said that blocking both BAFF and APRIL could lead to better clinical outcomes. Alpine is planning a Phase 2 proof-of-concept study in lupus, as well as open label studies in autoimmune disorders of the kidney, blood, and skin. The first of these studies is expected to begin in the first half of next year.
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Lupus is also a target for another Alpine immunology program, acazicolcept. This fusion protein is designed to block two signaling pathways that promote T cell activation: CD28 and ICOS. Two years ago, Alpine inked a deal with AbbVie that granted the pharmaceutical giant an exclusive option to license the drug, then known as ALPN-101. Alpine received $60 million up front and could receive up to $805 million more in option and milestone payments. The biotech is responsible for Phase 2 development of the drug. If AbbVie exercises its option, it would be responsible for further clinical development, as well as manufacturing and commercialization of the drug if it’s approved.
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