Vaccinex's lead drug misses the mark in Huntington phase 2; focus shifts to Alzheimer's

There is no cure for Huntington disease—just treatments that focus on addressing muscle and movement problems and drugs like antidepressants and antipsychotics that help manage neurological symptoms. Vaccinex is working on an antibody that it hopes could be the first disease-modifying treatment for the progressive brain disorder, but that program has just hit a snag in phase 2.

The treatment, pepinemab, failed to beat placebo in 179 patients with early-stage Huntington disease, missing the study’s co-primary endpoints. Although the drug showed a positive trend on two cognitive assessments of Huntington disease, its performance didn’t top placebo by a wide enough margin to be statistically significant.

The company pins the trial failure on a combination of the wrong endpoints and the wrong patient population.

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The endpoints were “a family of cognitive assessments that comes from the Huntington’s Disease Cognitive Assessment Battery” and the Clinical Global Impression of Change, an assessment by the treating physician of the change in a patient’s condition from baseline.

“The FDA had directed us to figure out which of the six different assessments that comprise the battery are most impactful in relation to our study and our treatment and we identified two we believed were most impactful,” Vaccinex CEO Maurice Zauderer, Ph.D., said. The company chose difficult tests because those measure the kinds of skills that people tend to lose early.

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“The harder the task, the earlier in disease progression you see deficits in performance. With easy tasks, it takes a lot of neurodegeneration before patients are not able to do them,” Zauderer said.

Problem is, the first signs of Huntington tend to be changes in motor control, and cognitive problems don’t show up until later. The study also tested the drug in patients with prodromal disease—that is, patients known to have the mutation that causes Huntington disease but haven’t shown symptoms yet—but Vaccinex doesn’t expect those results to be any better.

“In retrospect, it would have been better to select patients who were a little further advanced and already showing signs of cognitive difficulties,” Zauderer said.

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The company is already thinking about a follow-up study that would involve patients who are beginning to show cognitive decline, but it’s looking for a partner to carry that work forward while it goes full speed ahead on developing pepinemab in Alzheimer’s disease.

Pepinemab targets SEMA4D, a protein that is found in low levels in healthy brains but is expressed in high levels by neurons in the brains of people with Huntington disease. By blocking SEMA4D, Vaccinex hopes to tamp down on the inflammation in the brain that plays a role in neurodegenerative processes in various diseases, including Huntington and Alzheimer’s.

Vaccinex has already kicked off a trial in Alzheimer’s, where it expects pepinemab to do better, since “in Alzheimer’s, the primary deficit is cognition,” with few patients showing motor problems. The company picked up about $3 million from the Alzheimer’s Drug Discovery Foundation to bankroll the development of pepinemab in this disease.

“We’ve already had some partnering inquiries, and we are pursuing those,” Zauderer said. “We would like to continue our work in Alzheimer’s disease to establish proof of concept on our own, but we would like to continue in Huntington disease with a partner because of the possibility of combination therapies there as well.”