Vaccinex now testing pepinemab for mild Alzheimer’s in Phase 1b/2 trial

New SIGNAL-AD study has enrolled 50 adults at 14 US sites

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Enrollment is complete and testing underway in a Phase 1b/2 clinical trial of Vaccinex’s experimental therapy pepinemab, which aims to slow disease progression in people with mild Alzheimer’s.

One year of treatment for the 50 adults in the U.S. trial — called SIGNAL-AD (NCT04381468) and ongoing at 14 sites across the country — is expected to wrap up by by June 2024, according to a business update from Vaccinex.

After that, the company plans to assess pepinemab’s effects, versus a placebo, on markers of Alzheimer’s disease. A separate Phase 2 trial is testing pepinemab in patients with cancers of the head and neck; Vaccinex also is exploring the therapy’s use for people with Huntington’s disease, another neurodegenerative disorder.

“Over the last few months, Vaccinex achieved several important clinical milestones for pepinemab in both Alzheimer’s disease and head and neck cancer,” the company stated in a press release  that highlighted its second-quarter 2023 results.

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Although the causes of Alzheimer’s remain poorly understood, runaway inflammation in the brain is thought to play a central role in driving this disorder and many other neurodegenerative diseases.

Pepinemab is an antibody-based medication that’s designed to block semaphorin 4D, known as SEMA4D, a protein involved in the activity of several brain cells.

The stress and injury to nerve cells, or neurons, that characterize Alzheimer’s and other neurodegenerative diseases promote the production of SEMA4D by these cells. This molecule binds to its receptor proteins at the surface of neuron-supporting cells, such as astrocytes, prompting them to enter a pro-inflammatory state that can contribute to further neurodegeneration.

This can create a vicious cycle where signals from damaged neurons trigger inflammation, which in turn causes more damage to nerve cells and signals further inflammation.

By blocking SEMA4D, pepinemab is expected to disrupt this inflammatory process to slow neurodegeneration and disease progression.

This mechanism of action is notably distinct from more recently developed Alzheimer’s therapies like Leqembi (lecanemab), which earlier this year became the first disease-modifying treatment to win full approval for Alzheimer’s in the U.S.

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Leqembi and related medications such as Aduhelm (aducanumab) — which was granted accelerated approval in the U.S. in June 2021, but still needs to have its efficacy confirmed in clinical trials — work by targeting amyloid-beta, a protein that forms toxic clumps in the brains of people with Alzheimer’s.

The recent full approval of Leqembi by the U.S. Food and Drug Administration “enables the pathway to reimbursement and supports further investment in Alzheimer’s Disease drug development,” Vaccinex stated in the release.

The company believes pepinemab may become an alternative to amyloid-targeting therapies or could potentially be combined with these medications.

The SIGNAL-AD trial, funded in part by the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association, completed enrollment earlier this year with a full complement of patients, ages 55-85.

The participants were randomly assigned to receive either pepinemab or a placebo, administered intravenously, or via infusion into the bloodstream, once monthly.

The study’s main goal is to evaluate the therapy’s safety, while secondary goals include changes in brain metabolism and Alzheimer’s-specific cognition assessments.

Pepinemab’s ability to promote immune reactions also will be assessed, as will be changes in the levels of amyloid-beta and nerve damage and inflammatory markers in body fluids.