Vaccinex Announces Positive Results for SIGNAL-AD Phase 1b/2 Pepinemab Trial in Alzheimer's

Vaccinex, Inc., a clinical-stage biotechnology company based in Rochester, NY, announced encouraging results from its early-stage SIGNAL-AD clinical trial for treating Alzheimer’s disease (AD) with the pepinemab antibody. The trial's results were shared by Dr. Eric Siemers, the Principal Investigator, at the Alzheimer’s Association International Conference in Philadelphia on July 31, 2024.

The primary objective of the study was to assess the safety of pepinemab, which the trial successfully met, demonstrating that the treatment is well-tolerated by AD patients. Importantly, no serious treatment-emergent adverse events related to the drug were reported by the investigators across the 16 clinical sites involved. The only study discontinuation occurred in the placebo group. Vaccinex had previously observed pepinemab’s favorable safety profile in patients with Huntington’s disease (HD) and multiple sclerosis (MS).

A critical secondary endpoint of the study was to evaluate whether pepinemab could prevent a decline in brain metabolic activity, which is associated with astrocyte reactivity. This was assessed through FDG-PET imaging over a 12-month period. The findings indicated a statistically significant increase (p=0.0297) in FDG-PET signal in the medial temporal cortex of patients with Mild Cognitive Impairment (MCI) due to AD. This brain region, which includes the hippocampus and entorhinal cortex, is known to be affected early in the disease progression in many MCI patients. These results mirror previous findings from a phase 2 study of HD, pointing to mechanistic similarities between the two neurodegenerative diseases.

Although the study did not have enough power to detect significant cognitive effects or changes in some secondary endpoints, prior research indicated that pepinemab could improve cognitive and psychological measures in a larger study with HD patients displaying early cognitive deficits similar to MCI in AD.

Dr. Maurice Zauderer, CEO of Vaccinex, commented that the SIGNAL-AD study results suggest pepinemab could benefit patients with MCI due to AD, similar to its effects in HD. He emphasized that the treatment might be most effective in the very early stages of AD, therefore highlighting the importance of early diagnosis and treatment. Current AD treatments, such as anti-Aβ amyloid antibodies, have limitations, and pepinemab could serve as an alternative for patients at high risk of adverse events or as a complementary treatment to enhance the benefits of existing therapies.

The Alzheimer’s Association estimates that 12% to 18% of people aged 60 or older have MCI due to AD, with about one-third progressing to dementia within five years. A treatment that can delay this progression could significantly improve the quality of life for these individuals.

Pepinemab has been tested in over 600 patients across various neurological conditions, including AD, HD, and MS, with a strong safety profile. The SIGNAL-AD study received partial funding from the Alzheimer’s Association and investments from the Alzheimer’s Drug Discovery Foundation (ADDF). Vaccinex is actively seeking partnerships for further development of pepinemab in AD.

The SIGNAL-AD trial (NCT04381468) was a Phase 1b/2, double-blind, randomized, placebo-controlled study involving 50 patients with MCI due to AD or early Alzheimer’s dementia. The primary endpoint was safety and tolerability, and a key secondary endpoint was assessing brain metabolic activity via FDG-PET. Patients received pepinemab or placebo every four weeks for a total of 12 intravenous infusions.

Pepinemab is a humanized IgG4 monoclonal antibody designed to block SEMA4D, which is implicated in the loss of homeostatic functions in astrocytes and other brain cells. It has shown a favorable safety profile in multiple clinical trials across various indications, including neurological diseases and cancer.

Vaccinex continues to explore pepinemab’s potential in combination therapies for cancer and retains global commercial and development rights to the drug. The company collaborates with Merck Sharp & Dohme Corp. for the KEYNOTE-B84 study in head and neck cancer.

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