#AAN2022 – Pepinemab Appears to Help Patients With Cognitive Issues

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The experimental therapy pepinemab can aid cognition in people with early Huntington’s disease who showed signs of cognitive impairment when they started treatment, new analyses from the Phase 2 SIGNAL clinical trial indicate.

Findings were presented at the virtual American Academy of Neurology 2022 Annual Meeting in the poster, “Clinical evidence that treatment with pepinemab, a novel regulator of neuroinflammation, provides cognitive benefit to patients with Huntington’s and potentially other neurodegenerative diseases.”

Pepinemab is an antibody-based medicine being developed by Vaccinex to treat Huntington’s and other neurological disorders. The therapy is designed to normalize metabolism and lower inflammation by blocking the activity of a protein called SEMA4D. This protein is up-regulated in the brains of people with Huntington’s, meaning it’s found in higher amounts.

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Time Perception Impaired – but Only in Patients With Early Symptoms

In the SIGNAL trial (NCT02481674), 91 people with early Huntington’s were treated with pepinemab, given via monthly infusions for 18 months, and 88 other patients were randomized to a placebo.

SIGNAL also included some people with prodromal (before clinical diagnosis) disease, though data on these patients was not discussed in the AAN poster. The trial’s main goal was to assess the impact of treatment on cognitive outcomes, using measures such as the Huntington’s Disease Cognitive Assessment Battery (HD-CAB).

Top-line results, announced in 2020, showed that the therapy was generally well-tolerated. Cognitive outcomes tended to be better among patients given pepinemab than placebo; however, results did not reach statistical significance.

A team led by scientists at Vaccinex now conducted new analyses of trial data stratified by initial Montreal Cognitive Assessment (MoCA) scores. The MoCA is a standardized test to look for dementia and other cognitive problems; a score of 26 or higher is considered normal, while scores under 26 indicate impaired cognition.

Among early Huntington’s patients in SIGNAL with normal MoCA scores at the trial’s start, little difference was seen in HD-CAB scores among patients given pepinemab or placebo at all time points. However, there was a significant difference between treatment and placebo for patients with starting MoCA scores below 26.

Researchers also looked at clinician-reported health outcomes (Clinical Global Impression of Change) stratified by measures of total functional capacity (TFC), or a person’s ability to perform in day-to-day life. For people with early-stage Huntington’s, TFC scores typically range from 11 to 13 and higher scores indicate better function.

Among patients with a starting TFC score of 11, those given placebo were significantly more likely than those on pepinemab to experience an overall worsening in health by the trial’s end. By comparison, no significant difference between pepinemab and placebo was seen for patients with TFC scores of 12 or 13.

The researchers also noted that, by the trial’s end, significantly fewer patients given pepinemab than placebo reported apathy, a behavioral symptom of Huntington’s that has been linked with disease progression. Changes in brain metabolism and brain atrophy, or shrinkage, associated with Huntington’s also were lower with pepinemab’s use.

“Subgroup analysis of SIGNAL HD demonstrated treatment benefit in cognition and encourage continued development of pepinemab in [Huntington’s],” the researchers concluded.

Vaccinex is currently sponsoring another clinical trial of pepinemab in people with Alzheimer’s disease (NCT04381468), which is recruiting eligible patients at sites across the U.S.

Note: The Huntington’s Disease News team is providing coverage of the American Academy of Neurology (AAN) 2022 Annual Meeting.