Pepinemab’s Blockade of SEMA4D Expression Warrants Further Development in Huntington, Alzheimer Disease

Maurice Zauderer, PhD

This week, 2 new publications—one in Nature, and one in the Journal of Neuroinflammation—highlighted the ability of pepinemab (Vaccinex), a semaphorin 4D (SEMA4D)-blocking antibody, to reduce atrophy and promote cognitive benefit in patients with Huntington disease (HD), as well as the pathologic impact SEMA4D has on neuroinflammatory cells in HD and Alzheimer disease (AD).^1-3

The Nature publication featured data from cohort B of the phase 2 SIGNAL study (NCT02481674), months after the original results were presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, in Seattle, Washington. Here, pepinemab failed to meet statistical significance in its primary end point; although, a number of other positive outcomes and post hoc subgroup analysis—including additional cognitive measures and volumetric MRI and fluorodeoxyglucose (FDG)-PET imaging assessments—provided rationale and direction for further development.²

A total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD were randomly assigned 1:1 to receive 18 monthly infusions of pepinemab or placebo. At month 17, the differences between pepinemab and placebo in mean change of One-Touch Stockings of Cambridge (OTS) and Practice Transition Accreditation Program (PTAP) scores, the coprimary efficacy outcomes, were –1.98 (95% CI, –4.00 to 0.05; P = .028) and 1.43 (95% CI, –0.37 to 3.23; P = .06), respectively, both not statistically significant.

Changes in brain volumetric MRI detected by boundary shift integral showed a nominally significant 26% reduction in caudate atrophy for EM individuals treated with pepinemab relative to placebo over the 17-week treatment period (least square [LS] mean difference, –1.54; 95% CI, –2.79 to –0.29; P = .017). During that same period, the percentage change in ventricular volume BSI results in LS mean difference of –2.47 (95% CI, –5.04 to 0.10; P = .06). Those with EM HD, but not LP HD, had changes in the same direction observed for reduction in white matter volume and whole-brain atrophy.

A secondary end point evaluated the change in FDG-PET SUVR in 23 brain regions of interest (ROI), plus total white mater and 2 composite regions of extended frontal and additional cortical brain ROIs. Here, investigators found an increase in SURV that was observed in almost all ROIs following treatment with pepinemab, whereas those in the placebo group showed declines similar to natural history. The only regions pepinemab did not impact were of the basal ganglia, including the striatum (caudate and putamen) and globus pallidus.

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"Pepinemab treatment also prevented characteristic decline in brain metabolic activity in HD which multiple clinical trials in Alzheimer’s disease have previously shown to correlate with cognitive decline,” Maurice Zauderer, PhD, president and chief executive officer, Vaccinex, said in a statement.¹ "To our knowledge, pepinemab is the first intervention shown to reverse this trend in a neurodegenerative disease. Since we believe we have already demonstrated an effect of pepinemab on a key cognitive endpoint in HD together with the supporting FDG-PET biomarker that will be central to success in AD, we are excited to have initiated the SIGNAL-AD clinical trial in Alzheimer’s disease."

SIGNAL-AD (NCT04381468), an ongoing phase 1b/2a trial expected to enroll approximately 40 patients with AD, is evaluating the safety, tolerability, and effects on cognition and brain metabolic activity of pepinemab over a 48-week treatment period.

The second publication, published in the Journal of Neuroinflammation, highlighted the potential of SEMA4D as a molecular pathway that may preserve normal homeostatic maintenance and modify disease progression. Here, investigators assessed this expression in postmortem brain sections of patients with HD and AD, as well as in mouse models of HD and AD, by immunohistochemistry. All told, the most notable finding showed that SEMA4D is upregulated in neurons during the progression of neurodegenerative diseases and is a trigger of reactive astrocytes.³

"To summarize what we believe we have learned about the role of neuroinflammation in neurodegenerative diseases, including considerable prior work by other investigators, a primary injury, which is different in HD and AD, causes damage or stress to neurons which induces them to upregulate SEMA4D," Zauderer said. “Astrocytes that are in intimate contact with neurons express plexin-B1/B2 receptors for SEMA4D and this signal triggers them to undergo a dramatic physiological change, reactive astrogliosis, an inflammatory state. Through crosstalk among brain cells, astrocytes may also recruit microglia and other potentially inflammatory cells. These cells act together to neutralize or contain damage."

"These mechanisms contribute to good natural local defenses, but chronic inflammation over an extended period of disease progression can eventually cause loss of normal function and widespread neural dysfunction. Pepinemab binds to SEMA4D and inhibits its activity, thereby preventing the increase in damaging inflammation and preserving essential normal brain functions," he said.¹

REFERENCES
1. Vaccinex Inc’s phase 2 SIGNAL study to evaluate pepinemab antibody in Huntington disease is published in Nature Medicine along with detailed mechanism of action study in Journal of Neuroinflammation. News release. Vaccinex. August 8, 2022. Accessed August 8, 2022. https://www.globenewswire.com/news-release/2022/08/08/2494082/0/en/Vaccinex-Inc-s-Phase-2-SIGNAL-Study-to-Evaluate-Pepinemab-Antibody-in-Huntington-s-Disease-is-Published-in-Nature-Medicine-along-with-Detailed-Mechanism-of-Action-Study-in-Journal-.html
2. Feigin A, Evans EE, Fisher TL, et al. Pepinemab antibody blockade of SEMA4D in early Huntington’s disease: a randomized, placebo-controlled, phase 2 trial. Nature. Published online August 8, 2022. Doi:10.1038/s41591-022-01919-8.
3. Evans EE, Mishra V, Mallow C, Gersz EM, et al. Semaphorin 4D is upregulated in neurons of diseases brains and triggers astrocyte reactivity. J Neuroinflammation. 2022;19(200). doi:10.1186/s12974-022-02509-8