Background

Pepinemab is a humanized IgG4 monoclonal antibody to semaphorin 4D, a multifunctional membrane glycoprotein expressed by oligodendrocytes and astrocytes in the central nervous system. In response to stress or injury, neurons release soluble Sema4D, which binds to receptors on glia and activates inflammatory cytokine release. Sema4D inhibits axon extension and oligodendrocyte migration, and disrupts the blood-brain barrier (Smith et al., 2015). Pepinemab neutralizes Sema4D to prevent these actions (Fisher et al., 2016).

Semaphorins, a large family of signaling proteins, were first described in the nervous system. Sema4D, aka CD100, is expressed on macrophages and involved in monocyte migration, T cell activation, atherosclerosis, and other conditions (e.g. Hall et al., 1996; Elhabazi et al., 2003, Luque et al., 2018).

In preclinical work, pepinemab slowed brain atrophy and improved some behaviors in the YAC128 mouse model of Huntington’s disease (Southwell et al., 2015). According to data presented at the 2020 AAT-AD/PD conference, Sema4D expression rose as disease progressed in a second mouse model of HD, Q175 (Apr 2020 conference news).

At the same conference, the company reported that Sema4D was elevated in human postmortem HD brain, correlating with disease stage and neuronal death in several cortical regions. Where Sema4D expression was high, astrocytes withdrew their processes. Subsequently, the company published data on the upregulation of Sema4D in cortical neurons in people with AD (Evans et al., 2022).

Findings

In July 2015, the Phase 1/2 SIGNAL-HD trial began to test pepinemab in people with the CAG expansion that causes Huntington’s disease. The two-part study enrolled 301 patients. In Part A, 36 people in the late prodromal or early manifest stage of disease received monthly infusions of 20 mg/kg pepinemab or placebo for six months. After that, all received drug for an additional six months. In Part B, 265 participants were treated for 18 months with 20 mg/kg drug or placebo; the period was later extended to 36 months for some patients. The primary outcome of the trial is safety and tolerability. Secondary measures include MRI brain volumes, FDG-PET, and TSPO-PET, as well as immunogenicity of the antibody. Other secondary and exploratory endpoints comprise clinical measures of cognition, motor function, and behavior, as well as pharmacokinetic and pharmacodynamic assessments.

According to data presented at AD/PD 2020, pepinemab met its primary safety endpoint in Part A. In a preliminary analysis of 11 people on drug and eight on placebo, the FDG-PET signal dropped over six months in untreated controls but rose in the treatment group. The increases occurred in every brain region and were largest in the frontal and parietal cortices. When the placebo group crossed over to drug treatment, their FDG signals rose (Apr 2020 conference news). As of the conference, Part B was fully enrolled, with 179 people with early manifest HD and 86 with prodromal disease.

On September 22, 2020, Vaccinex announced top-line efficacy results of 18 months treatment of the early manifest group (press release). The two endpoints, based on results of exploratory outcomes in group A, were a combination of two tests from the Huntington Disease Cognitive Assessment Battery, as well as the Clinical Global Impression of Change (CGIC). Neither endpoint was significantly changed by treatment, though the company reports trends toward cognitive improvement and clinical stabilization.

The final results of Part B were published after peer review (Feigin et al., 2022; see also Zauderer and Evans, 2023). While the trial failed to meet its prespecified primary endpoints, it replicated Part A’s positive results on glucose uptake. Pepinemab also improved MRI measures of caudate atrophy, with a trend toward reduced ventricular expansion. The treatment group showed signals of improvement on exploratory cognitive measures, and appeared to preserve learning effects, which are typically lost early in disease. A post hoc subgroup analysis suggested that patients at a mildly advanced, not prodromal, stage of disease might have responded most to treatment. The study found no safety issues.

Pepinemab has both Orphan Drug and Fast-Track designation for Huntington’s disease from the FDA.

In May 2020, Vaccinex registered a Phase 1/2 trial in early AD. The plan was to enroll 60 people with PET or CSF evidence of amyloid positivity, and a CDR of 0.5 or 1 and randomize them to monthly infusions of 20 or 40 mg/kg pepinemab or placebo, up to a total of nine doses. The primary aim of the study is safety and tolerability. Secondary outcomes include changes in FDG-PET, standard measures of cognition, and immunogenicity of the drug. Exploratory measures are serum and CSF biomarkers of inflammation, amyloid, and neurodegeneration, as well as MRI measures of brain volume. Prior to the study’s start in July 2021, the 20 mg/kg dose arm was eliminated and enrollment was reduced to 40. The trial is supported by the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation.

At the October 2023 CTAD conference, Vaccinex said the trial was fully enrolled, with 50 patients who are being treated monthly for one year. No safety issues have arisen, and there have been no discontinuations. The study is active at 16 sites in the U.S., with topline results expected in October 2024.

In other trials, single doses from 1 to 20 mg/kg were well tolerated in a Phase 1 study in people with multiple sclerosis (LaGanke et al., 2017). The antibody is also in trials for non-small-cell lung and other cancers, where Sema4D expression on tumors and immune cells modulates tumor growth and anti-tumor immune responses (Shafique et al., 2021).

For details on pepinemab trials, see clinicaltrials.gov.