Semaphorin 4D (SEMA4D) plays a role in multiple cellular processes that contribute to pathophysiology of neuroinflammatory/neurodegenerative diseases, such as Huntington’s disease and multiple sclerosis. SEMA4D is, therefore, a unique target for therapeutic development. Pepinemab (VX15/2503) is a novel monoclonal antibody that blocks the activity of SEMA4D. Preclinical testing demonstrated the beneficial effects of anti-SEMA4D treatment in a variety of neurodegenerative disease models. Vaccinex is committed to the development of this potentially important antibody that has the potential to help people with different neurodegenerative disorders that share common mechanisms of pathology.
Vaccinex has successfully completed a Phase I, multi-center, randomized, double-blind, placebo-controlled, single-ascending dose clinical trial of pepinemab (VX15/2503) anti-SEMA4D antibody in 50 adult patients with multiple sclerosis. While 10 patients were treated with placebo, 40 patients were treated with single doses of pepinemab (VX15/2503) ranging from 1 to 20 mg/kg. pepinemab (VX15/2503) was well tolerated and no Maximum Tolerated Dose (MTD) was reached.
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Vaccinex is currently enrolling patients in a Phase 2, multi-center, randomized, double-blinded, placebo controlled study in subjects with late prodromal and early manifest HD to assess the safety, tolerability, pharmacokinetics, and efficacy of pepinemab (VX15/2503). The SIGNAL clinical trial builds upon preclinical studies in an animal model of HD and safety data from a Phase 1 dose-escalation clinical trial of pepinemab (VX15/2503) in MS patients that was completed in November 2014. Pepinemab (VX15/2503) has received Orphan Drug and Fast Track Designations for the treatment of HD from U.S. FDA. The study consists of two Cohorts, A and B. Thirty six participants were randomized into the now completed Cohort A to receive monthly infusions of either pepinemab (VX15/2503) or placebo for six months, in a double-blind fashion. All participants in Cohort A subsequently received open-label pepinemab (VX15/2503) for another five months, followed by a three-month safety follow-up.
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A significant relationship between decreasing volumetric magnetic resonance imaging (MRI) and disease progression in HD was previously demonstrated in the much larger PREDICT-HD and TRACK-HD studies. A major focus of the present SIGNAL study, therefore, includes the use of brain imaging measures, MRI and fluorodeoxyglucose-positron emission tomography (FDG-PET), in order to investigate the impact of treatment on changes in brain structure (MRI) and metabolic activity (FDG-PET). Analysis of imaging data from subjects in Cohort A suggests that treatment with the pepinemab (VX15/2503) antibody moderates or prevents the decrease in MRI volume and metabolic activity in many brain cortical regions which otherwise decreased at an annualized rate of 2% to 3% in the placebo control group. Although only 36 subjects were enrolled in Cohort A and the duration of treatment was relatively short, the data encourage further investigation of clinical effects of treatment. A second goal of the study was to collect data on the variance of potential treatment effects of pepinemab (VX15/2503) on quantitative motor and cognitive assessments. Accordingly, the results of motor and cognitive assessments provided important guidance for projecting the group size required to detect clinical effects in the continuing Cohort B study.
Graphical representations of changes in MRI volume as a percentage of baseline over the full 11-month treatment period for Cohort A subjects. In total, 31 brain regions of interest were assessed, the regions of frontal and parietal lobes showed the largest consistent treatment effects and are shown above. The pepinemab (VX15/2503) treated group (blue line) appears to be stabilized relative to the loss of MRI volume observed in the first 6 months of the placebo group (red line), which does, however, also appear to stabilize following cross-over to pepinemab (VX15/2503) at the end of 6 months.
Graphical representations of changes in FDG-PET signal as a percentage of baseline over the full 11-month treatment period for the regions of frontal and parietal lobes highlighted above that showed the largest consistent treatment effects. The pepinemab (VX15/2503) treated group (blue line) shows an initial increase in metabolic activity (FDG-PET signal) during the first 6 months followed by a more stabilizing effect of continuing treatment relative to the loss of metabolic activity observed in the first 6 months of the placebo group (red line), which does, however, show a sharp increase in metabolic activity following cross-over to pepinemab (VX15/2503) at the end of 6 months.
Mechanism of Action:
The mechanism of action of pepinemab (VX15/2503) in preclinical models was shown to involve several different cell types. These include oligodendrocyte precursor cells (OPCs), which have the potential to remyelinate damaged nerves, and microglia and astrocytes, the main innate inflammatory cells of the brain whose chronic activation is believed to contribute to neurodegenerative processes.
Astrocytes and microglia are key components of the brain that support neurons and shape neural networks by regulating formation and maintenance of synapses. Astrocytes cradle synapses through process extensions that express glutamate receptors and are involved in recycling 80% of free glutamate. Astrocytes, are also an important part of the neurovascular unit that mediate glucose uptake from circulation. This allows astrocytes to play a role in coupling the need for glucose transport with excitatory synaptic activity.
Under conditions of physiological stress or injury, astrocytes and microglia transition from their normal function to an inflammatory state that can trigger or exacerbate neurodegeneration. For example, during astrogliosis reactive astrocytes down-regulate both glutamate receptors and glucose transporters and secrete high concentrations of cytokines. Expression of the Huntington disease mutation in astrocytes alone has been shown to be sufficient to trigger the disease phenotype in an animal model. Conversely, reconstitution of HD transgenic mice with normal human astrocytes ameliorates disease. SEMA4D regulates the transition between normal and inflammatory states of astrocytes and microglia.
While it is widely believed that neuronal loss is irreversible, there is substantial evidence that other important elements that govern neurological activity, in particular, glial cells and synapses may be replenished or repaired with significant impact on disease progression.
Anti-SEMA4D was tested in several pre-clinical rodent models of experimental autoimmune encephalomyelitis (EAE). As shown in Figure 1, anti-SEMA4D had a statistically significant effect in ameliorating disease induced by active immunization with a myelin-derived peptide (PLP), as well as by adoptive transfer of myelin-specific T-cells into mice. In this latter model, the benefit of treatment with anti-SEMA4D antibody was comparable to IFN-β, an FDA approved drug for relapsing-remitting multiple sclerosis. Importantly, anti-SEMA4D antibody was also shown to ameliorate disease in a transgenic mouse model of Huntington’s disease. In this case, treatment with anti-SEMA4D antibody provided significant protection against the characteristic loss of brain volume in this disease model (Figure 2) as well as preventing loss of spatial memory and suppressing anxiety like behaviors.
Anti-SEMA4D treatment significantly inhibits cortical and corpus callosum degeneration in brains of 12-month-old YAC128 mice, a transgenic model of Huntington’s Disease. The open bars show volume measurements in normal control mice while filled bars represent the transgenic HD animals. Bars in the blue shaded boxes represent the animals that received preventive therapy with anti-SEMA4D antibody.