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Data suggest that pepinemab slows or prevents cognitive decline in Huntington’s Disease (HD)
Results highlight the potential for impact on other neurodegenerative and neuroinflammatory diseases including Alzheimer’s
The Nature Medicine article, titled “Pepinemab antibody blockade of SEMA4D in early Huntington’s Disease: a randomized, placebo-controlled, Phase 2 trial,” provides a comprehensive analysis of results from the Phase 2 study showing that while the trial did not meet its pre-specified primary efficacy endpoints, brain imaging measures showed a significant reduction in atrophy of the brain caudate nucleus (characteristic of HD) and prevented loss of metabolic activity in most brain regions (characteristic of both HD and AD). Multiple other exploratory and post-hoc assessments indicate a cognitive benefit to treatment. Pepinemab was well-tolerated by participants in the trial. The
These findings encourage continued development of pepinemab as a potential therapy for patients with early manifest symptoms of HD and potentially AD. Accordingly, a phase 1b/2a study of pepinemab in Alzheimer’s disease has been initiated and is actively enrolling patients (NCT04381468). The mechanism of action of pepinemab, targeting neuroinflammation2, may provide an alternative to other AD therapies that target aggregates of Aβ amyloid. The Nature Medicine publication is available online at https://www.nature.com/articles/s41591-022-01919-8 and
“Vaccinex is very pleased to publish the results of the Phase 2 SIGNAL HD study of pepinemab antibody in Nature Medicine demonstrating the effects of treatment along with a separate report in
“We believe that overall our clinical results provide compelling evidence of cognitive benefit to treatment with pepinemab. In surveys of HD patients and their families, cognitive decline is regularly identified as a major concern. It was, therefore, of particular interest that post-hoc subgroup analysis suggested that patients with early signs of mild cognitive deficits appeared to derive the greatest benefit from treatment. 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 decline3. 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. We are extremely grateful to work together with the community of patients and caregivers to evaluate new potential treatment options for these impactful neurodegenerative diseases.”
Summary of Key Findings from the SIGNAL HD trial Highlighted in the Nature Medicine Article
The Nature Medicine article highlights results that support the potential of pepinemab as a novel therapeutic approach for treating cognitive impairment in patients with HD, particularly those initially presenting with mild cognitive deficits. Key Findings from the Phase 2 SIGNAL HD trial include:
- significantly improved cognition in patients with early manifest disease, as reflected in the HD-Cognitive Assessment Battery of 6 different cognitive measures (HD-CAB Index, p=0.007).
- significantly reduced apathy severity (p=0.02), measured by the Problem Behaviors Assessment (PBA-s) which has previously been reported to correlate with cognitive decline.
- reduced atrophy (p=0.017) in the caudate nucleus, a brain region known to undergo early degeneration in HD.
- significantly improved brain metabolic activity as detected by FDG-PET in the majority of brain regions examined. FDG-PET signal has been reported to correlate with cognitive decline and clinical progression in AD.
- was well-tolerated with a low frequency of treatment-emergent adverse events (5% with pepinemab vs 9% with placebo) and a low treatment discontinuation rate (13/265) over the 18-month treatment period.
SIGNAL was a phase 2, multi-center, randomized, double-blinded, placebo-controlled clinical trial in 265 subjects including 179 early manifest and 86 late prodromal subjects all confirmed to carry the Huntington’s disease mutation. Subjects were randomized 1:1 for monthly intravenous infusion with either 20 mg/kg pepinemab or placebo for at least 18 months at 32 centers in the
About Huntington’s disease
Huntington’s disease (HD) is an inherited condition that compromises brain functions through progressive damage to neurons that is believed to be triggered by a mutation in the huntingtin gene. Data of our own and others suggest that the major inflammatory cells of the brain, astrocytes and microglia, contribute importantly to disease pathology2. People with HD develop problems with cognition, judgement, emotion, behavior, and motor activity which becomes progressively worse over time. There is no known cure for HD and currently no approved disease modifying treatment. Most patients start developing symptoms between the ages of 30 to 50 although HD can also occur in young adults. Today, there are approximately 41,000 patients in the
1. Feigin A et al. Nature Medicine 2022, https://www.nature.com/articles/s41591-022-01919-8; 2. Evans EE et al. J Neuroinflammation 19, 200 (2022). https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-022-02509-8; 3. Khosravi M et al. J Alzheimers Dis 70, 1197-1207 (2019). 4. https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/;
Pepinemab is a humanized IgG4 monoclonal antibody that inhibits SEMA4D, which regulates the actin cytoskeleton of cells that play an important role in both tumor immunity and in inflammatory reactions in the brain. Preclinical and clinical data show that by preventing inflammatory reactivity during disease progression2, pepinemab preserves the normal function of astrocytes and microglia, two types of glial cells that play a crucial role in maintaining the health and function of neurons in the brain2. Additional data show that in cancer pepinemab promotes infiltration and activation of dendritic cells and CD8+ T-cells and reverses immunosuppression within the tumor microenvironment. Pepinemab is being evaluated in several clinical studies in oncology and neurodegenerative disease.
Forward Looking Statements
To the extent that statements contained in this presentation are not descriptions of historical facts regarding
Source: Vaccinex, Inc.