SEMA4D blocking antibody, pepinemab, is a novel potential treatment for neurodegenerative disease: Clinical proof of concept in Phase 2 HD study supports ongoing clinical development in Phase 1/2 AD study

Abstract Background Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin receptors. SEMA4D is upregulated in neurons in response to stress and triggers activation of plexin‐positive astrocytes with concomitant loss of normal astrocyte functions. Drivers of glial cell activation may represent important novel targets to modify progression of neurodegenerative pathology. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in preclinical models, including Huntington’s disease (HD) and Alzheimer’s disease (AD). SIGNAL‐HD (NCT02481674), a completed Phase 2 trial, provided clinical rationale for the ongoing Phase 1/2 SIGNAL‐AD study (NCT04381468). Method The SIGNAL‐HD study included 301 subjects with late prodromal (LP) and early manifest (EM) HD. Subjects were treated with monthly infusions of pepinemab for at least 18 months and evaluated for safety and a variety of clinical parameters including cognition (HD‐CAB). Imaging endpoints included structural MRI to assess brain atrophy and FDG‐PET to assess brain metabolism. The SIGNAL‐AD study plans to include 40 subjects with early AD treated for approximately 1 year, with objectives including safety, change in brain metabolism via FDG‐PET, and clinical endpoints including cognition. Result In SIGNAL‐HD, pepinemab was well‐tolerated and was shown to cross the BBB to engage its target. Co‐primary efficacy outcome measures did not achieve statistical significance in this study, however, positive trends in the direction of pepinemab benefit were observed and analysis of secondary and exploratory endpoints was therefore pursued. In 179 EM subjects, a treatment benefit was observed in 6/6 components of the HD‐CAB cognitive assessment battery, with a significant treatment effect on HD‐CAB composite score (p = 0.007). Further changes in prespecified exploratory imaging endpoints suggest that pepinemab treatment reduced brain atrophy (volumetric MRI) and slowed or reversed decline in metabolic activity in 26/26 brain regions, with 15/26 regions showing a significant positive treatment effect (p≤0.05) by FDG‐PET imaging. Conclusion SIGNAL‐HD showed a favorable safety profile and positive trends in cognition and imaging endpoints that encourage continued development in both HD and AD. The Phase 1b/2a study in AD (SIGNAL‐AD), is currently enrolling and initial safety review is planned for end of February.