Pepinemab Improved Cognition But Not Huntington Disease Progression

As published in Nature Medicine, in the phase 2 SIGNAL study (NCT02481674) of pepinemab (SEMA4D; Vaccinex, Rochester, NY) primary endpoints were not met in individuals with Huntington disease (HD; n=295), but there was a positive effect on cognition. 

The differences between intravenous infusion 20 mg/kg pepinemab for 18 months and placebo in mean change  from baseline at month 17 for one-touch stockings of Cambridge (OTS) were −1.98 (95% CI: −4.00, 0.05) (one-sided P=.028), and for paced tapping (PTAP  1.43 (95% CI: −0.37, 3.23) (one-sided P= .06).There were no differences on the Clinical Global Impression of Change (CGIC).

There was also significantly improved cognition in participants with early manifest disease (n=179) as measured with the HD-Cognitive Assessment Battery of 6 different cognitive measures (HD-CAB Index, P=.007). A significant reduction of apathy severity (P=.02) was measured by the Problem Behaviors Assessment (PBA-s). Brain imaging measures showed a significant reduction in atrophy of the brain caudate nucleus (P=.017) and prevented loss of metabolic activity in most brain regions.

“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 disease (AD) have previously shown to correlate with cognitive decline. 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 AD. 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.” 

Pepinemab was well-tolerated with a low frequency of treatment-emergent adverse events (TEAS) (5% with pepinemab vs 9% with placebo) and only a 5% (13/265) treatment discontinuation rate. 

Based on these encouraging results a phase 1b/2a study (NCT04381468) in AD has begun, and phase 3 trials for HD are anticipated.