Abstract Details

Title Clinical evidence that treatment with pepinemab, a novel regulator of neuroinflammation, provides cognitive benefit to patients with Huntington’s and potentially other neurodegenerative diseases

Topic Movement Disorders

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 5-007

Background Semaphorin 4D (SEMA4D) triggers reactive inflammatory glia. Antibody neutralization of SEMA4D ameliorates neurodegenerative processes in preclinical models of HD and AD.

Objective Clinical investigation of cognitive benefit and biomarkers of disease progression in patients with Huntington’s Disease (HD) and Alzheimer’s Disease (AD).

Design/Methods SIGNAL (NCT02481674) is a phase 2 study that included 179 patients with early manifest HD. Study subjects were randomized for 18-months treatment with pepinemab SEMA4D neutralizing antibody or placebo. Co-primary endpoints included a cognitive family consisting of two defined components of the HD-Cognitive Assessment Battery (HD-CAB) and CGIC. A second Phase 1b/2a trial, SIGNAL-AD (NCT04381468), has been initiated and is planned to enroll 40 patients randomized to treatment with pepinemab or placebo for 48 weeks. Efficacy endpoints include CDR-SB, ADAS-Cog13 and FDG-PET.

Results Although the primary endpoints of the completed SIGNAL HD study did not achieve statistical significance, subgroup analysis by baseline Montreal Cognitive Assessment score (MoCA<26) demonstrated enrichment for treatment-related cognitive benefit in the pre-defined cognitive family. In addition, pepinemab treatment reduced disease progression relative to placebo as determined by CGIC in patients with baseline total functional capacity (TFC) scores of 11 (p= 0.041), but not in patients with less advanced TFC 12-13. Both apathy and FDG-PET are reported to correlate with disease progression and cognitive decline. Significant treatment-related reduction in apathy severity (p=0.0291) was observed. Importantly, pepinemab slowed or reversed decline in metabolic activity (FDG-PET) in 26/26 brain regions examined, with significant benefit in 15/26 regions (p≤0.05). MRI imaging analysis demonstrated reduced caudate atrophy (p=0.017) and a trend of reduced ventricular expansion (p=0.06). We will discuss the relation of clinical outcomes to mechanism of action and design of trials to treat patients with Stage 1-2 disease.

Conclusions Subgroup analysis of SIGNAL HD demonstrated treatment benefit in cognition and encourage continued development of pepinemab in HD and AD.

Authors/Disclosures
Elizabeth E. Evans, PhD (Vaccinex) PRESENTER	Dr. Evans has received personal compensation for serving as an employee of Vaccinex. Dr. Evans has stock in Vaccinex. Dr. Evans has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
John Leonard (Biogen Idec Pharmaceuticals)	No disclosure on file
Andrew S. Feigin, MD (NYU Langone Health)	Dr. Feigin has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ADCS/ATRI. Dr. Feigin has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC. Dr. Feigin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Annexon. Dr. Feigin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Aspen. Dr. Feigin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AskBio. Dr. Feigin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. The institution of Dr. Feigin has received research support from Huntngton Study Group. The institution of Dr. Feigin has received research support from Prilenia.
Eric R. Siemers, MD (Siemers Integration LLC)	Dr. Siemers has received personal compensation for serving as an employee of Acumen Pharmaceuticals. The institution of Dr. Siemers has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for Vaccinex Pharmceuticals. The institution of Dr. Siemers has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Cogstate Ltd. The institution of Dr. Siemers has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for Gates Ventures LLC. The institution of Dr. Siemers has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for US Green Valley Pharmaceuticals, Inc. Dr. Siemers has stock in Acumen Pharmaceuticals. Dr. Siemers has stock in Ell Lilly and Company. Dr. Siemers has received personal compensation in the range of $0-$499 for serving as a study section reviewer with National Institutes of Health. Dr. Siemers has a non-compensated relationship as a Volunteer with Alzheimer's Association that is relevant to AAN interests or activities. Dr. Siemers has a non-compensated relationship as a Board of Directors with Bright Focus Foundation that is relevant to AAN interests or activities. Dr. Siemers has a non-compensated relationship as a Board of Directors with Huntington Study Group that is relevant to AAN interests or activities.
	No disclosure on file