SIGNAL (Vaccinex) trial Huntington Disease


About the study 

SIGNAL is a Phase 2, multi-center, randomized, double-blind, placebo controlled study of VX15/2503 in subjects with late prodromal and early manifest Huntington's disease.


Vaccinex Inc.

About the experimental drug (VX15/pepinemab) 

Pepinemab, also known as VX15/2503, is a humanized monoclonal antibody that binds and blocks the activity of semaphorin 4D (SEMA4D) which is an extracellular signaling molecule that regulates the migration and function of immune and inflammatory cells.  Preclinical studies have demonstrated that the biological activities associated with antibody blockade of SEMA4D promotes immune cell infiltration into tumors and prevent neurological damage in neuroinflammatory and neurodegenerative disease models. 


There were two main groups of people in the SIGNAL trial, referred to as “Cohort A” and “Cohort B”. The people in Group A began and ended the trial first, and participated for a shorter period. Participants included in Cohort A received monthly infusions of VX15 or placebo for two consecutive periods of 6 months each, followed by a safety review phase of an additional 3 months. In cohort B, patients received VX15 or placebo for 18 or 36 months.


The study was designed to test whether pepinemab (also known as VX15) was safe for people with HD, and whether it could slow the effects of HD, like changes to the brain, and difficulties with thinking, movements, and behavior. Key results from the trial were announced recently, and the bottom line is that pepinemab did not benefit people with HD.

Study sites 

The study took place in 20 centers across the United States, involving 301 patients with Huntington's disease in the early stages or not yet symptomatic.


The SIGNAL trial began in 2015 and ended in September 2020. 

Inclusion Criteria 

  • Male or female and are at least greater than or equal to 21 years of age at screening
  • Late prodromal HD as defined by a CAP score of greater than 200 and DCL 2 or 3.
  • Early manifest HD as defined by a TFC greater than or equal to 11. Subject must have been determined to have a clinical diagnosis of HD by the Site Investigator as defined by a DCL of 4.
  • Have undergone genetic testing with a known CAG repeat greater than or equal to 36.
  • No features of juvenile HD (Westphal variant).
  • Are willing and capable of providing informed consent for study participation
  • Women of child bearing potential or male participants: Adequate contraception and birth control
  • Good general health

Why the study didn't reach phase 3

Key results from the trial were announced recently and although pepinemab was deemed safe and tolerable, the study has not achieved its 'primary endpoints’. That’s because the participants who received the drug did not perform better than those who received the placebo, on either the cognitive tests or the doctor’s assessment

Although slight improvements were registered in some tasks used to test cognitive activities, they did not reach “statistical significance”, which means that there was no mathematical difference between the placebo and drug groups. 

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