The purpose of this study is to evaluate the safety, tolerability, PK, and efficacy of Pepinemab in subjects with late prodromal and early manifest Huntington's disease.

VX15/2503-N-131 (SIGNAL-HD) is a Phase 2, multi-center, randomized, double-blind, placebo controlled study of VX15/2503 (pepinemab) in subjects with late prodromal and early manifest Huntington's disease. The primary objective is to evaluate the safety and tolerability of monthly IV administration of a single dosage of pepinemab (or placebo). Efficacy endpoints include determining the effect of pepinemab on brain volumes (MRI), FDG-PET imaging, 11C-PBR28 (TSPO) PET imaging (subset of Cohort B only) and clinical features of HD including cognition, motor function, behavior, functional abilities, global function and global measurement of change. Additional endpoints include PK / PD, immunogenicity, and exploratory biomarkers. Subjects in Cohort B that have received 12 months of pepinemab who volunteer will undergo a lumbar puncture at V13 to collect cerebral spinal fluid (CSF) to evaluate pepinemab mAb concentrations, total sSEMA4D levels, and other biomarkers in their CSF. Enrollment will involve approximately 276 individuals who are 21 years of age or older with late prodromal (CAG-age product score (CAP score) of greater than 200 and Diagnostic Confidence Level (DCL) of 2 or 3) or early manifest HD (Total Functional Capacity (TFC) greater than or equal to 11). The study will be divided into Cohort A and Cohort B. Cohort A is now complete and an unblinded analysis has been performed. Cohort A subjects were treated for 6 months with either drug or placebo (1:1) and then all subjects were treated with drug for 6 months, followed by 3 months of follow up. Treatment duration for each subject in Cohort A was 12 months. Participation in Cohort A included a Screening visit, a Baseline visit within 30 days of screening; 12 monthly treatment visits beginning at baseline and continuing through Month 12; follow-up safety phone call at one month and a follow-up safety visit three months after the final infusion. Cohort A subjects participated in the study for approximately 16 months. Based on the analysis of Cohort A, it was decided to extend the duration of treatment for a subset of subjects in Cohort B to evaluate the clinical response to pepinemab after 36 months. Additional enrolled subjects in Cohort B will be treated with drug or placebo (1:1). Participation in Cohort B will include a Screening visit, a Baseline visit within 30 days of screening; 18 or 36 monthly visits beginning at baseline and continuing through Month 18 or Month 36; follow-up safety phone call or visit, and for a subset of subjects, a follow-up safety visit three and six months after the final infusion. Cohort B subjects will participate in the study for approximately 19 and up to 37 months.

Inclusion Criteria Highlights:

1. Male or female and are at least greater than or equal to 21 years of age at Screening.

2. Must fulfill one of the following criteria at Screening:

   1. Late prodromal HD as defined by a CAP score of greater than 200 and DCL 2 or 3.
   2. 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.

3. Must fulfill both of the following criteria at Screening:

   1. Have undergone genetic testing with a known CAG repeat greater than or equal to 36.
   2. No features of juvenile HD (Westphal variant).

4. If female must be either surgically sterile, postmenopausal, or nonlactating and nonpregnant. Female subjects of childbearing potential must practice a highly effective method of contraception.

5. If male, must agree to use a reliable method of birth control (condoms with contraceptive foams or sexual abstinence) during the study and for 6 months after the last dose of study drug.

6. Are willing and capable of providing informed consent for study participation, CAG genotyping (all subjects).

7. Are capable of reading, writing, and communicating effectively with others.

8. Are taking stable doses of any concomitant medications (including tetrabenazine and deutetrabenazine) during the 1 month prior to the Baseline Visit, with the exception of newly prescribed anxiolytics for the use of pre-medication prior to imaging at screening, which will be permitted on a case-by-case basis.

9. Must meet all criteria required to move forward with the Randomization Authorization Flow (RAF) and be considered eligible by the RAF Reviewer.

Exclusion Criteria Highlights:

1. Have participated in an investigational drug or device study within 30 days of the Baseline Visit, or 180 days if previous investigational drug was a MAb therapeutic, or previously participated in SIGNAL Cohort A. This does not apply to Cohort B subjects who are being offered the option to participate in the extension of Cohort B.

2. Have had previous neurosurgery for Huntington's disease or other movement disorders.

3. Are a suicide risk, as determined by meeting any of the following criteria:

   1. suicide attempt within one year prior to Baseline.
   2. suicidal ideation as defined by a positive response to question 5 on the C-SSRS (Baseline visit form) suicidal ideation section, within 60 days of the Baseline Visit.
   3. significant risk of suicide, as judged by the site Investigator.

4. Have marked cognitive impairment with a Montreal Cognitive Assessment (MoCA) Score less than or equal to 22.

5. Have a presence of clinically significant psychosis and/or confusional states, in the opinion of the site Investigator.

6. Have clinically significant laboratory or ECG abnormalities at Screening, in the opinion of the site Investigator.

7. Have clinically relevant hematologic, hepatic, cardiac, or renal disease.

8. Have a medical history of infection with human immunodeficiency virus, hepatitis C and/or hepatitis B, or found to have an abnormality at Screening.

9. Have a history of substance abuse (based on DSMIV criteria) within the past 12 months prior to Screening.

10. If female are pregnant or breastfeeding.

11. Have a known allergy to any ingredient in the study drug.

12. Have a history of malignancy of any type within 2 years prior to Screening. A history of surgically excised non-melanoma skin cancers, and superficial bladder or prostate cancer is permitted.

13. Have a clinically significant medical, surgical, laboratory, or behavioral abnormality which in the judgment of the site Investigator makes the subject unsuitable for the study.

14. Have any significant findings not related to HD on the screening MRI which in the judgment of the site Investigator makes the subject unsuitable for the study.

15. Have any of the following conditions (which would exclude MRI participation):

    1. An implant/device/condition that is contraindicated for MRI (e.g. pacemaker, severe claustrophobia, prosthetic heart valve, any metal fragments in the eyes or body--in some cases, an X-ray may be needed before an MRI scan, to ensure it is safe to enter the scanner).
    2. Body habitus that would impede completion of MRI scan. (Subject weight above 158 kg should be discussed with the Medical Monitor).

    NOTE: If PET is done on PET-MRI all the above conditions apply for PET-MRI.

16. Are undergoing FDG-PET and have received research-related radiation exposure that exceeds institutional guidelines in the prior year if applicable.

17. Are undergoing a LP for CSF collection and have any of the following conditions: uncorrected bleeding or clotting disorders, skin infections near the site of the LP, suspicion of increased intracranial pressure, allergies to numbing medications (local anesthetics), acute spinal trauma, history of migraines.

18. Are undergoing a LP for CSF collection and taking any of the following types of anticoagulants: coumarins and indandiones, Factor Xa inhibitors, heparins, or thrombin inhibitors.