A Study in Subjects With Late Prodromal and Early Manifest Huntington's Disease (HD) to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of Pepinemab (VX15/2503)

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:
4. suicide attempt within one year prior to Baseline.
5. 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.
6. significant risk of suicide, as judged by the site Investigator.
7. Have marked cognitive impairment with a Montreal Cognitive Assessment (MoCA) Score less than or equal to 22.
8. Have a presence of clinically significant psychosis and/or confusional states, in the opinion of the site Investigator.
9. Have clinically significant laboratory or ECG abnormalities at Screening, in the opinion of the site Investigator.
10. Have clinically relevant hematologic, hepatic, cardiac, or renal disease.
11. Have a medical history of infection with human immunodeficiency virus, hepatitis C and/or hepatitis B, or found to have an abnormality at Screening.
12. Have a history of substance abuse (based on DSMIV criteria) within the past 12 months prior to Screening.
13. . If female are pregnant or breastfeeding.
14. . Have a known allergy to any ingredient in the study drug.
15. . 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.
16. . 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.
17. . 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.
18. . Have any of the following conditions (which would exclude MRI participation):
19. 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).
20. 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.

1. . Are undergoing FDG-PET and have received research-related radiation exposure that exceeds institutional guidelines in the prior year if applicable.
2. . 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.
3. . 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.