• Additional assessment of hippocampal function by MWM [ Time Frame: 20 Weeks ]
  Percent of time spent in the correct quadrant during MWM probe test during the neflamapimod-treatment period compared to that during the placebo-administration period.
• To evaluate the effects of neflamapimod on the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning task. [ Time Frame: 20 Weeks ]
  Number of overall errors in the CANTAB paired associates learning task, in addition to larger battery, during the neflamapimod-treatment period compared to that during the placebo-administration period.
• To evaluate tolerability and safety of neflamapimod in subjects with HD. [ Time Frame: 20 Weeks ]
  Safety as determined by the number of related adverse events and general tolerability reported during the neflamapimod treatment period compared to the placebo administration period.

• Drug: neflamapimod
  40 mg neflamapimod capsule
  Other Name: VX-745
• Other: Placebo
  matching placebo capsule

• Experimental: neflamapimod
  40 mg hard gelatin capsules, taken twice daily with food.
  Intervention: Drug: neflamapimod
• Placebo Comparator: placebo
  hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food.
  Intervention: Other: Placebo

Inclusion Criteria:

1. Men and women age 30 to 70 years, inclusive.
2. Willing and able to provide informed consent.

3. Must have genetically confirmed HD and identified cognitive deficits:

   1. Stage 1, as defined by Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) score >10, and,
   2. CANTAB Paired Associate Learning Total Adjusted Error Score of >16.
4. Normal or corrected eye sight and auditory abilities, sufficient to perform all aspects of the cognitive and functional assessments.
5. No history of learning difficulties that may interfere with the subject's ability to complete the cognitive tests.

Exclusion Criteria:

1. A profile of impairment that is not consistent with HD.
2. Diagnosis of any other ongoing central nervous system condition other than HD, including, but not limited to, vascular dementia, dementia with Lewy bodies, and Parkinson's disease.
3. Suicidality, defined as active suicidal thoughts within 6 months before Screening or at Baseline, defined as answering yes to items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS), or history of suicide attempt in previous 2 years, or, in the Investigator's opinion, at serious risk of suicide.
4. Ongoing major and active psychiatric disorder, moderate to severe depressive symptoms, and or other concurrent medical condition that, in the opinion of the Investigator, might compromise safety and/or compliance with study requirements.
5. Diagnosis of alcohol or drug abuse within the previous 2 years.
6. Poorly controlled clinically significant medical illness, such as hypertension (blood pressure >180 mmHg systolic or 100 mmHg diastolic); myocardial infarction within 6 months; uncompensated congestive heart failure or other significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that would preclude treatment with p38 mitogen activated protein (MAP) kinase inhibitor and/or assessment of drug safety and efficacy.
7. Anemia with a hemoglobin ≤10 g/dL, clinically significant thyroid function abnormality, electrolyte abnormalities.
8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 × the upper limit of normal (ULN), total bilirubin >1.5 × ULN, and/or International Normalized Ratio (INR) >1.5.
9. Known human immunodeficiency virus; or active hepatitis B or hepatitis C virus infection; evidence of active or latent tuberculosis.
10. Subject participated in a study of an investigational drug less than 3 months or 5 half-lives of an investigational drug, whichever is longer, before enrollment in this study.
11. History of previous neurosurgery to the brain.
12. Female subjects who are pregnant or breast-feeding.
13. Male subjects with female partners of child-bearing potential who are unwilling or unable to adhere to contraception requirements specified in the protocol (see Section 5.8).
14. Female subjects who have not reached menopause or have not had a hysterectomy or bilateral oophorectomy/salpingo-oophorectomy and are not willing or unable to adhere to contraceptive requirements specified in the protocol (see Section 5.8).
15. Requires concomitant use of cytochrome P450 (CYP) 3A4 inhibitors or anti-tumor necrosis factor-alpha therapies during study participation.
16. Known allergy to any ingredient of the trial medication or placebo.