Tolerability, Safety, and Activity of SRX246 in Irritable Subjects With Huntington's Disease

SRX246 is a first-in-class vasopressin 1a (V1a) receptor antagonist that crosses the
blood-brain barrier following oral administration. The molecule exhibits high affinity and
high selectivity for its target receptor. Preclinical pharmacology studies have demonstrated
significant CNS effects in models of irritability, including impulsive aggression,
depression, and anxiety. In an experimental medicine fMRI study in healthy volunteers, SRX246
treatment significantly attenuated the effect of intranasal AVP in brain circuits known to
modulate emotional responses to stimuli that elicit aggression/fear. Together, these findings
suggest that SRX246 has potential as a novel therapeutic agent for major neuropsychiatric
symptoms seen in HD patients.

This is a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12 week, dose
escalation study of SRX246 in irritable Subjects with early symptomatic HD.

Following an initial screening visit, Subjects fulfilling the study inclusion and exclusion
criteria will enter a pre-treatment screening phase to permit evaluations to confirm
eligibility for inclusion into the study. This screening phase will be no longer than 30
days. At the completion of the screening period, eligible Subjects will be randomized at
baseline visit to receive either placebo or final doses of SRX246 of 120 mg twice daily or
160 mg twice daily during the double-blind treatment phase. At baseline, Subjects in the
active groups will receive 80 mg twice daily for 2 weeks, then escalate to 120 mg twice daily
for 4 weeks. Then one group of Subjects will continue to take 120 mg of SRX246 twice daily
for an additional 6 weeks, and the second group of Subjects will increase their dose to 160
mg of SRX246 twice daily for 6 weeks. Total dosing duration is 12 weeks.

Subjects in the placebo group will receive a similar number of capsules that are identical in
appearance to the capsules that contain SRX246 during the trial, in order to preserve the
blind.

In all groups, dose escalation will occur (stepwise) if patients have not experienced
dose-limiting adverse effects. Patients who cannot tolerate their final dose of drug (or
placebo) can have this dose reduced without compromising the blinding.

Subjects will have periodic visits either "in-person" or by "telephone", to assess
tolerability, safety, and several measures of irritability and other problem behaviors, and
clinical assessments for activity signals.

Inclusion Criteria:

1. Male and female Subjects aged 18 years or older

2. Subjects must have clinical features of HD, which can include motor, cognitive, or
behavioral symptoms

3. A confirmatory family history of HD; OR CAG repeat expansion ≥ 37

4. Total Functional Capacity (TFC) score of 5-13

5. Evidence of irritability; a score of at least 2 or greater on the severity measure of
either the UHDRS Irritability question (30b) or Aggression question (Disruptive or
Aggressive Behavior, 31b)

6. Women of childbearing potential (i.e., those not postmenopausal or surgically sterile)
must have a negative pregnancy test, be non-lactating and use adequate contraception
methods during the study. Adequate birth control includes: abstinence; oral, implanted
or injected contraceptives, e.g., birth control pills; intra-uterine device; barrier
(vaginal ring or diaphragm/cervical cap with spermicide); transdermal patch. Reliable
contraception must have been in use 30 days prior to the Baseline Visit. Partner(s)
contraception (e.g., male partner with vasectomy or other surgical contraception) is
acceptable.

7. Men must agree not to father a child during the study and one month after and to use
contraception. Barrier with spermicide or surgical contraception is acceptable.
Partner(s) contraception (e.g., female partner taking birth control pills or
surgically sterile) is acceptable.

8. Subjects must be able to swallow study drug capsules whole.

9. Sufficient English skills to complete all assessments without assistance of an English
language interpreter. Subjects with HD who cannot read or write might qualify for
enrollment in the study. Site PIs will have to decide in each case whether the Subject
can understand and fully participate with help from his/her Informant.

10. Availability of a responsible Informant (referred to as a "study partner" in the
consent document) who has good English skills, is familiar with the Subject, and is
able and willing to comply with all required study procedures, ensuring that the
patient attends all study visits and takes the study medicine as instructed. The study
partner must spend time with the patient a minimum of 4 times per week on 4 separate
days, and must monitor the patient's compliance and adverse events, participate in
caregiver assessments, and use the eDiary.

11. Subject has provided written, informed consent or, if Subject lacks the capacity to
provide informed consent (as determined by an independent assessment by a qualified
healthcare provider not directly involved in other study activities), a legally
authorized representative (LAR) has provided written informed consent and the Subject
has provided assent.

Exclusion Criteria:

1. Any significant neurologic disease other than HD at Screening.

2. Severe psychotic features or other severe psychiatric symptoms within the last three
months which could lead to difficulty complying with the protocol.

3. History of active alcohol or substance abuse within the past two years or Subject is
unable to refrain from substance abuse throughout the study.

4. Any chronic disability, significant systemic illness or unstable medical condition at
Screening or Baseline that could lead to difficulty complying with the protocol.

5. Use of any investigational drugs within 30 days of Screening.

6. Subject has known allergy to any of the components of study medication.

7. Subject is currently pregnant, breast-feeding and/or lactating.

8. Subject acknowledges present use of illicit drugs at Screening.