Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 3 Study to Evaluate the Efficacy and Safety of OV101 in Pediatric Individuals With Angelman Syndrome (NEPTUNE)

Ovid Therapeutics Inc. (Ovid) is developing OV101 (gaboxadol) for the treatment
of rare genetic disorders that are associated with severe developmental and
behavioral challenges that have no approved therapies, such as Angelman
syndrome (AS) and Fragile X syndrome. Gaboxadol was initially developed for the
treatment of insomnia by H. Lundbeck A/S and Merck, but its development was
discontinued in 2007. Extensive nonclinical and clinical data were generated
during the initial stages of development, including data from exposure to
gaboxadol in more than 4,300 adult subjects with insomnia and approximately 500
adult subjects in non insomnia related studies.

Angelman syndrome is a severe, complex, and rare neurogenetic disorder with a
prevalence estimated at 1 in every 10,000 to 24,000 live births (16;20;12). The
condition is associated with impaired expression of the ubiquitin protein
ligase E3A gene (UBE3A). While UBE3A is expressed from both gene copies in the
cells of other tissues, in neurons the paternal allele is preferentially
silenced through the epigenetic process known as imprinting. Therefore, any
alteration in the maternal copy of UBE3A results in AS. Clinical findings range
in severity and include developmental delay/intellectual disability, movement
and/or balance disorder, and tremulous movement of limbs. Unique behavioral
characteristics include the combination of a happy, smiling demeanor with
easily provoked laughter and excitability (exhibited by hand-flapping and
stereotypic movements). Individuals with AS frequently have motor dysfunction
related to gait and balance, severe disruptions in sleep, little to no speech,
short attention span, anxiety, and seizures with characteristic abnormal
electroencephalogram patterns.

Current treatments are aimed at managing symptoms and include antiepileptic
medications for seizure control and medications for sleep and behavioral
problems (eg, anxiety). Other therapies include speech therapy, physical
therapy, occupational therapy, and educational resources. Notably, current
treatments do not target the underlying brain deficits.

OV101 is the first highly selective, extrasynaptic gamma-aminobutyric acid
(GABA) receptor agonist that binds as an orthosteric agonist to the *4- and *-
containing subunit of extrasynaptic GABA receptors. Research has shown that
absence (or dysfunction) of Ube3a results in an aberrant increase in the uptake
of GABA, which is the main inhibitory neurotransmitter in the brain. The
extrasynaptic GABA receptors mediate tonic inhibition and sleep maintenance. In
a mouse model of AS, OV101 was shown to restore tonic inhibition in
Ube3a-deficient cerebellar neurons and correct motor abnormalities in
Ube3a-deficient mice. These results suggest that OV101 may alleviate the motor
dysfunction observed in individuals with AS. Importantly, OV101*s ability to
potentiate tonic inhibition is unlike any other GABAergic agent, including
benzodiazepines, zolpidem, zaleplon, zopiclone, barbiturates, neurosteroids,
and drugs that act on GABA metabolism or uptake. Unlike many of these drugs
that are allosteric modulators and therefore require endogenous GABA to
function, OV101 is a GABA agonist and can function when GABA is deficient or
absent. In addition to the data on presynaptic dysfunction leading to reduced
tonic inhibition, there are additional studies which speak to the potential of
OV101 in AS, including modulation of sleep and cognition domains that are
impaired in subjects with AS.

Phase 2 and Phase 3 studies in adult subjects with primary insomnia
demonstrated that OV101 is effective in restoring classical sleep parameters
(sleep induction and sleep maintenance) and slow wave sleep, resulting in an
improvement in the quality and restorative effects of sleep.

All efficacy study objectives will be assessed in the pediatric AS study
population of subjects who are 4 to 12 years old. All safety study objectives
will be assessed in the pediatric AS study population of subjects who are 2 to
12 years old.

Primary Objective:
* To evaluate the efficacy of OV101 versus placebo as assessed by the Clinical
Global Impressions-Improvement-Angelman syndrome (CGI-I-AS) score at Week 12.

The secondary efficacy objectives of this study are:
* To evaluate the efficacy of OV101 versus placebo:
on latency of sleep onset (LSO), sleep efficiency, and daytime sleep assessed
by actigraphy.
on Communications, Socialization, Daily Living Skills, Motor Skills, and
Maladaptive Behavior domains assessed by the Vineland Adaptive Behavior Scale,
3rd Edition (VABS 3).
on the Clinical Global Impressions-Severity-Angelman syndrome (CGI-S-AS)
Symptoms Overall score.
* To evaluate the relationships of CGI-S-AS Symptoms Overall and CGI-S-AS
domains at baseline with CGI-I-AS at Week 12.

The tertiary efficacy objectives of this study are to evaluate the efficacy of
OV101 versus placebo:
* on total sleep time and total activity assessed by actigraphy
* based on sleep diary data (caregiver reported)
* based on the Children*s Sleep Habits Questionnaire (CSHQ)
* based on the Pediatric Quality of Life Inventory* (Peds QL*) (Cerebral Palsy,
Multidimensional Fatigue, and Family Impact modules).

Pharmacokinetic Objectives:
The pharmacokinetic (PK) objectives of this study are to estimate systemic
plasma exposure to OV101 (maximum plasma concentration [Cmax] and area under
the concentration-time curve [AUC]) following a single oral dose using sparse
sampling and a population PK approach as well as to evaluate estimated PK
parameters in the context of a validated physiologically-based PK (PBPK) model
for the pediatric study population 2 to 12 years old.

Safety Objectives:
The safety objectives of this study are to evaluate the safety and tolerability
of OV101 in subjects 2 to 12 years old, including seizure diary data and
assessment of suicidality.

The study will comprise a screening period within the 28 days preceding Day 1;
a visit on Day 1 for baseline assessments, the first dose of study drug, and
sparse sampling of blood; subsequent doses of study drug taken each evening
approximately 30 minutes before bedtime for 12 weeks starting on Day 2; and
study site visits for efficacy and safety assessments over a 12 week treatment
period. After the baseline visit, the study site visits will occur at Week 6
and Week 12 (end of treatment [EOT]). Phone safety visits will occur during
up-titration of the study drug (Day 6 and Day 11). Unless a subject decides to
participate in the ELARA open-label extension study, an end of study (EOS)
phone safety visit will occur approximately 2 weeks after the last dose of
study drug to assess safety and tolerability associated with discontinuation of
treatment. Subjects eligible for and willing to enroll in the ELARA study will
have the NEPTUNE EOT visit be their NEPTUNE EOS visit, and their NEPTUNE EOT
visit will serve as their ELARA baseline visit. A subject will be considered to
have completed the NEPTUNE study after completing the EOS visit. The total
duration of the study for a subject will be approximately 18 weeks.

Random assignment of subjects for efficacy assessment (to either OV101 or
placebo treatment in a 1:1 ratio) will be stratified by age at baseline across
all study sites, with a maximum of 12 subjects per study site (unless
authorized by Sponsor). The randomization strata will be 9 to 12 years old
(inclusive) and 4 to 8 years old (inclusive), with at least 24 subjects per
stratum. Up to 5 subjects 2 to 3 years old (inclusive) will be enrolled for
safety and PBPK assessments only and will be assigned to treatment with OV101.
Within each age group, dosing will be assigned based on body weight at
screening.

For each subject, screening assessments will be completed within the 28 days
preceding Day 1 (baseline). On Day 1, each subject who meets all eligibility
criteria will receive the first assigned blister cards of study drug capsules
according to the treatment code, sufficient to last until the Week 6 visit,
when blister cards will be collected and unused study drug will be counted.
Study drug will be similarly dispensed at the Week 6 visit, and blister cards
(or bottles for ages 2 to 3 years) will be collected and unused study drug will
be counted at the Week 12 visit. Caregivers/LARs will be provided an additional
blister card in case of unexpected delays for study visits.

On Day 1, subjects will take their first dose of study drug at the study site
during the daytime, and blood will be sampled 45 minutes ± 15 minutes, 90
minutes ± 15 minutes and 4 hours ± 30 minutes after dosing for determination of
OV101 concentrations (sparse sampling for population PK modeling). Subjects
will take all subsequent doses approximately 30 minutes before anticipated
bedtime, starting with the evening of Day 2.

Each subject*s dose of study drug (OV101 or placebo) will be adjusted from the
starting dose to the maintenance dose according to the titration schedule, as
tolerated by the subject. On Days 1 through 5, each subject will receive the
starting dose. On Day 6, each subject will up-titrate to the maintenance dose.
Phone calls to assess tolerability will occur on Day 6 and Day 11. The
maintenance dose will be set based on the subject*s weight at screening and
will be continued to the EOT.

Downward dose adjustments may be permitted to mitigate tolerability concerns
with OV101. These adjustments will be at the investigator*s discretion and
should be discussed with the medical monitor or his/her delegate. Unscheduled
study site visits are optional at any time to confirm tolerability.

Subject assignment to treatment will be stratified and staged by age and gated
by an Independent Data Monitoring Committee (IDMC). Subjects 9 to 12 years old
at baseline will begin treatment first. Initial enrollment of randomized
subjects will be used to collect at least 3 evaluable OV101 PK samples in each
efficacy age group and these subjects will be termed *sentry subjects.* No age
cohort may begin treatment without IDMC review of tolerability and PK in sentry
subjects in the previous older cohort. The tolerability assessment of the
sentry subjects at Day 11, 5 days after initiation of the maintenance dose,
will be forwarded to the IDMC for review as blinded data. If the IDMC considers
the tolerability and PK acceptable, subjects 4 to 8 years old at baseline may
begin treatment (initiation of treatment in the 9 to 12 age group continues
during the review). Similarly, following IDMC review and approval of the
tolerability in the sentry subjects 4 to 8 years old, subjects 2 to 3 years old
may begin treatment (initiation of treatment in the 4 to 8 age group continues
during the review).

The LARs/caregivers will complete sleep diaries on behalf of subjects over the
periods where the subject is scheduled to wear the actigraph. An actigraph will
be issued to each subject at the screening visit, so that actigraphy data can
be collected for 7 consecutive days before travel for the baseline visit.
Subjects will be given 3 attempts within the 28-day screening window to wear
the actigraph for at least 7 consecutive days, and subjects will be excluded
after 3 unsuccessful attempts to wear the actigraph for 7 consecutive days.
Actigraphy data collected during the first 7-consecutive day period that
includes 2 weekend days during screening will be used as the baseline
actigraphy assessment. These 7 consecutive days should include 2 consecutive
weekend days and should not include any travel days. The actigraph it is to be
worn for a maximum of 14 days preceding travel for the scheduled study site
visits at Week 6 and Week 12 visits to collect at least 7 consecutive days of
data including 2 consecutive weekend days. If the subject requires an
additional attempt to keep the actigraph on for 7 consecutive days (including 2
consecutive weekend days) after the Week 6 visit, the subject will be given an
actigraph to be worn for 7 days after Week 6.

The LAR/caregivers will complete paper seizure diaries on behalf of subjects
throughout the study, from issuance during screening (and at study visits)
through Week 12 (EOT).

Safety information will be collected during phone calls on Day 6 and Day 11 and
during the EOS visit, as well as during every study site visit. Each subject*s
LAR/caregiver will be instructed to contact the study center if the subject
experiences any adverse events (AEs), is unable to take the study drug as
prescribed, or is unable to tolerate wearing the actigraph.

At the investigator*s discretion throughout the study, subjects may be
evaluated at unscheduled clinic visits for reasons related to subject safety.
At unscheduled visits, subjects will be queried about AEs and changes in
concomitant medications and evaluated for suicidality. Safety laboratory
assessments may be conducted. Periodic interim review of safety data will be
performed by the IDMC and as part of routine pharmacovigilance activities.

Study drug dosage will be assigned based on body weight at the screening visit.
Study drug will be titrated from the starting dose to the maintenance dose
according to Table 1.
If at randomization on Day 1 a subject is assigned to placebo, the number of
capsules per dose will correspond to the number of OV101 capsules for a subject
of the same weight.
Dosing will be initiated at the starting dose for the first 5 days. On Day 6,
tolerability will be assessed by the investigator. If there are no tolerability
concerns (eg, excessive somnolence, dizziness, vomiting, negative behavior
changes) and no AE related to the study drug has been observed since Day 1 by
the LAR/caregiver or the investigator, then the dose of OV101 will be increased
to the maintenance dose for the duration of the study. The maintenance dose
identified at screening will remain consistent throughout the study. If
tolerability concerns are observed on Day 6, the subject will discontinue study
drug.
The subject*s maintenance dose for the duration of the study will be set based
on the subject*s weight at the screening visit, and the subject should continue
taking the maintenance dose after the Day 6 assessment until the EOS.
Tolerability will again be assessed during the Day 11 phone call while the
subject is taking the maintenance dose. The investigator may initiate
down-titration on Day 11 by 1 capsule (Table 2) based on investigator
assessments of tolerability and AEs, or medical necessity. If down-titration is
initiated, then the investigator should reassess tolerability with the modified
dose regimen within 3 days of the dosing change. No further changes in dose
regimen should be made after Day 15.
If tolerability is not acceptable at any other time during the 12 weeks of
treatment, the investigator should discuss the situation with the medical
monitor or his/her delegate. Any intolerability must be documented as an AE.
The daily dose may not be lower for any subject than the reduced maintenance
dose indicated in Table 2. If a subject cannot tolerate the reduced maintenance
dose, that subject must discontinue treatment. Any dose adjustments or changes
in dosing must be documented in the electronic case report form and supporting
rationale must be documented in the medical record or other appropriate source
document.

OV101 has been studied in adult and adolescent subjects with AS. In this study,
58 patients were treated with OV101 either once daily (15 mg at bedtime) or
twice daily (10 mg in the morning, 15 mg at bedtime) and 29 patients were
treated with placebo. The side effects seen commonly (occurring in 10 or more
out of 100 of the participants) in all subjects receiving OV101 were the
following:
* GI (gastrointestinal)* vomiting, nausea (feeling the need to vomit),
diarrhea, decreased appetite
* Behaviour * somnolence (sleepiness), irritability, aggression
* Neurologic * seizure
* Other * pyrexia (fever), nasopharyngitis (runny nose, sore throat), upper
respiratory tract infection (cold), rash

There were no deaths linked to these side effects.

OV101 has been previously tested in over 3,396 subjects at dosage of 5 to 20 mg
in 3 other studies for participants who have insomnia (problem with sleeping).
The side effects seen commonly (occurring in 2 out of 100 of the participants)
with 15 mg dose are:
* Dizziness
* Somnolence (Sleepiness)
* Nausea
* Vomiting
* Headache