An Open-Label Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of OV101 in Individuals with Angelman Syndrome (ELARA)

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 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 for
commercial reasons. Extensive nonclinical and clinical data were generated
during the initial stages of development, including data from exposure to
gaboxadol in more than 4000 adult subjects (950 subject years) with insomnia
and approximately 500 adult subjects in non-insomnia-related studies.
Angelman syndrome is a severe, complex, and rare neurogenetic disorder with the
prevalence of approximately 1 in every 10,000 to 24,000 live births. The
condition is associated with impaired expression of the ubiquitin protein
ligase E3A gene (UBE3A). While ubiquitin protein ligase E3A (UBE3A) is
expressed bi-allelically 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 orthosterically to the δ-subunit of
extrasynaptic GABA receptors. The mechanism of action of OV101 is unique among
GABAergic agents, including benzodiazepines, zolpidem and other zolpidem-like
drugs, neurosteroids, and drugs that act on GABA metabolism or uptake. 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. OV101 is the first highly selective GABA receptor agonist that
acts on α4δ-containing GABA A-receptors. These 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.
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.

The primary objective of this study is to evaluate the long-term safety and
tolerability of OV101 in individuals with AS assessed by the incidence and
severity of AEs and SAEs in subjects who are at least 2 years old.
The secondary objectives of this study are the following:
• To evaluate the long-term efficacy of OV101 treatment assessed by changes in
behavior and sleep in subjects with AS who are at least 4 years old
• To evaluate the long-term safety and tolerability of OV101 treatment assessed
by changes in suicidality assessments, vital sign measurements, laboratory
assessments, physical examinations, and seizure frequency in subjects with AS
who are at least 2 years old
The exploratory objectives of this study are to evaluate changes in motor and
adaptive function and quality of life with OV101 in subjects with AS who are at
least 4 years old and to explore the relationships among study endpoints (eg,
behavior and sleep), where appropriate.

This will be an open-label, long-term safety study for evaluation of treatment
with OV101 in up to 200 subjects with AS who either have completed previous
Ovid studies (OV101-15-001, OV101-16-001, or OV101-19-001) or are siblings
(with AS) of subjects with AS who have completed previous Ovid studies of
OV101.

As this study will enroll subjects who may have completed previous studies for
different periods of time before entering this study (as well as subjects with
AS who have not been themselves enrolled in an Ovid study), subjects may be
required to complete screening and baseline visits before receiving OV101 under
this protocol.

The study will comprise a screening period of up to 30 days; a baseline visit
on Day 1 for baseline assessments; a first dose of study drug to be taken in
the evening of Day 1 (at bedtime); and clinic visits for safety and efficacy
assessments over a 3-year treatment period. After the baseline visit, the
clinic visits will occur at Weeks 12, 36, 64, 96, 128, and 160 (EOT). Phone
visits will occur at Weeks 24, 48, 80, 112, and 144. A follow-up phone safety
visit at the EOS will occur approximately 14 days after the last dose of study
drug (EOT) to assess safety and tolerability associated with discontinuation of
treatment. A subject will be considered to have completed the study after
completing the EOS phone visit.

The following subjects will be required to complete screening and baseline
visits (and assessments) to determine eligibility before receiving OV101 under
this protocol:
• Subjects who completed OV101-15-001 or OV101-16-001
• Subjects who are siblings of subjects who have completed OV101-15-001,
OV101-16-001, or OV101-19-001
• Subjects who completed treatment in OV101-19-001 more than 2 weeks before
completing the baseline visit under this protocol (OV101-18-002)
For subjects required to complete the screening and baseline visits, the
planned duration of study participation is approximately 166 weeks from the
start of screening to the EOS visit, including 160 weeks of treatment with
OV101.

For subjects completing the EOT visit for OV101-19-001 two weeks or less before
enrolling in this OV101-18-002 protocol, the OV101-19-001 EOT visit may serve
as the baseline visit for OV101-18-002. Clinical laboratory results assessed at
EOT in OV101-19-001 will serve as baseline clinical laboratory results in
OV101-18-002. For such subjects, the planned duration of study participation
would be 162 weeks.

Subjects who meet all eligibility criteria will be enrolled on Day 1 (baseline
visit) and start the study drug that evening at bedtime (not in the clinic).
Each subject*s LAR/caregiver will receive a package of study drug at the
baseline visit, sufficient to last until the Week 12 visit.
Each subject*s dose of OV101 will be titrated to a maintenance dose, as
tolerated by the subject. The maximum tolerated dose (up to 15 mg at bedtime)
will be maintained to the EOT. Subjects 2 to 12 years old (inclusive) weighing
more than 64 kg and subjects at least 13 years old will have a targeted maximum
dose of 15 mg. Subjects 2 to 12 years old (inclusive) weighing 64 kg or less
will have a target maximum dose determined by their weight.

Phone calls to manage titration will occur on Days 6, 11, and 15 for all
subjects. Subjects 2 to 12 years old (inclusive) weighing 64 kg or less will
have their body weight measured at every clinic visit after the initial
titration to allow for adjustment of the maximum dose to a greater weight.
Phone calls to manage dose titration, if needed due to weight gain, will occur
5 days later to assess tolerability.

At the Week 12, 36, 64, 96, and 128 visits, each subject*s LAR/caregiver will
receive a package of study drug sufficient to last until the next scheduled
clinic visit at the maximum possible dose. Unused study drug will be collected
at Week 12, 36, 64, 96, 128, and 160 clinic visits.
The LAR/caregivers will complete sleep diaries on behalf of subjects over the
7-day periods immediately preceding Baseline and the Week 12, 36, 64, 96, 128,
and 160 clinic visits.
The LAR/caregivers will complete seizure diaries each day during the 160 weeks
of treatment.

Safety information will be collected during phone calls and during clinic
visits. If a subject experiences any AEs or is unable to take the study drug as
prescribed, the caregiver/LAR is instructed to contact the study center. Dose
adjustments are permitted for subjects who are unable to tolerate the specified
dosing regimen.
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, changes in
concomitant medications, and suicidality, and safety laboratory assessments may
be conducted. Periodic interim review of safety data will be performed as part
of routine pharmacovigilance activities and to support regulatory submission.

OV101 will be supplied as capsules containing 5-mg, 2-mg, or 0.5-mg of study
drug.
Each subject will be titrated to his/her maximum tolerated daily dose, up to a
maximum daily dose of 15 mg (see Study Design, above).
Subjects will take all doses orally (assisted by an LAR/caregiver, if
necessary), in the evening at bedtime. Capsules may be opened, with the
contents sprinkled onto up to 1 teaspoon of low-fat semiliquid food (eg,
applesauce, yogurt, pudding) for ingestion, but this approach must be followed
consistently throughout the study.

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*
*Pyrexia (fever), seizure, and rash occurred more frequently in those receiving
OV101 than placebo.

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

Blood draw
Obtaining blood may sometimes cause pain/discomfort at the site where the blood
is drawn, including bruising, bleeding, occasional light-headedness, and,
rarely, infection or fainting. Approximately 37mL of blood will be collected
during the entire study.

Questionnaires about your child*s well-being and behaviour
Some questions in the questionnaires may cause the LAR to distress or make the
LAR feel uncomfortable.