Sleep Onset Latency, min n LS mean change from baseline (SE) Total Sleep Time at Night, min n LS mean change from baseline (SE) Total Sleep Time During Day, min n LS mean change from baseline (SE) Wake After Sleep Onset, min n LS mean change from baseline (SE) Nocturnal Awakenings, n n LS mean change from baseline (SE) Sleep Efficiency, % n LS mean change from baseline (SE) Daily Activity Level, min n LS mean change from baseline (SE) Snooze Time, min n LS mean change from baseline (SE)

1614.68 (6.560)

11-11.00 (8.494)

122.61 (7.238)

16-12.77 (22.379)

111.35 (30.899)

12-72.88 (25.150)

1817.69 (21.971)

14-32.44 (25.860)

154.21 (23.699)

16-8.56 (4.897)

11-1.77 (6.582)

12-9.14 (5.483)

16-1.96 (3.582)

112.52 (4.670)

12-6.25 (3.854)

16-0.01 (1.782)

113.64 (2.447)

12-2.40 (1.979)

17-10.91 (11.898)

131.58 (14.300)

12-11.00 (13.819)

16-1.70 (4.843)

11-9.21 (6.635)

125.10 (5.720)

OV101 QDPlacebo OV101 BID Placebo OV101 QD OV101 BID

263 (11.5)

250.16 (0.293)

260.08 (0.298)

240.11 (0.064)

24-0.05 (0.065)

0.0704

259 (36.0)0.0522

250.84 (0.269) —

—

0.0935

260.77 (0.315)

0.1170

267 (26.9)

2614 (53.8)0.0889

2714 (51.9)0.0929

268 (30.8)0.1729

245.79 (2.162)

24-0.47 (2.149)

0.0340

260.06 (0.062)

0.5663

25-0.79 (2.120)

0.0250

249.68 (3.271)

240.56 (3.273)

0.0406

242.80 (3.271)

0.1239

BSID-III (Overall Motor Response)nResponse, n (%)*P value vs placebo

BSID-III (Gross Motor Response)nResponse, n (%)*P value vs placebo

PEDI-CAT (Mobility Summary Score)nChange from baseline, mean (SE)§

P value vs placebo

nChange from baseline, mean (SE)||

P value vs placebo

n

P

Zeno™ Walkway (Mean Cadence; steps/min)nLS mean change from baseline (SE)P value vs placebo

PEDI-CAT (Daily Activity Summary Score)

Zeno™ Walkway (Mean Stride Velocity; cm/sec)nLS mean change from baseline (SE)P value vs placebo

CHAQ (Disability Index)

LS mean change from baseline (SE) value vs placebo

Zeno™ Walkway

BSID-III: post hoc analysis

PEDI-CAT: post hoc analysis†,‡

CHAQ

Domain

Overall clinical change

Sleep

Motor

Behavior

Quality of life

• Clinical Global Impressions–Improvement (CGI-I)• Clinical Impression of 9 Domains: Sleep, Gross Motor Ability, Fine Motor Ability, Irritability/Agitation/Crying, Lethargy/Social Withdrawal, Stereotypic Behavior, Hyperactivity, Inappropriate Laughter or Hyperexcitability, Anxiety • Clinical Global Impressions–Severity (CGI-S)

• Modified Performance-Oriented Mobility Assessment–Gait tool (mPOMA-G)• Bayley Scale of Infant and Toddler Development, Third Edition (BSID-III) Motor Subscale• Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT)• Childhood Health Assessment Questionnaire (CHAQ)• Zeno™ Walkway

• EuroQoL 5-Dimension 5-Level (EQ-5D-5L)• 36-Item Short Form Health Survey (SF-36)• Parent Global Impression (PGI)

• Aberrant Behavior Checklist (ABC)• Anxiety, Depression and Mood Scale (ADAMS)

• eDiary of Sleep Pattern by Caregiver• Actigraphy

Assessment

Pyrexia

Rash

Seizure

Enuresis

Myoclonic epilepsy

Otitis media

Viral infection

2 (6.9) 7 (24.1)

1 (3.4) 3 (10.3)

0

0

0

0

0

2 (6.9)

1 (3.4)

2 (6.9)

1 (3.4)

2 (6.9)

1 (3.4)

2 (6.9)

1 (3.4)

2 (6.9)

2 (6.9)

1 (3.4)

3 (10.3)

Incidence, n (%)Placebo

n=29OV101 QD

n=29OV101 BID

n=29

5 (17.2) 5 (17.2)

5 (17.2) 3 (10.3)

9 (31.0)

5 (17.2)

4 (13.8)

5 (17.2)

2 (6.9)

4 (13.8)

3 (10.3)

4 (13.8)

7 (24.1)

5 (17.2)

5 (17.2)

1 (3.4)

1 (3.4)

1 (3.4)

Incidence, n (%)

Vomiting

Somnolence

Irritability

Aggression

Pyrexia

Upper respiratory infection

Placebo n=29

OV101 QDn=29

OV101 BIDn=29

Placebon=29

OV101 QDn=29

OV101 BID*n=29

Mean age, years (SD)

Gender, n (%) Male Female

Race, n (%)†

American Indian or Alaska Native Black or African American Native Hawaiian/Other Pacific Islander White

Ethnicity, n (%) Hispanic Not Hispanic or Latino

22.0 (6.70)

15 (51.7)14 (48.3)

00

1 (3.4)29 (100.0)

3 (10.3)26 (89.7)

23.1 (7.76)

20 (69.0)9 (31.0)

1 (3.4)2 (6.9)1 (3.4)

28 (96.6)

6 (20.7)23 (79.3)

22.8 (6.51)

18 (62.1)11 (37.9)

1 (3.4)1 (3.4)

029 (100.0)

5 (17.2)23 (79.3)

All subjects*N=87

22.6 (6.95)

53 (60.9)34 (39.1)

2 (2.3)3 (3.4)2 (2.3)

86 (98.9)

14 (16.1)72 (82.8)

Demographic

Screening

Assessment Point (Week)-2 0 6 12

Placebo (placebo morning, placebo night)

OV101 QD (placebo morning, 15 mg night)

OV101 BID (10 mg morning, 15 mg night)

Baseline &Randomize

(1:1:1)

Irritability, Agitation, and Crying

Lethargy, Social Withdrawal

Stereotypic Behavior

Hyperactivity

Inappropriate Laughter or Hyperexcitability

Anxiety

-0.03 (0.198) -0.19 (0.196)

0.04 (0.156) -0.02 (0.155)

-0.11 (0.099) -0.03 (0.098)

-0.22 (0.168) -0.10 (0.167)

-0.22 (0.142) -0.14 (0.141)

-0.77 (0.307)* -0.45 (0.305)†

-0.26 (0.180) 0.19 (0.178)

-0.07 (0.173) 0.16 (0.172)

-0.04 (0.174) -0.10 (0.173)

OV101 QD (n=27)vs Placebo (n=27)

OV101 BID (n=28)vs Placebo (n=27)LS mean difference (SE)

Sleep

Gross Motor Ability

Fine Motor Ability

Sleep

Global Function

MotorBSID-III

PEDI-CATCHAQ

Zeno™ Walkway

ActigraphyClinical

Impression: Sleep

CGI-I

1

2

3

4†

5

6

7

Mea

n CG

I-I S

core

Placebo (n=27) OV101 QD (n=27) OV101 BID (n=28)

3.58

P=0.3446

3.00

P=0.00063.79

0

10

20

30

40

50

60

70

80

90

100 P

ropo

rtion

of R

espo

nder

s (%

)

Placebo (n=28) Combined OV101 (n=57)

27.4% difference

P=0.0206

66.7%

39.3%

10.7

29.6

7.4

32.1

37.0

14.8

50.0

33.3

70.4

3.6

7.4

3.6

0 20 40 60 80 100

OV101 BID (n=28)

OV101 QD (n=27)

Placebo (n=27) 1 - Very Much Improved

2 - Much Improved

3 - Minimally Improved

4 - No Change

5 - Minimally Worse

6 - Much Worse

7 - Very Much Worse

Subjects in each CGI-I score category (%)

22.2

66.6

42.8

GABA transporter (GAT1)

GABA

Presynaptic Neuron

GABA Production

Angelman syndrome

Extrasynaptic

Synaptic

Postsynaptic Neuron

ABNORMALHEALTHY

OV101

β

ααβ

βα δ

Lynne M. BirdDisclosure:• Consultant: Ovid Therapeutics• Research Support: Ovid Therapeutics

Rebecca D. BurdineNo conflicts of interest to disclose.

Matthew During, Ovid TherapeuticsDisclosure:• Employee: Ovid Therapeutics• Stock or Equity: Ovid Therapeutics

Joseph GriecoDisclosure:• Formerly employed by Ovid Therapeutics• Stock or Equity: Ovid Therapeutics

Alexander Kolevzon, MDDisclosure:• Advisory Board: Klingenstein Third Generation Foundation• Consultant: 5AM Ventures, Coronis, Ovid Therapeutics, sema4• Grant Support: AMO Pharma• Stock or Equity: Therapy Lab

Clarice Lee, Ovid TherapeuticsDisclosure:• Employee: Ovid Therapeutics• Stock or Equity: Ovid Therapeutics

Ronald ThibertDisclosure:• Advisory Board: Roche Pharmaceuticals• Consultant: Ovid Therapeutics

Jeannie Visootsak, Ovid TherapeuticsDisclosure:• Employee: Ovid Therapeutics• Stock or Equity: Ovid Therapeutics

Sponsored by Ovid Therapeutics

INTRODUCTION

Background• Angelman syndrome (AS) is a complex, chronic disorder with high unmet medical need and

no approved therapies1

- Estimated prevalence: ≈1 in 12,000–1 in 20,0001

- No current AS-specific scales or assessment tools• Features of AS include global impairments in motor, sleep, behavior, and other

neurological domains2

- Main characteristics include global developmental delays, intellectual disability, severe speech impairment, and ataxia

• The condition is associated with impaired expression of the ubiquitin protein ligase E3A gene (UBE3A) causing aberrant increases in the uptake of ɣ-aminobutyric acid (GABA), which results in reduced extrasynaptic GABA (Figure 1)3-6 - Reduced extrasynaptic GABAergic neurotransmission results in decreased tonic

inhibition and is thought to contribute to the development of AS

• OV101 (gaboxadol) is a highly selective extrasynaptic GABA receptor agonist7-10

- Binds to the δ-subunit–containing extrasynaptic GABA receptors as an orthosteric agonist (Figure 2)

- Restores deficits in tonic inhibition as noted in mouse models of AS

Objectives• Primary: To evaluate the safety and tolerability of two different doses of OV101 in adult and

adolescent subjects with AS after 12 weeks of treatment• Exploratory: To explore the efficacy of OV101 in subjects with AS

Primary Endpoint: Safety and Tolerability• A total of 25/29 (86.2%) subjects in the placebo group experienced at least 1 adverse event; rates in the OV101

every day (QD) and twice a day (BID) groups were 27/29 (93.1%) and 25/29 (86.2%), respectively - The majority of AEs were mild; the most common AEs are summarized in Table 3 - AEs occurring more frequently in either OV101 arm vs placebo are summarized in Table 4• Four subjects discontinued treatment due to AEs - Placebo, n=1 (irritability) - OV101 QD, no discontinuations - OV101 BID, n=3 (myoclonus [n=1], seizure [n=1], irritability/anxiety/sleep disorder [n=1])• SAEs of seizure were reported in 2 subjects: - OV101 QD, 1 event of seizure in 1 subject (not related) - OV101 BID, 2 events of seizure in 1 subject (possibly related)

Subjects• 88 individuals (adults and adolescents) with AS• Study design shown in Figure 3

Key Inclusion criteria• Age 13–49 years, inclusive• Molecular confirmation of AS• Receiving a stable regimen of concomitant medications for

at least 4 weeks prior to baseline

Key Exclusion criteria• Poorly controlled seizure activity• Concomitant use of minocycline, levodopa, zolpidem, zaleplon,

eszopiclone, ramelteon, or benzodiazepines for sleep as well as cannabinoid derivatives or any other investigational agent, device, and/or procedure within 4 weeks prior to study baseline

• Non-ambulatory

Assessments• Safety and tolerability - Frequency and severity of adverse events (AEs) and serious

adverse events (SAEs)• Efficacy (Table 1)

Table 1: Efficacy Assessments

Figure 3: Study Design

Figure 4: Response Based on CGI-I and Clinical Impression of 9 Domains of OV101 Combined vs Placebo at Week 12 (Fisher’s Exact Test)

Figure 6: CGI-I at Week 12

Figure 5: Mean CGI-I at Week 12 (MMRM)*

METHODS

RESULTS

Demographics and Baseline Clinical Characteristics• Of 88 subjects randomized (Table 2), 78 completed the study• >90% of subjects had a prior history of seizure• OV101 was used as adjunctive therapy to commonly used medications in AS, including benzodiazepines

for non-sleep problems, antiepileptics, melatonin, antidepressants, and gastrointestinal (GI) therapies

Exploratory Endpoints: Efficacy CGI-I • Global improvement was observed at Week 12 based on CGI-I compared with placebo (Figure 4)

CGI-I and Clinical Impression of 9 Domains • CGI-I was analyzed as a continuous variable (MMRM, Figure 5, Figure 6)• Each domain of the Clinical Impression of 9 Domains was individually analyzed as a continuous variable (MMRM, Table 5) - Improvement in the clinical impression of sleep domain at Week 12 was found in the OV101 QD (Diff=-0.77, P=0.0141)

group compared with the placebo group. The OV101 BID group did not separate from placebo (Diff=-0.45, P=0.1407)• Clinical Global Impressions–Severity (CGI-S) was assessed at baseline, Week 6, and Week 12. Changes in the CGI-S were

minimal and not statistically significant

Table 5: Clinical Impression of 9 Domains at Week 12 (MMRM)

Table 2: Subject Demographics

Statistical Analysis• Safety analyses were performed using the Safety Analysis Set, which included all subjects who were randomized and received ≥1 dose of study drug • Efficacy analyses used a modified Intention-To-Treat (mITT) Set, which included all randomized subjects who received ≥1 dose of study drug and had ≥1 efficacy evaluation after receiving

study drug, unless otherwise noted• Response based on Clinical Global Impressions–Improvement (CGI-I) was defined by a score of ≤3 at Week 12 on any domain of the Clinical Impression of 9 Domains or the CGI-I• Response based on CGI-I was compared between combined OV101 and placebo using Fisher’s exact test - If Week 12 responses were not available, then response was evaluated using Week 6 scores as a method of imputation - If both Week 6 and Week 12 responses were missing, the subject was not included in the analysis• CGI-I was analyzed as a continuous variable, as was each domain of the Clinical Impression of 9 Domains, using the mixed model for repeated measures (MMRM) method• A fixed-sequence testing approach was used to account for multiplicity

*Excludes 1 randomized subject who did not receive treatment. † In each treatment group, several individuals identified with multiple race groups. BID, twice a day; QD, every day; SD, standard deviation.

*Response defined as improvement of ≥3 points in motor skills. †PEDI-CAT Per Protocol Analysis, Mobility: Placebo, n=24, mean change from baseline=0.08, SE=0.294; OV101 QD, n=23, mean change from baseline=0.91, SE=0.281, P=0.0475. ‡PEDI-CAT Per Protocol Analysis, Daily Activity: Placebo, n=25, mean change from baseline=0.00, SE=0.300; OV101 QD, n=24, mean change from baseline=0.79, SE=0.340, P=0.0869. §T-test, excluding outliers, defined as subjects whose mobility score changed from screening to baseline by ≥3 points. ||T-test. BID, twice a day; BSID-III, Bayley Scale of Infant and Toddler Development, Third Edition; CHAQ, Childhood Health Assessment Questionnaire; LS, least squares; PEDI-CAT, Pediatric Evaluation of Disability Inventory Computer Adaptive Test; QD, every day; SE, standard error.

BID, twice a day; LS, least squares; MMRM, mixed model for repeated measures; QD, every day; SE, standard error.

BSID-III, Bayley Scale of Infant and Toddler Development, Third Edition; CGI-I, Clinical Global Impressions–Improvement; CHAQ, Childhood Health Assessment Questionnaire; PEDI-CAT, Pediatric Evaluation of Disability Inventory Computer Adaptive Test; QD, every day.

*LS mean difference, drug–placebo (95% CI), was -0.78 (-1.22, -0.35) with OV101 QD and -0.21 (-0.64, 0.22) with OV101 BID. †Value of 4 represents no change on CGI-I. BID, twice a day; CGI-I, Clinical Global Impressions–Improvement; CI, confidence interval; LS, least squares; MMRM, mixed model for repeated measures; QD, every day.

CGI-I, Clinical Global Impressions–Improvement.

*P=0.0141. †P=0.1407.BID, twice a day; LS, least squares; MMRM, mixed model for repeated measures; QD, every day; SE, standard error.

AE, adverse event; BID, twice a day; QD, every day.

AE, adverse event; BID, twice a day; QD, every day.

• AS is an area of high unmet medical need with no approved therapies and no specific scales or assessment tools

• The Phase 2 STARS study is the first industry-sponsored, randomized, double-blind, placebo-controlled clinical trial in AS

- Study groups in STARS were well-balanced with a high study completion rate• STARS achieved its primary endpoint of safety and tolerability - OV101 was well-tolerated with an overall favorable safety profile - The majority of AEs were mild and similar across all study groups • STARS implemented currently available as well as innovative tools to assess multiple, relevant domains in AS,

demonstrating a positive clinical improvement in overall AS symptoms (Figure 7) - Global function - There was a robust improvement in CGI-I in the OV101 QD treatment group - Sleep - There was an improvement in sleep onset latency as measured by actigraphy and improvement in

overall sleep as measured by clinical impression of sleep domain in the OV101 QD treatment group - Reduction of latency to sleep onset is clinically relevant to the sleep dysfunction in AS and may be

indicative of target engagement - Motor - Motor domain improvement was noted in the BSID-III, consistent with observed treatment effects in

PEDI-CAT, CHAQ Disability Index, and the Zeno™ Walkway - Behavior - PGI reported improvements in communication, challenging behavior, and anxiety among subjects

who showed clinically meaningful improvement in CGI-I• These results suggest that the improvement in CGI-I observed in OV101 QD treatment group may be driven

by improvements in sleep and motor function• Taken together, the results indicate that OV101 seems to positively impact several relevant clinical features

of AS (global functioning, sleep, motor disruption) and therefore support further clinical development of OV101 in AS

Behavior • Among subjects who showed improvement on the CGI-I, Parent Global Impression (PGI) reported

improvements in communication, challenging behavior, and anxiety. However, no significant differences were found on the Aberrant Behavior Checklist (ABC) or Anxiety, Depression and Mood Scale (ADAMS)

Quality of Life • No differences were found between groups on EuroQoL 5-Dimension 5-Level (EQ-5D-5L),

36-Item Short Form Health Survey (SF-36), or PGI

Disclosures

Sleep• Actigraphy data were collected in subjects who tolerated the device - Latency to sleep onset was improved in OV101 QD group compared with placebo

(Diff=-25.7 minutes, P=0.0147) (Table 6)• Reduction in mean total sleep time during day (≈50 minutes) and improvement in sleep efficiency

(3.65%) were seen in OV101 QD group compared with placebo• Sleep as reported by caregiver diary showed no changes

Motor• Improvement (≥3 points) in Bayley Scale of Infant and Toddler Development, Third Edition (BSID-III)

Overall Motor Response was observed in the OV101 QD group compared with placebo (Table 7) - Improvement was seen in Gross Motor Response - No improvement was seen in Fine Motor Response (not shown) - Changes in motor skills were assessed using responder analysis • Signal of improvement was observed in the Disability Index of the Childhood Health Assessment Questionnaire

(CHAQ) as well as the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Mobility and Daily Activity Summary Scores in OV101 QD group compared with placebo (Table 7)

• Zeno™ Walkway showed a reduction in mean cadence and stride velocity compared with placebo• No difference was reported between OV101 treatment groups and placebo for Modified Performance-

Oriented Mobility Assessment–Gait (mPOMA-G)

DISCUSSION/CONCLUSIONS

STARS: Results From a Phase 2 Adult and Adolescent Angelman Syndrome Clinical Trial: A Randomized, Double-blind, Safety and Efficacy Study of OV101

Lynne M. Bird,1 Rebecca D. Burdine,2 Matthew During,3 Joseph Grieco,3 Jeannie Visootsak,3 Clarice Lee,3 Alexander Kolevzon,4 Ronald Thibert5 on behalf of the STARS clinical investigators 1University of California, San Diego, and Rady Children’s Hospital, San Diego, CA, United States; 2Department of Molecular Biology, Princeton University, Princeton, NJ, United States; 3Ovid Therapeutics, New York, NY, United States; 4Seaver Autism Center for Research & Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States;

5Angelman Syndrome Program, MassGeneral Hospital for Children, Boston, MA, United States. Clinical Trials Registration Number: NCT02996305.

Table 3: Most Common AEs in Any Treatment Group

Table 6: Change From Baseline in Sleep Parameters as Assessed by Subject Actigraphy Watch at Week 12 (MMRM)

Figure 7: Domains With Observed Changes With 15 mg OV101 QD

Table 7: Change From Baseline in Motor Efficacy at Week 12

Table 4: AEs Occurring More Frequently in Either OV101 Treatment Group vs Placebo

References: 1. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/angelman-syndrome/. Accessed September 27, 2018. 2. Williams CA et al. Am J Med Genet. 2006;140A:413-418. 3. Brickley SG, Mody I. Neuron. 2012;73:23-34. 4. Deidda G et al. Front Cell Neurosci. 2014;8:119. 5. Egawa K, Fukuda A. Front Neural Circuits. 2013;7:170. 6. Ramamoorthi K, Lin Y. Trends Mol Med. 2011;17:452-462. 7. Meera P et al. J Neurophysiol. 2011;106:2057-2064. 8. Bilelli D et al. J Neurosci. 2005;25:11513-11520. 9. Brown N et al. Br J Pharmacol. 2002;136:965-974. 10. Egawa K et al. Sci Transl Med. 2012;4:163ra157.Copies of this poster obtained through the QR code are for personal use only and may not be

reproduced without permission of the authors.

© 2018 Ovid Therapeutics AACAP, 65th Annual Meeting, October 22-27, 2018, Seattle, WA

Figure 1: GABA Signaling in Physiologic Condition vs Angelman Syndrome Figure 2: OV101 Binding to δ-Subunit–Containing Extrasynaptic GABA Receptor

BID, twice a day; QD, every day.

BID, twice a day; CGI-I, Clinical Global Impressions–Improvement; QD, every day.