Master Slide. From Model Systems to Clinical Trials in Phelan-McDermid Syndrome. Alexander Kolevzon, MD

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1 Master Slide From Model Systems to Clinical Trials in Phelan-McDermid Syndrome Alexander Kolevzon, MD Clinical Director, Seaver Autism Center Director, Child and Adolescent Psychiatry Mount Sinai Health System

2 Disclosures of Potential Conflicts Source Research funding Advisor/ consultant Employee Speakers Bureau Books, Intellectual Property In-Kind Services Stock of Equity Honorarium Seaver Foundation X NIH/NINDS X New York Community Trust X Simons Foundation X American Psychiatric Publishing X Amo Pharma X Coronis X Ovid X 5AM Ventures X sema4 X Labcorp X *Mount Sinai and Joseph Buxbaum hold a shared patent for IGF-1 in Phelan-McDermid syndrome The following presentation contains information concerning a use that has not been approved by the U.S. Food and Drug Administration

3 Developmental Synaptopathies Consortium To comprehensively characterize PMS using standard medical, behavioral, and cognitive measures. Track the natural history using repeated longitudinal assessments Develop biomarkers and novel, naturalistic measures for objective assessment. Evaluate safety, tolerability, and feasibility of novel therapeutics.

4 From Model Systems to Clinical Trials PMS Novel Therapeutics Gene Discovery (SHANK3) Drug Development Model Systems (e.g., mice; rats; human neurons) Pathophysiology

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9 Costales & Kolevzon, 2016

10 A Double-Blind Placebo-Controlled Crossover Trial of IGF-1 in Children with Phelan-McDermid Syndrome Placebo wash-out Placebo 12 weeks 12 weeks IGF-1 4 weeks IGF-1

11 28 gauge ½ inch needle Dose depends on weight and is twice a day with food Finger stick glucose levels are monitored before each dose

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13 Change in scores at week 12 in social withdrawal and restricted behavior

14 Change in scores at week 12 in hyperactivity

15 Change in scores at week 12 in sensory reactivity

16 Potential Side Effects In clinical studies with 71 subjects over 3.9 years, 5% or more patients had the following side effects: Hypoglycemia with loss of consciousness/seizures Tissue swelling Bruising Ear infection Snoring/tonsillar hypertrophy Headache Dizziness Convulsions Vomiting Cardiac murmur Arthralgia Pain in extremities Thymus hypertrophy (immune system organ behind the sternum/chest) In 19 patients with PMS, 2 or more patients had the following side effects: Hypoglycemia Tissue swelling Bruising at injection site Constipation Increased appetite Sleep disturbance Irritability Decreased energy Increased chewing/biting

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20 Placebo 12 weeks OXT 12 weeks OXT

21 OXT Study Procedures Visit Baseline Week 4 Week8 Week 12 Week 16 Week 20 Week 24 Week 28 Phase Double Blind Open Label Medical/Psych History X EEG X - - X X Eye Tracking X X X X X X X x VEP X X X X X X X X CGI X X X X X X X X SAND X X X X X X X X ADOS-2 X - - X - - X X Mullen X - - X - - X - PEP X - - X - - X - Vineland X - - X - - X - ADI X Parent forms X X X X X X X X Study Drug Administration X X X X X X - -

22 OXT Potential Side Effects Headache Rapid heart rate Slow heart rate Nausea/vomiting Irregular heartbeat Rash Elevated blood pressure Mood changes / irritability Weight gain Insomnia Agitation / aggression Hyperactivity Syntocinon Package Insert Syntocinon (oxytocin) is a synthetic, (1-6) cyclic nonapeptide. Chemically, oxytocin is designated as Glycinamide, L-cysteinyl-L- tyrosyl-l-isoleucyl-l-glutaminyl-l-asparaginyl-l-cysteinyl-l-prolyl- L-leucy1-, cyclic (1-6)-disulfide. The structural formula is: Syntocinon (oxytocin) injection is provided as a sterile solution for intravenous or intramuscular administration. Each 1 ml of solution contains 10 USP or International Units of oxytocin and the following inactive ingredients: acetic acid, NF, qs to.. ph 4 ± 0.3 alcohol, USP % by vol. chlorobutanol, NF.,. 0.5% sodium acetate, USP, 1 mg sodium chloride, USP mg water for injection, USP, qs to 1 ml

23 An open-label study to investigate the safety, tolerability and efficacy of a 6-hour intravenous infusion of AMO-01 to treat adolescents and adults with Phelan-McDermid syndrome and epilepsy C 28 H 34 N 2 O 4 MW =

24 Ras-ERK Pathway Inhibitor The Mitogen Activated Protein Kinases (MAPKs) are critical mediators of neuronal survival and synaptic plasticity: AMO-01 targets activation of the MAPK Extracellular signal Regulated Kinase (ERK) AMO-01 PREVENTS ANCHORING AND ACTIVATION OF RAS TYROSINE KINASE RECEPTOR Ras Raf MLK MEK ERK TRANSCRIPTION WITHIN NUCLEUS

25 perk ½ Ras-ERK Pathway in PMS The activity of the Ras-ERK pathway was assayed in various tissues of the shank3 knockout (KO) transgenic mouse model of PMS. Levels of phosphorylated ERK (perk) used an index of activation. Ras-ERK pathway activity was markedly increased in the cortex of the shank3 KO mouse. In contrast, Akt was only slightly activated The Ras-ERK pathway was also activated in lymphocytes of shank3 KO mice WT KO WT KO WT KO Hippocampus Cortex Activation of the Ras-ERK pathway in Wild Type (WT) and shank3 knockout (KO) mice as indexed by perk levels in hippocampus and cortex Peripheral activation of the Ras-ERK pathway in Wild Type (WT) and shank3 knockout (KO) mice as indexed by perk levels in lymphocytes

26 AMO-01 in Shank3-knockout mouse A single dose of 30 mg/kg i.p. AMO-01 or placebo was administered to a shank3 KO mouse model of PMS (N=10) or controls; 30 mg/kg i.p. produces plasma levels of AMO-01 that have been readily achieved in human subjects in clinical studies in the oncology area; AMO-01 rescued multiple aspects of the PMS phenotype: Increased anxiety (light dark box test) Excessive grooming (skin lesions) Impaired social recognition and response to social novelty Sensory-motor dysfunction (beam walking) Species typical behavior deficits (marble burying) Seizure threshold (audiogenic seizures)

27 Study Aims To evaluate the safety and tolerability of a single 6-hour intravenous infusion of AMO-01 To evaluate the efficacy of AMO-01 in reducing seizure frequency by at least 25 percent as measured by a caregiver completed seizure diary To evaluate the efficacy of AMO-01 as measured by cliniciancompleted rating scales, caregiver completed diaries, functional assessments and biomarker assessments

28 Inclusion Criteria Exclusion Criteria Diagnosis of PMS Age at screening Diagnosis of epilepsy with a witnessed seizure event in the 28 days prior to screening, and a minimum of 4 seizures monthly in the 6 months prior to screening Medications and therapies must remain stable within 4 weeks prior to screening until the last study assessment Known hypersensitivity to farnesylated dibenzodiazepinone or any of the formulation components History of uncontrolled hypotension or hypertension Coumadin or heparin in the 2 weeks prior to screening

29 Challenges for Clinical Trial Readiness

30 Solution: Biomarkers Behavior Biomarkers A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers Definitions Working Group, 2001 Genes

31 Biomarkers: Examples Behavior Biomarkers Genes Genes Brain function (MRI, EEG) Brain structure (MRI) Eye tracking Proteins Heart rate Blood levels Pupil response

32 Biomarkers: Key Features Objective Reliable Quantifiable Sensitive

33 Biomarkers: Uses Diagnosis Autism Diagnosis and screening Treatment effectiveness Biomarker Profile A Profile B Early efficacy Treatment Treatment A; Medium Dose Treatment A; Higher Dose Treatment B Target engagement Stratification

34 Electrophysiological Markers Identify subtypes of neurodevelopmental disorders based on excitatory/inhibitory (E/I) profiles Inform personalized treatment approaches Monitor treatment response and determine optimal responders Identify associations between electrophysiological responses and clinical outcomes P. Siper, PhD J. Foss-Feig, PhD

35 Transient Visual Evoked Potentials (VEP) Typically developing controls Phelan-McDermid syndrome (PMS) Siper, PM

36 From Preclinical Models to Clinical Trials

37 Improvement in VEPs after IGF-1 in PMS n=6; p=.048 Siper, PM

38 Sensory Assessment for Neurodevelopmental Disorders (SAND) Clinician-administered observation and corresponding caregiver interview capturing DSM-5 sensory reactivity symptoms in children with neurodevelopmental disorders Siper, PM et al., 2017

39 Siper, PM Association between VEP and sensory reactivity

40 Effects of IGF-1 on Sensory Reactivity n=6, p =.037 Siper, PM

41 VEP in PMS and Idiopathic Autism A subset of ~30% of iasd patients fall within 1 SD of the PMS P 60 -N 75 mean and are defined as PMS-like Siper, PM Foss-Feig, J

42 IGF-1 in Idiopathic Autism

43 Study Contacts Jordana Weissman

44 Acknowledgments Seaver Center Team Joseph Buxbaum Paige Siper Danielle Halpern Pilar Trelles Ting Wang Michelle Gorenstein Jennifer Foss-Feig Yitzchak Frank Reymundo Lozano Hala Harony-Nicolas Silvia De Rubeis Elodie Drapeau Michael Breen Sven Sandin PMS Consortium Latha Soorya Elizabeth Berry-Kravis Audrey Thurm Jon Bernstein Craig Powell Neuropsych Group Deborah Pearson Thomas Frazier Boston Children s Team Mustafa Sahin April Levin Chuck Nelson