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

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

*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

sema4 X

Labcorp X

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.

PMS

Pathophysiology

Drug Development

Novel Therapeutics

Gene Discovery (SHANK3)

Model Systems (e.g., mice; rats; human neurons)

From Model Systems to Clinical Trials

Costales & Kolevzon, 2016

A Double-Blind Placebo-Controlled Crossover Trial of IGF-1 in Children with

Phelan-McDermid Syndrome

Placebo Placebo

IGF-1 IGF-1

12 weeks 12 weeks

wash-out

4 weeks

Dose depends on

weight and is twice a day with food

Finger stick glucose levels are

monitored before

each dose

28 gauge ½ inch needle

PMSvideos.m4v

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

Change in scores at week 12 in hyperactivity

Change in scores at week 12 in sensory reactivity

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

Placebo

OXT

OXT

12 weeks 12 weeks

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 - -

OXT Study Procedures

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………………………. 0.61 % by vol. chlorobutanol, NF……….,………………. 0.5%

sodium acetate, USP …,…………………… 1 mg

sodium chloride, USP …………………… 0.017 mg

water for injection, USP, qs to ………………… 1 mL

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

C28H34N2O4

MW = 462.25

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)

TYROSINE KINASE

RECEPTOR

Ras

MLK Raf

MEK

ERK

TRANSCRIPTION

WITHIN

NUCLEUS

AMO-01 PREVENTS

ANCHORING AND ACTIVATION OF RAS

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

Hippocampus Cortex

p

ER

K ½

WT KO

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

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)

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 clinician-

completed rating scales, caregiver completed diaries, functional

assessments and biomarker assessments

Inclusion Criteria

• Diagnosis of PMS

• Age 12-45 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

Exclusion Criteria

• 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

Challenges for Clinical Trial Readiness

Solution: 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

Behavior

Biomarkers

Genes

Biomarkers: Examples

Genes

Brain function (MRI, EEG)

Brain structure (MRI)

Eye tracking

Proteins

Heart rate

Blood levels

Pupil response

Behavior

Biomarkers

Genes

Biomarkers: Key Features

Objective

Reliable

Quantifiable

Sensitive

Diagnosis and screening

Treatment effectiveness

Early efficacy

Target engagement

Stratification Treatment

Biomarker

Diagnosis Autism

Profile A

Treatment A; Medium Dose

Treatment A; Higher Dose

Profile B

Treatment B

Biomarkers: Uses

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

Transient Visual Evoked Potentials (VEP)

Siper, PM

Phelan-McDermid

syndrome (PMS)

Typically developing

controls

From Preclinical Models to Clinical Trials

Improvement in VEPs after IGF-1 in PMS

n=6; p=.048

Siper, PM

Clinician-administered observation and corresponding caregiver interview capturing DSM-5 sensory reactivity symptoms in children with

neurodevelopmental disorders

Sensory Assessment for Neurodevelopmental Disorders (SAND)

Siper, PM et al., 2017

Association between VEP and sensory reactivity

Siper, PM

Effects of IGF-1 on Sensory Reactivity

n=6, p = .037

Siper, PM

VEP in PMS and Idiopathic Autism

A subset of ~30% of iASD

patients fall within 1 SD of the

PMS P60-N75 mean and are

defined as “PMS-like”

Siper, PM Foss-Feig, J

IGF-1 in Idiopathic Autism

Study Contacts

Jordana Weissman

jordana.weissman@mssm.edu 212-241-3072

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