Full professor at Tel-Aviv University with a specialization in Neurobiology and biological clocks

Gluck Chair of Neuropharmacology and ALS Research Founder and Chief Scientific Officer of Neurim

Pharmaceuticals, a drug discovery and development company in Tel Aviv

Has authored with her students and collaborator scientists over 200 original research and review papers in peer-reviewed journals

Prof Nava Zisapel, PhD

Paediatric insomnia (difficulty to initiate and/or maintain sleep) is classified mainly as Organic Insomnia

Pediatric insomnia is often reported by a care-giver

Disturbed child’s sleep, specifically frequent awakenings during the night, commonly results in the disturbed sleep of their parents and siblings

Disturbed child’s sleep has a negative impact on the whole family’s health and well-being and impairs their proper employment or further education

Insomnia in pediatric populations

Primary pediatric populations at high risk for insomnia are:

1) Autism Spectrum Disorder (ASD; including autistic disorder, Asperger’s disorders and pervasive developmental disorder)

2) Neurogenetic neurodevelopmental disorders (NDD; e.g. Rett's disorder, Tuberous Sclerosis, Smith-Magenis syndrome and Angelman syndrome)

3) Children with a variety of other medical conditions or psychiatric comorbidities and sleep disorders associated with insomnia symptoms (e.g. ADHD, depression, anxiety)

Insomnia in Pediatric Populations

ASD are neurodevelopmental disorders that affect about 1 in 68 children

The diagnosis of autism is based on a triad of core symptoms, alterations of social interactions, deficits in communication, and the occurrence of repetitive/perseverative behaviors

Hyperactivity (ADHD) and sleep-pattern (circadian) alterations are frequently present ; Up to 75% of individuals with ASD also have ADHD symptoms and 50-75% have sleep problems

ASD is usually diagnosed in the first three years of life

Males are affected four times more often than females

Diagnostic and Statistical Manual of Mental Disorders (5th ed.) (2013) American Psychiatric Association; Perry W. et al. Sensorimotor gating deficits in adults with autism (2007) Biol. Psychiatry 61: 482-6; Glickman G. Circadian rhythms and sleep in children with autism (2010) Neurosci. Biobehav. Rev. 34: 755-68; Murphy P. Cognitive functioning in adults with attention-deficit/ hyperactivity disorder (2001) J. Atten. Dis. 4: 203-211

Autism Spectrum Disorders (ASD)

1-6% of the general pediatric population suffer from Insomnia 25-55% of ADHD population reports disturbed sleep patterns 50-75% of ASD population have sleep problems Sleep problem severity is similar across ADHD and non-ADHD ASD

subgroups

Prevalence of sleep disturbances among children

Mindell JA. et al. Pharmacologic management of insomnia in children and adolescents: consensus statement (2006) Pediatrics 117; e1223-32; Efron D. et al. Use of sleep medication in children with ADHD (2014) Sleep Med. 15: 472-5; Johnson K.P. and Malow B.A. Sleep in children with autism spectrum disorders (2008) Curr. Treat. Options Neurol. 10: 350-9; Green J.L. et al. Association between autism symptoms and functioning in children with ADHD (2016) Arch. Dis. Child. 101: 922-928

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

Japan EU5 USA

Num

ber o

f Chi

ldre

n

Sleep problems in children with ASD Insomnia No Insomnia

0

1,000,000

2,000,000

3,000,000

4,000,000

5,000,000

6,000,000

7,000,000

8,000,000

USAEU5Japan

No Insomnia Insomnia

Sleep problems in children with ADHD

https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm559535.pdf

Sleep- a challenging health effect of autism FDA’s Patient Focused Drug Development Initiative, AUTISM May 2017

Reduced sleep issues are among the most important benefits in choosing treatment options for ASD

FDA’s Patient Focused Drug Development Initiative, AUTISM, May 2017

https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm559535.pdf

Insomnia symptoms in ASD

37

26

22

12 3

63

Difficulty InitiatingSleepDifficulty MaintainingSleepEarly Awakening

Other

Sleep Disorders

Taira M, Takase M, Sasaki H. Sleep disorder in children with autism. Psychiatry Clin Neurosci. 1998;52:182–3 Krakowiak P et al. Sleep problems in children with autism spectrum disorders, developmental delays, and typical development: A population-based study. J Sleep Res. 2008;17:197–206

Consequences of insomnia in children with ASD Chronic sleeping difficulties in ASD are associated with

impaired children’s memory consolidation of typically developing (TD) and children with ASD.

exacerbated cognitive performance deficits, daytime behavioral problems, school performance and neurocognitive abilities

more severe parental perception of the child’s adaptive functioning and severity of autism symptoms; increased Aberrant Behavior scores

internalizing problems (non-disruptive negative behaviors that are focused inward include fearfulness, social withdrawal, and somatic complaints) in children with ASD/ADHD

more challenging behaviors and ability to regulate emotion during the day

delayed development and growth

Phung J.N. and Goldberg W.A. Poor sleep quality is associated with discordant peer relationships among adolescents with Autism Spectrum Disorder (2017) Res. Autism Spect. Dis. 34:10-18; Chadiarakos M.M. et al. Sleep Related Behavioural and Cognitive Functioning (2017) IMFAR Abstract 161.097; Stedman IA. Et al. Relationship Between Medical Comorbidity and Problem Behavior in Children with Autism Spectrum Disorder (2017) MFA Abstract 126.178; Zachor D.A. and Ben-Itzchak E. Specific Medical Conditions Are Associated with Unique Behavioral Profiles in Autism Spectrum Disorders (2017) IMFAR Abtsract 126.185; Reynolds K.C. et al. Parent-Reported Sleep Problems in Children with Comorbid Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder (2017) IMFAR Abstract 126.174; Devnani P.A. and Hegde A.U. Autism and sleep disorders (2015) J. Pediatr. Neurosci. 10: 304-307.

Impact of sleep disturbances in children with ASD on general health and caregivers’ distress TST and sleep maintenance problems are most prevalent in patients

with ASD and NDD and are most important aspects for families

Sleep problems in ASD have been associated with:

increased maternal distress and parental sleep disruption

poor caregiver’s quality of life

discordant peer relationships among adolescents with ASD

Reduced TST correlates with Childhood Autism Rating Scale (CARS) severity and inversely related to social quotient

Increased aggression, hyperactivity, and social difficulties could be indicators for poor mental health outcomes due to sleep disturbance in children with ASD

Mindell J.A. et al. Pharmacologic management of insomnia in children and adolescents: consensus statement (2006) Pediatrics. 117: e1223-32; Gail William P. et al. Sleep problems in children with autism (2004) J. Sleep Res. 13:265-8; May T. et al. Sleep in high-functioning children with autism: longitudinal developmental change and associations with behavior problems (2015) Behav. Sleep Med. 13:2-18; Appleton R.E. et al. the use of melatonin in children with neurodevelopmental disorders and impaired sleep: a randomised, double-blind, placebo-controlled, parallel study (MENDS) (2012) Health Technol. Assess. 16:doi: 10.3310/hta16400; Cuomo B. et al. Sleep Problems in Children with Autism Spectrum Disorders: Impact on Caregiver Quality of Life (2017) IMFAR Abstract 144.246; Devnani P.A. and Hegde A.U. Autism and sleep disorders (2015) J. Pediatr. Neurosci. 10: 304-307.

Diagnosis and treatment of sleep disturbances in children with ASD/NDD

Clinical guidelines recommend sleep hygiene and/or behavioural intervention as the first line treatment

- Only 25% respond to such therapy

However, many patients face limited access and outcomes are dependent on physician expertise/compliance

Most patients go straight to pharmacological treatment; especially where access/compliance to behavioural intervention is challenging (e.g. low-income house, limited caregiver time) and if they have comorbid ASD/NDD

None of the pharmacological therapies are licensed for the treatment of paediatric insomnia & some are targeted at symptoms of neurological diseases

Therapeutic pathway

Diagnosis

Sleep hygiene Behavioural intervention

Malow B.A. et al. A Practice Pathway for the Identification, Evaluation, and Management of Insomnia in Children and Adolescents With Autism (2012) Pediatrics 130 Suppl 2:S106-242; Kleeman J. (2017) Sleep problems mounting in children, NHS, http://www.bbc.co.uk/news/health-39140836 (accessed on 12/05/2017); NICE Guidelines for sleep disturbances in children, https://www.nice.org.uk/advice/esuom2/ifp/chapter/about-melatonin (accessed: 16/05/2017); Gringras P. et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial (2012) BMJ 345:e6664.

Inadequate response

Adequate response

Many patients receive pharmacological treatment

as first line

~25%4

~75%

Off-label

Pharmacological options used depending on comorbidity pattern Circadin®

(Prolonged-release (PR) melatonin)

Immediate release (IR) melatonin

(food supplement or pharmacy preparations)

Anti-Psychotics risperidone

Off-label

Antihistamines (OTC)

Clonidine/ methylphendate (hypertensive/ADHD)

Off-label

Off-label

Anti-Depressants and Sedatives (e.g. Clonazepam)

Off-label

Effectiveness of sleep-based interventions for children with ASD

Parent Education

Behavioral Intervention

Benzodiazepines/Z drugs Clonidine Risperidone Melatonin Intervention

Parameter

10 2 - 15 - 187 Sleep Latency

9 7 - 48 113 116 Sleep Duration

- - - - - 32 Longest Sleep Episode

248 68 - 16 - 35 Night Waking

1 182 - 4 - - Morning Waking

13 4 - - - 187 Bedtime Resistance

3 146 - - - 165 Co-sleeping 410 243 - - - - Self settling

Cuomo B.M. et al. Effectiveness of Sleep-Based Interventions for Children with Autism Spectrum Disorder: A Meta-Synthesis (2017) Pharmacotherapy 37:555-578

Etiology of sleep problems in ASD

The etiology of sleep disorders in ASD children is multifactorial, with genetic, environmental, immunological, and neurological factors thought to play a role.

A region of genetic susceptibility has been identified on chromosome 15q that contains GABA-related genes

Mutations in genes encoding core melatonin production pathway components are associated with susceptibility to ASD

Mutations in core Clock genes may be involved in the modulation of melatonin and also in the integrity of synaptic transmissions in ASD

Melatonin may be crucial for appropriate cognitive development particularly during the first 3 years of life. Low melatonin production (6-Sulfatoxymelatonin Levels) at 16 weeks of age predicted abnormal development at 3 as well as at 6 months of age

Disrupted or reduced melatonin secretion rhythm can result in difficulty initiating and maintaining sleep

Hu V.W et al. Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism (2009) Autism Res. 2: 78-97; Jonsson L. et al. Mutation screening of melatonin-related genes in patients with autism spectrum disorders 2010) BMC Med. Genomics. DOI: 10.1186/1755-8794-3-10; Pagan C. et al. Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with intellectual disability (2011) BMC Med Genet. 12:17. Melke J. et al. Abnormal melatonin synthesis in autism spectrum disorders (2008) Mol. Psychiatry 13: 90-8; Tordjman S. et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder (2012) Psychoneuroendocrinology 37: 1990-7; Glickman G. Circadian rhythms and sleep in children with autism (2010) Neurosci. Biobehav. Rev. 34: 755-68; Tauman et al Melatonin production in infants (2002) Pediatr. Neurol. 26: 379-82; Bourgeron T. The possible interplay of synaptic and clock genes in autism spectrum disorders (2007) Cold Spring Harb. Symp. Quant. Biol. 72:645–54. McCauley J.L et al. A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism (2004) Am. J. Med. Genet. B Neuropsychiatr Genet. 131B:51-9.

The roles of melatonin in sleep Circadian rhythms are physical, mental & behavioural changes, including

sleep/ wakefulness, that follow a roughly 24-hour cycle An intrinsic body clock regulates the circadian rhythms including the sleep-

wake cycle and melatonin production in synchrony with the light-dark cycle Melatonin is released over the night by the pineal gland and is an important

time cue to the circadian clock/endogenous sleep regulator

Disrupted or reduced melatonin secretion rhythm can result in difficulty initiating and maintaining sleep

[Czeisler C.A and Gooley J.J. Sleep and circadian rhythms in humans (2007) Cold Spring Harb. Symp. Quant. Biol. 72: 579-597; BrainWise: The Sandhills Neurologists Blog, https://www.sandhillsneurologists.com/2015/04/melatonin-and-sleep/ (accessed on:16/05/2017).

Typical melatonin secretion levels 4:30am Lowest body temperature

7:30am Melatonin secretion

stops

10am Highest

alertness

9pm Melatonin secretion

starts

2am Deepest

sleep

Sleep

Sleep

Day/night urinary melatonin metabolite (6SMT) excretion rates (Mean+SD)

Total 24h urinary 6SMT excretion (median)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Day Night

Urin

ary

6SM

T (m

icro

gram

/hr)

Control

Autism

*

*

P<0.05

0

1

2

3

4

5

6

7

8

9

10

Control Autism

6SM

T m

icro

gram

/24

hour

s

*

Abnormal melatonin secretion in children with ASD

Tordjman S. et al. Day and night time excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder (2012) Psychoneuroendocrinology 37: 1990-7

Rationale for melatonin treatment in ASD Sleep disorders in children with ASD are associated with

disrupted melatonin secretion.

low 6-SMT levels were associated with disturbed sleep architecture in children with ASD

When nocturnal melatonin production/secretion is inappropriately timed or impaired in relation to the environment, timed melatonin replacement therapy will often be beneficial.

Melatonin substitution therapy has shown to improve the sleep patterns in children with ASD

A parental online survey by the Autism Research Institute in 1105 children with ASD, reported improvement in 65% of patients with melatonin usage

Melke J. et al. Abnormal melatonin synthesis in autism spectrum disorders (2008) Mol. Psychiatry 13: 90-8; Richdale A.L. Sleep problems in autism: prevalence, cause, and intervention (1999) Dev. Med. Child Neurol. 41: 60-6; Tordjman S. et al. Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder (2005) Biol. Psychiatry 57: 134-8; Leu R.M. et al. Relation of melatonin to sleep architecture in children with autism (2011) J. Autism Dev. Disord. 41:427-33; Glickman G. Circadian rhythms and sleep in children with autism (2010) Neurosci. Biobehav. Rev. 34: 755-68; Tauman et al Melatonin production in infants (2002) Pediatr. Neurol. 26: 379-82; Tordjman S. et al. Day and night time excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder (2012) Psychoneuroendocrinology 37: 1990-7; Cortesi F. et al. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial (2012) J. Sleep Res. 21:700-9; Kulman G. et al. Evidence of pineal endocrine hypofunction in autistic children (2000) Neuro Endocrinol. Lett. 21: 31-4; Khan S. et al. Melatonin for non-respiratory sleep disorders in visually impaired children (2011) Cochrane Database Syst. Rev. 11:CD008473. Jan J.E. et al. Neurophysiology of circadian rhythm sleep disorders of children with neurodevelopmental disabilities (2012) Eur. J. Paediatr. Neurol. 16:403-12; Rossignol D.A. Novel and emerging treatments for autism spectrum disorders: a systematic review (2009) Ann. Clin. Psychiatry 21:213-36

Prolonged-release (PRM)- vs. immediate-release (IRM) melatonin pharmacokinetic profile

IR melatonin has a rapid onset to high levels and rapid decline

PRM mimics the endogenous profile of melatonin

Circadin® professional information, www.swissmedicinfo.ch Adapted from Arendt J et al Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab. 1985 Jun;60(6):1166-73.

Melatonin treatment: efficacy & safety in children with ASD and NDD Many studies show benefit of melatonin therapy in children with intellectual disabilities:

A meta-analysis of 9 RCTs of melatonin (IRM and PRM) including 183 individuals (children and adults) with intellectual disabilities

A meta-analysis of 5 RCTs of melatonin (IRM and PRM) including 61 children with neurodevelopmental disorders

A large scale placebo controlled study of IRM

A large scale placebo controlled study of CRM

A long term open label study with PRM (Circadin) Braam W. et al. Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis (2009) Dev. Med. Child. Neurol. 51:340-9; Rossignol D.A. and Frye R.E. Melatonin in autism spectrum disorders: a systematic review and meta-analysis (2011) Dev. Med. Child Neurol. 53:783-92; Rossignol D.A. Novel and emerging treatments for autism spectrum disorders: a systematic review (2009) Ann. Clin. Psychiatry 21:213-36; Gringras P. et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial (2012) BMJ 345:e6664; Cortesi F. et al. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial (2012) J. Sleep Res. 21:700-9; De Leersnyder H. et al. Prolonged-release melatonin for children with neurodevelopmental disorders (2011) Pediatr. Neurol. 45:23-26; Appleton R.E. and Gringras P. Melatonin: helping to MEND impaired sleep (2013) Arch. Dis. Child. 98: 216-7

Melatonin treatment: efficacy & safety in children

Braam W. et al. Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis (2009) Dev. Med. Child. Neurol. 51:340-9.

Sleep Latency

Total Sleep Time

Meta analysis, Braam et al., 2009

Setting: Randomised, double-blind, placebo-controlled, multi-centre

Subjects: 146 Children aged 3-15 years with neuro-developmental delay (including children with autism) and severe sleep-onset and maintenance problems (>1h ; < 6h) who were refractory to behavioral interventions

The MENDS Study: IRM vs. placebo in children with NDD and impaired sleep

Gringras P. et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial (2012) BMJ 345:e6664

Sleep hygiene (4 wks)

IR Melatonin 05,2,6,12 mg

Dose escalation 4 wks

Placebo Dose escalation

4 wks

IR Melatonin final dose 8 wks

Placebo at final “dose” 8 wks

Adjusted difference in mean sleep latency between the melatonin and placebo groups was −37.5 (−55.3 to -19.7) minutes (p<0.001)

Adjusted difference in mean total sleep time between the melatonin and placebo groups was 22.4 (0.5 to 44.3) minutes (p=0.04; shorter than expected from the improvement in SL)

Earlier waking times with melatonin than placebo 29.9 (13.6 to 46.3) minutes compatible with advance of the circadian clock

No major safety concerns

The MENDS Study: IR melatonin vs. placebo

Gringras P. et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial (2012) BMJ 345:e6664

Results

Controlled-release melatonin vs. behavioral therapy for insomnia in children with ASD Controlled-release melatonin (CRM) singly and combined with

cognitive behavioral therapy in children with ASD Setting: Randomised, double-blind, placebo-controlled in Italy Subjects: 160children with ASD, aged 4-10 years, suffering from sleep

onset insomnia and impaired sleep maintenance

Cortesi F. et al. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial (2012) J. Sleep Res. 21:700-9

CBT+ CR melatonin

3mg

CBT+ CR melatonin

3 mg

CBT+ CR melatonin

3 mg

CBT+ CR melatonin

3 mg

CBT CBT CBT CBT

CR melatonin 3mg

CR melatonin 3mg

CR melatonin 3mg

CR melatonin 3mg

Placebo Placebo Placebo Placebo

12 Weeks

Controlled release melatonin improved sleep latency vs placebo

Controlled-release melatonin for insomnia in children with ASD

Sleep onset latency at baseline and at 12-week assessment repeated measure ANOVA (p=0.001).

0

10

20

30

40

50

60

70

80

90

100

Sle

ep o

nse

t la

ten

cy [

min

]

Baseline 12-week

Cortesi F. et al. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial (2012) J. Sleep Res. 21:700-9

PRM use in children with NDDs: literature survey Improved sleep onset, maintenance, quality, day time function in and quality of life with no major AE’s

Safety Efficacy (sleep) Outcome Time Dose N/Age/ Gender Condition Type Study

No AEs Earlier sleep onset, longer sleep episodes, less

awakenings

Sleep maintenance

4-5 mg 2 / 5-8 / f

Delayed sleep onset

Non-epyleptic

myoclonous

Case report

Jan et al. 1999

1 patient stopped due to

excessive sedation.

Improvement in sleep maintenance: sleep

fragmentation and early morning awakening. FR-

improved in sleep latency only.

Sleep onset / maintenance

2.8y 2-10 mg (5.7 mg avg) Vs. FR 5-25

mg

42 / 4-21 /

20m,22f

Neurodevelopmental

disabilities. Sleep-wake

cycle disorders

Clinical use

Jan et al. 2000

No AEs Delayed sleep onset and awakening time, longer

TST improved sleep architecture. Day time

behavior improved. Parents’ improved

Sleep onset / maintenance

/ TST

2m 6 mg 10 / 4-18 / 6m,

4f

Smith-Magenis

Syndrome

Open label

De-Leersnyder

et al. 2003

Small number (11) of

AEs

Decreased sleep latency (44%); increased TST (1h),

decreased awakenings (75%); Improved sleep

quality (82%).

SOL / maintenance / TST / quality

6-72m

4-6 mg 88 / 6-12 /

42m, 46f

Neurodevelopmental disorders

Open label

De-Leersnyder

et al. 2011

Long term efficacy and safety of PRM in children with NDD Setting: Compassionate use program in France (88 children)

The dose Circadin ranged from 4 to 6 milligrams nightly (Average: 2-3 tablets/day)

Treatment duration ranged from 6 to 72 months (Average (±SD): 33.9 ± 20.9 months)

De Leersnyder H. et al. Prolonged-release melatonin for children with neurodevelopmental disorders (2011) Pediatr. Neurol. 45:23-26.

Real life safety data on PRM since launch The safety of Circadin® is routinely monitored in accordance

with the European Union Legislation of Pharmacovigilance including Periodic Safety Update Reports (PSUR).

According to IMS data the number of children treated with Circadin® (2009-2011) is estimated at 85,000.

The percentage and severity of reports is low and similar across age groups. Main reports in children involve off label use, overdose and symptoms related to their disease

Age group Total reports Non Serious reports Serious Reports

0-18 474 371 (78.3%) 103 (21.7%)

19-54 310 232 (74.8%) 78 (25.2%)

≥ 55 423 324 (76.6%) 99 (23.4%)

IMS Health Data 2009/2011; Circadin® professional information, www.swissmedicinfo.ch

Despite the severity of sleep issues in children with ASD/NDD, there are no approved medications for treatment of insomnia in children and adolescents

Physicians prescribe drugs without proven records of safety and efficacy in children or determination of pediatric dosing regimen

Melatonin food supplement and compounded products are used without proof of quality, efficacy and safety and no pharmacokinetics pharmacodynamics and dose recommendations

Circadin® provides quality and safety but: Used off label in ASD/NDD Approved for short term (3 months) use in adults aged >55

years Dose not adjusted (need 2-3 tablets per day) May be difficult to swallow as whole Crushing may help swallowing but will lose some prolonged

release properties Great need for efficacious and safe products that can be used for

long-term therapy of sleep problems in children with ASD/NDD

Pediatric insomnia in ASD/NDD: Unmet Medical Need

Johnson K.P. and Malow B.A. Assessment and pharmacologic treatment of sleep disturbance in autism. Child Adolesc. Psychiatr. Clin. N Am. 17:773-85; Mindell et al, Pharmacologic management of insomnia in children and adolescents: consensus statement (2006) Pediatrics 117;e1223-32; Barbanoj M.J. et al. Sleep laboratory study on single and repeated dose effects of paroxetine, alprazolam and their combination in healthy young volunteers (2005) Neuropsychobiology 51:134-47; Seibt J. et al. the non-benzodiazepine hypnotic zolpidem impairs sleep-dependent cortical plasticity (2008) Sleep 31:1381-91; http://www.cdc.gov/ncbddd/adhd/prevalence.html

Requirements for ideal drug for pediatric insomnia

Mindell J.A. et al. Pharmacologic management of insomnia in children and adolescents: consensus statement (2006) Pediatrics 117;e1223-35; Felt B.T. and Chervin R.D. Medications for sleep disturbances in children (2014) Neurol. Clin. Pract. 4:82-87; Hack S, et al. Pediatric psychotropic medication compliance: a literature review and research-based suggestions for improving treatment compliance (2001) J. Child Adolesc. Psychopharmacol. 11:59-67; Owens J.A. et al. the use of pharmacotherapy in the treatment of pediatric insomnia in primary care: rational approaches. A consensus meeting summary (2005) J. Clin. Sleep Med. 1:49-59.

USA National Sleep Foundation Consensus Statement recommendations for pharmacologic management of insomnia in children and adolescents

Novel paediatric-appropriate prolonged-release melatonin formulation

Mimics the endogenous melatonin secretion, by releasing melatonin over a predefined extended period of time

Designed to improve sleep onset and maintenance, Easy to swallow Developed to regulatory Rx standard Possibility of long term treatment

PedPRM mini-tablets

Phase III – PedPRM clinical trial design Week 1-4 5-6 7-19 20-32 33-110 111-112

Duration (weeks) 4 2 13 13 78 2

N 267 125 104 95 50*

Phase Sleep Hygiene Run-In SB Double-

Blind

Open label

Open-label

Long Term

Run-Out SB

IP None Placebo Ped-PRM 2--5/Plc

Ped-PRM 2/5mg

Ped-PRM 2/5/10mg Placebo

31 sites in EU and US

To assess the short and long term efficacy and safety of Ped-PRM vs placebo for sleep problems in children with ASDs/neurogenetic disorders Primary endpoint: TST after 13 weeks . Secondary endpoints: SL and sleep maintenance Safety

https://clinicaltrials.gov/ct2/show/NCT01906866

Phase III – PedPRM clinical trial results On 2nd November 2016 Neurim Pharmaceuticals announced positive

top-line results from the pivotal phase III trial of PedPRM for sleep disturbances in children with ASD

PedPRM met the primary efficacy endpoint demonstrating statistically significant improvement in total sleep time (TST) compared to placebo

Secondary efficacy endpoints demonstrating improvements in sleep initiation and maintenance were also met

Safety profile was similar between PedPRM and placebo-treated groups

“Short and long term prolonged release melatonin treatment for sleep disorders in children with autism spectrum disorders –results of a phase III randomized clinical trial” will be presented by Prof P Gringras at the upcoming World Sleep 2017 in Prague, Czech Republic (Oral 02 Monday, October 9, 2017) and by Dr. RL Findling at the American Academy of Child and Adolescent Psychiatry (AACAP)'s 64th Annual Meeting in Washington, DC, October 23 - October 28, 2017

https://www.telegraphindia.com/pressrelease/prnw/34755/neurim-pharmaceuticals-announces-positive-top-line-results-f.html

Concluding remarks There is a great unmet need for efficacious and safe products

that can be used for long-term therapy of sleep problems in children with ASD/NDD including comorbid ADHD

Melatonin is evidence-based treatment option for sleep problems in these children-but there is no properly developed drug for this indication and safety data are lacking

Prolonged-release melatonin is effective and safe for treatment of sleep disorders in children with ASD/NDD

The compliance and adherence of pediatric-specific formulation is important in a population that often has significant difficulties in swallowing

PedPRM phase III study results will be presented at the World Sleep in Prague, and AACAP's 64th Annual Meeting in Washington, 2017