ASDERA – Overview

Develop novel drugs for high unmet needs Mission by utilizing a computational biostatistics platform (US 7,664,616), the first to identify genetic risk factors for complex diseases

1800 Gauss-Legendre 1948 Hoeffding Drug ‹ ‹ 1900 1965 1985 2001 Discovery Ohdner IBM PC GPU Platform 9 Byte 256 kB 16 MB 4 GB ANOVA PCA Bayes u-Stat

Validation: Confirmation of known drug targets in epilepsy Proof-of-Concept: L-fucose in Crohn’s disease (in phase 3) Time-Pipeline Current lead: lead: ASD-002 Mefenamic against acid against mutism mutism in autism in autism (phase(phase 3 ready) 3 ready) Next drug: Preventing metastases in breast cancer (pat. pending) Outlook: Delaying Alzheimer ’s and Parkinson ’s (pat. pending)

ASDERA – Overview

Develop the first drug to prevent lack-of-language in autism ( unmet need ) Focus by utilizing a computational biostatistics platform (US 7,664,616), the first platform to identify genetic risk factors for complex diseases

Disruption of Active Language Development (DALD) Lead Indication: in toddlers developing Autism Spectrum Disorders (ASD) by childhood migraines causing them to Mutism • become non-verbal (primary outcome) and in Autism • develop life-long intellectual disability (ID) Children will still develop autism, but will be verbal (“Asperger’s”).

Product ASD-002: Market-exclusive ester-prodrug of mefenamic acid (MFA)

Patent filed in US and EU. Orphan Drug Designation for MFA pending Status Preparing CMC / manufacturing for a short 505(b)(2) regulatory pathway for the single phase 2b/3 trial needed for a breakthrough drug.

Defects in social recioprocity and communication, Autism Autism Repetitive and stereotypical behaviors

Incidence 20,000 children per year in the US alone of DALD • become non-verbal (primary outcome) in autism • develop lifelong intellectual disability Economic USD 10 M lifetime for assisted living per child Impact of DALD USD 200 B (total 400B) per year for US society The only approved drugs in autism are antipsychotics: Unmet • Risperdal ® (J&J) temporarily reduces aggression need • Abilify ® (BMS) temporarily reduces irritability No treatment against migraines causing mutism . Non-Verbal Autism

ASDERA – 2nd Year of Life as the Window of Treatment Opportunity Cortical density declines Pathology after 24 months (of age).

Cochlear implants before 24 months preserve language. Epidemiology Romanian orphans older then 24 months in 1990 developed “quasi-autism ”.

Imaging “Patches of disorganization ” are seen in the language cortex (fMRI) of non-verbal children after 24 months.

Language regression is typically seen at 12 –15 months. Physiology Early symptoms justifying a pharmaceutical intervention can only be detected from 9 months (by pediatrician at the routine “well-child visit”).

© ASDERA (2017) Confidential Information 4 ASDERA’s Novel Discovery Technology and Mefenamic Acid Hit The platform screens not only for individual genetic ‘letter’ positions (SNPs) Discovery but genetic ‘words’ (up to six neighboring SNPs). Platform It also accounts for genetic ‘grammar’ (neighborhood, compound hetero- (US 7,664,616) zygosity, recombination hotspots, ...) within the statistical method . Feasible only since 2001 (32-bit OS), it already yielded several hits. Results from two independent ASD populations http:// www.nature.com /articles/tp2013124 npg Genetic showed lack-of-language associated with results • Ion channels (excitation/inhibition imbalance), including • Known migraine genes (FHM). Guglielmi (2015) identified the same potassium (K +) channels and showed Independent • gain -of-function in inward and Confirmation • loss -of-function in outward K+ channels impairing ability of neurons to adjust to stress (hyperpolarization).

Mode of Action Mefenamic acid (MFA) activates outward K+ channels.

ASDERA – Ion Channel Dysfunction in Migraines / CAE / DALD

FHM 1/2/3 i: familial hemiplegic migraine SCA6/EA2 i: ataxias SMEI i: severe myo- clonic epilepsy AHC i: alternating hemiplegia of childhood i: disease of infancy

CAE: childhood absence epilepsy

Pre-Clinical in vitro , MFA activates outward K + channels (>10 studies). (MoA) In mice, this reduction of hyperexcitability prevents seizures (>7 studies).

Abdominal migraines in ASD children turn headache migraines in adults. ASD children All forms of migraines and DALD share have migraines • Individual and familial co-occurence Migraineurs • Genes (familial hemiplegic migraine, K + channels) as a ‘model’ • Epileptiform EEGs • Avoidance of social contacts (in autism: “regression”)

Clinical Trials Four clinical trials have shown that MFA is effective in migraine of MFA • treatment and (PoC) • prevention.

MFA is approved for the treatment of dysmenorrhea, including US approval prevention of menstrual migraines with poor response to COX-NSAIDs.

ASDERA – Safety of MFA and pro-MFA in Pediatric Use

MFA is approved in juvenile arthritis UK Approval • for chronic use Pediatric Use • from 6 months of age.

MFA is an NSAID (like Infant Motrin ®), not a ‘psycho-active drug’. In 3 – 36 month old children UK Safety Data for MFA • only 6 AEs were reported • in 50+ years of use. EMA, 2012: “no specific signal has been identified.”

Pro-MFA prevents MFA from being acidic in the intestine, which reduces the risk of Improved Safety for pro-MFA • Convulsions (from( accidental overdose) • Diarrhea (intestinal complications are already common with ASD) • Kidney problems (from diarrhea)

Human Genetics î Association: K+ ion channels associated with lack of language.

Published Ä Cellular defect: K+ outward loss-of-function causes mutism. Activity: MFA activates outward K+ channels (>10 MoA studies). in vitro, animal, Efficacy: MFA prevents induced seizures, (>7 animal studies). human î Model system: Migraineurs (co-occurance, genes, EEG, regression). Å Results Effectiveness: MFA is effective against migraines, (4 PoC studies). Age: 12 – 24 mo is the window of opportunity. Agency findings Safety/dose: 50+ years of chronic use from 6 months of age (UK). Function Activity Model system Effectiveness A complete puzzle Efficacy Association Age Safety/Dose

ASDERA – Pro-MFA Formulation / Next Stage: Single Phase 2b/3 trial

dissolves at pH ≈7.4 (plasma) hydrolysis

Pro-MFA esterification stable at pH ≈1.2 an ester (gastric fluid) of MFA MFA promefenamate (pro-MFA) …

New Clinical FDA: “Esterification does not create a ‘New Chemical Entity’ ” Indication (precedent: propacetamol/Ofirmev ®)

FDA: “Published results and Agency findings can be used for phase 1/2 505(b)(2) (precedent: Abilify ® in Tourette)

1st in Mutism A breakthrough drug can be approved after a single phase 2b/3 trial only.

Behavioral abnormalities: validated parental questionnaire required by BehavioralBehavioral abnormalities: abnormalities: validated validated parental parental questionnairequestionnaire identified by pediatrician at “9-month well-child visit” Medicaid 40,000 ASD 120,000 TD NeuronalNeuronalNeuronal excitability:excitability: excitability: epileptiformepileptiform epileptiform EEG EEGEEG (at (at(home) home) home)

24,000 ASD 8,000 TD Maladaptation:Maladaptation: eye-trackingeye-tracking covered by CMS 22,000 ASD 4,000 TD IdiopathicIdiopathic autism:autism: geneticgenetic testing covered by CMS 21,000 ASD 4,000 TD

ASDERA – Clinical Phase 2b/3 Trial Design / Funding Milestones Size / Duration 240 outpatient study (conducted by a contract research organization, CRO) Primary Endpoint 12 months to primary outcome (#words spoken NCT01013545 , see Ampyra ®)

No words: Early exit to active drug (avoids child-specific IRB hurdles) At 3 months Typical development: Treatment interruption (restart in case of regression).

At 80 subjects Interim futility analysis (end of phase 2b)

Phase II Phase III $0.25 M é $0.75 M é $1.0 M é $2.0 M é $3.5 M é

US/EU patent , expiration 2034 IP Protection (IDS Feb 2017) Orphan drug designation pending Market (amended Mar 2016) US: 7.5 years from NDA ( 7 years + 0.5 years pediatric) Exclusivity EU: 12.0 years from NDA (10 years + 2.0 years pediatric)

High litigation risk for physicians No off-label use No incentive for parents because of of MFA • health insurance for approved drugs (precedent: Avastin ®) • patient assistance

Since July 2016, FDA enforces compounding law (no Macena risk) No off-label use Pro-MFA not approved for other indications: no ANDA option of pro-MFA Few new indications for controlled-release NSAID (fever, pain) Low price elasticity : 2.5% price = 50% market (Avastin ®: 50 vs 2000 USD)

ASDERA – Market Projection

Target Population: 50,000 children / yr (US+EU), identified at routine visit Ponstel ® : USD 36,000 / yr (q.i.d., USD 25 / pill ) Market Size (1965) w/coupon Pro-MFA (e.g.): USD 100,000 / yr / child US/EU Market: ~ 50,000 × USD 100,000 = USD 5B / yr

® 505(b)(2) Vyvanse(2008) , pro- D-amphetamine (1937) USD 2B (2016, US) ® Precedents Soolantra (2015) , Ivermectin (1981) USD 3B (2016)

® Forecasting Year 1/2/3: USD 0.2 / 1.0 / 2.0 B; Vyvanse sold for USD 2.6B (2007)

• Licensing • Joint Development Partnership with options for consideration: Partnering ◦ Milestones Options ◦ Royalty ◦ Right-to-acquire option ◦ Regional or global commercialization rights

© ASDERA (2017) Confidential Information 14 ASDERA – Virtual Company Team / Partners* Management: inVentiv Health Clinical will lead FDA interactions from pre- IND to NDA and assume all management responsibilities during the trial. Therapeutic areas: generics / pediatrics Phase III: full range of clinical trial services Knut M. Wittkowski , PhD ScD Consulting: small molecules / 505(b)(2) Senior Research Associate, The Rockefeller Univ. http://www.inventivhealthclinical.com/ Director, Biostatistics, Epidemiology & Research Design Center for Clinical and Translational Science apl. Professor, Eberhard-Karls-University, Tübingen Drug Development: Regis Technologies Gabrielle Gold-von Simson , MD MSc Partners with pharmaceutical/biotech companies to help expedite drugs to market Assistant Professor of Pediatrics cGMP Custom Services http://www.registech.com/ Medical Director, Inpatient Pediatrics Director Clinical Research Center, NYU School of Medicine PI, Drug Development Educational Programm (NIDDK) New York Univ. Langone Medical Center Orphan Drug Regulation: Bert Spilker , PhD MD Independent Consultant on Regulatory Affairs Clin. Professor of Pharmacy Practice, U of Minnesota Sr. VP Scientific/Regulatory Affairs, PhRMA (1998–2001) John Jay Gargus , MD PhD President/Co-founder, sold Orphan Medical, Inc in 2005 Professor of Pediatrics, Physiology & Biophysics http://www.bertspilker.com/ Director, Center for Autism Research and Translation PI, Drug Discovery Platform for Autism Univ. California Irvine 505(b)(2) Regulation: Camargo Comprehensive drug development services specialized for the 505(b)(2) approval pathway http://www.camargo.com/ * Terms being finalized © ASDERA (2017) Confidential Information 15

ASDERA – Summary

Human Genetics î Association: K+ ion channels associated with mutism.

FDA 505(b)(2) path for an NSAID ester prodrug (Ofirmev ®, propacetamol) Plan forward PTO Strong IP protection (patent / orphan drug pending, see Avastin ®) (Precedents) single Phase 2b/3 outpatient trial (breakthrough drug) $$$ ® 2–3 years from a lucrative market (Vyvanse , pro-amphetamine (1937) ) - The same platform identified novel drugs in breast cancer, PD, and AD Outlook r and identifies genetic risk factors for non-response in phase 2/3 trials. © ASDERA (2017) Confidential Information 16 ASDERA – PI Brochure 1. Epidemiology and impact of Disruption of Active Language Development 2. Data from human genetics, epidemiology, and physiologic studies 3. Proposed pharmaceutical intervention: mefenamic acid (MFA) 4. MFA: Mechanism of action from in-vitro and observational studies 5. Preclinical studies of MFA 6. Model systems for the use of MFA to prevent DALD 7. Pediatric use of MFA 8. Prodrugs of MFA 9. Development plan

Dbl-Click for Text and References viewable as pdf:

PI Brochure

Text available below (after FAQs)

ASDERA – Frequently Asked Questions 1. Why do you get GWAS results where others can’t ? 2. What is ASD-002’s “Mechanism of Action (MoA)? 3. What is ASD-002’s “Proof-of-concept” (PoC) ? 4. Isn’t it difficult to diagnose ASD? 5. Why not just treat the migraines (eg, with triptans)? 6. Isn’t it difficult to assess effectiveness? 7. Drug development / management experience ?

© ASDERA (2017) Confidential Information 18 ASDERA – FAQ: Why do you get GWAS results where others can’t ? If a disease are caused by a single genetic ‘letter’ variation (SNP), Genetics of that variation is ‘selected against’ in just a few generations. Heritable Most heritable diseases are ‘epistatic’. Some variations of SNPs (‘words’) Diseases cause the disease and are selected against, but the individual letters remain in the populations and recombine (no need for de-novo mutations). Most bioinformatics tools in genetics are based on the statistical methods Limitations of that were feasible in the 20 th century, where memory was scarce. Hence, Bioinformatics most GWAS are analyzed one SNP at a time and, thus, can detect only Tools recent ( de novo ) mutations (‘letters’), but not the common cis-epistatic risk factors (‘words’). Others ignore the sequence of the letters ( rwdo = word ). The ASDERA platform is based u-statistics for multivariate data, which The ASDERA were conceived in the 1940s, but never fully developed, because of Discovery memory constraints. Only after 2001 (32-bit OS) became it possible to Platform extend u-statistics to incorporate genetic ‘grammar’ (letter sequence, ...) to increase power and avoid artifacts (US 7,664,616). Result Where others fail with 100,000s of subjects, ASDERA succeeds with 100s.

ASDERA – FAQ: What is ASD-002’s “Mechanism of Action” (MoA) ?

When neurons are “stressed” (to many signals), they increase the threshold for new action potential to start a signal (hyperpolarize) by exporting potassium (K +). Biological + model Loss-of-function in outward K channels causes • epilepsy (ezo-/retigabine) • migraines (Zhang 2013) and • lack-of-language in ASD. (Guglielmi 2015)

MFA activates outward K+ channels and inward Cl − channels. Activity MFA antagonizes inward K+ channels and outward Cl − channels.

MFA reduces excitability in rodent and human neurons. Efficacy MFA prevents induced seizures in rodents.

Effectiveness (see FAQ: Proof of Concept)

Fenamates activate outward K+ current in • human KCNMA1 in jejunum smooth muscle cells [Farrugia 1993, MFA /FFA] MFA • pig KCNMA1 in smooth muscle cells [Ottolia 1994, MFA /FFA/NFA; Teramoto 2003, MFA ] activates • human KCNMA1 in embryonic kidney cells [Gribkoff 1996; NFA/FFA] outward • human corneal epithelial cells [Bockman 1998; FFA] potassium • human KCNQ2/3 in hamster ovary cells [Peretz 2005, CFA/DCF] channels • human KCNT2 in xenopus oocytes [Dai 2010, NFA; Garg 2012, MFA ...; Thomson 2015] • Guinea-pig KCNMA1 in vascular smooth muscle cells [Li 2013, FFA/NFA]

MFA reduces neuronal hyperexcitation and, thereby, MFA • PTZ-induced convulsions in rats [Wallenstein 1984] prevents • penicillin-induced seizures in rats [Wallenstein 1987; Ikonomidou-Turski 1988] induced • PTZ-induced excitation in rats [Wallenstein 1991] seizures • theophylline-induces seizures [Hoffman 1994] • ischemic brain damage in rats [Khansari 2009; Khansari 2012]

ASDERA – FAQ: What is ASD-002’s “Proof-of-concept” (PoC) ?

ASD-002 is not for the treatment of autism spectrum disorders (ASD). It treats/prevents migrianes in infants developing ASD. Indication Treating childhood migraines prevents mutism . Note: Infants cannot report migraines, so they cannot be treated (triptans).

Model ASD-002 is to prevent migraines; hence migraineurs are the “model”.

MFA in the Hall (1968): MFA ~ ergotamine/caffein, three attacks per drug treatment of Migraines Peatfield (1983): MFA > APAP, three attacks per drug

MFA in the Johnson (1986): MFA > propranolol > placebo, one month per drug prevention ns of Migraines Al-Waili (2000): MFA > placebo, one menstrual period per drug

MFA is at least as effective as other drugs in treating/preventing migraines. Summary ASD-002 has the same active moiety as MFA.

ASD-002 is not for the treatment of autism spectrum disorders (ASD). It treats migrianes to prevent mutism in children developing autism. Indication After ASD-002 has prevented mutism, children will still develop ASD, but they will be verbal (have “Asperger’s”)

Mutism is to autism what pneumonia is to the common cold: Precedent • we can’t treat the common cold / autism , but • we can treat pneumonia / mutism . At 9–12 months, we cannot have a formal diagnosis of autism , but we can see risk factors for mutism in routine tests covered by CMS: Risk • “red flags” in the routine parentel questionnaire for developmental delay Detection • epileptiform discharges in night-time EEG (at home) • prodromal signs of avoidance of social contacts in eye-tracking. Of the 25,000 children treated every year, Prediction >21,000 will develop ASD, >13,500 would become non-verbal (conservative estimates)

ASDERA – FAQ: Why not just treat the migraines (eg with triptans) ? Infants cannot report having migraines. Childhood migraines equivalents have atypical symptoms: Indication • infantile colic, cyclic vomiting, abdominal migraines, • ocular/retinal/convusional migraine, Alice in Wonderland syndrome • paroxysmal vertigo / torticollis Treatments (abortive therapies): Abortive • ibuprofen, acetaminophen, naproxen have been tried Drugs • triptans are approved for children >6 years, 1/wk Treatments (maintenance/prevention): Preventive • triptans not suitable ( ≤1/wk to prevent overuse headache) Drugs • valproic acid/gabapentin have been tried • CHAMP trial (8–17 yr) amitriptyline/topiramate/pacebo) aborted for futility MFA (the active moiety) ASD-002 • prevents migraines by targeting the ion channels involved in mutism, Benefit • is (UK) approved for chronic treatment in children from 6 months of age.

The primary outcome is Outcome • not a measure of autism, • but the number of words spoken at 24 months.

In 2009, Autism Speaks sponsored a study on the effectiveness of Precedent I Augmentative Communication (AAC). NCT01013545 The primary outcome was “Number of words spoken spontaneously during language sample”.

In 2005, Accorda sponsored two phase 3 studies on the effectiveness of dalfampridine (Ampyra ®), a potassium channel blocker for the treatment of Precedent II patients with Multiple Sclerosis. The primary outcome was not a measure of MS, but “Timed 25 Foot Walk ”.

ASDERA – FAQ: Drug development / management experience ? ASD-002 is an ester-prodrug of an approved small molecule (MFA). Drug An ester-prodrug is not a new chemical entity (NCE). development The prodrug will be produced by Regis, NJ. experience ASD-002 is not a NCE, but a New Clinical Indication (NCI). The ASDERA team as broad experience in designing clinical trials. • John Jay Gargus, MD PhD: Pediatrics, Drug Discovery Clinical • Knut M. Wittkowski, PhD ScD: Clinical trial design trial • G. Gold-von-Simson, MD MSc: Pediatrics, Clinical research experience • Bert Spilker, PhD MD: sold Orphan Medical to Jazz, $122M • Camargo, Services: 505(b)(2) approval pathway • inVentive Health, CRO: Clinical trial services Full-time The clinical trial for the NCI (not a NCE) will be outsourced to a CRO. management inVentiv Health Clinical will lead FDA interactions from pre-IND to NDA and team will assume all management responsibilities during the trial. CEO TBD in consultation with investors