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 (2017) Confidential Information 1 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. © ASDERA (2017) Confidential Information 2 ASDERA – Market Need / Opportunity 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 (2017) Confidential Information 3 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 (2017) Confidential Information 5 ASDERA – Ion Channel Dysfunction in Migraines / CAE / DALD FHM 1/2/3 i: familial hemi- plegic 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 © ASDERA (2017) Confidential Information 6 ASDERA – in vitro / Animal / Clinical Evidence for Efficacy of MFA 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 (2017) Confidential Information 7 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) © ASDERA (2017) Confidential Information 8 ASDERA – Scientific, Pre-clinical and Clinical Support Human Genetics Association: K+ ion channels associated with lack of language. Published 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 Model system: Migraineurs (co-occurance, genes, EEG, regression). 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 (2017) Confidential Information 9 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. © ASDERA (2017) Confidential Information 10 ASDERA – Market size: 25,000 US Children/yr (Orphan Indication) Autism Spectrum Disorders (ASD) Typical Development (TD) 60,000 ASD 3,940,000 TD 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 (2017) Confidential Information 11 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 © ASDERA (2017) Confidential Information 12 ASDERA – IP Protection and Market Exclusivity 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 (2017) Confidential Information 13 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