Piper Jaffray Healthcare Conference. November 30, 2016

Transcription

1 Piper Jaffray Healthcare Conference November 30, 2016

2 Forward Looking Statement This presentation includes certain estimates and other forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, including statements with respect to anticipated operating and financial performance, clinical results, potential partnerships, licensing opportunities and other statements of expectation. Words such as expects, anticipates, intends, plans, believes, assumes, seeks, estimates, should and variations of these words and similar expressions, are intended to identify these forward-looking statements. While we believe these statements are accurate, forward-looking statements are inherently uncertain and we cannot assure you that these expectations will occur and our actual results may be significantly different. These statements by the Company and its management are based on estimates, projections, beliefs and assumptions of management and are not guarantees of future performance. Important factors that could cause actual results to differ from those in the forward-looking statements include the factors described in the Company s filings with the U.S. Securities and Exchange Commission. The Company disclaims any obligation to update or revise any forward-looking statement based on the occurrence of future events, the receipt of new information, or otherwise. 2

3 Executive Summary NFC 1 Programs Advancing mglur+ ADHD (SAGA) Enrollment ongoing; top-line data expected Q mglur+ prevalence rate of ~25% confirmed US market opportunity of $2B $3B 22q Deletion Syndrome Study initiated at CHOP Initial data expected in H Anti-LIGHT Program Successfully transferred IND FDA Type B meeting completed Initiating signal finding study Initial data expected in H Pipeline Development MDGN/CAG translational research continues to produce potential development targets 3

4 Genomic Medicine Approach

5 MDGN/CHOP - Genetic Discoveries to Drugs Exclusive option to the genomic discoveries in Rare and Orphan diseases made by Center for Applied Genomics (CAG) Identification of disease causing genetic mutations allows for repurposing drug development programs Genomically Validated Target Rational Search & Acquisition Genomically Guided Product Development Targeted Launch Medgenics Role: Match unique genetic discoveries with potential therapies Acquire the rights to programs that have been abandoned Ideal program: Correct MOA Excellent safety profile Inadequate efficacy in heterogeneous patient populations Lead development and commercialization 5-7 years of development time and of millions of dollars can be saved with this approach. Programs de-risked by genomic biomarker. 5

6 Center for Applied Genomics (CAG) at CHOP CAG s pediatric biobank contains a high percentage of rare genetic variants ~1.2M patient visits / year 10% of all R/O disease patients in N. America are treated at CHOP Population is unique in that it represents the most severe forms of common diseases Global reach in many therapy areas Highly scalable infrastructure to support translational research Biobank (BB) Fully automated robotic biorepository Datasets (Genomics EMR) Over 75K pediatric and 150K related adult patients GWAS genotyped with associated longitudinal EMR since 2006 Data Analytics End to end internal Next- Gen sequencing capabilities Integrated bioinformatics Rapid identification of novel genetic biomarkers Consented Patients 85% of the BB patients are consented for longitudinal follow up and are eligible for call back for future studies In the last 9 years CAG has had over 600 peer reviewed publications focused on novel genetic discoveries 6

7 Benefits of Genomic Guided Drug Development Genomic biomarkers improve overall program outcomes Smaller, faster, clinical trials Increased probability of regulatory success Targeted launch Improved response rates Higher Value Medicines Potential label expansion in adjacent genetic diseases 7

8 NFC-1 Program Update

9 ADHD: Rationale for Genomic Medicine Approach Most prevalent neurodevelopmental disorder in children (5-11%) Highly heritable* (70%); Heterogeneous, suggesting multiple causes Early studies focused on individual genes failed to identify causal associations Novel discovery from CAG, based on network biology, identified an underlying cause of disease in a subset (22-25%) of ADHD patients** ADHD Inattention Hyperactivity Impulsivity * Farone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention-deficit / hyperactivity disorder. Biol Psychiatry 2005; 57: **Nature Genetics 44, (2012). 9

10 CAG Breakthrough Discovery Research by Dr. Hakonarson indicated approximately 20% of ADHD patients have an underlying mglur network mutations 10 fold increased frequency of copy number variations (CNV) in the mglur gene network detected in ADHD population vs. normal controls Dr. Hakonarson found these mutations in several related neuropsychiatric diseases Elia, Glessner et al. Nature Genetics,

11 mglur Mutations Highly Predictive of ADHD In a blinded study of 155 mglur+ patients assessed in CHOP psychiatry >98% were diagnosed with ADHD H. Hakonarson, data presented at 63rd Annual American Academy of Child and Adolescent Psychiatry in Oct

12 NFC-1: First-in-class mglur Neuromodulator Dr. Hakonarson identified NFC-1 as a drug with potential to address mglur network disruptions caused by genetic mutations Small molecule, non-stimulant agonist of multiple mglurs: 1, 3, 5, 7, 8 Up-regulates GABA B receptors Positive effects seen in animal models Ameliorate cognitive impairment Reduce hyperactivity Enhance memory Antipsychotic activity 12

13 NFC-1 GREAT Study: Design and Execution Two-part Phase 1b trial, n=30 Part 1 Single Ascending Dose(SAD) / Pharmacokinetics(PK) SAD 24 hour PK mg Part 2 Ascending Dose Trial 1 week of placebo followed by 4 weeks active therapy Dose escalated: 50mg BID*-400mg BID* weekly (x4) Efficacy endpoints CGI, Vanderbilt, exploratory Single-blinded (to patients / families) Trial completed Q *Twice a day 13

14 Strong Efficacy Signal in Key Endpoints Treatment effect appeared more robust over time and at higher doses CGI-I: Proportion of Responders at Each Week for All Subjects Vanderbilt Scores: Proportion of Patients Improved from Pre-Study Baseline for All Patients Response rates for both scales (CGI-I and Vanderbilt Parent Rating Scale) approx 80% CGI-I, Clinical Global Impression of Symptom Improvement Responder Global rating of much or very much improved 14

15 mglur Network Mutation Classification: Genetic Tiers Genetic Tiers Defined by Proximity to mglur Network Tier 1 Mutations in genes in mglur receptors or that directly influence mglur signaling. n=17 Tier 1 79 Genes 10% of ADHD Tier 2 Mutations in genes that encode proteins that influence mglur. n=7 Tier Genes 20% of ADHD Tier 3 Mutations in genes that encode for proteins that interact with Tier 1 and 2 genes. n=6 Tier Genes 30% of ADHD Genetic tiers optimized for Tier 1 (not balanced) Prevalence of ADHD estimated 15

16 Core Mutations (Tier 1/2) Predict Higher Response CGI-I: Proportion of Responders at Week 5 by Genetic Tier (with 95% confidence intervals) Vanderbilt: Proportion of Responders at Week 5 by Genetic Tier (with 95% confidence intervals) Response rate appears to be correlated to the proximity to the core mglur genes Note: Data is for the subset of patients who titrated to the highest dose (N=18). Genetic tiers were not balanced. 16

17 Statistically Significant Improvement in Key Endpoints Improvement magnitude comparable to best in class drugs in complex, severe patients Average CGI - I score at the end of each week all patients Week 1 Week 2 Week 3 Week 4 Week 5 Mean P < Average Vanderbilt score at each week all patients Week 1 Week 2 Week 3 Week 4 Week 5 Mean P < Repeated Measures Analysis: mean scores by week CGI-I Scale: 1-7 Vanderbilt Scale (Questions 1-18):

18 NFC-1: GREAT Trial Study Summary Strong efficacy signal in multiple validated ADHD scales Improvement magnitude comparable to best in class drugs in complex, severe patients Improvement in multiple symptoms noted by caregivers Inattention, hyperactivity, anxiety, mood disorders Treatment effect more robust over time & at higher doses Genetic biomarker predictive of response to NFC-1 (Tier 1 & 2) Confirmation of PK profile Comparable to previous PK study; BID dosing Well tolerated, no treatment related serious adverse events Majority of patients enrolled in the long-term safety trial 18

19 NFC-1: ADHD Program Phase 2/3 (SAGA) mglur+ ADHD, Adolescents N=90, Ages ADHD Phenotype / Genotype Pediatrics, Adolescents N=1,000+ Objectives: Confirm prevalence of mglur+ Characterize mglur+ phenotype Expedite enrollment in Phase 2/3 interventional trials Design: Non-interventional Multi-center (25) Genotype 1,000+ ADHD subjects, age 6-17, identifying patients who are mglur+ Phase 3 mglur+ ADHD, Pediatrics N= TBD, Ages 6-12 Phase 3 mglur+ ADHD, Children N=TBD, Ages

20 SAGA: Phase 2/3 Study in Adolescents with mglur+ ADHD Objective: Optimize dose in adolescents, confirm Phase 1b results Endpoints: ADHD-RS, CGI-I FPFV June 2016 Topline Data: Q Phenotype / Genotype Multi-center: 25 sites GluR+ ADHD subjects: age Phase 2/3 mglur+, N=90 Placebo controlled 1:1 Randomization Same sites as Phen / Geno FPFV: June 2016 NFC-1 6 weeks 1 week follow-up Placebo 6 weeks 1 week follow-up 20

21 ADHD Phenotype/Genotype Study 25 ADHD Investigational Sites Across the U.S. 1,000+ ADHD patients ages 6-17 years Design: Objectives: Non-interventional Multi-center (25) Confirm prevalence of mglur+ Phenotypic differences in mglur+/- Expedite enrollment in Phase 2/3 interventional trials Timing: Ongoing Saliva Collection Study site obtains saliva sample and sends to CAG for DNA extraction Consented Patients 95% of the study subjects have agreed to be contacted for future studies CHOP/CAG Biobank DNA extraction Genetic Sequencing BioBanking of DNA Medgenics Database Evaluation of genotype and phenotype data Identification of subjects for future trials 21

22 Mutation Prevalence Confirmed in Phenotype/Genotype Study Age Group mglur+ (n) Total (n) % Pediatrics (ages 6-12) % Adolescents (ages 13-17) 271 1,274 21% Addressable pediatric/adolescent patient population: 1.2M - 1.5M Data presented at 63 rd Annual American Academy of Child and Adolescent Psychiatry Meetings (AACAP) in Oct

23 mglur+ ADHD Patients: Higher Prevalence of Negative Symptoms (n=1013) In mglur+ patients*: Symptoms associated with emotional dysregulation most prominent: disruptive behavior, anger control Emotional dysregulation often has significant life consequences** Majority of symptoms more prevalent *Data presented at 63 rd Annual American Academy of Child and Adolescent Psychiatry Meetings (AACAP) in Oct 2016 **Shaw, et al, Emotion Dysregulation in Attention Deficit Hyperactivity Disorder American Journal of Psychiatry, Volume 171, Issue 3, March 2014, pp

24 NFC-1: Potential for Superior Product Profile NFC-1 clinical profile in mglur+ ADHD patients Effective non-stimulant (non-scheduled) Excellent safety profile in >1,000 patients No evidence of growth retardation, addiction, sleep disturbance No evidence of cardiovascular risk No expectation for black box warning Potential to address co-morbid symptoms (e.g., emotional dysregulation) Potential for increased compliance and adherence Average time to discontinuation of current medication is 4 months; fully compliant for only 2 months* *Chacko A et al. Improving medication adherence in chronic pediatric health conditions: a focus on ADHD in youth. Curr Pharm Des 2010; 16(22):

25 mglur+ ADHD: Market Opportunity Overall US ADHD Market 2015 Sales in excess of $10B* ~6M pediatric / adolescent patients** Stimulants dominate market: 90+% of total prescriptions mglur+ ADHD Market, ages M - 1.5M patients (~25% mglur+) $2B - $3B market opportunity based upon current pricing and compliance / adherence Potential upside for premium pricing with superior product profile *IBIS World.com ** Trends in the Parent-Report of Health Care Provider-Diagnosed and Medicated Attention-Deficit / Hyperactivity Disorder: United States, , Journal of the American Academy of Child & Adolescent Psychiatry, Volume 53, Issue 1, January 2014, Pages e2 25

26 Financials & Milestones

27 Financial Update $47.3M cash balance (cash and cash equivalents) at 9/30/16 Current resources estimated to fund operations through Q ~37.1M shares outstanding at 10/31/16 27

28 Upcoming Milestones R&D Programs Timing NFC-1 Complete enrollment in Phenotype / Genotype study Initiate enrollment in SAGA: Phase 2/3 mglur+ ADHD Adolescent Trial Top line data Q1 17 Initiate enrollment in Phase 1/2 22q Deletion Syndrome Trial Q4 16 Initial open-label responder data H1 17 Anti-LIGHT mab Initiate Signal Finding Study Q4 16 Initial open-label responder data H

29 Thank You

30 Anti-LIGHT mab Program

31 Anti-LIGHT mab Program First-in-Class Biologic from Kyowa Hakko Kirin Initial development in Severe Pediatric Onset IBD Phase 2 ready antibody Strong regulatory exclusivity and robust intellectual property portfolio High value commercial opportunity with potential for indication expansion Rapid and capital-efficient global development pathway Minimal investment to POC Single pivotal trial for registration Program Update Successfully transferred IND FDA Type B meeting completed Agreement on plan to requalify trial supply Agreement on design of first POC trial in patients 8 weeks active treatment 31

32 Rationale for Anti-LIGHT Approach DcR3 is strongly linked to Severe Pediatric Onset IBD 1 Initial strategy to augment DcR3 Very short half life Toxicity reported with previous DcR3 analog Rational Search based on biological pathway LIGHT overexpressed in IBD DcR3 LOF increases LIGHT 2 Decoy Receptor 3 DcR3 Immune Cell LIGHT HVEM LTbR Our Approach: Therapeutic antibody which mimics DcR3 regulation by binding LIGHT 1 Hakonarson, et al Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nature Genetics 40 (10): Mauri DN, et al LIGHT, a new member of the TNF superf amily, and lymphotoxin alpha are ligands for herpesvirus entry mediator.immunity 8 (1):

33 Rapid Development Pathway to Approval Severe Pediatric Onset IBD POC Trial Single Phase 3 Pivotal Registration Trial Anticipated Phase 1b design: Single center (CHOP) N = up to 12 patients Duration 8 weeks Ascending dose Long Term Safety Trial Endpoints: Endoscopic Evaluation, Crohn s Disease Activity Index (CDAI), Safety Estimated Cost: ~$2M 33

34 Severe Pediatric Onset IBD: Top Down Treatment Paradigm Step-up approach Top-down approach to more aggressive disease Treatment Objectives: Induce remission with anti-tnfα immediately so patients can develop normally Avoid steroids and IMs Manage utilization of anti-tnf alphas to extend time before resistance develops Opportunity: 30% of patients do not respond to anti-tnfα Up to 50% of patients who initially respond, resistance will develop within 3 years 1 Creates significant opportunity for new Therapies / MOAs, that can treat anti-tnf alpha failures 1 Altwegg & Vincent (2014) TNF Blocking Therapies and Immunomonitoring in Patients with Inflammatory Bowel Disease. Mediators of Inflammation. doi: /2014/

35 Severe Pediatric Onset IBD: Anti-LIGHT Opportunity (US Pop.) Initial Target: anti-tnfα failure with DcR3 Loss of Function 2,000 3,000 IBD patients in US $300-$400M opportunity (based conservative pricing) Pediatric IBD Prevalence: 71/100,000 1 (52,000) Anti-TNF Usage 35-55% 2 (24,500) Potential Upside Pediatric anti-tnfα failures: 15,000 16,000 IBD Patients in US Pediatric indications with DcR3 LOF (juvenile idiopathic arthritis, psoriasis, etc.) Responders (70%) 3 (17,000) Resistance to anti- TNF s (50%) 4 (8,500) Non-responders (30%) 3 (7,350) DcR3 LOF (15%) (1,100) DcR3 LOF (15%) 1 Kappleman et al. (2007) Clin Gastro Hepat 2 Oliva-Hemker (2015) J Pedtr 3 Remicade Monograph 4 Altwegg-Vincent (2014) Mediators of Inflamm (1,275) 35

36 22q11.2 Deletion Syndrome (DS) Overview 36

37 Orphan Opportunity - 22q11.2 DS Micro deletion occurs in chromosome 22 90% of 22q11.2DS patients have at least one mglur network related deletion (RANBP1) Hypothesis: neuropsychiatric symptoms in 22q11.2DS patients are causally related to mglur CNV/mutations and will respond to NFC-1 37

38 Orphan Opportunity - 22q11.2 DS Prevalence estimates range from 1/2,000 to 1/4,000 Physical Symptoms Heart defects Cleft palate Gastrointestinal problems Poor wound healing Skeletal abnormalities Surgical / medical therapies mortality <4% after CV surgery (excluding critically ill infants) Psychiatric Symptoms* No effective therapy Approx. 40% progress to schizophrenia *Jonas et al Biol Pyschiatry 2015;75:

39 22q11.2 Patients in GREAT Study Two 22q11.2 patients in the trial; one deletion and one duplication Parents reported significant symptom improvement in both Marked improvement in CGI-I and Vanderbilt Both families elected to enroll in long-term safety trial to maintain access to NFC-1 39

40 Phase 1/2 Study in 22q Deletion Syndrome Objective: Explore symptoms from three neuropsychiatric disorders: ADHD, Anxiety, and Autism Spectrum Disorders (ASD) Endpoints: CGI-I, ADHD-RS, PARS, CARS-2 FPFV June 2016 (pending final CHOP approval) H2 2016: Responder rate data from open-label phase Open-label Phase N=30, age weeks dose optimization FPFV: June 2016 Single center: CHOP Responders Randomized Non Responders NFC-1 Fixed dose 7 weeks Placebo 7 weeks Exit Study 40