COMPANY OVERVIEW. June 2016

Transcription

1 COMPANY OVERVIEW June 2016

2 Disclaimers Forward-Looking Statements This presentation contains forward-looking statements, including: statements about: the timing, progress and results of preclinical studies and clinical trials for AVXS-101, including statements regarding the timing of initiation and completion of studies or trials and related preparatory work, the period during which the results of the trials will become available and our research and development programs; our ability to obtain and maintain regulatory approval of AVXS-101; our expectations regarding the size of the SMA patient population; our ability to expand development of AVXS-101 into SMA Type 2 and, possibly, Type 3; our ability to build a pipeline of gene therapy treatments beyond SMA; our manufacturing capabilities and strategy; our ability to successfully commercialize AVXS-101; and our future pursuit of additional neurogenetic programs. These statements involve substantial known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. The forward-looking statements in this presentation represent our views as of the date of this presentation. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements at some point in the future, we have no current intention of doing so except to the extent required by applicable law. You should, therefore, not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this presentation. 2

3 Our Strategy Strategic Focus & Investment Vision: Leader in rare and life-threatening neurological genetic diseases Build pipeline of gene therapy treatments beyond SMA Expand development of AVXS-101 into SMA Types 2 and, possibly, 3 Establish foundational presence in SMA Type 1 Time 3

4 SMA Types: A Devastating Disease TYPE 1 TYPE 2 TYPE 3 TYPE 4 SMN2 Copy Number Two Three or Four Three or Four Four to Eight Onset Before 6 Months 6-18 Months Early childhood to early adulthood (juvenile) Adulthood (20s-30s) usually after 30 Incidence per Live Birth Approximately 60% Approximately 27% Approximately 13% Uncommon; limited information available Developmental Milestones Will never be able to sit without support Difficulty breathing & swallowing Can t crawl/will never walk Will never be able to walk or stand without support Stand alone and walk but may lose ability to walk in 30s-40s Stand alone and walk but may lose ability to walk in 30s-40s (Same as Type 3) Survival <10% Event free* by two years of age 68% alive at age 25 Normal Normal *Event = Death or 16-hr/day ventilation continuously for 2 wks, in the absence of an acute reversible illness 4

5 AVXS-101 Targets the Primary SMN Gene NORMAL INDIVIDUAL SMA-AFFLICTED INDIVIDUAL SMN Genes SMN1 Primary SMN2 Back up SMN Genes SMN1 SMN2 Back up SMN Protein SMN Protein SMA-AFFLICTED INDIVIDUAL TREATED WITH AVXS-101 SMN Genes SMN1 SMN2 Back up AVXS-101 Primary SMN Protein Functional SMN Protein Not-functional SMN Protein 5

6 Natural History of SMA Type 1 90% of SMA Type 1 patients will not survive to the age of 2 % Event-Free Survival* Holds head steady alone; brings hands to mouth Rolls over in both directions 75% survival* 8.1 mos Sits alone; crawls 50% survival* 10.5 mos Cruises; may stand alone * Survival = no death, or no need for 16-hr/day ventilation continuously for 2 weeks, in the absence of an acute reversible illness 25% survival* 13.6 mos Walks alone; may run and walk up stairs; eats with a spoon 8% survival* 20 mos n = 23 (2 copies of SMN2) Climb furniture alone; kicks and throws a ball Age (mos) Onset of SMA Type 1 by 6 months Symptoms may present floppy baby syndrome muscle weakness (legs more than arms) poor head control belly breathing bulbar muscle weakness (weak cry, difficulty swallowing, aspiration) will never sit unsupported Finkel et al. Observational Study of Spinal Muscular Atrophy Type I and Implications for Clinical Trials. Neurology. August Milestone for a healthy infant SMA Type 1 survival rates 6

7 SMA Type 1 is a Motor Neuron Disease with both Central and Systemic Features HALLMARKS OF SMA TYPE 1 Defective/loss of SMN1 gene (primary SMN producer) Motor neurons are most susceptible to diminished SMN levels Rapid loss of motor neurons throughout brain, brain stem and spinal cord (CNS) Autonomic & systemic involvement - Heart rate - Swallowing - Muscle (e.g. respiratory) Addresses underlying cause of SMA defective/loss of primary SMN gene Targets motor neurons Provides rapid onset of effect and continuous and sustained SMN expression Crosses blood brain barrier allowing IV dosing route Effectively targets both central and systemic features - CNS - Heart - Muscle AVXS-101 7

8 Our Solution: AVXS-101 An Innovative Treatment Approach for SMA Gene therapy is the right approach for SMA: Monogenic mutation that drives the pathology Recombinant AAV9 Capsid Shell scaav ITR Continuous Promoter Human SMN Transgene scaav ITR KEY COMPONENTS Recombinant AAV9 Capsid Shell scaav ITR (Self-complementary DNA technology) PURPOSE Ability to deliver across the blood brain barrier (BBB) and into the spinal cord - Avoids the need for intrathecal delivery when treating infants Non-replicating virus does not modify the existing DNA of the patient. Enables rapid onset of effect which is key in a quickly deteriorating population Continuous Promoter Activates the transgene to allow for continuous and sustained SMN expression Human SMN Transgene Full copy of a stable, functioning SMN gene that is introduced into the cell s nucleus Rendering adapted from DiMattia et al. Structural Insight into the Unique Properties of Adeno-Associated Virus Serotype 9. J. Virol. June

9 IV Preclinical Proof-of-Concept THE HIGHLIGHTS In the severe SMA mouse model, a single IV injection of AVXS-101 (3.3e14 vg/kg) increased survival and improved motor function. - Median survival was 265 days in this cohort. More than 30% survived 400 days. 1 In non-human primates, a single injection of AVXS-101 led to sustained SMN transgene expression in motor neurons, multiple organs and muscles. 2 Multiple, positive safety and tolerability studies in newborn mice and non-human primates with no evidence of toxicity up to 24 weeks following a single IV injection of AVXS-101. DOSE-RESPONSE FOR SURVIVAL 1 MOTOR NEURON TARGETING* IN NHP MOTOR FUNCTION Percent Survival Proposed Therapeutic Dose 3.3x10 14 vg/kg Low Dose 6.7x10 13 vg/kg AAV9-GFP Control p90 p30 p1 *Lumbar spinal cord Righting time (sec) GFP-treated Control SMN-treated Untreated Age (d) Time (days) 1. Foust et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat. Biotechnol. March Bevan et al. Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders. Mol. Ther. November

10 Phase 1 Trial Design Study Site Principal Investigator Jerry R. Mendell, M.D. KEY ENROLLMENT OBJECTIVES CRITERIA TRIAL OVERVIEW Trial Design Open-label, doseescalation Route of Administration One-time intravenous infusion through peripheral limb vein OBJECTIVES Inclusion 9 months of age / 6 months of age¹ and younger at day of vector infusion with SMA Type 1 as defined by the following features: Bi-allelic SMN1 gene mutations (deletion or point mutations) 2 copies of SMN2 Onset of disease at birth to 6 months of age Hypotonia by clinical evaluation with delay in motor skills, poor head control, round shoulder posture and hypermobility of joints Exclusion Active viral infection (includes HIV or serology positive for hepatitis B or C) Use of invasive ventilatory support (tracheotomy with positive pressure)* or pulse oximetry <95% saturation Patients with Anti-AAV9 antibody titers >1:50 as determined by ELISA binding immunoassay Abnormal laboratory values considered to be clinically significant Patient with signs of aspiration based on a swallowing test and unwilling to use an alternative method to oral feeding * Patients may be put on non-invasive ventilator support (BiPAP) for less than 16 hours per day at the discretion of their physician or study staff Clinicaltrials.gov Identifier = NCT ¹ Inclusion criteria was 9 months of age and younger for the first nine patients. 6 months of age and younger for the last six patients. Primary Safety and Tolerability Secondary Time from birth until death or time to 16-hour ventilation continuously for >2 weeks in the absence of an acute reversible illness Exploratory Standard Motor Milestone Development Survey Children s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Compound Motor Action Potentials (CMAP) Motor Unit Number Estimation (MUNE) Electrical Impedance Myography (EIM) ACTIVE-mini (Ability Captured Through Interactive Video Evaluation-mini) 10

11 Survival Data Ongoing Phase 1 Trial 01Apr2016 Cohort 1 6.7E13 vg/kg Age (months*) SURVIVAL DATA Cohort 2 2.0E14 vg/kg 4/4 reached 8% event-free 9/9 reached 25% event-free 9/9 reached 50% event-free PNCR (Finkel) 2014 Natural History Study: 75% event-free 50% event-free 25% event-free 8% event-free Day of Gene Transfer * A month is defined as 30 days 11

12 CHOP INTEND vs. Age: Cohort 1 Only 01Apr2016 E.01 CHOP INTEND Scores Baseline Age (months): 5.9 [median], 6.3 [mean] Current Age (months): 25.7 [median], 26.7 [mean] Mean CHOP INTEND Increase: 8.7 points E.03 E.01 E.02 E E Age (months) 1 month = 30 days Dashed line denotes missing data for reasons noted below: E.01 follow-up on Month 17 cancelled due to SAE hospitalization; full CHOP INTEND not conducted on Months 19, 20, and 21 due to broken right arm; full CHOP INTEND not conducted on Months 26 and 27 due to family reasons; follow-up on Month 28 cancelled due to family reasons. E.02 CHOP INTEND not conducted on Month 14 due to broken left leg; full CHOP INTEND not conducted on Months 23 and 24 due family reasons. E.03 follow-up on Months 17 and 18 cancelled due to SAE hospitalization; CHOP INTEND not conducted on Month 19 due to SAE recovery; CHOP INTEND not conducted on Month 22 due to family reasons; full CHOP INTEND not conducted on Months 23 and 25 due to family reasons. 12

13 CHOP INTEND Scores CHOP INTEND vs. Age: Cohort 2 Only 01Apr * * * * Age (months) 1 month = 30 days * Patient experienced non-treatment related SAE hospitalization within last 3 mos Dashed line denotes missing data for reasons noted below: E.04 full CHOP INTEND not conducted on Months 14 and 15 due to body cast for scoliosis; CHOP INTEND not conducted on Month 19 due to scoliosis surgery recovery; CHOP INTEND not conducted on Month 20 due to SAE hospitalization; full CHOP INTEND not conducted on Month 21 due to SAE hospitalization. E.07 follow-up on Months 12 and 13 cancelled due to family reasons. E.08 follow-up on Months 13, 15 and 17 cancelled due to family reasons; full CHOP INTEND not conducted on Month 18 due to left leg fracture. E.09 follow-up on Month 12 cancelled due to family reasons. * * Baseline Age (months): 3.1 [median] 3.4 [mean] Current Age (months): 11.7 [median] 12.3 [mean] Mean CHOP INTEND Increase: 19.2 points 75% Cohort 2 (9 of 12) reached CHOP INTEND >40 points 58% Cohort 2 (7 of 12) reached CHOP INTEND >50 points 17% Cohort 2 (2 of 12) reached CHOP INTEND of 64/64 points 13 E.04 E.05 E.06 E.07 E.08 E.09 E.10 E.11 E.12 E.13 E.14 E.15

14 CHOP INTEND vs. Age 01Apr2016 CHOP INTEND Scores Age (months) 1 month = 30 days COHORT 1 (n=3) Baseline Age (months): 5.9 [median], 6.3 [mean] Current Age (months): 25.7 [median], 26.7 [mean] Mean CHOP INTEND Increase: 8.7 points Cohort point avg increase in CHOP INTEND Cohort point avg increase in CHOP INTEND COHORT 2 (n=12) Baseline Age (months): 3.1 [median], 3.4 [mean] Current Age (months): 11.7 [median], 12.3 [mean] Mean CHOP INTEND Increase: 19.2 points 14 E.01 E.02 E.03 E.04 E.05 E.06 E.07 E.08 E.09 E.10 E.11 E.12 E.13 E.14 E.15

15 Nutritional Support 01Apr2016 Natural History and Standard of Care Nutritional Support Status of AVXS-101 Patients in Cohort 2 Bulbar weakness in SMA Type I leads to impaired swallowing, malnutrition, and growth failure Median age to growth failure is 7 months of age 2 Standard of Care currently recommends nutritional support as soon as feeding difficulties are present (NG/NJ tube or Gastrostomy) Natural history indicates median age to nutritional support is 8 months of age in Type 1 patients, IQR 6-13 months 1 Median age of patients is approximately 12 months 7 of 7 (100%) of AVXS-101 patients that did not require feeding support before Gene Transfer continue to thrive without nutritional support 5 patients had G tube prior to gene therapy and one patient who had G-tube placement before Gene Transfer is also feeding orally. 1. Finkel et al. Observational Study of Spinal Muscular Atrophy Type I and Implications for Clinical Trials. Neurology. August Sproule, D. et al. Age at Disease Onset Predicts Likelihood and Rapidity of Growth Failure Among Infants and Young Children With Spinal Muscular Atrophy Types 1 and 2. J Child Neurol 27, (2012). 15

16 Pulmonary Support 01Apr2016 Natural History and Standard of Care Bulbar muscle weakness, skeletal muscle weakness in the neck and intercostal muscle weakness lead to Respiratory impairment Poor clearance of airway secretions Risk of aspiration and Recurrent infections leading to death or permanent ventilation Respiratory Support Status of AVXS-101 Patients No patient requires permanent ventilation Cohort 1 patients (n=3) are over 24.0 months of age, when <8% are predicted to be surviving or free of permanent ventilation 1 Cohort 2 patients (n=6) are over 13.6 months of age, when 25% are predicted to be surviving or free of permanent ventilation 1 Inexorable progression to respiratory failure is expected Median age to permanent ventilation* or death is 10.5 months, IQR months 1 By 13.6 months only 25% of SMA type 1 patients are alive and free of permanent ventilation 1 8/10 (80%) of Cohort 2 patients that did not require BiPAP support before Gene Transfer continue without any respiratory support 2 exceptions were children hospitalized in Q for severe respiratory illness placed on BiPAP to aid recovery 1. Finkel et al. Observational Study of Spinal Muscular Atrophy Type I and Implications for Clinical Trials. Neurology. August

17 Safety Data Ongoing Phase 1 Trial 01Apr confirmed AEs and 22 were deemed SAEs AVXS-101 appears to have a favorable safety profile and appears to be generally well-tolerated in patients studied to date SAFETY AND TOLERABILITY OBSERVATIONS Only two of the SAEs were treatment-related on the basis of laboratory tests showing elevated liver function enzymes (LFEs), experienced by two patients without clinical manifestations and were resolved following prednisolone treatment. Of the 20 unrelated SAEs, 16 were related to the pulmonary system, including 3 resolved events of respiratory syncytial virus (RSV) infections. Of the 52 non-serious adverse events, all were mild or moderate in severity. Three of the mild or moderate non-serious AEs (elevated LFEs) were treatment-related and experienced by two patients. Other non-treatment-related AEs were expected and associated with SMA. 17

18 Summary: Ongoing Phase 1 Data 01Apr2016 All patients in both dosing cohorts remain event free o Median age of all 15 patients is 14.9 months; oldest is 28.9 months Cohort 1 patients (n=3) are over 24.0 months of age (<8% predicted Finkel 2014) Cohort 2 patients (n=6) are over 13.6 months of age (25% predicted Finkel 2014) All patients have sustained increases in CHOP INTEND vs baseline and response appears to be dose-dependent o Cohort 1 (n=3) increased average 8.7 from Baseline 16.3 CHOP INTEND o Cohort 2 (n=12) increased average 19.2 from Baseline 28.2 CHOP INTEND 75% Cohort 2 (9 of 12) reached CHOP INTEND >40 points 58% Cohort 2 (7 of 12) reached CHOP INTEND >50 points 17% Cohort 2 (2 of 12) reached CHOP INTEND of 64/64 points AVXS-101 appears to have a favorable safety profile and appears to be generally well tolerated o A total 74 adverse events, 22 SAEs and 52 non-serious AEs 2 SAEs were treatment related and included elevated LFE 3 mild/moderate AEs were treatment related and included LFE 7 of 7 patients in Cohort 2 who did not require nutritional support prior to gene transfer continue to not require nutritional support. 8 of 10 patients in Cohort 2 with no respiratory support prior to gene transfer continued with no respiratory support, except two patients who initiated respiratory support (BiPAP) to aid in recovery from recent hospitalizations for respiratory distress. 18

19 Clinical Development Milestones Dec 2015: Completed enrollment of 15 patients in Phase 1 Trial Start of 2016: Quarterly updates on ongoing Phase 1 trial 1H 2017: Initiate SMA Type 1 pivotal trial in U.S. and EU Type 1 Program Type 2 Program 2H 2016: Initiate Phase 1 safety and dosing study in SMA Type 2 via intrathecal (IT) delivery Q1 2017: 13.6 months of data for all patients in the SMA Type 1 Phase 1 trial 19

20 Manufacturing Strategy Executing a Parallel Path Approach (CMO and AveXis Build) to Enable both Clinical Trial and Commercial Long-term Sustainable Supply Manufacturing Overview Contract Manufacturing Organizations (CMOs) AveXis Build Continue to utilize Contract Manufacturing Organizations (CMOs) and Third-Party Suppliers - Ongoing tech transfer from NCH to SAFC - Evaluate and develop process improvements for existing process Execute AveXis Build to establish our own manufacturing facility - Manufacturing becomes a strategic capability - Enhances supply chain control and business continuity - Increases supply capacity for AVXS-101 and potentially other products We expect to use a combination of internal and third-party manufacturing sources to ensure long-term continuous supply for both clinical trials inside and outside of the U.S. and commercial demand 20

21 Financial Position (dollars in millions) Cash and cash equivalents of $148.2 million as of March 31, 2016 Three months ended 3/31/16 Three months ended 3/31/15 R&D Expense 16.1* 4.8 G&A Expense 4.8** 0.6 Net Loss *Includes $11.5 million of stock-based compensation **Includes $2.1 million of stock-based compensation 21

22 Key Investment Highlights AVXS-101 is a gene therapy for SMA Type 1 with clinical POC 15 patients dosed in two distinct dosing cohorts; appears to be generally well tolerated Median age of ~26 months (cohort 1) and ~12 months (cohort 2) at 4/1/16 with encouraging survival data in both dosing cohorts Early and sustained motor function improvements above baseline, with some patients achieving normal scores Appears to affect need for pulmonary and nutritional support Differentiated approach to SMA treatment AVXS-101 is designed to address the mono-genetic root cause of SMA Treatment is designed to replace the lost or defective primary SMN gene Only clinical-stage gene therapy in development for SMA Encouraging preliminary safety, survival and motor function data across both dosing cohorts Broader gene therapy platform focused on neurodegenerative diseases Initial focus on IV delivery for SMA Type 1 Near-term plan to expand into SMA Types 2 (and possibly 3) via Intrathecal delivery Will pursue additional neuro-genetic programs over time Experienced management team Several catalysts to drive value Seasoned management team with gene therapy and rare disease expertise Track record of building and operating innovative biotechnology companies Successfully developed and commercialized drugs at leading biopharma companies Quarterly updates from ongoing Phase 1 trial 13.6 months of data for all patients in the Phase 1 trial in Q Initiate Phase 1 safety and dosing study in SMA Type 2 via intrathecal delivery in 2H 2016 Initiate SMA Type 1 pivotal trials in U.S. and EU 1H

23 Thank You