37 th Annual J.P. Morgan Healthcare Conference

Transcription

1 37 th Annual J.P. Morgan Healthcare Conference January 2019 T H E R A P E U T I C S Courageous Patients. Bold Effort.

2 Safe Harbor Except for statements of historical fact, any information contained in this presentation may be a forward-looking statement that reflects the Company s current views about future events and are subject to risks, uncertainties, assumptions and changes in circumstances that may cause events or the Company s actual activities or results to differ significantly from those expressed in any forward-looking statement. In some cases, you can identify forward-looking statements by terminology such as may, will, plan, expect, estimate, anticipate, intend, goal, strategy, believe and similar expressions and variations thereof. Forward-looking statements include statements regarding the Company s business strategy; potential growth opportunities; clinical development activities; the timing and results of Investigational New Drug application and Clinical Trial Authorisation submissions; the timing and results of preclinical studies and clinical trials; the nature and timing of potential regulatory approvals; and the likelihood of future commercialization of product candidates. Although the Company believes that the expectations reflected in such forward-looking statements are reasonable, the Company cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval is inherently uncertain. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including those described under the heading Risk Factors in documents the Company has filed with the SEC. These forward-looking statements speak only as of the date of this presentation, and the Company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. Certain information contained in this presentation may be derived from information provided by industry sources. We believe such information is accurate and that the sources from which it has been obtained are reliable. However, we cannot guarantee the accuracy of, and have not independently verified, such information. The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products. 2

3 Audentes Therapeutics A clinical stage biotechnology company developing innovative gene therapy products to treat serious, life-threatening rare diseases Multi-product pipeline with compelling clinical results in lead program Internal large-scale GMP manufacturing facilitates quality, scalability, and commercial readiness Deep AAV gene therapy expertise and research capabilities driving future pipeline growth focused on neuromuscular diseases ~$450M proforma cash and equivalents at September 30, 2018, expected to fund the company into

4 Robust Pipeline Applying leading AAV science to monogenic diseases with high potential for transformative clinical benefits Indication Stage of Development Proof-of-Concept IND Enabling Phase 1/2 Commercial Rights XLMTM AT132 Pompe Disease AT845 Crigler-Najjar Syndrome AT342 CASQ2-CPVT AT307 Undisclosed AT720 4

5 Robust Internal Large-scale cgmp Manufacturing High quality material produced in-house since inception of development programs Large-scale cgmp capacity Robust process Commercial readiness 2x500L bioreactor scale Internal process & analytical development, fill/finish, and QC testing Additional capacity (~5,000L) possible in existing lease footprint Mammalian serum-free suspension culture process Demonstrated scalability, reproducibility, applicability across constructs/products Excellent yields and impurity profiles Facility designed and commissioned to support global licensure Same process, facility, and scale utilized from inception of clinical studies BLA readiness and validation efforts underway, consistent with recent FDA gene therapy guidance 5

6 AT132 X-Linked Myotubular Myopathy (XLMTM) Courageous Patients. Bold Effort. T H E R A P E U T I C S

7 X-Linked Myotubular Myopathy (XLMTM) A fatal disease with no treatment options Serious, life-threatening rare disease Significant impairment of respiratory and neuromuscular function Incidence ranges from ~1 in 40-50K newborn males Estimated 50% mortality by 18 months; 10-year survival of ~75% thereafter Significant clinical disease burden Of those surviving past infancy: >80% require ventilator support Motor milestones are substantially delayed High rates of healthcare utilization, hospitalization, and surgical intervention Monogenic disease, well-understood biology MTM1 gene encodes myotubularin, an enzyme required for normal development and function of skeletal muscle Muscle tissue is otherwise reasonably healthy and exhibits no dystrophic or inflammatory change 7 Beggs AH, et al. Muscle Nerve 2018;57: Jungbluth H, et al. Orphanet J Rare Dis. 2008;3:26 Vandersmissen I, et al. Neuromuscul Disord 2018;28: Mack DL, et al. Mol Ther 2017;25: Hnia K, et al. J Clin Invest 2011;121:70 85

8 ASPIRO Phase 1/2 Clinical Study of AT132 Open-label, ascending-dose, safety and preliminary efficacy study Inclusion criteria Subject is male <5 years old, or enrolled in INCEPTUS Genetically confirmed XLMTM Requires ventilator support AT132 administration Neuromuscular CHOP INTEND Development al milestones Key efficacy assessments Respiratory Maximal inspiratory pressure (MIP) Ventilator use Muscle biopsy Vector copy number Protein expression Histology Cohort vg/kg Cohort vg/kg Enrollment Pt # a Untreated control Baseline age (years) a Weeks 1 8 Prednisolone 1mg/kg/day Weeks 9 16 taper INCEPTUS Subjects BL Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6 Wk 7 Wk 8 Wk 9 Wk 10 Wk 11 Wk 12 Wk 13 Wk 14 Wk 15 Wk 16 6 mo 9 mo 12 mo Assessments Neuromuscular Respiratory Developmental milestones Muscle biopsy 8 Enrollment status as of September 26, 2018

9 CHOP INTEND score Significant Improvements in Neuromuscular Function All treated patients showed rapid and clinically meaningful increases in CHOP INTEND scores Maximum score = 64 points (typically reached by healthy infants around 3 to 6 months of age) Cohort 1: 1 x vg/kg; Cohort 2: 3 x vg/kg Ctrl, untreated control (Cohort 1) * Limited by halo traction device for treatment of pre-existing scoliosis Age (years) 9 Cohort #: Patient # 1: Patient 1 1: Patient 2 1: Patient 3 1: Patient 5 1: Patient 6 1: Patient 7 1: Pt 4 (Ctrl) 2: Patient 8 CHOP INTEND score Baseline score in ASPIRO Most recent score Change from baseline, score (%) (Wk 48) +27 (+93%) (Wk 48) +19 (+42%) (Wk 36) 0 (0%)* (Wk 24) +17 (+47%) (Wk 16) +13 (+33%) (Wk 16) +10 (+23%) (Wk 36) -2 (-4%) (Wk 4) +19 (+53%) Interim data as of September 26, 2018

10 Motor Milestones Achieved and maintained multiple motor developmental milestones Cohort 1 a Cohort 1 Expansion a Cohort 2 b First-year developmental milestones in healthy children Patient 1 Patient 2 Patient 3 Pt 4 (Ctrl; Patient 5 Patient 6 Patient 7 Patient 8 (0.8 y) c (4.1 y) c (2.6 y) c 4.0 y) c (1.0 y) c (0.8 y) c (0.8 y) c (1.2 y) c BL W48 BL W36 BL W24 BL W24 BL W24 BL W16 BL W16 BL W4 Rolling over Head control Sitting unassisted >5sec a Cohort 1: 1 x vg/kg; b Cohort 2: 3 x vg/kg; c Age at ASPIRO baseline; BL, ASPIRO baseline; W, week 10 Interim data as of September 26, 2018

11 MIP (cm H 2 O) Significant Improvements in Respiratory Function All treated patients showed clinically meaningful increases in MIP MIP 80 cmh 2 O: Estimated lower limit of normal in healthy children less than 5 years of age Maximum inspiratory pressure (cmh 2 O) Cohort #: Patient # Baseline MIP in ASPIRO Weeks after ASPIRO baseline (BL) 1: Patient 1 1: Patient 2 1: Patient 3 1: Patient 5 1: Patient 6 1: Patient 7 1: Pt 4 (Ctrl) 2: Patient 8 Most recent MIP Change from baseline (Wk 24)* +170% (Wk 48) +155% (Wk 24) +170% (Wk 24) +457% (Wk 12) +149% (Wk 12) +134% (Wk 24) -21% (Wk 4) +116% * Unable to collect at Week 48 due to lack of cooperation by the patient Cohort 1: 1 x vg/kg; Cohort 2: 3 x vg/kg MIP, maximal inspiratory pressure 11 Interim data as of September 26, 2018

12 Ventilator dependence over prior 24 hours (hours) Significant Reductions in Ventilator Use in All Patients by Week 24 Ventilator independence achieved by 3 patients Weeks after ASPIRO baseline (BL) Cohort 1: 1 x vg/kg; Cohort 2: 3 x vg/kg BiPAP, bilevel positive airway pressure; Ctrl, untreated control (Cohort 1); Inv, invasive 12 Cohort #: Patient # 1: Patient 1 1: Patient 2 1: Patient 3 1: Patient 5 1: Patient 6 1: Patient 7 Ventilator status Status at baseline (h/day) Most recent status Change from baseline BiPAP (12h) 0 (Wk 48) -100% Inv (22h) 6 (Wk 48) -73% Inv (24h) 0 (Wk 40) -100% Inv (24h) 12 (Wk 24) -50% Inv (24h) 0 (Wk 20) -100% Inv (23.5h) 10 (Wk 20) -57% 1: Pt 4 (Ctrl) BiPAP (12h) 12 (Wk 36) 0% 2: Patient 8 0 hours = Ventilator independence Inv (22.5h) 23.3 (Wk 4) +4% Interim data as of September 26, 2018

13 Clinical Assessment Videos Patient 1 Please: no photography or video recording of patient videos Courageous Patients. Bold Effort. T H E R A P E U T I C S

14 Muscle Biopsy Results Courageous Patients. Bold Effort. T H E R A P E U T I C S

15 Muscle Biopsy: Robust Tissue Transduction and Myotubularin Expression at 1x1014 vg/kg Ladder KO -D6 KO 100%KO 100% Ladder (kda) #1696 -D6 #1696 (kda) # Std SUMO KO MTM1(pg) KO 100% LadderKO W24 MTM1(pg) KO -D6 -D6 -D6 W24 100% 100% 5 -D6 W24 W24 LadderKO 100% W24 100% Std SUMO -D6-D6 W24 100% Std SUMO KO W24 Ladder W24MTM1(pg) KO 100%KO StdW24 SUMO MTM1(pg) -D6 100% 100% # D6 W24 100% Std SUMO MTM1(pg) (kda) #1696 (kda) #1696 #1696 #1696 (kda) 40# # # Week Patient WT Baseline Std SUMO M VCN: 6.2 per dg MTM1 vs. WT: ~120%* WT Week WT Baseline Baseline Week 24 WT Patient 3 Patient 2 35 VCN: 7.1 per dg MTM1 vs. WT: ~250%* VCN: 2.7 per dg MTM1 vs. WT: ~80%* Baseline Week 24 Patient 5 VCN: 2.2 per dg MTM1 vs. WT: ~52%* Cohort 1: AT132 1 x 1014 vg/kg VCN = vector copy number; dg = diploid genome; WT = wild type *The standard is currently being titrated and the linear range of the assay extended. Protein expression numbers may change in future presentations 15 Interim data as of September 20,

16 Histology: Week 24 Structural Improvements Consistent Across All Treated Patients Patient 1 Baseline Week 24 Patient 2 Baseline Week 24 H&E H&E NADH NADH Patient 3 Baseline Week 24 Patient 5 Baseline Week 24 H&E H&E NADH NADH Cohort 1: 1 x vg/kg H&E, hematoxylin and eosin; NADH, nicotinamide adenine dinucleotide 16

17 AT132 for XLMTM Next Steps Completed productive initial interactions with FDA and EMA to discuss potential registration pathways; plan to provide additional details Q1:19 Leveraging RMAT and PRIME designations Plan to dose an additional 3-5 patients in Cohort 2 expansion arm (3x10 14 vg/kg) in early 2019 Next clinical data update planned at ASGCT in May 2019 CMC BLA readiness and process validation activities underway Approach is consistent with recent FDA gene therapy guidance All clinical material manufactured utilizing substantially the same process, scale, and facility intended to supply the commercial market 17

18 AT845 Pompe Disease Courageous Patients. Bold Effort. T H E R A P E U T I C S

19 Pompe Disease A rare, severe, progressive neuromuscular disease Serious, life-threatening rare disease Severe muscle weakness, respiratory failure, and in infants, increased cardiac mass and heart failure Estimated incidence of 1 in 40K Monogenic, well-understood biology Gene encodes lysosomal enzyme acid alpha-glucosidase (GAA), deficiency leads to accumulation of lysosomal glycogen Target for AAV gene therapy Clear clinical measures Program status Efficacy of ERT limited by poor cellular uptake, no neuronal exposure, and immune reaction to exogenous GAA Audentes approach: systemic administration to express GAA directly in tissues affected by the disease, including skeletal and cardiac muscle, and the nervous system Encouraging results from recent studies in animal model AT845 IND filing planned in Q3:19 19 Lipinksi, Shawn. Molecular Genetics and Metabolism, 2012; Lacana, et al., Amer. J. Medical Genetics, 2012; International Pompe Association, Pompe Community and United Pompe Foundation

20 AT342 Crigler-Najjar Syndrome Courageous Patients. Bold Effort. T H E R A P E U T I C S

21 Crigler-Najjar Syndrome An inherited metabolic disease that leads to neurological damage & death Serious, life-threatening rare disease Significant bilirubin accumulation that can lead to irreversible neurological damage and death Current treatments: 10 to 12 hours/day of phototherapy, liver transplant Estimated incidence of 1 in 1 million newborns Monogenic, well-understood biology UGT1A1 gene encodes enzyme required for bilirubin metabolism and excretion Target for AAV gene therapy AAV8 effectively penetrates the liver Preclinical models have demonstrated that 5% - 8% of normal UGT1A1 expression maintained life-long low total bilirubin levels Dose ranging study of AT342 in a knockout mouse model rapidly reduced and normalized bilirubin levels 21 Bortolussi et. al, Human Gene Therapy, 2014; Orphanet.com

22 VALENS Phase 1/2 Clinical Study Design Open-label, ascending-dose, safety & preliminary efficacy study Inclusion Criteria Genetically confirmed Crigler- Najjar 1 year of age Subject receives daily phototherapy for 6 hours within a 24 hour period Key Efficacy Assessments bilirubin from baseline (BL) to 12 wks bilirubin from BL to 18 wks phototherapy (PT) from BL to 18 wks Successful weaning from PT Liver biopsy Design N=12, roll-over from LUSTRO 3 ascending-dose cohorts - 1.5x10 12 vg/kg - 6.0x10 12 vg/kg - 1.5x10 13 vg/kg AT342 administration Weeks 1 8 Prednisolone 1mg/kg/day Weeks 9 16 taper Normal prescribed phototherapy dose Weeks weaning Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6 Wk 7 Wk 8 Wk 9 Baseline Wk 10 Wk 11 Wk 12 Wk 14 Wk 16 Wk 18 Wk 24 Bilirubin Phototherapy Liver Biopsy 22

23 Total Bilirubin Levels (mg/dl) Initial Proof-of-Concept Established Rapid and meaningful but temporary decline in total bilirubin levels in patient 1 Total Bilirubin Levels (mg/dl) AT342 has been well-tolerated with no treatment-related serious adverse events Similar efficacy result observed with low doses of AT342 in a dose ranging study in the mouse model of Crigler-Najjar, while higher doses demonstrated durable bilirubin reduction Enrollment in VALENS Phase 1/2 study ongoing 16 Patient 1 Bilirubin (mg/dl) 12-year-old male, Dose 1.5x10 12 vg/kg 16 Mouse MED Study Bilirubin (mg/dl) By Dose, n= Vehicle control vg/kg vg/kg vg/kg vg/kg Days Relative to Dosing Days Relative to Dosing 23 May 2018

24 Summary Courageous Patients. Bold Effort. T H E R A P E U T I C S

25 Audentes Highlights Compelling Pipeline AAV Manufacturing Leadership Treating devastating diseases with high unmet medical need Potential for transformational disease impact Robust internal research, analytical and large-scale cgmp manufacturing capabilities AT132 BLA readiness and validation activities underway Upcoming Catalysts Strong Balance Sheet AT132: Additional regulatory updates throughout Q1:19 AT132: Next data update planned at ASGCT in May 2019 AT845: Plan to file IND in Q3:19 AT720: Plan to provide program overview in Q2:19 ~$450M of proforma cash and equivalents at Sep. 30, 2018 Resources are expected to fund operations into

26 37 th Annual J.P. Morgan Healthcare Conference January 2019 T H E R A P E U T I C S Courageous Patients. Bold Effort.