Gaining Momentum in Gene Therapy

Transcription

1 Gaining Momentum in Gene Therapy Corporate Presentation September 2018

2 Forward-looking Statements Statements contained in this document regarding matters that are not historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of Such statements include, but are not limited to, statements regarding plans and milestones related to Adverum s product candidates, clinical studies, and regulatory filings, the therapeutic and commercial potential of its product candidates and the sufficiency of Adverum s resources to fund lead programs, all of which are based on certain assumptions made by Adverum on current conditions, expected future developments and other factors Adverum believes are appropriate in the circumstances. Adverum may not consummate any of these plans or these product, clinical development or regulatory goals in a timely manner, or at all, or otherwise carry out the intentions or meet the expectations or projections disclosed in its forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, the risk that Adverum s resources will not be sufficient for Adverum to conduct or continue planned development programs and planned clinical trials, the risk of a delay in the enrollment of patients in Adverum s clinical studies or in the manufacturing of products to be used in such clinical studies, risks and uncertainties inherent in the product development and the regulatory approval process, the risk that Adverum will not be able to successfully develop or commercialize any of its product candidates and the risk that Adverum will be delayed in receiving or fail to receive required regulatory approvals. Risks and uncertainties facing Adverum are described more fully in Adverum s periodic reports filed with the SEC, particularly in the section titled Risk Factors. All forward-looking statements contained in this document speak only as of the date on which they were made. Adverum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. This document contains estimates, projections and other information concerning Adverum s industry, business and the markets for certain drugs, including data regarding the estimated size of those markets, their projected growth rates and the incidence of certain medical conditions. Information that is based on estimates, forecasts, projections or similar methodologies is inherently subject to uncertainties and actual events or circumstances may differ materially from events and circumstances reflected in this information. Unless otherwise expressly stated, we obtained this industry, business, market and other data from reports, research surveys, studies and similar data prepared by third parties, industry, medical and general publications, government data and similar sources believed to be reliable, but the accuracy or completeness of such information is not guaranteed by, and should not be construed as representations made by, Adverum. 2

3 Adverum is a Clinical-stage Gene Therapy Company with Industry-leading Expertise Robust pipeline: ADVM-043 for A1AT deficiency ADVANCE Phase 1/2 preliminary data expected by YE18 ADVM-022 for wet AMD Phase 1 initiation expected in 4Q18 ADVM-053 for HAE Plan to submit IND in 4Q18 Industry-leading AAV platform and capabilities: Next-generation vectors Scalable manufacturing process ~$235M in cash* to fund development of lead programs into 2020 Leadership team with extensive industry expertise *Cash, cash equivalents, and short-term investments as of June 30, 2018 (unaudited). 3

4 Advancing Gene Therapies for Serious Rare and Ocular Diseases Gene Therapy Candidate Research Preclinical Phase 1/2 Phase 3 Lead Programs Worldwide Rights ADVM-043 ADVANCE Trial for Alpha-1 Antitrypsin (A1AT) Deficiency ADVM-022 Wet Age-related Macular Degeneration (wamd) ADVM-053 Hereditary Angioedema (HAE) Partnered Programs Up to 5 Undisclosed Targets X-linked Retinoschisis and 3 Undisclosed Targets Inherited Retinal Disease Ophthalmic Disease 4

5 Adverum s Lead Gene Therapy Programs ADVM-043 ADVM-022 ADVM-053 Alpha-1 Antitrypsin (A1AT) Deficiency 100,000 U.S. patients 1 Wet Age-related Macular Degeneration (wamd) 1.2M U.S. patients 2 Hereditary Angioedema (HAE) 8,000 U.S. patients 3 1 Healthcare Provider s Guide. The Alpha-1 Foundation. Version 2.0 (2015). 2 Prevalence of Age-Related Macular Degeneration in the United States, Arch Ophthalmol. 2004;122(4): doi: /archopht Decision Resources Group; November Wu, Jing; Anderson, Sarah. 5

6 A1AT Deficiency: Unmet Medical Need A1AT Deficiency Compliance Challenges Genetic mutation results in very low levels of A1AT A1AT deficiency is associated with premature emphysema Market Overview 100,000 U.S. patients 1 $1.2B Global Treatment Market 2 in Treating A1AT Deficiency Patients with Emphysema 4 approved A1AT replacement therapies Approved therapies present compliance challenges Need for weekly IV infusions 3 ($100K annually) 4 Worsening lung function from underdosing 1 Healthcare Provider s Guide. The Alpha-1 Foundation. Version 2.0 (2015). 2 Alpha 1 Antitrypsin Deficiency Treatment Market. Transparency Market Research (2017) 3 GLASSIA, PROLASTIN-C, ARALAST NP, ZEMAIRA 4 6

7 Phenotype A1AT Serum Level: Indicator of lung protection At Risk for Emphysema A1AT Serum Level by Phenotype 1 No Increased Risk of Emphysema Effect of A1AT Augmentation Therapy on Lung Density Decrease Rate 2 MM SS MZ SZ ZZ Null-null Therapeutic Target (~570 µg/ml, 11 µμ) α1at Serum Level (µm) Serum levels of A1AT correlate with risk of developing emphysema 570 µg/ml (11µM) is considered the threshold for decreased risk Augmentation of serum A1AT levels can slow loss of lung parenchyma 1 Based on data from: Guidelines for the Approach to the Patient with Severe Hereditary Alpha-1-Antitrypsin Deficiency. Am Rev Respir Dis Vol. 140 (Nov 1989) 2 Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). The Lancet Vol. 5 (Dec 1, 2016), McElvaney, et al. 7

8 AAV1: Dose-dependent, Sustained Expression up to 5 Years AGTC Phase 2 Data for raav1-cb-haat Administered Intramuscularly (IM) Linear Dose Response 1 Durability of Protein Expression x vg/kg (High Dose), HSV 1.9 x vg/kg (Mid Dose), HSV 6.0 x vg/kg (Low Dose), HSV 8.6 x vg/kg, TFX raav1-cb-haat administered with 100 IM injections demonstrated clear linear relationship between dose and expression of protein Sustained expression (1-5 years) seen in patients receiving raav1-cb-haat 1 Phase 2 Clinical Trial of a Recombinant Adeno-Associated Viral Vector Expressing A1-antitrypsin: Interim Results. Human Gene Therapy (October 2011), Flotte, et al. 2 5-Year Expression and Neutrophil Defect Repair after Gene Therapy in Alpha-1 Antitrypsin Deficiency. Molecular Therapy (June 2017), Mueller, et al 8

9 ADVM-043: Designed to Treat A1AT Deficiency with a Single IV Administration AAVrh.10-A1AT vector, highest serum A1AT expression compared to 24 other serotypes 1 Targets the liver where A1AT is primarily expressed Single IV administration Dose can be escalated to increase protein expression 1 High Levels of Persistent Expression of A1-Antitrypsin Mediated by the Nonhuman Primate Serotype rh.10 Adenoassociated Virus Despite Preexisting Immunity to Common Human Adeno-associated Viruses, Mol Ther Vol. 13, No. 1 (January 2006), De et al. 9

10 Human α1at Level in Serum (μg/ml) ADVM-043 PoC Study: Stable, Long-term ha1at Expression Above Normal Level after Single Administration Human A1AT Expression in Serum after Single ADVM-043 Administration in Mice Intravenous (IV) Delivery gc AAVrh.10ha1AT Therapeutic Target 2 (~570 µg/ml) Normal Level 2 (~1.2 mg/ml) Time Post Administration (Weeks) 1 Company data on file 2 Therapeutic Target is based on serum levels demonstrated by approved standard-of-care therapies. 1.2 mg/ml is approximately equivalent to 20µM; 570 µg/ml is approximately equivalent to 11µM. 10

11 ADVM-043: ADVANCE Phase 1/2 Trial for A1AT Deficiency Preliminary Data Expected from Cohorts 1-3 Expected YE18 Baseline assessment Treatment evaluation Follow-up Weeks Screening & 8-week washout for patients on augmentation therapy ADVM-043 injection Primary endpoint (Safety) Secondary endpoints (Efficacy) Inclusion Criteria 18 years of age A1AT genotype ZZ or Z Null FEW1 >35% predicted No evidence of liver disease Neutralizing antibody titer less than 1:5 Cohort 1: 1x10 12 vg/kg (8x10 13 vg) * IV n=2 DMC Safety Review Cohort 2: 5x10 12 vg/kg (4x10 14 vg) * IV n=2 DMC Safety Review Cohort 3: 1.5x10 13 vg/kg (1.2x10 15 vg) * IV n=2-5 patients DMC Safety Review Patients will be administered a tapering prophylactic corticosteroid regimen Additional Dose Escalation Cohort(s) Primary Endpoint Safety and tolerability of ADVM- 034 in patients with A1AT deficiency at 52 weeks Secondary Endpoints Total plasma concentrations of A1AT up to 52 weeks M-specific plasma concentrations of A1AT up to 52 weeks ClinicalTrials.gov under trial identifier number NCT *All based on an 80 kg patient 11

12 Advancing ADVM-043 for A1AT Deficiency NEXT STEPS ADVANCE Phase 1/2 preliminary data expected by YE18 12

13 Adverum s Lead Gene Therapy Programs ADVM-043 ADVM-022 ADVM-053 Alpha-1 Antitrypsin (A1AT) Deficiency 100,000 U.S. patients 1 Wet Age-related Macular Degeneration (wamd) 1.2M U.S. patients 2 Hereditary Angioedema (HAE) 8,000 U.S. patients 3 1 Healthcare Provider s Guide. The Alpha-1 Foundation. Version 2.0 (2015). 2 Prevalence of Age-Related Macular Degeneration in the United States, Arch Ophthalmol. 2004;122(4): doi: /archopht Decision Resources Group; November Wu, Jing; Anderson, Sarah. 13

14 wamd: Large Market with Significant Opportunity to Improve Treatment Paradigm Wet AMD Wet age-related macular degeneration Intermediate AMD - 20/20-20/30 Vision Vision loss from abnormal blood vessel proliferation and leakage due to vascular endothelial growth factor (VEGF) activity Market Overview Wet AMD at Diagnosis - 20/80 Vision 1.2M U.S. patients 1, 3M globally $9.2B global sales for approved anti-vegf therapies 2 1 Prevalence of Age-Related Macular Degeneration in the United States, Arch Ophthalmol. 2004;122(4): doi: /archopht Based on 2017 public financial statements 14

15 Intravitreal Injections Visual Acuity (ETDRS Letters) Significant Opportunity to Improve wamd Treatment Monthly Injections are Challenging Inability to Maintain a Regular Treatment Schedule Leads to Vision Loss 2 Optimal Therapeutic Benefit Vision loss at wamd onset Monthly therapy provides vision stability Vision loss at lower dosing frequencies -2.0 Recommended Injections Actual Injections Clinical Trial Duration Years 1 Clinical utilization of anti-vegf agents and disease monitoring in neovascular age-related macular degeneration, Am J Ophthalmol. 2014;157(4): , Holekamp NM, et al. 2 Multiple studies (MARINA/ANCHOR & HORIZON/SEVEN-UP, SECURE, CATT) indicate that vision benefits are lost at less than recomended dosing frequencies 15

16 ADVM-022: Designed to Treat wamd with a Single Intravitreal Injection Proprietary vector AAV.7m8 delivers an anti-vegf standard-of-care therapy (aflibercept) with intravitreal injection Efficacy demonstrated in non-human primates (NHPs) comparable to an anti-vegf standard of care therapy Robust protein levels seen in NHP vitreous up to 52 weeks post injection Single Intravitreal injection and method of delivery of current standard of care

17 Route of Administration is an Important Consideration When Developing Gene Therapies for Ocular Injection Intravitreal Injection Subretinal Injection STEP 1 STEP 2 Outpatient visit STEP 1 STEP 2 Requires Surgical Setting Intravitreal injection has potential for wide distribution of vector, thus improving the surface area of retina transduction Intravitreal injection can be performed as an outpatient procedure in the doctor s office, and is the same route of administration currently used for standard of care anti-vegfs Subretinal injection is limited by amount of vector that can be infused and the localized transduction of cells under or near the bleb Other potential drawbacks of subretinal injection include: Risks associated with the procedure (i.e. cataracts) Potential for difference in surgical technique generating variable clinical outcomes Limited access to qualified surgery centers 1 Hossein S, et al. Overview of retinal differentiation potential of mesenchymal stem cells: A promising approach for retinal cell therapy. Annals of Anatomy - Anatomischer Anzeiger,Vol 210, 2017: 52 17

18 Industry-standard Model Used to Test New wamd Therapies Retinal Image after Laser Treatment Choroidal neovascularization (CNV) is induced experimentally by laser Nine lesions per eye are graded for severity (grades I-IV) Efficacy is assessed by reduction of the number of most severe, clinically relevant (grade IV) lesions Source: European Society of Gene and Cell Therapy (ESGCT) Conference, October

19 % Grade IV CNV Lesions 13-Month Efficacy in NHPs Comparable to Aflibercept Post Single Intravitreal Injection of ADVM-022 ADVM-022 Long-term Efficacy (AAV.7m8-aflibercept) 50% 40% 40% 13 months post-administration * p < vs. vehicle 30% 20% 10% 5% * 6% * 0% Vehicle (n=8 eyes) Aflibercept (n=8 eyes) ADVM-022 (n=8 eyes) Note: Data at 13 months is consistent with previously reported data at 28 days Source: Poster Presentation from the American Society of Gene and Cell Therapy (ASGCT) 21st Annual Meeting, May

20 Robust and Sustained Aflibercept Levels Detected in Vitreous up to 52 Weeks after Single Injection ADVM-022 ADVM-022 NHP Study 1 (2x10 12 vg/eye, n=2-4 eyes 1 ) ADVM-022 NHP Study 2 (2x10 12 vg/eye, n=14 eyes) n=2 eyes 1 ADVM-022 Study 1: 2 NHPs (4 eyes) at weeks 4, 8, and 12; 1 NHP (2 eyes) at weeks 26 and 52 Source: Targeting Ocular Disorders and the Retina Society, September

21 ADVM-022: OPTIC Phase 1 Study Design Baseline assessment Treatment evaluation Follow-up Weeks Screening & aflibercept injection Baseline Assessment ADVM-022 injection aflibercept rescue therapy administered as needed Primary endpoint (Safety) 24 weeks Secondary endpoints (Efficacy) Inclusion Criteria Adults under active treatment for wamd and responsive to anti-vegf with 2-6 injections in last 8 months Demonstrate aflibercept response (assessed by SD- OCT during screening) BCVA 20/40 to 20/320 ( 73 and 24 ETDRS letters) Anti-AAV.7m8 neutralizing antibodies <1:5 titer Cohort 1: 6x10 11 vg n=6 DMC Safety Review (4 weeks) Cohort 2: 2x10 12 vg n=6 DMC Safety Review (4 weeks) Cohort 3: 6x10 12 vg n=6 DMC Safety Review (4 weeks) Patients will be administered a tapering prophylactic corticosteroid regimen Primary Endpoint Safety and tolerability of ADVM- 022 in patients with wamd at week 24 Secondary Endpoint BCVA at 24 weeks SD-OCT central retinal thickness at 24 weeks Percentage of subjects needing rescue injections Mean number of rescue injections OCT = Optical Coherence Tomography BCVA = Best Corrected Visual Acuity ETDRS = Early Treatment Diabetic Retinopathy Study 21

22 Advancing ADVM-022 for wamd NEXT STEPS Plan to initiate Phase 1 in 4Q18 22

23 Adverum s Lead Gene Therapy Programs ADVM-043 ADVM-022 ADVM-053 Alpha-1 Antitrypsin (A1AT) Deficiency 100,000 U.S. patients 1 Wet Age-related Macular Degeneration (wamd) 1.2M U.S. patients 2 Hereditary Angioedema (HAE) 8,000 U.S. patients 3 1 Healthcare Provider s Guide. The Alpha-1 Foundation. Version 2.0 (2015). 2 Prevalence of Age-Related Macular Degeneration in the United States, Arch Ophthalmol. 2004;122(4): doi: /archopht Decision Resources Group; November Wu, Jing; Anderson, Sarah. 23

24 HAE is an Orphan Disease That is Challenging to Manage Hereditary Angioedema (HAE) Genetic mutation results in low levels of functional C1-esterase inhibitor (C1EI) Compliance Management Strategy Low C1EI levels lead to HAE attacks characterized by sudden swelling/edema of respiratory airways, GI tract, and extremities Market Overview 8,000 U.S. patients 1 Prophylaxis requires regular ongoing treatments Breakthrough attacks still occur and can be life threatening 1 Decision Resources Group; November Wu, Jing; Anderson, Sarah. 24

25 ADVM-053 Orphan Drug Designation: Designed to Prevent HAE Attacks ADVM-053 (AAVrh.10-C1EI) has the potential to protect from unpredictable and debilitating HAE attacks Robust C1EI expression and C1EI protein expression above therapeutic levels in preclinical models Single IV administration Dose can be escalated to increase protein expression 25

26 Percentage of Intervals with Angioedema Attack ADVM-053 PoC Study: Protein Expression at Levels Capable of Reducing Vascular Permeability Attack rate dropped to near zero with daily C1-INH infusion 1 (not clinically practical) ADVM-053 induced expression above therapeutic level in mice ADVM-053 showed decrease in vascular permeability to wild type levels Efficacy in C1EI Deficient Mouse Model Once Weekly 20 Twice Weekly Daily Interval Between C1-INH Infusions (Days) Time after Vector injection (weeks) Normal Level (low) 0.7 U/ml Therapeutic Target 0.4 U/ml Wild Type 2 S63 C1EI Deficient 24 Weeks Post Injection S63 ADVM- 053 Presence of pathology will result in dye leaking into tissues (vasodilation) 1 Safety and Efficacy of Prophylactic Nanofiltered C1-inhibitor in Hereditary Angioedema, Amer J Med 2012;125, 938.e1-938.e7, Zuraw BL and Kalfus I 2 Wild type picture is two weeks post injection 26

27 Advancing ADVM-053 for HAE NEXT STEPS Conducting ongoing IND-enabling studies Transferring technology to a contract manufacturing organization to prepare clinical material Planning to submit an IND Application in 4Q18 Partnering with HAE experts worldwide 27

28 Dual Manufacturing Strategy: Leveraging In-house Expertise & External Capacity Process development capabilities to deliver scalable process to GMP contract manufacturing organizations (CMOs) Baculovirus/Sf9 production system applicable to multiple AAV serotypes State-of-the-art bioindustry technology for purification Process is readily transferred to CMO Assay development capabilities and GMP quality control to optimize product release for human use Potential to expand manufacturing capabilities Scale up manufacturing process at 2000 liter scale Ability to leverage in-house cgmp manufacturing capacity in addition to CMO usage 28

29 Proprietary Platform in Novel Vector Development Next-generation Vectors Directed evolution and rational design of AAV capsids: Enhanced transduction efficiency for specific tissues or altered transduction properties (e.g., crossing retinal inner limiting membrane or the blood brain barrier) Opportunity for novel tropism in cell types that were previously incompatible with existing raav vectors Immune response evasion Adverum s Unique Advantages Proprietary cell library technology to overcome the challenge of cross-packaging, improving the odds of finding a desired variant upon screening Ability to generate large amounts of AAV capsid libraries allows for screening in NHPs instead of rodents, to increase the probability that selected variants work in humans Minimizing the rate of false positives during capsid rescue results in highly efficient screening 29

30 Leadership in Ophthalmic Gene Therapy Drives Collaborations Next-generation AAVs CRISPR-based Genome Editing Expertise Next-generation AAVs Proprietary Molecules & Ophthalmology Expertise Up to 5 ophthalmic indications CRISPR technology delivery $1M upfront to evaluate next-generation AAV vectors Up to a mid-teen, million-dollar amount in development and commercialization milestones for each product Tiered royalties from mid-single digits to low-teens on net sales of each product Initial research period extended through 4Q18 Up to 8 ocular therapeutic targets (4 already identified) AVA-311 for juvenile X-Linked Retinoschisis (XLRS) as first collaboration program Adverum has option to share up to 35% on profits and development costs for two targets $8M initial payment, up to $640M in payments upon achievement of milestones, low to mid-single digit royalties on WW net sales Initial 3-year collaboration term extended by additional 3 years to May

31 2018: Year of Clinical, Regulatory, & Manufacturing Execution ADVM-043 for A1AT Deficiency Dosed first patient in Cohort 2 of ADVANCE Phase 1/2 clinical trial Dosed first patient in Cohort 3 Expect to report preliminary data from patients in Cohorts 1-3 of ADVANCE trial 2Q18 3Q18 YE18 ADVM-022 for wamd Presented long-term preclinical efficacy data at ASGCT IND Active Plan to initiate Phase 1 ADVM-053 for HAE Orphan Drug Designation (ODD) Plan to submit IND In-house Manufacturing Capabilities Signed lease for future expansion of manufacturing capabilities 2Q18 3Q18 4Q18 3Q18 4Q18 2Q18 ~$235M in cash* to fund further development of lead programs *Cash, cash equivalents, and short-term investments as of June 30, 2018 (unaudited). 31

32 Team with Significant Industry Experience Name Background Experience Leone Patterson Interim President and Chief Executive Officer SVP, Chief Financial Officer 20+ years experience in management and financial operations Mehdi Gasmi, Ph.D. Chief Science and Technology Officer Linda Neuman, M.D. Interim Chief Medical Officer Jennifer Cheng, Ph.D., J.D. VP and General Counsel Katherine Bock VP, Investor Relations and Corporate Communications 20+ years experience developing gene therapy vectors 25+ years experience in clinical practice and leading drug development programs with successful IND Applications and NDAs 15+ years experience in biotechnology companies, including legal and intellectual property counsel and research 15+ years experience in the life sciences industry, including research, finance, corporate development and investor relations 32

33 Nasdaq: ADVM