Visionary Science for Life Changing Cures 2018

Transcription

1 Visionary Science for Life Changing Cures

2 Forward Looking Statements Today s presentation includes forward-looking statements intended to qualify for the Safe Harbor from liability established by the Private Securities Litigation Reform Act of These forward-looking statements reflect AGTC's plans, estimates, assumptions and beliefs. Forward-looking statements include information concerning possible or assumed future results of operations, business strategies and operations, preclinical and clinical product development and regulatory progress, potential growth opportunities, potential market opportunities and the effects of competition. Forward-looking statements include all statements that are not historical facts and can be identified by terms such as"anticipates,""believes,""could," "seeks,""estimates," "expects," "intends," "may," "plans," "potential," "predicts," "projects," "should," "will," "would" or similar expressions and the negatives of those terms. Actual results could differ materially from those discussed in the forward-looking statements, due to a number of important factors. Risks and uncertainties that may cause actual results to differ materially include, among others: gene therapy is still novel with only a few approved treatments so far; AGTC cannot predict when or if it will obtain regulatory approval to commercialize a product candidate or receive reasonable reimbursement; uncertainty inherent in clinical trials and the regulatory review process; risks and uncertainties associated with drug development and commercialization; factors that could cause actual results to differ materially from those described in the forward-looking statements are set forth under the heading"risk Factors" in the Company s most recently filed Annual Report on Form 10-K. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Also, forward-looking statements represent management's plans, estimates, assumptions and beliefs only as of the date of this presentation. Except as required by law, AGTC assumes no obligation to update these forward-looking statements publicly or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future. 2

3 Company Highlights AGTC is developing genetic therapies for patients with inherited diseases. Treatments are precisely designed to meet the needs of each specific genetic disorder Clear Vision Become leader in ophthalmology gene therapy & leverage to otology Deep Expertise Extensive IP Portfolio Broad Pipeline In vector selection, design, manufacturing and delivery >100 patents/applications covering genes, capsids, process, delivery Multiple opportunities to provide long-term value to patients Key Partnership Broad collaboration with Biogen for multiple indications 3

4 AGTC s Comprehensive Platform Genetic therapies are complex with interdependent components that must work in harmony Greater than fifteen years of gene therapy experience allows AGTC to design and construct all critical gene therapy elements and bring them together to develop promising treatments for patients 4

5 Lead Product Pipeline Multiple Shots on Goal Phase Patients US & EU Partner Key Platform Next Milestone XLRS RS1 35,000 Topline interim six-month data by end of 2018 ACHM CNGB3 14,000 Wholly Owned Complete dose escalation in the first quarter of 2019 CNGA3 7,000 Wholly Owned Complete dose escalation XLRP RPGR 20,000 Complete dose escalation in the first quarter of 2019 Optogenetics Unique ChR Multiple Indications Bionic Sight, LLC File IND in the first half of 2019 ALD ABCD1 -- Option Decision Discovery Programs -- Target Announcement 5

6 Extensive preclinical data FDA Recognized Evidence of safe, targeted delivery in human trials Approved product in US Why Ophthalmology Significant Unmet Medical Need Sight is critical to the human experience Poor visual function hinders daily living: driving, riding a bike, playing outside Many people fear blindness more than death Vision in people with inherited eye diseases not correctable with eyeglasses No current treatments for target indications Growing Scientific Support 20/20 20/200 X 6

7 The Eye The Retina - a highly organized tissue Iris Pupil Lens Cornea Retinal pigment epithelial cell Vitreous humour Rod cell Cone cell Retina Mueller cell Horizontal cell Rod diseases Bipolar cell Rod diseases Amacrine cell Fovea Optic nerve Cone diseases Ganglion cell Optogenetics Light enters retina 7

8 8 Lead Product Candidates

9 X-linked Retinoschisis (XLRS) Disease Missing structural protein results in poor vision not correctable with eyeglasses ~35,000 patients in US and EU No current treatments Retinal layers: XLRS eye Retinal layers: normal eye Impact Poor vision (20/100) detected by school age Difficulty reading, driving, and recognizing faces 30% chance of retinal detachment or vitreous hemorrhage at any age Positioned for Success Robust analysis of tissue targeting and functional improvement in animal models Understanding of human disease phenotype from natural history Accepted clinical endpoints Strong IP position 9

10 XLRS Study Design Dose level High Group 3 n=3 DSMC Group 4 n=10 Middle Group 2 n=3 DSMC Group 2A n=5 DSMC Low Group 1A n=3 DSMC Group 1B n=3 Study Design Dose escalation in adults followed by expansion group at maximum tolerated dose in both children and adults to generate additional data Additional middle dose group in children (6-17 year old) Later cohorts include patients with better baseline visual acuity (20/50) Primary endpoint is safety 10

11 XLRS -Phase 1/2 Current Status 9 active trial sites in U.S. All are leading centers and KOLs for inherited retinal diseases Initial targeted enrollment completed Dose escalation phase (low, middle, and high dose) 12 patients enrolled Additional middle dose pediatric group 5 children enrolled High dose expansion group 10 adults enrolled Currently enrolling 5 additional pediatric patients Extension of high dose expansion group 11

12 XLRS -Potential Approvable Efficacy Endpoints Visual Acuity Best corrected visual acuity measured by ETDRS letter score 8 to 10 letter change significant in inherited retinal diseases Visual Fields Visual sensitivity across retinal surface Compare hill of vision sensitivity to normal, calculate sensitivity defect Decrease in sensitivity defect would indicate improved retinal function Change in letter score Example from AGTC LCA trial Sensitivity (decibels) Patient Normal Months after treatment Sensitivity defect Normal minus patient 12

13 XLRS -Supportive Efficacy Endpoints Retinal Structure Optical coherence tomography (OCT) to characterize anatomic features Decrease in size of cyst cavities would indicate improved retinal structure Retinal layers: XLRS eye Retinal Function Electroretinography (ERG) to quantify electrical activity from retinal cells B-wave decreased in XLRS Increase in B-wave would indicate improved retinal function Retinal layers: normal eye 13

14 Disease Achromatopsia (ACHM) 70% of ACHM is caused by mutations in the A3 and B3 genes. AGTC is currently working on these two genetics mutations that result in severely impaired vision and day blindness Missing cone photoreceptor protein results in poor vision not correctable with eyeglasses ~28,000 patients in US and EU No current treatments Normal Bright light ACHM Impact Extremely poor vision, legally blind Extreme light sensitivity (day blind) Complete loss of color discrimination Positioned for Success Robust animal models showing potential to improve visual function Understanding of human disease phenotype from natural history Accepted clinical endpoints Strong IP position Dim light 14

15 ACHM-B3 -Study Design Dose level Highest DSMC Group 4 n=3 DSMC Group 5 n=15 Adult/Ped High Group 1 n=4 Middle DSMC Group 3 n=3 Low DSMC Group 2 n=2 Study Design Dose escalate in adults Expansion group at maximum tolerated dose (MTD) to include adults and children Primary Endpoint is Safety Establish MTD 15

16 ACHM-A3 -Study Design Dose level Highest DSMC Group 3 n=3 DSMC Group 4 n=15 Adult/Ped Middle Group 2 n=3 Low Group 1 n=3 DSMC Study Design Dose escalate in adults Expansion group at maximum tolerated dose (MTD) to include adults and children Primary Endpoint is Safety Establish MTD 16

17 ACHM -Phase 1/2 Current Status Enrollment as of Sept conference call ACHM-B3 Group 1: Original Dose: 4 patients enrolled Group 2: Low Dose: 2 patients enrolled Group 3: Middle Dose: 2 patients enrolled ACHM-A3 Group 1: Low Dose: 2 patients enrolled Site status ACHM-B3: 5 sites actively enrolling patients ACHM-A3: 5 sites actively enrolling patients Actively identifying and initiating several additional sites 17

18 ACHM - Potential Approvable Efficacy Endpoints Visual Acuity Best corrected visual acuity measured by ETDRS letter score 8 to 10 letter change significant in inherited retinal diseases Example from AGTC LCA trial Color Vision Three standard assessment methods Changes for each can be quantified HRR plates Change in letter score Months after treatment D15 test CAD test 18

19 ACHM -Supportive Efficacy Endpoints Light Discomfort Testing Measure light intensity causing discomfort Discomfort at lower intensity (lux) in ACHM Increase in ability to tolerate brighter light would be clinically important to patients Retinal Function Electroretinography (ERG) to quantify cone photoreceptor responses Increase in cone ERG response would indicate improved retinal function Log lux Example from ACHM dog study Before treatment After treatment Log lux Stimuli 30 Hz cone response 1 µv 100 msec 1 0 Normal ACHM visit 1 ACHM visit 2 19

20 X-linked Retinitis Pigmentosa (XLRP) Disease Missing protein results in degeneration of rods and cones ~20,000 patients in US and EU No current treatments Photoreceptor Preservation in Dog Model of XLRP Untreated area Treated area Constriction of Visual Field Photoreceptor nuclei blue Primate Rod/Cone Targeting Impact Early night blindness, progressive constriction of visual fields Legally blind by age 45 Positioned for Success Robust animal models showing potential to improve vision Primate photoreceptor targeting Understanding of human disease phenotype from natural history Accepted clinical endpoints Strong IP position 20

21 XLRP -Study Design Dose level Highest PAUSE DSMC Group 3 n=3 DSMC PAUSE Group 4 n=6 Adult/Ped Middle Group 2 n=3 Low Group 1 n=3 PAUSE DSMC Age: 18 years BCVA: <=20/50 Study Design Dose escalation phase in adults Expansion group at maximum tolerated dose (MTD) in both children and adults to generate additional data Primary Endpoint is Safety 21

22 XLRP -Phase 1/2 Current Status First Patient Treated April 16 th 2018 Earned $2.5M BIIB milestone Fourth Patient Treated July 17 th 2018 Earned $10.0M BIIB milestone Total of 5 patients enrolled as of Sept conference call 3 sites actively enrolling patients Actively identifying and initiating several additional sites 22

23 Capsid Comparison in Non-Human Primate Photoreceptors Purpose: Determine expression efficiency of three clinically-relevant AAV capsids Inflammatory Score per Eye Relative GFP Expression AAV2tYF capsid AAV5 capsid AAV8 capsid Time Post Injection (weeks) Transgene expression continues to increase, reaching stable levels as inflammation resolves 23

24 Optogenetics -Bionic Sight Collaboration The Bionic Sight system bypasses damaged tissue of the input side of the retina and provides direct stimulation to the output cells in order to send visual information to the brain. Normal Photoreceptors Ganglion cells Standard Prosthetic Comp Electronics case Light Image code sent to the brain Light Image code sent to the brain Blind Bionic Sight Light Light No code transmitted Image code sent to the brain Encoder (Transducer) Photoresponsive ganglion cells* 24

25 Project Status Pre-IND Meeting completed with FDA to get guidance on toxicology, CMC & clinical trial plans IND-enabling GLP mouse tox study completed GMP Clinical Trial Material in-process Clinical trial planning underway Will include safety evaluation and preliminary light sensitivity testing IND submission targeted for first half

26 Why Otology Significant Unmet Medical Need Common sensory deficit ~30M patients in USA No current treatments for orphan indications Lack of innovation since advent of hearing aids and cochlear implants Provides limited improvement Hearing loss has devastating effects: inability to listen to music, hear a loved one s voice More than 70 genes identified that cause hearing loss Growing Scientific Support The ear is a small contained organ; shares characteristics with the eye Robust genetic models Hearing function evaluated with non-invasive and quantitative tests clear clinical endpoints Demonstrated POC 26

27 AGTC Capabilities And Technology Fit Lessons Learned In The Eye Are Directly Applicable To The Ear AGTC has significant expertise in the design & manufacture -at commercial scale -of AAV Gene Therapy Products Ocular Otology Fit with current technology Monogenic / well understood ++ + Suitable delivery approach ++ + Limited volumes required Anatomically well defined Clear end-points and dev. path Competitive modalities + + Otology: Significant limitations to current therapies Multiple genes shown to improve sensory transduction in the auditory hair cells The ear is well defined, small contained space, limited immune issues, identified target cells Well understood outcome measures 27

28 Otology Research Status Routes of Administration Animal Models Capsid Tropism Cochlear-specific Promoters Gene of Interest Immunogenicity Test different routes of injection for optimal transduction with minimal damage to ear: Round window membrane Cochleostomy Evaluate capsid tropism & distribution, promoter activity, safety evaluation: Mouse, Guinea pig, Non-human primate (NHP) Test novel capsid variants with improved cellular tropism and penetrability of ocular cell layer in the cochlear system: Preliminary data indicates AGTC vectors efficiently target IHC, OHC, and supporting cells Identify novel, proprietary synthetic promoters for cochlear-specific cell types Preparing for in vivo testing Evaluate vectors that carry gene-optimized coding sequence for target(s) of interest On-going for one target Monitoring cochlear response and developing strategies to overcome/mitigate immune response to AAV Investigating contribution of vector components and manufacturing process in NHPs Impact of pre-existing neutralizing antibodies 28

29 Capsid & Promoter Identification In process of testing many different capsid variants across three different animal models Positive datais emerging for capsids showing selective cell tropism profiles Data to right shows selective expression in different cells with different capsids from top to bottom Final verification in NHP Promoter work advancing to testing stage 29

30 30 Realizing the Promise of Gene Therapy

31 Experienced Team Sue Washer Chief Executive Officer Stephen Potter Chief Business Officer Mark Shearman, Ph.D. Chief Scientific Officer Bill Sullivan Chief Financial Officer Matt Feinsod, M.D. Chief Medical Officer Lanita Scott, M.D. VP, Clinical Research Karen Carroll, RN VP, Clinical Operations 31

32 Manufacturing Expertise and Capacity Manufacturing strength Suspension system scalable to large volumes Process adaptable to any serotype Productivity Actual Phase 1/2 process; 25 L batch provides >2000 doses New pivotal process; 10 fold higher productivity Expertise Successfully transferred to multiple parties 7 successful cgmp batches completed Completely integrated process & analytics Analytics advancing to late stage readiness 32

33 Advances in Characterization Analytics progressing to late phase readiness Validation protocols in review for platform assays Example of assays changing to more advanced methods These capabilities accelerate us from positive clinical data to the market Assay Previous Current Purity Identity Aggregation Qualitative gel image quantified with software Yes/No for known serotypes, but not capable of distinguishing small changes or new serotypes Dynamic light scattering provides hydrodynamic particle radius Analytes separated, quantified by area& further analysis possible (mass spec) Mass spectroscopy capable of detecting individual amino acid changes in the capsid, even for known serotypes Size exclusion HPLC aggregate provides size and allows capture for characterization 33

34 Financial Summary Strong Balance Sheet $104.9 Million Cash & Investment as of 6/30/2018 Represents > two years of cash Sufficient Cash to: Complete enrollment and analysis of full data set from the ongoing Phase 1/2 human clinical trials for XLRS and both of the planned ACHM Phase 1/2 human clinical trials Initiate and analyze initial data from the Phase 1/2 human clinical trial for XLRP Move pre-clinical optogenetic program into the Clinic and fund planned R&D and PD 34

35 Lead Product Pipeline Multiple Shots on Goal Phase Patients US & EU Partner Key Platform Next Milestone XLRS RS1 35,000 Topline interim six-month data by end of 2018 ACHM CNGB3 14,000 Wholly Owned Complete dose escalation in the first quarter of 2019 CNGA3 7,000 Wholly Owned Complete dose escalation XLRP RPGR 20,000 Complete dose escalation in the first quarter of 2019 Optogenetics Unique ChR Multiple Indications Bionic Sight, LLC File IND in the first half of 2019 ALD ABCD1 -- Option Decision Discovery Programs -- Target Announcement 35

36 Company Highlights AGTC is developing genetic therapies for patients with inherited diseases. Treatments are precisely designed to meet the needs of each specific genetic disorder Clear Vision Become leader in ophthalmology gene therapy & leverage to otology Deep Expertise Extensive IP Portfolio Broad Pipeline In vector selection, design, manufacturing and delivery >100 patents/applications covering genes, capsids, process, delivery Multiple opportunities to provide long-term value to patients Key Partnership Broad collaboration with Biogen for multiple indications 36

37 Visionary Science for Life Changing Cures