Clinical Development and Regulatory Review for LUXTURNA TM (voretigene neparvovec-rzyl), First Gene Therapy Approved for a Genetic Disease in the US

Transcription

1 Clinical Development and Regulatory Review for LUXTURNA TM (voretigene neparvovec-rzyl), First Gene Therapy Approved for a Genetic Disease in the US LUXTURNA is an adeno-associated virus vector based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation associated retinal dystrophy. Patients must have viable retinal cells as determined by the treating physician(s). Jim Wang, PhD Head of Regulatory Affairs Strategy, Spark Therapeutics Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA P-RPE65-US

2 Introduction Review of the Disease State and Mechanism of Action Gene Therapy for Biallelic RPE65 Mutation Associated Retinal Dystrophy Review of Clinical Development Program Overview of Regulatory Interactions for LUXTURNA (voretigene neparvovec-rzyl) Summary of Challenges and Strategies for Orphan Drug Development 2

3 How Vision Works Role of photoreceptors RODS (vision in low light) Light PERIPHERAL VISION PERIPHERAL VISION Further bending of light and fine focusing is done by the lens CENTRAL VISION PERIPHERAL VISION Light is focused sharply on the macula of the retina Light from an object is bent by the cornea PERIPHERAL VISION PERIPHERAL VISION CONES (color vision) 3

4 Role of RPE65 in the Visual Cycle The RPE65 gene encodes a protein, RPE65 1,2 RPE65 is a critical component in the visual cycle RPE65 is necessary for vitamin A metabolism in photoreceptor cells Mutations in the RPE65 gene lead to vision loss due to loss of function (or death) of RPE cells and eventual degeneration of photoreceptors 2,3 Rod and Cone Photoreceptor Cells Target Location Retinal Pigment Epithelium (RPE) Cells Visual Cycle Light 11-cis-retinal all-trans-retinal RDH12/8 RDH5 ABCA4 11-cis-retinol all-trans-retinol RPE65 LRAT retinyl ester 4

5 Biallelic RPE65 Mutation Associated Retinal Dystrophy Age at onset Infancy Nyctalopia Flat/severely reduced ERG Young adulthood Adulthood Signs and symptoms Nystagmus Failure to fix and follow Light-seeking behavior Peripheral field loss Clinical diagnosis Leber congenital amaurosis Retinitis pigmentosa SECORD, EOSRD, ECRP Confirmatory test Genetic testing SECORD, severe early childhood-onset retinal dystrophy; EOSRD early-onset severe retinal dystrophy; ECRP, early childhood-onset retinitis pigmentosa. 5

6 RPE65-Mediated IRD Vision Loss Progression Nighttime NORMAL VISION 6 Images presented for illustrative purposes only

7 RPE65-Mediated IRD Vision Loss Progression Nighttime DECREASED LIGHT SENSITIVITY 7 Images presented for illustrative purposes only

8 RPE65-Mediated IRD Vision Loss Progression Nighttime VISUAL FIELD LOSS 8 Images presented for illustrative purposes only

9 Understanding the Natural Disease History of Biallelic RPE65 Mutation Associated Retinal Dystrophy Mutation and Disease Prevalence Biallelic RPE65 mutation associated retinal dystrophy is an ultra-rare disease 1-9 LCA n=~335 RP n=~1430 Estimated prevalence: 1 in 200, individuals Disease progression Blindness Limited information available 22.5% 8.5% Non-RPE65 30% 2.0% Unknown 69% RPE65 68% Approximately 1000 to 2000 in the United States 9

10 RPE65 mutation associated retinal dystrophy Mutations in the RPE65 gene lead to disruption of the visual cycle, manifesting as retinal disease 1 Age of disease onset is variable, and presentation is heterogeneous 2,3 Complexity of disease signs and symptoms makes diagnosis challenging Genetic testing needed to confirm diagnosis Retrospective study of inherited retinal dystrophy patients with biallelic RPE65 mutations contributed to understanding of the natural history of disease 4,5 Patients with biallelic RPE65 mutation associated retinal dystrophy experienced gradual worsening of VA beginning around 15 to 20 years of age, subsequent rapid acceleration of the rate of VA loss after the age of 20, and VF constriction progressing gradually from the earliest available measurements in the first decade of life 4,5 1. LUXTURNA [package insert]. Philadelphia, PA; Spark Therapeutics, Inc American Academy of Ophthalmology (AAO). Clinical statement: recommendations on clinical assessment of patients with inherited retinal degenerations Accessed January 29, Stone EM, et al. Ophthalmology Sep;124(9): Chung DC et al. ARVO; May 1-5, 2016; Seattle, WA. 5. Reape KZ et al. ARVO; May 7-11, 2017; Baltimore, MD. 10

11 Gene Therapy for Biallelic RPE65 Mutation Associated Retinal Dystrophy Please see Important Safety Information Included in this presentation and Spark representative for NOT US Full FOR Prescribing DISSEMINATION Information for LUXTURNA INFORMATION ACCURATE AS OF DECEMBER 22,

12 Ocular Gene Therapy Research Viral vectors may be used as carriers Therapeutic gene packaged inside a viral vector for delivery into target cells AAV vector containing therapeutic gene DNA Nucleus Cell Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 12

13 RPE65 and AAV2 for Ocular Gene Therapy LUXTURNA (voretigene neparvovec-rzyl) Photoreceptor cell RDH5 RDH12/8 ABCA4 RPE65 LRAT RPE cell Viral vector is generated 1,2 LUXTURNA is a suspension of an adeno-associated virus vector based gene therapy for subretinal injection LUXTURNA is a live, nonreplicating adeno-associated virus serotype 2 which has been genetically modified to express the human RPE65 gene LUXTURNA is derived from naturally occurring adenoassociated virus using recombinant DNA techniques LUXTURNA for subretinal injection Transduction of RPE cells 2 Injection of LUXTURNA into the subretinal space results in transduction of some retinal pigment epithelial cells with a cdna encoding normal human RPE65 protein, thus providing the potential to restore the visual cycle 2 Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 13

14 Clinical Development of LUXTURNA (voretigene neparvovec-rzyl): a Gene Therapy for Biallelic RPE65 Mutation Associated Retinal Dystrophy Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 14

15 LUXTURNA (voretigene neparvovec-rzyl): Development History Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 15

16 LUXTURNA (voretigene neparvovec-rzyl): Select Dosage and Administration The recommended dose of LUXTURNA for each eye is 1.5 x vector genomes (vg), administered by subretinal injection in a total volume of 0.3 ml 1 LUXTURNA is administered via subretinal injection only 1 The individual administration to each eye takes place at an Ocular Gene Therapy Treatment Center and should be performed on separate days within a close interval, but no fewer than 6 days apart In the phase 3 study, bilateral subretinal injections of LUXTURNA were administered sequentially in 2 separate surgical procedures with an interval of 6 to 18 days Systemic oral corticosteroids equivalent to prednisone at 1 mg/kg/day (maximum of 40 mg/day) for a total of 7 days (starting 3 days before administration of LUXTURNA to first eye), and followed by a tapering dose during the next 10 days 1 The same regimen applies for administration to the second eye and replaces the taper for the first eye if the tapering is not completed 3 days prior to the administration to the second eye Prior to the administration of LUXTURNA, adequate anesthesia is given to patients 1 After a vitrectomy is complete, LUXTURNA is administered via subretinal injection 1 Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 16

17 LUXTURNA (voretigene neparvovec-rzyl): Phase 3 Trial Design Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 17

18 LUXTURNA (voretigene neparvovec-rzyl): MLMT Primary Efficacy Endpoint 1 Mobility course layout (1 of 12 standardized templates) 1-3 The 7 levels of illumination, referred to as lux levels, were chosen to represent lighting in everyday locations 2,3 MLMT Patients were observed while navigating a course with obstacles of varying height under different levels of illumination 1-3 After 40 minutes of dark adaptation, patients completed a configuration of the course with one eye patched, completed a new configuration with the other eye patched, and completed a third configuration using both eyes 1 This process was repeated until failing and passing light level thresholds were identified for each eyepatched condition 1 Patients were graded based on accuracy and speed 1 Passing was defined as completion of the course at the specified lux level with fewer than 4 errors and within 3 minutes 1 Lux levels To quantify patient performance over time, an MLMT score change was calculated by assigning score codes to each lux level 3 The score change is the difference between the score of the lowest lux level passed before treatment and 1 year after treatment 3 Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 18

19 MLMT: Validation Study Designed to characterize construct and content validity 26 normal-sighted, 28 inherited retinal dystrophy (IRD) Normal-sighted participants Baseline results consistent at 1 year 26 (100%) passed at lowest level (1 lux) IRD patients No improvements observed from baseline to 1 year 8 (28.5%) patients declined in performance over 1 year Chung DC, et al. Clin Exp Ophthalmol. July

20 LUXTURNA (voretigene neparvovec-rzyl): Full-Field Light Sensitivity Threshold Test Provides a physiological test of retinal function that is relevant to the visual deficits experienced by patients with inherited retinal dystrophy Measures the lowest illumination detectable over the entire visual field Sensitivity to light is measured over a >5 log unit range An algorithm calculates the minimum luminance at which the subject perceives light for each eye 40 min Dark adapted Eyes tested separately by eye patching Ganzfeld dome Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 20

21 LUXTURNA (voretigene neparvovec-rzyl): Phase 3 Results Efficacy Outcomes 1 MLMT score change for bilateral eyes, median (min, max) MLMT score change for first-treated eye, median (min, max) LUXTURNA (n=21) CONTROL (n=10) DIFFERENCE (LUXTURNA minus Control) P Value 2 (0, 4) 0 (-1, 2) (0, 4) 0 (-1, 1) Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 21

22 LUXTURNA (voretigene neparvovec-rzyl): Trial Participant MLMT Videos (Bilateral Testing) Baseline visit at 1 lux (Fail) 1-year visit after LUXTURNA administration at 1 lux (Pass) Representative of clinical trial participant with clinically meaningful score change (2 or greater) from baseline. Reference: Data on file. Spark Therapeutics, Inc Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 22

23 LUXTURNA (voretigene neparvovec-rzyl): Bilateral MLMT Time-Course over Two Years At year 1, the median bilatera; MLMT score change for participants treated with LUXTURNA was 2, while the control group had a median MLMT score change of 0 (P=0.001) 1,a Each box represents the middle 50% of distribution of MLMT score change. Vertical dotted lines represent additional 25% above and below the box. The horizontal bar within each box represents the median. The dot within each box represents the mean. The solid line connects the mean MLMT score changes over visits for the treatment group, including five visits during the first year and one visit at Year 2. The dotted line connects the mean MLMT score change over visits for the control group, including five visits during the first year without receiving LUXTURNA (voretigene neparvovec-rzyl), and four visits within the second year after crossover at Year 1 to receive LUXTURNA. 1 Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 23

24 LUXTURNA (voretigene neparvovec-rzyl): Additional Clinical Outcomes Analysis of white light FST testing showed statistically significant improvement from baseline to Year 1 in the LUXTURNA (voretigene neparvovec-rzyl) treatment group compared with the control group 1 The change in visual acuity from baseline to Year 1 was not significantly different between the LUXTURNA (voretigene neparvovec-rzyl) and control groups 1 Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 24

25 Safety Profile of LUXTURNA (voretigene neparvovec-rzyl) Important Safety Information Warnings and Precautions Endophthalmitis may occur following any intraocular surgical procedure or injection. Use proper aseptic injection technique when administering LUXTURNA, and monitor for and advise patients to report any signs or symptoms of infection or inflammation to permit early treatment of any infection. Permanent decline in visual acuity may occur following subretinal injection of LUXTURNA. Monitor patients for visual disturbances. Retinal abnormalities may occur during or following the subretinal injection of LUXTURNA, including macular holes, foveal thinning, loss of foveal function, foveal dehiscence, and retinal hemorrhage. Monitor and manage these retinal abnormalities appropriately. Do not administer LUXTURNA in the immediate vicinity of the fovea. Retinal abnormalities may occur during or following vitrectomy, including retinal tears, epiretinal membrane, or retinal detachment. Monitor patients during and following the injection to permit early treatment of these retinal abnormalities. Advise patients to report any signs or symptoms of retinal tears and/or detachment without delay. Increased intraocular pressure may occur after subretinal injection of LUXTURNA. Monitor and manage intraocular pressure appropriately. Expansion of intraocular air bubbles: instruct patients to avoid air travel, travel to high elevations or scuba diving until the air bubble formed following administration of LUXTURNA has completely dissipated from the eye. It may take one week or more following injection for the air bubble to dissipate. A change in altitude while the air bubble is still present can result in irreversible vision loss. Verify the dissipation of the air bubble through ophthalmic examination. Cataract: subretinal injection of LUXTURNA, especially vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression. 25

26 Safety Profile of LUXTURNA (voretigene neparvovec-rzyl) Adverse Reactions In clinical studies, ocular adverse reactions occurred in 66% of study participants (57% of injected eyes), and may have been related to LUXTURNA, the subretinal injection procedure, the concomitant use of corticosteroids, or a combination of these procedures and products. The most common adverse reactions (incidence 5% of study participants) were conjunctival hyperemia (22%), cataract (20%), increased intraocular pressure (15%), retinal tear (10%), dellen (thinning of the corneal stroma) (7%), macular hole (7%), subretinal deposits (7%), eye inflammation (5%), eye irritation (5%), eye pain (5%), and maculopathy (wrinkling on the surface of the macula) (5%). Immunogenicity Immune reactions and extra-ocular exposure to LUXTURNA in clinical studies were mild. No clinically significant cytotoxic T-cell response to either AAV2 or RPE65 has been observed. In clinical studies, the interval between the subretinal injections into the two eyes ranged from 7 to 14 days and 1.7 to 4.6 years. Study participants received systemic corticosteroids before and after subretinal injection of LUXTURNA to each eye, which may have decreased the potential immune reaction to either AAV2 or RPE65. Pediatric Use Treatment with LUXTURNA is not recommended for patients younger than 12 months of age, because the retinal cells are still undergoing cell proliferation, and LUXTURNA would potentially be diluted or lost during the cell proliferation. The safety and efficacy of LUXTURNA have been established in pediatric patients. There were no significant differences in safety between the different age subgroups Please see Spark representative for US Full Prescribing Information for LUXTURNA. AAV2, adeno-associated viral 2; RPE, retinal pigment epithelium. 26

27 LUXTURNA (voretigene neparvovec-rzyl): Ocular Adverse Reactions Ocular Adverse Reactions Following Treatment with LUXTURNA Adverse Reactions Subjects (n=41) Treated Eyes (n=81) Any ocular adverse reaction 27 (66%) 46 (57%) Conjunctival hyperemia 9 (22%) 9 (11%) Cataracts 8 (20%) 15 (19%) Increased intraocular pressure 6 (15%) 8 (10%) Retinal tear 4 (10%) 4 (5%) Dellen (thinning of the corneal stroma) 3 (7%) 3 (4%) Macular hole 3 (7%) 3 (4%) Subretinal deposits a 3 (7%) 3 (4%) Eye inflammation 2 (5%) 4 (5%) Eye irritation 2 (5%) 2 (2%) Eye pain 2 (5%) 2 (2%) Maculopathy (wrinkling on the surface of the macula) 2 (5%) 3 (4%) Foveal thinning and loss of foveal function 1 (2%) 2 (2%) Endophthalmitis 1 (2%) 1 (1%) Foveal dehiscence (separation of the retinal layers in the center of the macula) 1 (2%) 1 (1%) Retinal hemorrhage 1 (2%) 1 (1%) Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA 27

28 Regulatory Overview of LUXTURNA (voretigene neparvovec-rzyl) From Pre-IND through FDA approval and post marketing follow up Please see Important Safety Information Included in this presentation and Spark representative for US Full Prescribing Information for LUXTURNA

29 FDA Meetings and Interactions: Clinical Development Pre-IND August 2005 IND submission June 2007 Orphan Designation for treatment of LCA due to RPE65 mutations, June 2008 Phase 3 discussions- clinical development and primary endpoints EOP II/Pre-phase III, January 2009 FDA feedback on phase III protocol, January 2010 Meeting with FDA on Phase 3 design, September 2010 CBER Cellular, Tissue & Gene Therapies Advisory Committee June 2011 recommended novel endpoints for measuring functional vision Feedback from a number of groups within FDA (CBER, CDER, and CDRH) on phase 3 protocol and MLMT test, May

30 Agreement on Primary Endpoints: MLMT Multiple discussions with FDA throughout product development Clinically meaningful endpoint for patient population desired Suggested a measurement of subjects ability to perform vision-dependent ADL (activities of daily living) would be clinically meaningful Existing lab/community based evaluations for mobility testing did not incorporated a quantitative measure of light sensitivity Designed for use in pediatric and adult populations at 7 different light levels Navigate course independently and accurately within time limit Integrates input from VA, VF and light sensitivity FST Data on file. Spark Therapeutics, Inc. Chung DC, et al. Clin Exp Ophthalmol. July Russell S, et al. Lancet 2017; 390(10097):

31 FDA Meetings and Interactions: Pre- and Post-BLA submission FDA pre-bla meeting, March 2016 Orphan drug designation amendment to align with proposed indication, Nov 2016 Final rolling submission of BLA, May 2017 BLA filed with priority review and rare pediatric disease designation, July 2017 Mid-cycle review meeting, Sep 2017 FDA advisory committee meeting, Oct 12, 2017 Late cycle review meeting, Nov 2017 BLA Approval, Dec 19, 2017 Data on file. Spark Therapeutics, Inc. 31

32 Interaction with FDA on Alignment of Indication with Orphan Designation Orphan Designations Granted for: 1 Treatment of Leber congenital amaurosis (LCA) due to RPE65 mutations was granted on 24 June 2008 Treatment of Retinitis Pigmentosa due to autosomal recessive RPE65 gene mutations was granted on 18 March 2015 During the course of clinical development, classification of these disorders shifted away from clinical descriptors toward a molecular based diagnosis 2,3 Supporting an indication based on confirmation of genetic diagnosis and presence of vial retinal cells Discussed with FDA at the Pre-BLA meeting: 1 Final indication would be a review issue depending on the latest science with respect to disease classification, the population studied and improvement shown rather than clinical signs and symptoms. FDA recommended reaching out to Office of Orphan Products Development (OOPD) to seek clarification 1. Data on file. Spark Therapeutics, Inc. 2. American Academy of Ophthalmology (AAO). Clinical statement: recommendations on clinical assessment of patients with inherited retinal degenerations Accessed January 29, Stone EM, et al. Ophthalmology Sep;124(9):

33 Amendment to the Orphan Designation, Enabling Alignment with Proposed Indication Amendment submitted to the RP orphan designation, Aug 2017 RP is a different name for the same genetic disease, >20 clinical diagnoses due to mutations in RPE65 gene. MOA: recovery of biochemical activity of the RPE65 protein, and restoration of the visual cycle, by gene augmentation, is not dependent on the clinical diagnosis, but rather on the confirmed genetic diagnosis and the presence of sufficient viable retinal cells. As gene mutations are identified for more forms of inherited retinal disease, the classification is shifting from a clinical diagnosis to a genetic diagnosis. FDA OOPD granted amendment, Nov 2017: Treatment of Retinitis Pigmentosa treatment of Inherited Retinal Disease due to biallelic RPE65 mutations Data on file. Spark Therapeutics, Inc. 33

34 Approach in Managing and Characterizing the Potential Risks Only Administered at Ocular Gene Therapy Treatment Centers With expertise in IRDs and the ability to properly receive, store, and prepare the product Surgical and pharmacy training program and manuals Further characterize the risks via long term follow up study and safety registry study Risk management plan was discussed early with FDA and EMA during pre-submission meetings prior to submission of the BLA/MAA Data on file. Spark Therapeutics, Inc. 34

35 Activities to Monitor Long-Term Safety and Administration: Ongoing Follow-up Study All clinical trial patients enrolled in 15-year follow-up study Safety Assessments Annual history Physical exam Ophthalmic exam Clinical labs Efficacy Assessments MLMT FST Visual acuity Visual function questionnaire Visual field Data on file. Spark Therapeutics, Inc. 35

36 Activities to Monitor Long-Term Safety: Post-Approval Registry Prospective, observational safety registry All patients treated in the first 5 years 5 years of monitoring Collect and assess ocular AEs related to product or procedure Collect and assess AEs potentially related to gene therapy Yearly ophthalmic examination data will be collected as well Data on file. Spark Therapeutics, Inc. 36

37 FDA Pharmacovigilance BLA Memorandum Review of safety data does not substantiate a need for a REMS, a safety PMR study, or a safety PMC study: Administration of the product is considered within the scope of a fellowship-trained retina specialist. LUXTURNA (voretigene neparvovec-rzyl) is distributed only through specially trained centers. This plan can be conducted on a voluntary basis by the applicant. The applicant is voluntarily conducting a 15-year follow-up study of the clinical trial patients and a registry with a 5- year follow-up on patients post marketing. Data on file. Spark Therapeutics, Inc. 37

38 Review and Agreement on Product Labeling Proactive interaction with FDA in the alignment of proposed indication with orphan designation prior to BLA submission Four-letter suffix is required for new nonproprietary biologics as per January 2017 FDA Guidance for Industry Approached FDA early to agree on mockup texts on carton and product vial labels to minimize delay of product launch post approval Very often space is very limited and allow only essential information Be prepared for intense labeling negotiations prior to approval Need rapid alignment and response Provide good justification to substantiate view point Ready to present alternative proposal if agreement cannot be reached Data on file. Spark Therapeutics, Inc. Nonproprietary Naming of Biological Products Guidance for Industry. U.S. Department of Health and Human Services. Food and Drug Administration Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). January

39 Summary of Challenges/Strategies for Orphan Drug Development Few patients available for study, chronic, progressive, serious, life-threatening with unmet medical need Natural history incompletely understood: conduct natural history study earlier on to understand progression of the disease Specific endpoints, outcome measures, tools, instruments and biomarkers usually lacking: engage FDA and EMA early on and throughout development process esp. on acceptable endpoints Often, pediatric population Target tissue delivery (e.g., ocular and CNS): optimize delivery tools/techniques early on and think ahead how this could be implemented in the real world after approval 39

40 We don t follow footsteps. We create the path. Please see Spark representative for US Full Prescribing Information for LUXTURNA 40