Horizon Scanning Research January 2016 & Intelligence Centre SPK-RPE65 gene therapy for inherited retinal dystrophies due to mutations in the RPE65 gene LAY SUMMARY Inherited retinal dystrophies are a group of eye diseases caused by one or more abnormal genes (or ‘mutations’). These diseases all eventually lead to blindness, and at the moment there is no treatment This briefing is that either slows this down or improves sight after it has been lost. based on information available at the time Mutations in the RPE65 gene is one cause of inherited retinal of research and a dystrophies, particularly a condition called Leber’s congenital limited literature amaurosis, which leads to blindness in childhood. SPK-RPE65 is a search. It is not gene therapy that could treat mutations in the RPE65 gene, and may intended to be a improve the sight of people with an inherited retinal dystrophy caused definitive statement by these mutations. SPK-RPE65 is injected directly into the eye by a on the safety, surgeon. efficacy or effectiveness of the SPK-RPE65 is currently being studied to see how well it works and health technology whether it is safe to use. If SPK-RPE65 is licensed for use in the UK, it covered and should will be the first treatment available for people with this type of inherited not be used for retinal dystrophy. commercial purposes or commissioning NIHR HSRIC ID: 10177 without additional information. This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre TARGET GROUP • Inherited retinal dystrophies (IRDs) due to mutations in the RPE65 gene. TECHNOLOGY DESCRIPTION SPK-RPE65 (AAv2-hRPE65v2) is a gene therapy that addresses specific forms of inherited retinal dystrophy caused by mutations in the RPE65 gene. The therapy utilises an adeno- associated viral vector (AAV) to deliver the functional gene for human RPE65 to the retinal pigment epithelium during a surgical procedure. In clinical trials, SPK-RPE65 was administered subretinally at 1.5x1011 vector genomes in 300µl volume per eye to both eyes via surgical procedures on separate days. SPK-RPE65 does not currently have Marketing Authorisation in the EU for any indication. INNOVATION and/or ADVANTAGES If licensed, SPK-RPE65 will provide an additional, potentially sight improving treatment option for this patient group, for whom there are currently no effective treatments available. DEVELOPER Spark Therapeutics. AVAILABILITY, LAUNCH OR MARKETING SPK-RPE65 is a designated orphan drug in the EU and USA. In phase III clinical trials. PATIENT GROUP BACKGROUND IRDs are a group of blinding eye diseases recognised to be caused by hundreds of different gene defects, mainly affecting photoreceptor cells and the retinal pigment epithelium (RPE)1. RPE65 is an abundant protein in the RPE2 and is critical for the regeneration of the visual pigment necessary for both rod and cone-mediated vision3. Mutations in the RPE65 gene cause Leber’s congenital amaurosis (LCA) and other forms of autosomal recessive retinitis pigmentosa which are associated with early onset-blindness3. Retinitis pigmentosa is characterised by night blindness, often starting in adolescence, followed by progressive loss of peripheral vision and subsequent loss of central vision4. LCA usually becomes evident during the first year of life and the condition is characterised by severely reduced visual acuity or blindness5,6. Symptoms of LCA include sluggish pupillary responses, roving eye movement, photophobia, far-sightedness, nystagmus, and convergent strabismus (squint) depending on the genetic cause6. Affected children may also poke, press and rub their eyes with a knuckle or finger, which may contribute to the deep-set eyes and keratoconus (cone- shaped cornea) which are associated with this condition7,8. Of all the retinal dystrophies, LCA has the earliest age of onset and can be the most severe7. 2 Horizon Scanning Research & Intelligence Centre NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: • National Service Framework for long-term conditions (2005). • NHS England. 2013/14 NHS Standard Contract for medical genetics (all ages). E01/S/a. CLINICAL NEED and BURDEN OF DISEASE There are many different IRDs, and more than 190 genes have been identified as the cause of various forms of IRD4. Retinitis pigmentosa is the most common form, accounting for around 50% of IRDs4, with a worldwide prevalence of 1 in 4,000 births9. Mutations in the RPE65 gene account for approximately 2% of cases of recessive retinitis pigmentosa3, as well as around 6-16% of cases of LCA7,10. The prevalence of LCA is estimated to be 2-3 per 100,000 births7. It is the most common cause of inherited blindness in childhood, representing more than 5% of all IRDs7 and 20% of blindness in school age children6. In 2014-15, there were 83 hospital admissions in England due to IRDs (ICD-10 H35.5) accounting for 84 finished consultant episodes and 21 bed days11. The population likely to be eligible to receive SPK-RPE65 could not be estimated from available published sources. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • No relevant guidance identified. Other Guidance • Monaciano Symposium. Advancing therapeutic strategies for inherited retinal degeneration: Recommendations from the Monciano Symposium. 201512. CURRENT TREATMENT OPTIONS There are currently no curative or disease modifying treatments available for IRDs, including retinitis pigmentosa and LCA1,13. Management is focused on accurate diagnosis, specialised genetic counselling, strategies to improve the use of residual vision, social and educational support, and is best provided as part of specialised multidisciplinary services13. Treatment options are limited and focus on visual rehabilitation, including the use of low vision aids, specialised computer software and mobility training12,13. EFFICACY and SAFETY Trial NCT00999609, AAV2- NCT01208389, AAV2- NCT00516477, AAV2- hRPE65v2-301; adults and hRPE65v2-102, 10- hRPE65v2-101, 2006-6- children aged ≥3 years; 007752; adults and 4787; adults and children SPK-RPE65 vs no children aged ≥8 years; aged ≥8 years; SPK- intervention; phase III. SPK-RPE65; phase I/II. RPE65; phase I. Sponsor Spark Therapeutics. Spark Therapeutics. Spark Therapeutics. 3 Horizon Scanning Research & Intelligence Centre Status Ongoing. Ongoing. Ongoing. Source of Trial registry14, press Trial registry16, Publication17, trial information release15, manufacturer. manufacturer. registry18, manufacturer. Location USA. USA. USA. Design Randomised, controlled. Non-randomised, Non-randomised, uncontrolled. uncontrolled. Participants n=31 (planned); aged 4-44 n=11 (planned); aged ≥8 n=12 (planned); aged ≥8 years; LCA due to RPE65 years; LCA due to RPE65 years; LCA due to RPE65 mutation; sufficient viable mutation; sufficient viable mutation; sufficient viable retinal cells; visual acuity retinal cells; visual acuity ≥ retinal cells visual acuity ≤ <20/60 (both eyes) and/or light perception; 20/60 or visual field <20 visual field <20 degrees participated in study degrees in the eye to be (both eyes). NCT00516477. injected. Schedule Randomised to SPK- All participants receive All participants receive RPE65, 1.5x1011 vector SPK-RPE65, 1.5x1011 SPK-RPE65 via subretinal genomes per eye to both vector genomes injection to one eye with eyes via surgical subretinally to the dose escalation to the next procedures on separate contralateral, previously cohort dependent on days; or no intervention. uninjected eye. safety assessment at least Control group cross over 4 weeks following the and receive active injection. treatment after 1 year. Follow-up Active treatment for 1 year; 15 years follow-up. 5 years follow-up. 15 years follow-up. Primary Mobility testing change Safety and tolerability. Safety and tolerability. outcome/s score, bilateral. Secondary Full field sensitivity testing; Visual acuity; visual field; No quality of life measures outcome/s visual acuity; visual/retinal pupillary light response; included in trial outcomes. function; ophthalmic and mobility testing; full-field physical examinations; light threshold sensitivity immunology studies; testing; contrast sensitivity. safety; visual/retinal No quality of life measures function; ophthalmic included in trial outcomes. examinations; physical examinations; immunology studies; safety; visual function questionnaire; orientations and mobility assessments. Key results Compared to the control - The amplitude of pupillary group, SPK-RPE65 constriction and the demonstrated improved constriction velocity were functional vision measured increased in the treated by change in bilateral eye compared to the mobility testing (p=0.001), untreated eye at 1 year full-field light sensitivity and 3 years, threshold testing demonstrating stability of (p<0.001), and the mobility improved pupillary light test change score for the reflexes. first injected eye (p=0.001). Visual acuity did not show statistically significant evidence of benefit (p=0.17). The intervention subjects in the modified intention-to-treat efficacy analysis population achieved a mean improvement of 4 Horizon Scanning Research & Intelligence Centre approximately 2 lines (9.0 letters averaged across both eyes) on the