Date: 2017-01-09
Type of
information: Results
phase: 1
Announcement: results
Company: Spark Therapeutics (USA - PA)
Product: voretigene neparvovec - SPK-RPE65
Action
mechanism: gene therapy. Voretigene neparvovec is a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2). Voretigene neparvovec has received both breakthrough therapy and orphan product designations from the FDA, as well as orphan product designation from the European Medicines Agency.
Disease: inherited retinal disease (IRD) caused by biallelic RPE65 mutations.
Therapeutic
area: Rare diseases - Genetic diseases - Ophtalmological diseases
Country: USA
Trial
details: The study is a follow-on to a Phase 1 dose-escalation and safety study (closed to enrollment as of June 2009). Up to twelve adults and children with molecular diagnosis of LCA2, who have participated in the earlier Phase 1 study, and who meet all study eligibility criteria, will receive AAV2-hRPE65v2 vector in the previously uninjected, contralateral eye to evaluate the safety of bilateral, sequential subretinal administration of AAV2-hRPE65v2. One dose of AAV2-hRPE65v2 in a total volume of 300 microL was subretinally injected into the contralateral, previously uninjected, eyes of 11 children and adults (aged 11–46 years at second administration) with inherited retinal dystrophy caused by RPE65 mutations, 1·71–4·58 years after the initial subretinal injection. (NCT01208389)
Latest
news:
- ,• On January 9, 2017, Spark Therapeutics announced new four-year data from a Phase 1 clinical trial and natural history study findings that enhance the understanding of investigational voretigene neparvovec for Inherited Retinal Disease (IRD) caused by biallelic RPE65 mutations.
- Mean improvements in functional vision and visual function were maintained through four years as measured by both the multi-luminance mobility test (MLMT) and full field light sensitivity threshold (FST) testing in a Phase 1 clinical trial in which voretigene neparvovec was administered to the contralateral, or second previously uninjected, eye. This cohort of participants (n = 8) received the same dose of voretigene neparvovec that was administered in the Phase 3 trial and would have met the Phase 3 eligibility criteria.
- MLMT evaluates functional vision by documenting the participants' ability to navigate a mobility course under a variety of specified light levels ranging from one lux (equivalent to a moonless summer night) to 400 lux (equivalent to an office environment). Results after four years showed a sustained average durability of effect across the Phase 1 clinical trial cohort, with a mean lux score change of 2.4 ± 0.46 at year four, compared to 2.6 ± 0.56 at year one.
- Average improvement in FST testing, which reflects underlying physiological function by measuring light sensitivity of the entire visual field, were similarly maintained. Results after four years continued to show a more than 100-fold average improvement in the Phase 1 clinical trial cohort, with light sensitivity measures of -3.82 ± 0.98 log10(candela.m/sec2) at year four, compared to -4.27 ± 1.21 log10(candela.m/sec2) at year one.
- Safety results in the clinical program have been consistent to date. No serious adverse events (SAEs) associated with voretigene neparvovec or deleterious immune responses have been observed. There was one SAE in one eye of a Phase 3 participant related to the surgical procedure, rather than to the product candidate. The participant exhibited foveal thinning and a sustained reduction in visual acuity (VA) over the first year of follow-up, but did show an improvement on the MLMT and a gain in FST testing. An additional SAE occurred in one eye of a Phase 1 participant; in this case, the treatment for bacterial endophthalmitis led to elevated intraocular pressure and subsequent optic atrophy.
- Natural History Study Shows Early, Profound Vision Loss with Continuous Decline in Patients with IRD Caused by RPE65 Gene Mutations: To bolster knowledge of the natural disease course of IRD due to RPE65 gene mutations and enhance understanding of the clinical significance of the voretigene neparvovec clinical trial results in this disease, Spark Therapeutics conducted a retrospective natural history study (n = 70). The data showed that biallelic RPE65 mutations are characterized by a continuous decline in visual function beginning in early childhood. The study was a retrospective chart review of longitudinal ocular history and visual function testing data (primarily VA and visual field (VF)), designed to describe the natural course of degeneration in individuals with confirmed biallelic mutations in the RPE65 gene. Participants in the study, enrolled from seven centers worldwide, all had confirmed biallelic RPE65 mutations and were followed at the centers for up to 33 years (mean duration of observation time was 7.3 years).
- In the natural history study cohort, a statistically significant effect of age on VA (p < 0.001) was observed. While there was individual variability, the rate of decline in VA appeared to accelerate later in the course of disease, presumably corresponding to continued irreparable damage to retinal pigment epithelium and photoreceptor cells. The majority of participants in the natural history cohort were legally blind (VA of 20/200 or worse in the better-seeing eye) by the time they were 18 years of age. There also was a correlation between advancing age and declining VF that was statistically significant (p < 0.0001 for both the III4e and V4e Goldmann test stimuli). As with VA, progressive VF loss adversely impacts functional vision, with the natural history study cohort experiencing a rapid decline in VF during the first and second decades of life.
- • On July 1, 2016, Spark Therapeutics announced the publication in The Lancet of long-term data from a Phase 1 trial of voretigene neparvovec (SPK-RPE65) for the treatment of inherited retinal disease (IRD) caused by mutations in the RPE65 gene. The publication details safety and efficacy results in 11 subjects that underwent administration of voretigene neparvovec to the contralateral, or second previously uninjected eye. All subjects participated in a prior Phase 1 study in which the worse of the two eyes had been injected with voretigene neparvovec. The publication is the first to report full cohort results of injection of the second eye with an AAV vector, and demonstrated the overall safety of the approach. In addition, the data showed long-term stable and persistent benefit for at least 3 years, with observation ongoing, in retinal and visual function and functional vision after voretigene neparvovec injection. During the third quarter, Spark plans to present efficacy analyses of both the initial one-year post-administration data from the crossover subjects (n=9) and the two-year follow-up data from the intervention subjects (n=20) in the pivotal Phase 3 trial. In addition, during the fourth quarter, Spark plans to present efficacy analyses on the four-year follow-up data from the relevant cohort of the second Phase 1 trial (n=8). Spark has initiated a rolling submission of the BLA with the FDA on voretigene neparvovec.
Is
general: Yes
