information: Publication of results in a medical journal
Announcement: publication of results in The Lancet
Company: Spark Therapeutics (USA - PA)
Product: voretigene neparvovec - SPK-RPE65
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 dystrophy (IRD) caused by RPE65 mutations - Leber Congenital Amaurosis (LCA) 2
area: Rare diseases - Genetic diseases - Ophtalmological diseases
details: The study is a Phase 3, open-label, randomized controlled trial of gene therapy intervention by subretinal administration of AAV2-hRPE65v2. At least twenty-four subjects, three years of age or older, will be recruited. The intervention group will receive AAV2-hRPE65v2 vector at either The Children's Hospital of Philadelphia or University of Iowa to determine if it improves visual and retinal function in individuals with LCA2. (NCT00999609)
- • On July 13, 2017, Spark Therapeutics announced that The Lancet has published Phase 3 clinical trial data of voretigene neparvovec for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal disease ("Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in subjects with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label Phase 3 trial"). In the trial, voretigene neparvovec improved functional vision, light sensitivity and visual field in study participants with RPE65-mediated IRD. A natural history study has shown that people with this IRD eventually progress to complete blindness.
- The publication presents the results of the Phase 3 trial, including the intent-to-treat population of all randomized subjects, through the one-year timepoint. Results showed a statistically significant and clinically meaningful difference between intervention (n=21) and control participants (n=10) at one year, per the clinical trial's primary endpoint, mean bilateral multi-luminance mobility testing (MLMT) change score (difference of 1.6; 95% CI, 0.72, 2.41; p=0.0013). Participants maintained functional gains observed 30 days post-administration at the one-year primary endpoint. 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, for example, a moonless summer night) to 400 lux (equivalent to, for example, an office environment).
- Improvements seen in MLMT were accompanied by statistically significant improvements in two secondary endpoints, including full-field light sensitivity threshold (FST) testing averaged over both eyes (p=0.0004). A third secondary endpoint, the change in visual acuity averaged over both eyes, was not statistically significant between intervention and control participants (p=0.17). An additional protocol-specified endpoint using the Goldmann III4e test stimulus to measure the visual field area of the original intervention group showed significant improvement (p=0.0059), nearly doubling at year one, while a slight decrease was observed in the control group over the same time period.
- No serious adverse events (SAEs) associated with voretigene neparvovec or deleterious immune responses were observed. Most ocular events were mild in severity with the most common ocular adverse events (AEs) being transient mild ocular inflammation, transient elevated intraocular pressure, cataracts and intraoperative retinal tears. Two participants in the intervention group, one with a pre-existing complex seizure disorder and another who experienced complications from oral surgery, had SAEs unrelated to study participation.
- • On October 14, 2016, Spark Therapeutics announced that Principal Investigator Albert M. Maguire, M.D., professor of ophthalmology at the Perelman School of Medicine of the University of Pennsylvania, presented one-year efficacy data from the crossover group and two-year durability data from the original intervention group for the Phase 3 trial of voretigene neparvovec (formerly SPK-RPE65) during Retina Subspecialty Day at the American Academy of Ophthalmology 2016 Annual Meeting in Chicago. The crossover group consists of nine subjects who, after one year of undergoing the same retinal and visual function testing as the original intervention group, elected to cross over and receive voretigene neparvovec in both eyes. One year after administration, the mean improvement among all nine subjects, as measured by the primary endpoint, a multi-luminance mobility test (MLMT), was 2.1 lux levels. Dr. Maguire also presented data that showed that the original intervention group subjects who received voretigene neparvovec (n=20) maintained improvement demonstrated at year one, as measured in MLMT and full-field light sensitivity threshold (FST) testing, for at least two years. The mean MLMT improvement of 1.9 lux levels was sustained after two years. The more than 100-fold average improvement in FST testing observed in the original intervention group at one year similarly was maintained through at least two years.Visual Field Data Show Statistical Significance Across Two Measures: For the first time, Dr. Maguire presented data on visual field (VF), another protocol-specified endpoint in the Phase 3 trial of voretigene neparvovec. VF is total field area of a person’s retinal sensitivity, or vision, that extends from a central fixation point to the periphery. Data collected using two VF measures showed statistically significant responses.
- Using the Goldmann III4e test stimulus, the intervention group saw a mean increase of 302.1 sum total degrees from baseline at year one, while the control group saw a mean decrease of 76.7 sum total degrees, resulting in a difference of 387.7 sum total degrees (nominal p=0.006). Additionally, using the Humphrey macula threshold measure, the visual field increased by a mean of 7.7 decibels (dB) from baseline for the intervention group, compared to a decrease of 0.2 dB for the control group, resulting in a difference of 7.9 dB (nominal p<0.001).
- • On August 10, 2016, Spark Therapeutics announced new data from the continuation of the Phase 3 trial of voretigene neparvovec (SPK-RPE65) for the potential treatment of inherited retinal disease (IRD) caused by mutations in the RPE65 gene. In the pivotal portion of the Phase 3 trial, voretigene neparvovec was administered to both eyes of 20 subjects in the modified intent to treat (mITT) intervention group, and there were nine additional subjects in the mITT control group. The mITT population (n = 29) includes all subjects that received voretigene neparvovec, either in the randomized controlled portion of the Phase 3 trial (301 study) or in the crossover portion of the Phase 3 trial (302 study). In the fourth quarter of 2015, the Company announced statistically and clinically significant improvement in the intervention group compared to the control group on the primary endpoint, change in bilateral mobility testing (MT) between baseline and one year. The first two secondary endpoints – full-field light sensitivity threshold testing (FST) for white light and MT for the assigned first eye – also showed highly statistically significant improvement. A third secondary endpoint, visual acuity, did not meet statistical significance.
- Expanded Phase 3 dataset at one-year reaffirms earlier trial results: After one year of undergoing the same retinal and visual function testing as the intervention subjects in the 301 study, all nine subjects in the mITT control group elected to cross over and receive voretigene neparvovec in both eyes.
- One year after administration, eight of the nine subjects in the 302 study improved, as measured by MT, with all eight responders being able to navigate the course at 1 lux, demonstrating the maximum improvement measurable. The mean improvement among all nine subjects in the 302 study was 2.1 lux levels, compared to the 1.9 lux level improvement seen in the group of 20 subjects. On FST testing, eight of the nine subjects improved, with an average improvement of nearly 200-fold, compared to the more than 100-fold improvement average seen in the 301 study subjects. Subjects in the 302 study demonstrated an average visual acuity improvement of 4.5 letters, averaged across both eyes, compared to an average improvement of eight letters by the same analysis in the 301 study.
- The safety profile of the 302 study was largely consistent with prior studies. There were no product candidate-related serious adverse events, or SAEs, however, there was one SAE, in one eye, that was determined to be related to the surgical procedure rather than voretigene neparvovec. This subject exhibited a reduction in visual acuity after the surgical procedure and did not return to baseline, however, this subject improved on the MT and also exhibited a gain in FST.
- Durability of benefit out at least two years in Phase 3 cohort: As announced on July 1, 2016, Spark Therapeutics had positive follow-up data from the second Phase 1 trial of voretigene neparvovec, referred to as the 102 study. This study used the same dose, and assessed essentially the same endpoints, as the Phase 3 study. These data, published in The Lancet, provide insight into the long-term safety, as well as stable and persistent benefit, observed over at least 3 years after administration of voretigene neparvovec in the contralateral eye, or the second, previously uninjected eye.
- Now Spark Therapeutics reported that durability of benefit, as measured by change in MT and FST, was maintained for at least 2 years in the mITT intervention group (n = 20) of the 301 study. The mean durability of benefit was sustained at 1.9 lux levels after two years, compared with the improvement of 1.9 lux levels after one year. The more than 100-fold improvement average seen in the original intervention group at one year similarly was maintained through at least two years.