Spark Therapeutics Presents Three Post-hoc Analyses from Phase 3 Clinical Trial of LUXTURNA® (voretigene neparvovec-rzyl) at American Academy of Ophthalmology Annual Meeting

Use of different measurement for best-corrected visual acuity of participants in the Phase 3 clinical trial of LUXTURNA achieved statistically significant improvement versus control group

Mutation subtype analysis reveals no correlation between mutation variants and treatment response or adverse events associated with LUXTURNA

Analysis of full-field light sensitivity threshold (FST) testing data suggest LUXTURNA may improve both rod and cone function in patients with biallelic RPE65 mutation-associated inherited retinal disease (IRD)

PHILADELPHIA, Oct. 29, 2018 (GLOBE NEWSWIRE) -- Spark Therapeutics (NASDAQ: ONCE), a fully integrated, commercial gene therapy company dedicated to challenging the inevitability of genetic disease, today announced findings from three post-hoc analyses of data from the Phase 3 clinical trial of LUXTURNA® (voretigene neparvovec-rzyl) at the American Academy of Ophthalmology Annual Meeting in Chicago. LUXTURNA is a one-time gene therapy for the treatment of patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations and viable retinal cells. One of these analyses will be the subject of the oral presentation, “Visual Acuity Outcomes in the Voretigene Neparvovec Phase 3 Trial” today at 3:51pm CT in room S405 at McCormick Place in Chicago.

In the Phase 3 clinical trial of LUXTURNA, visual acuity was measured using a scale adapted from the Holladay method, which assigns LogMAR values for off-chart vision measurements. Best-corrected (with optimal glasses/contact lens prescription) visual acuity improvement averaged over both eyes for participants in the intervention group was not statistically significant as compared to the control group (p=0.17) at year one. In this post-hoc analysis, visual acuity data were revisited using the Lange method, which is a less conservative off-chart vision scale when quantifying the difference between counting fingers and hand motions. Results at year one using this method showed a statistically significant improvement from baseline versus the control group in best-corrected visual acuity averaged over both eyes (nominal p<0.05).

No adverse events associated with a reduction in visual acuity have been reported across the LUXTURNA clinical development program. In the post-marketing setting, one adverse event of reduced visual acuity has been reported within the immediate post-operative period following administration. It was considered non-serious and is reported to be resolving.

“These data further deepen our understanding of the biology of RPE65 mutation-associated inherited retinal disease and the Phase 3 clinical trial of LUXTURNA,” said Katherine A. High, M.D., president and head of research & development at Spark Therapeutics. “An important component of clinical research is to complete additional analyses on data to gain further insight into the current understanding of the science. This is particularly important in gene therapy, where there is the potential to restore function in the setting of previously untreatable diseases. We look forward to our continued engagement with the ophthalmology clinical and research communities as a leader in gene therapy research.”

Spark Therapeutics also presented two posters at the meeting. One explored potential correlations between mutation subtype and baseline visual function, response to LUXTURNA treatment and adverse events. Among the 29 participants who received LUXTURNA in the Phase 3 clinical trial, 25 unique genotypes were reported. For this post-hoc analysis, the mutations were characterized into subtypes based on both the mutation type and the likeliness of pathogenicity. No correlations were found between RPE65 mutation subtype and baseline visual function, treatment response or adverse events associated with administration.

The second poster reports an analysis suggesting that administration of LUXTURNA resulted in improvements in the function of retinal cone cells, one of the two primary cell types supporting visual function in the retina (in addition to the other primary cell type, rod cells). Cone cells are responsible for sharpness and color vision, while rod cells are responsible for light sensitivity and peripheral vision. RPE65 mutation-associated inherited retinal disease has been understood to be primarily a rod-mediated disease. Without the properly functioning protein encoded by the RPE65 gene, the visual cycle is disrupted with an inability to regenerate visual pigment, which leads to the accumulation of toxic materials and byproducts, particularly compromising light capture in rod cells, which lack another process for regenerating visual pigment.

Mean values averaged over both eyes for white light FST testing that assesses rod function, blue light FST testing that assesses rod and cone function and red light FST testing that assesses cone function all demonstrated statistically significant improvements from baseline versus the control group at year one (p<0.001, nominal p=0.002 and nominal p<0.001, respectively). The improvements in rods were greater than in cones. This analysis provides scientific support for why some patients may experience improvement in cone function including color and sharpness of vision in addition to improvement in light sensitivity and peripheral vision after treatment with LUXTURNA.

Indication and Important Safety Information
LUXTURNA® (voretigene neparvovec-rzyl) 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 physicians.

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.

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. 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 the full U.S. Prescribing Information for LUXTURNA here.

Clinical Trial Overview of LUXTURNA (voretigene neparvovec-rzyl)
The safety and efficacy of LUXTURNA were assessed in one open-label, dose-exploration Phase 1 safety study (n=12), a second Phase 1 follow-on study to establish the safety of injection of the contralateral eye (n = 11) and one open-label, randomized, controlled Phase 3 efficacy and safety study (n=31) in pediatric and adult participants (range 4 to 44 years) with biallelic RPE65 mutation-associated retinal dystrophy and sufficient viable retinal cells.

Of the 31 participants enrolled in the Phase 3 study, 21 were randomized to receive subretinal injection of LUXTURNA and 10 were randomized to the control group. One participant in the intervention group discontinued from the study prior to treatment and one participant in the control group withdrew consent and was discontinued from the study. All nine participants randomized to the control group elected to crossover and receive LUXTURNA after one year of observation. All participants in these studies continue to be followed for long-term safety and efficacy. LUXTURNA Phase 3 clinical trial data, including data from the intervention group of all randomized participants through the one-year time point has been previously reported in (The Lancet).

The efficacy of LUXTURNA in the Phase 3 study was established based on the multi-luminance mobility test (MLMT) score change from baseline to one year. MLMT was designed to measure changes in functional vision as assessed by the ability of a participant to navigate a course accurately and at a reasonable pace at seven different levels of illumination, ranging from 400 lux (corresponding to a brightly lit office) to one lux (corresponding to a moonless summer night). Each light level was assigned a score ranging from zero to six, with a higher score indicating that a participant could pass MLMT at a lower light level. A score of negative one was assigned to participants who could not pass MLMT at a light level of 400 lux. MLMT score change was defined as the difference between the score at baseline and the score at one year with a positive score change indicating that a participant was able to complete MLMT at a lower light level. Additional clinical outcomes included white light full-field light sensitivity threshold (FST) testing and visual acuity.

LUXTURNA Phase 3 clinical study results showed a statistically significant difference between the intervention group (n=21) and control participants (n=10) at one year in median bilateral MLMT score change (intervention minus control group difference of 2; p=0.001) and median first-treated eye MLMT score change (intervention minus control group difference of 2; p=0.003). After crossing over to receive LUXTURNA, participants in the control group showed a similar response to those in the intervention group. The median bilateral MLMT score change of two was observed for the intervention group at the 30-day timepoint. This change score has been sustained for at least three years for the original intervention group and at least two years in the crossover group in the Phase 3 clinical study. In addition, participants who received LUXTURNA showed a statistically significant improvement from baseline to one year in white light FST in the intervention group compared to the control group. The change in visual acuity from baseline to one year was not significantly different between the intervention and control participants.

The U.S. Prescribing Information for LUXTURNA includes the following Warnings and Precautions: endophthalmitis; permanent decline in visual acuity; retinal abnormalities; increased intraocular pressure; expansion of intraocular air bubbles; and cataract. The most common adverse reactions (incidence ≥ 5%) were conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), macular hole, subretinal deposits, eye inflammation, eye irritation, eye pain and maculopathy (wrinkling on the surface of the macula).

About Spark Therapeutics
At Spark Therapeutics, a fully integrated, commercial company committed to discovering, developing and delivering gene therapies, we challenge the inevitability of genetic diseases, including blindness, hemophilia, lysosomal storage disorders and neurodegenerative diseases. We have successfully applied our technology in the first FDA-approved gene therapy in the U.S. for a genetic disease, and currently have three programs in clinical trials, including product candidates that have shown promising early results in patients with hemophilia. At Spark, we see the path to a world where no life is limited by genetic disease. For more information, visit www.sparktx.com, and follow us on Twitter and LinkedIn.

Cautionary note on forward-looking statements
This release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the company's product LUXTURNA™ (voretigene neparvovec-rzyl). The words ‘‘anticipate,’’ ‘‘believe,’’ ‘‘expect,’’ ‘‘intend,’’ ‘‘may,’’ ‘‘plan,’’ ‘‘predict,’’ ‘‘will,’’ ‘‘would,’’ ‘‘could,’’ ‘‘should,’’ ‘‘continue’’ and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Any forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that LUXTURNA may not improve both rod and cone function in patients with biallelic RPE65 mutation-associated IRD. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the "Risk Factors" section, as well as discussions of potential risks, uncertainties and other important factors, in our Annual Report on Form 10-K, our Quarterly Reports on Form 10-Q and other filings we make with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Spark undertakes no duty to update this information unless required by law.