Spark Therapeutics Announces Positive CHMP Opinion for One-time Gene Therapy LUXTURNA® (voretigene neparvovec) in the European Union

LUXTURNA would be first gene therapy for a genetic disease approved in both U.S. and EU

LUXTURNA would be first and only gene therapy approved in EU to treat patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations and who have sufficient viable retinal cells, a condition leading to total blindness in most patients

Positive opinion based on robust data package supporting safety, efficacy and durability of response for up to three years after one-time treatment with LUXTURNA

PHILADELPHIA, Sept. 21, 2018 (GLOBE NEWSWIRE) -- Spark Therapeutics (NASDAQ: ONCE), a fully integrated, commercial gene therapy company dedicated to challenging the inevitability of genetic disease today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending approval of LUXTURNA® (voretigene neparvovec), a one-time gene therapy for the treatment of adult and pediatric patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations and who have sufficient viable retinal cells.

"We are encouraged by today's decision, which further affirms our pioneering clinical program and brings LUXTURNA one step closer to patients with inherited retinal disease (IRD) caused by mutations in both copies of the RPE65 gene in the European Union," said Katherine A. High, M.D., president and head of research & development at Spark Therapeutics. "Along with Novartis, we look forward to continuing our productive, ongoing dialogue with EMA toward potential marketing authorization to make LUXTURNA the first and only treatment for appropriate patients with this inherited retinal disease (IRD) in the European Union."

The positive CHMP opinion is based on data from a Phase 1 clinical trial, its follow-up trial and a Phase 3 trial that together enrolled 43 participants with inherited retinal disease caused by mutations on both copies of the RPE65 gene. The Phase 3 trial was the first randomized, controlled Phase 3 gene therapy trial for a genetic disease. Spark Therapeutics has received orphan product designation for LUXTURNA from EMA for the treatment of inherited retinal dystrophies.

"Inherited retinal diseases are a heterogenous group of degenerative conditions that represent the major cause of blindness in childhood and active working life. This opinion represents a hopeful milestone for current and future patients who may ultimately benefit from gene therapy," said Christina Fasser, president of Retina International, an umbrella organization of more than 43 patient organizations worldwide promoting research to find treatments for inherited retinal degenerative diseases.

A marketing authorization decision from the European Commission is anticipated approximately within two months. If approved, the authorization will be valid in all 28-member states of the European Union, as well as Iceland, Liechtenstein and Norway. In January 2018, Spark Therapeutics entered into a licensing and supply agreement with Novartis to commercialize LUXTURNA when and if approved in Europe and all markets outside the U.S.

LUXTURNA (voretigene neparvovec-rzyl) was approved by the U.S. Food & Drug Administration (FDA) in December 2017.

Clinical Trial Overview of LUXTURNA® (voretigene neparvovec)
The safety and efficacy of LUXTURNA were assessed in one open-label, dose-exploration Phase 1 safety study (n=12), a second open-label Phase 1 safety study to assess the safety of injection of the contralateral eye (n=11) and an 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 disease 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 (non-intervention) 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 cross over to 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, have been previously reported in The Lancet.

The efficacy of LUXTURNA in the Phase 3 study was established based on the binocular 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, both averaged over both eyes. Secondary endpoints included white light full-field light sensitivity threshold (FST) testing averaged over both eyes, first assigned eye MLMT 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 mean binocular MLMT score change (intervention minus control group difference of 1.6; 95% CI, 0.72, 2.41; p=0.001). After crossing over to receive LUXTURNA, participants in the control group showed a similar response to those in the intervention group. This score change 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 (p<0.001) and first assigned eye MLMT change score (p=0.001) 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.

Three ocular serious adverse events (SAEs) were reported in the clinical program. One SAE related to the surgical procedure in one eye of a Phase 3 participant, in which there was foveal thinning and a sustained reduction in VA. One additional Phase 3 participant reported an SAE of retinal detachment 4 years after vector administration assessed as related to the administration procedure. The third ocular SAE was reported in one eye of a Phase 1 participant in which the treatment for bacterial endophthalmitis led to elevated intraocular pressure and subsequent optic atrophy. There were three non-serious AEs of retinal deposits (subretinal precipitate) in three participants (three eyes) that were considered to be related to LUXTURNA. All three of these events were mild in intensity, transient in nature and resolved without consequences. No deleterious immune responses have been observed. The most common adverse reactions related to LUXTURNA reported in 5 percent or greater of the combined Phase 1 and Phase 3 trial participants included 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).

Indication and Important Safety Information for LUXTURNA in the U.S.
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 greater than or equal to 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 the full U.S. Prescribing Information for LUXTURNA here.

About Inherited Retinal Disease (IRD) Caused by Confirmed Biallelic RPE65 Mutations
Inherited retinal diseases (also known as inherited retinal dystrophies) are a group of rare blinding conditions caused by one of more than 220 different genes, often disproportionally affecting children and young adults. Based on Spark Therapeutics' assessment of available epidemiology data, the prevalent population in the U.S., Europe and select additional markets in the Americas and Asia/Pacific is up to approximately 6,000 individuals, in total, with biallelic RPE65 mutations.

People living with IRD due to biallelic RPE65 gene mutations nearly all progress to complete blindness. They often experience night blindness (nyctalopia) due to decreased light sensitivity in childhood or early adulthood and involuntary back-and-forth eye movements (nystagmus). As the disease progresses, individuals may experience loss in their peripheral vision, developing tunnel vision and eventually, they may lose their central vision as well, resulting in total blindness. Independent navigation becomes severely limited, and vision-dependent activities of daily living are impaired.

About the Novartis and Spark Therapeutics Licensing and Supply Agreement 
In January 2018, Spark Therapeutics entered into a licensing and supply agreement with Novartis covering development, registration and commercialization rights to LUXTURNA in markets outside the U.S. Commercialization rights will be transferred to Novartis upon successful completion of registration and issuance of marketing authorization. Novartis has exclusive rights to pursue development, registration and commercialization in all other countries outside the U.S., and Spark Therapeutics would supply the gene therapy to Novartis.

About Gene Therapy
Gene therapy is an approach to treat or prevent genetic disease by seeking to augment, replace or suppress one or more mutated genes with functional copies. It addresses the root cause of an inherited disease by enabling the body to produce a protein or proteins necessary to restore health or to stop making a harmful protein or proteins, with the potential of bringing back function in the diseased cells and/or slowing disease progression. To deliver the functional gene into the cell, a vector is used to transport the desired gene and is delivered either intravenously or injected into specific tissue. The goal is to enable, through the one-time administration of gene therapy, a lasting therapeutic effect.

About Spark Therapeutics 
At Spark Therapeutics, a fully integrated company committed to discovering, developing and delivering gene therapies, we challenge the inevitability of genetic diseases, including blindness, hemophilia 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(TM) (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: (i) our MAA submitted for LUXTURNA may not be approved by EMA when expected, or at all; and (ii) the improvements in functional vision demonstrated by LUXTURNA in our clinical trials may not be sustained over extended periods of time. 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.