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Date: 2017-07-31

Type of information: Submission of a Market Application in the EU

Product name: Luxturna™ (voretigene neparvovec - SPK-RPE65)

Compound: adeno-associated viral vector type 2 expressing human recombinant retinal pigment epithelial 65KDa protein gene

Therapeutic area: Ophtalmological diseases - Rare diseases

Action mechanism:

  • gene therapy. Voretigene neparvovec (SPK-RPE65) uses a neutralized virus as a vector, to transport a functional RPE65 gene into the affected tissue in the eye. Once inside the eye, the new genetic material enables patients to produce the protein that is missing as a result of their genetic mutation.

Company: Spark Therapeutics (USA - PA)

Disease: retinitis pigmentosa due to autosomal recessive RPE65 gene mutations/inherited retinal dystrophy due to biallelic RPE65 mutations

Latest news:

  • • On July 31, 2017, Spark Therapeutics announced that it has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Luxturna™ (voretigene neparvovec) for the treatment of patients with vision loss due to Leber congenital amaurosis or retinitis pigmentosa caused by confirmed biallelic RPE65 mutations. The MAA includes data from three clinical trials that enrolled 41 participants with RPE65-mediated inherited retinal dystrophy (IRD), including the first randomized, controlled Phase 3 trial for a gene therapy for a genetic disease. This gene therapy is currently under Priority Review with the FDA, with an assigned Prescription Drug User Fee Act (PDUFA) date of Jan. 12, 2018.
  • • On July 20, 2017, Spark Therapeutics announced that the Offices of Orphan Products Development and Pediatric Therapeutics of the FDA have designated voretigene neparvovec as a drug for a rare pediatric disease. Under FDA's Rare Pediatric Disease Priority Review Voucher program, companies who receive approval for a new drug application or Biologics License Application (BLA) for a rare pediatric disease may be eligible to receive a voucher for a Priority Review of a subsequent marketing application for a different product. The Priority Review Voucher may be used by the company or sold to a third party.
  • • On July 17, 2017, Spark Therapeutics announced that the FDA has accepted for filing the Biologics License Application (BLA) and granted Priority Review for voretigene neparvovec, an investigational, potential one-time gene therapy candidate for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal disease (IRD). The investigational gene therapy, which has the proposed trade name Luxturna™ (voretigene neparvovec), has the potential to be both the first pharmacologic treatment for IRD and the first gene therapy for a genetic disease in the United States . The FDA has assigned a PDUFA date of January 12, 2018 .Investigational Luxturna™ is intended to be administered one time per eye in patients with vision loss due to biallelic RPE65-mediated IRD.
  • The safety and efficacy of Luxturna™ were assessed in two open-label Phase 1 trials, which continue to follow participants who received Luxturna™ between 2007 and 2012, and one open-label, randomized, controlled Phase 3 trial. Following the one-year control period of the Phase 3 study, all control participants elected to cross over and received Luxturna™; long-term safety and efficacy continue to be assessed in the Phase 3 participants who received Luxturna™ between 2013 and 2015. The clinical trial program included 41 participants with vision loss aged four to 44 at the time of first administration. Confirmed biallelic RPE65 mutations and the presence of sufficient viable retinal cells were established in all participants.
  • Luxturna™ Phase 3 clinical trial data, including data from the intent-to-treat population of all randomized participants through the one-year time point, were published in The Lancet. 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=0.001). In addition, participants who received  Luxturna™ showed a marked difference compared to control participants across the first two secondary endpoints: full-field light sensitivity threshold (FST) testing (p<0.001) and the mobility test change score for the first injected eye (p=0.001). A third secondary endpoint, the change in visual acuity (VA) averaged over both eyes, was not statistically significant between intervention and control participants (p=0.17).
  • On average, participants in the original Phase 3 intervention group maintained functional gains observed by the day-30 visit through at least two years, as measured by MLMT and FST. The more than 100-fold (or greater than two log units) average improvement in FST testing observed in the original intervention group at one year, similarly, was maintained through at least two years.
  • In continuation of the trial to include crossover of the control group to receive  Luxturna™, 93 percent (27 of 29) of all treated Phase 3 trial participants saw a gain of functional vision as assessed by bilateral MLMT over the follow-up period of at least one year from administration of  Luxturna™ to each eye. Additionally, 72 percent (21 of 29) of all Phase 3 trial participants receiving  Luxturna™ successfully completed MLMT at the lowest light level evaluated (1 lux) at one year.
  • No serious adverse events (SAEs) associated with  Luxturna™ or deleterious immune responses have been observed. Two ocular SAEs were reported in the clinical program. There was 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 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 deposit (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. The most common adverse reactions related to  Luxturna™ reported in 10 percent or greater of the combined Phase 1 and Phase 3 trial participants included conjunctival hyperemia, cataract, intraocular pressure increased, and retinal tear.
  • • On May 18, 2017, Spark Therapeutics announced the completion of the rolling submission of a Biologics License Application (BLA) with the FDA for voretigene neparvovec for the treatment of patients with vision loss due to confirmed biallelic RPE65 mutation-associated retinal disease. The BLA submission includes data from three clinical trials that enrolled 41 participants with RPE65-mediated IRD, including the first randomized, controlled Phase 3 trial for a gene therapy for a genetic disease.
  • • On January 9, 2017, Spark Therapeutics announced that the FDA has granted a request to amend the orphan drug designation for voretigene neparvovec to "the treatment of inherited retinal dystrophy due to biallelic RPE65 mutations." This expanded designation aligns with the proposed indication for voretigene neparvovec. As reported previously, voretigene neparvovec has received breakthrough therapy and orphan product designations from the FDA, as well as orphan product designation from the European Medicines Agency (EMA). Spark Therapeutics has initiated a rolling submission of the Biologics License Application (BLA), which is expected to be completed in early 2017.
  • • On March 18, 2015, the FDA has granted orphan drug designation for adeno-associated viral vector type 2 expressing human recombinant retinal pigment epithelial 65KDa protein gene for the treatment of retinitis pigmentosa due to autosomal recessive RPE65 gene mutations.

Patents:

Submission of marketing authorization application USA : 2017-05-18

Submission of marketing authorization application UE: 2017-07-31

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization:

UE authorization:

Favourable opinion UE:

Favourable opinion USA:

Orphan status USA: 2015-03-18

Orphan status UE: 2012-04-02

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes