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Date: 2018-11-22

Type of information: Granting of a Market Authorisation in the EU

Product name: Luxturna™ (voretigene neparvovec-rzyl - 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.
  • Luxturna works by delivering a normal copy of the RPE65 gene directly to retinal cells. These retinal cells then produce the normal protein that converts light to an electrical signal in the retina to restore patient’s vision loss. Luxturna uses a naturally occurring adeno-associated virus, which has been modified using recombinant DNA techniques, as a vehicle to deliver the normal human RPE65 gene to the retinal cells to restore vision.
  • Hereditary retinal dystrophies are a broad group of genetic retinal disorders that are associated with progressive visual dysfunction and are caused by mutations in any one of more than 220 different genes. The RPE65 gene provides instructions for making an enzyme (a protein that facilitates chemical reactions) that is essential for normal vision. Mutations in the RPE65 gene lead to reduced or absent levels of RPE65 activity, blocking the visual cycle and resulting in impaired vision. Individuals with biallelic RPE65 mutation-associated retinal dystrophy experience progressive deterioration of vision over time. This loss of vision, often during childhood or adolescence, ultimately progresses to complete blindness.
  • Luxturna™ was developed and is marketed in the US by Spark Therapeutics. If approved, voretigene neparvovec will be commercialized by Novartis in markets outside the U.S.

Company: Spark Therapeutics (USA - PA) Novartis (Switzerland)

Disease:

  • retinitis pigmentosa due to autosomal recessive RPE65 gene mutations
  • inherited retinal dystrophy due to biallelic RPE65 mutations

Latest news:

  • • On November 22, 2018, the European Commission has granted marketing authorization for 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. This authorization is valid in all 28-member states of the EU, as well as Iceland, Liechtenstein and Norway. Luxturna® is the first gene therapy for a genetic disease that has received regulatory approval in both the U.S. and EU. In January 2018, Spark Therapeutics entered into a licensing agreement with Novartis to commercialize Luxturna® when approved in Europe and all other markets outside the U.S. Under the licensing agreement, Novartis has exclusive rights to pursue development, registration and commercialization in all countries outside the U.S. Upon the transfer of the marketing authorization from Spark to Novartis, Novartis can commercialize Luxturna® in the EU/European Economic Area (EEA). Spark Therapeutics entered into a separate agreement with Novartis to manufacture and supply Luxturna® to Novartis.
  • • On September 21, 2018, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended granting a marketing authorisation for the gene therapy Luxturna™ (voretigene neparvovec), for the treatment of adults and children suffering from inherited retinal dystrophy caused by RPE65 gene mutations. Luxturna™ is meant for patients with confirmed biallelic mutations of the RPE65 gene and who have sufficient viable retinal cells. It is the first gene therapy to be recommended for approval for a retinal disease. Luxturna™ was studied in 41 patients. In the main clinical trial supporting the approval of the therapy, patients treated with the medicine showed a significant improvement of night vision, one of the typical symptoms of the disease, after one year, while no improvement was seen in the control group. The most common side effects were conjunctival hyperaemia (eye redness), cataracts and increased intraocular pressure. Given the novelty of the treatment and the limited number of treated patients, the CHMP requires the company to ensure the long-term follow-up of patients to confirm Luxturna’s continuing efficacy and safety. Follow-up studies were agreed, including a post-authorisation safety study (PASS) based on a disease registry in patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations, as well as a 15-year follow-up programme of efficacy and safety outcomes for all patients treated in the clinical programme. Luxturna™ will be available as concentrate (5 x1012 vector genomes/ml) and solvent for solution for injection. The benefits with Luxturna™ are its ability to improve night vision. The most common side effects are conjunctival hyperaemia, cataract and increased intraocular pressure. It is proposed that Luxturna™ be administered by a retinal surgeon experienced in performing macular surgery. 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 patients with inherited retinal disease caused by mutations in both copies of the RPE65 gene. The Phase 3 trial was the first randomized, controlled Phase 3 gene therapy trial for an inherited disease.
  • • On December 19, 2017, the FDA approved Luxturna® (voretigene neparvovec-rzyl), a new gene therapy, to treat children and adult patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy that leads to vision loss and may cause complete blindness in certain patients. Luxturna® is the first directly administered gene therapy approved in the U.S. that targets a disease caused by mutations in a specific gene. This gene therapy  should be given only to patients who have viable retinal cells as determined by the treating physician(s). Treatment with Luxturn®a must be done separately in each eye on separate days, with at least six days between surgical procedures. It is administered via subretinal injection by a surgeon experienced in performing intraocular surgery. Patients should be treated with a short course of oral prednisone to limit the potential immune reaction to Luxturna®.
  • The safety and efficacy of Luxturna® were established in a clinical development program with a total of 41 patients between the ages of 4 and 44 years. All participants had confirmed biallelic RPE65 mutations. The primary evidence of efficacy of Luxturna® was based on a Phase 3 study with 31 participants by measuring the change from baseline to one year in a subject’s ability to navigate an obstacle course at various light levels. The group of patients that received Luxturna® demonstrated significant improvements in their ability to complete the obstacle course at low light levels as compared to the control group.
  • The most common adverse reactions from treatment with Luxturna® included eye redness (conjunctival hyperemia), cataract, increased intraocular pressure and retinal tear. The FDA granted this application Priority Review and Breakthrough Therapy designations. The sponsor is receiving a Rare Pediatric Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the 13th rare pediatric disease priority review voucher issued by the FDA since the program began.
  • To further evaluate the long-term safety, the manufacturer plans to conduct a post-marketing observational study involving patients treated with Luxturna®.
  • The FDA also announced that the agency is currently focused on establishing the right policy framework to capitalize on this scientific opening. Next year, the FDA will begin issuing a suite of disease-specific guidance documents on the development of specific gene therapy products to lay out modern and more efficient parameters — including new clinical measures — for the evaluation and review of gene therapy for different high-priority diseases where the platform is being targeted.
  • • 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: 2017-12-19

UE authorization: 2018-11-22

Favourable opinion UE: 2018-09-20

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