Inherited retinal dystrophies (IRD) are a group of rare genetic diseases that result in blindness. The most common category of these diseases is retinitis pigmentosa (RP), a disorder that causes retinal cells to die, primarily affecting photoreceptor (rods and cones) and pigment epithelial function. RP leads to progressive retinal degeneration and dysfunction and the loss of ability to transmit these visual electrical signals to the brain. Individuals with RP will experience vision symptoms, including night blindness, loss of central and peripheral vision (or "tunnel vision"), and nystagmus. Treatment to slow the progression includes light avoidance, use of low-vision aids, and vitamin A supplementation. Leber congenital amaurosis (LCA) is a less common but more severe form of RP that is present at birth. The visual impact includes early and rapid vision loss. Treatment of LCA includes correction of farsightedness and the use of low-vision aids. When left untreated, patients lose the ability to detect light of any intensity. They become severely limited in their ability to independently navigate, and any vision-dependent activities of daily living are impaired.
Individuals with IRD may have a genetic biallelic variation(s) in human retinal pigment epithelial–specific 65-kDA protein (RPE65), which is critical for the regeneration of the visual pigment necessary for both rod- and cone-mediated vision.
Voretigene neparvovec-rzyl (Luxturna™) was approved by the US Food and Drug Administration (FDA) on December 19, 2017, for the treatment of individuals with confirmed biallelic RPE65 mutation–associated retinal dystrophy after confirmation by the treating physician(s) that the individual has viable retinal cells.
Voretigene neparvovec-rzyl (Luxturna) is an adenoassociated virus vector type 2 (AAV2) that contains a functioning copy of human RPE65 protein. It is intended as a one-time gene therapy to slow the disease progression to complete blindness by supplying the RPE65 protein into the targeted cells, which will utilize the cell to express the protein, thereby regenerating the cells.
PEER-REVIEWED LITERATURE
Summary
The safety and effectiveness of voretigene neparvovec-rzyl (Luxturna) in individuals ages 4 years or older with inherited retinal dystrophy were studied in a Phase 3, open-label, randomized controlled trial (RCT) over 1 year. Individuals were required to have a confirmed genetic diagnosis of biallelic RPE65 gene variation(s), both eyes had visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both. Other inclusion criteria comprised sufficient viable retinal cells as determined by retinal thickness on spectral domain optical coherence tomography (>100 microns within the posterior pole), fundus photography, and clinical examination; and the ability to perform a standardized multi-luminance mobility test (MLMT) (i.e., obstacle course) within the luminance range evaluated, but unable to pass the MLMT at 1 lux, the lowest luminance level tested (described as a moonless summer night or indoor nightlight).
Individuals were randomly assigned (2:1) to receive voretigene neparvovec-rzyl (Luxturna) (N=20) in the intervention group, or no injection in the control group (N=9). (The control group became eligible to receive voretigene neparvovec-rzyl [Luxturna] 1 year after their baseline evaluations, provided they still met all of the eligibility criteria). The subretinal injection of 1.5 × 1011 vector genomes (vg) voretigene neparvovec-rzyl (Luxturna) was administered under general anesthesia. The first eye that was injected was chosen based on which eye had the worst visual acuity, subject preference, or both. The second eye was injected 6 to 18 days after the first procedure.
The primary efficacy endpoint was change in MLMT performance 1 year after baseline. Participants were assessed with MLMT at baseline, with subsequent assessments at 30, 90, 180, and 365 days after randomization (control group) or after the second injection (intervention group). MLMT was a 5' × 10' obstacle course created to evaluate vision by having participants navigate around obstacles in or adjacent to the path in varying environmental illuminations, including very low light levels, integrating aspects of visual acuity, visual field, and light sensitivity. Participants navigated the path with one eye patched, then another configuration of the path with the other eye patched, then again with both eyes open. This process was repeated with varying light levels to discover which levels caused participants to pass or fail the course. Passing was defined as completion of the course at the specified light level with fewer than four errors (corresponding to an accuracy score of <0.25) and within 3 minutes. Each light level was assigned a discrete lux score from 0 to 6, with lower light levels corresponding to higher lux scores. The graders who assessed primary outcome were masked to treatment group to avoid bias.
At the 1-year mark, there was a statistically significant difference between treatment groups in regards to the mean bilateral MLMT change score (1.8 light levels in the intervention group vs. 0.2 in the control group) (P=0.0013). Thirteen (65%) of 20 participants in the intervention group, but no participants in the control group, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. All but one participant in the intervention group had advanced at least one light level.
One of the three secondary endpoints reviewed in the study was full-field light sensitivity threshold (FST) testing. FST is a measure of visual function, generally assessed per eye, that tests the underlying physiologic function of the rod photoreceptors. FST measures the lowest illumination perceived (i.e., light sensitivity) over the entire visual field. FST test-retest variability has been stated as 0.3 log and a meaningful change has been suggested as 10 dB or 1 log. The results reported a statistically significant (P=0.0004) difference between the intervention and control group regarding the mean FST over 1 year of study.
There were no serious adverse events or deleterious immune responses caused by voretigene neparvovec-rzyl (Luxturna). Most ocular events were mild in severity. Safety and efficacy will be monitored for at least 5 years through assessments at annual visits, including safety, mobility testing, and retinal and visual function testing, and for 15 years via questionnaires at annual visits or telephone visits.
Voretigene neparvovec-rzyl (Luxturna) appears to have durable effects to at least 4 years in a small number of individuals with follow-up. Other gene therapies tested in early-phase trials have shown improvements in retinal function but variable durability of effect; some individuals from two cohorts who initially experienced improvements have subsequently experienced declines after 1 to 3 years. Adverse events of gene therapy tended to occur early; most were mild to moderate and diminished over time. Seven of 41 persons treated with voretigene neparvovec-rzyl (Luxturna) have had a loss of 15 letters or more in at least one eye. Most studies have reported minimal immune response.
Fischer et al. (2024) published follow-up results from the PERCEIVE trial, an ongoing, postauthorization, prospective, multicenter observational study. A total of 103 individuals were treated with voretigene neparvovec-rzyl (Luxturna) and followed up for a maximum of 2.3 years (median, 0.8 years). A total of 34% of the individuals experienced ocular treatment-emergent adverse events, which were most commonly chorioretinal atrophy. Intraocular inflammation and/or procedure-related infection occurred in seven individuals. Visual acuity changes from baseline were not clinically significant. Mean changes from baseline in full-field light-sensitivity threshold testing (white light) at 1 month, 6 months, 1 year, and 2 years were −16.59 dB (51 eyes), −18.24 dB (42 eyes), −15.84 dB (10 eyes), and −13.67 dB (13 eyes), respectively.
Additional publications will need to evaluate the outcomes in a larger sample size, determine which patient characteristics are most appropriate for treatment (e.g., age, visual acuity, how early in disease progression treatment is initiated), the longevity of treatment, the possibility for re-treatment, and the clinical relevance of various outcome measures.
OFF-LABEL INDICATION
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
