Spark Therapeutics announced that Clinical and Experimental Ophthalmology has published a prospective, observational study that provides robust evidence for the construct and content validity of the multi-luminance mobility test (MLMT) to assess functional vision in people with inherited retinal diseases (IRDs). MLMT was used as the primary endpoint of the phase 3 clinical trial of Luxturna (voretigene neparvovec), an investigational, potential one-time gene therapy for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated IRD.
MLMT measures functional vision, which refers to a person’s ability to perform, on his or her own, visually dependent activities of daily living. Visual function is measured by tests typically performed on each eye individually, such as light sensitivity as measured by full-field light sensitivity threshold (FST) testing, visual acuity and visual field. Measuring functional vision, rather than visual function, may be a more appropriate means to evaluate changes in vision loss in patients with IRDs.
In the study of the mobility test, which was conducted at Children’s Hospital of Philadelphia and sponsored by Spark Therapeutics, construct validity refers to the ability to differentiate participants with normal vision from those with impaired vision. Content validity references the test components of speed and accuracy score at defined levels of illumination during MLMT course navigation runs.
“Traditional mobility measures for people with IRDs lacked approaches to quantify mobility at varying light levels, which is important for people living with biallelic RPE65-mediated IRD, who progressively lose their ability to perceive light,” Katherine A. High, MD, president and chief scientific officer at Spark Therapeutics and co-author of the paper, said in a company news release. “MLMT introduced a robust approach to assess functional vision at varying light levels. The study results provide robust evidence for the construct and content validity of MLMT as a tool to assess functional vision in Spark Therapeutics’ clinical study of Luxturna.”
The study compared the ability of 29 participants with normal vision and 31 participants diagnosed with an IRD prior to enrollment, all between the ages of 4 and 40, to navigate a randomized mobility course at varying light levels over the course of 1 year. Each participant’s course navigation run was recorded on video and graded for both accuracy and time. More than 3,800 videos were recorded and assessed by independent graders across all course navigation runs, which included runs from all the sponsor’s studies using mobility as an endpoint. Twenty-six normal-sighted and 28 visually impaired participants completed four visits over 1 year.
MLMT demonstrated high overall reproducibility and clearly differentiated visually impaired participants from those with normal vision, according to Spark Therapeutics. All normal-sighted participants passed every MLMT attempt at all tested light levels, but visually impaired participants’ MLMT performances varied widely. Concordance of performance on two baseline visits was high; correlations for accuracy score were 94 percent and 98 percent for the lowest common and highest common lux levels, respectively. Lux is a unit of illumination that measures the amount of light falling onto (illuminating) and spreading over a given surface area. Please refer to the paper, “Novel mobility test to assess functional vision in patients with inherited retinal dystrophies,” for the full description of the design and results of this study.
Investigational Luxturna is currently under Priority Review with the FDA for the treatment of patients with vision loss due to confirmed biallelic RPE65 mutation-associated retinal dystrophy.
Clinical Trial Overview of Luxturna (voretigene neparvovec)
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 1-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 4 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 1-year time point, were published in The Lancet. Results reported in The Lancet showed a statistically significant and clinically meaningful difference between intervention (n=21) and control participants (n=10) at 1 year, per the clinical trial’s primary endpoint, mean bilateral multi-luminance mobility test (MLMT) change score (difference of 1.6; 95% CI, 0.72, 2.41; P=0.0013). 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 averaged over both eyes (P=0.0004) and MLMT change score for the first injected eye (P=0.0005). 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 2 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 1 year was similarly maintained through at least 2 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 1 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 1 year.
Data from a cohort of the phase 1 clinical trial, in which investigational Luxturna was administered to the contralateral, or second previously uninjected eye, showed mean improvements in functional vision and visual function. These improvements were maintained through at least 3 years, as measured by both MLMT and FST testing. This cohort of participants (n=8) received the same dose of Luxturna that was administered in the phase 3 trial and would have met the phase 3 eligibility criteria.
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 IOP 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. 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, increased IOP and retinal tear.