Rare Daily Staff

GenSight Biologics said the phase 3 REFLECT study of its experimental gene therapy Lumevoq for the rare, degenerative retinal disease Leber hereditary optic neuropathy failed to meet its primary endpoint, but that results showed better visual acuity improvements from bilateral intravitreal injections of the gene therapy compared to a unilateral injection.

Leber hereditary optic neuropathy (LHON) is a maternally inherited, mitochondrial, genetic disease, characterized by the degeneration of retinal ganglion cells that results in irreversible vision loss that can lead to legal blindness, and mainly affects adolescents and young adults. LHON is associated with painless, sudden loss of central vision in the first eye, with the second eye sequentially impaired. It is a symmetric disease with poor functional visual recovery. Some 97 percent of subjects have bilateral involvement at less than one year of onset of vision loss, and in 25 percent of cases, vision loss occurs in both eyes simultaneously.

Lumevoq targets LHON by leveraging a proprietary mitochondrial targeting sequence technology platform, which specifically addresses defects inside the mitochondria using an AAV vector. The gene of interest is transferred into the cell to be expressed and produces the functional protein, which is then shuttled to the mitochondria through specific nucleotide sequences in order to restore the missing or deficient mitochondrial function.

“Following the rigorous guidelines of pivotal clinical trials, the data from REFLECT confirm that Lumevoq gene therapy improved best-corrected visual acuity, also the primary outcome for REVERSE and RESCUE,” said Robert Sergott, director of the neuro-ophthalmology service at Wills Eye Hospital and founding director and CEO of the William H. Annesley EyeBrain Center at Thomas Jefferson University in Philadelphia. “The surprising, ground-breaking, bilateral improvement with unilateral injection was found again, certainly not a chance event in three independent trials.”

Designed under a Special Protocol Assessment with the FDA, the REFLECT trial is a randomized, double-masked, placebo-controlled phase 3 trial involving 98 subjects with vision loss due to LHON caused by a mutated ND4 mitochondrial gene. The study enrolled ND4 subjects who had vision loss up to one year from onset. The ND4 mitochondrial mutation is associated with the most severe clinical form of LHON, with poor overall visual outcomes.

All subjects received an intravitreal injection of Lumevoq in their first affected eye. The second affected eye was randomized to either a second intravitreal injection of Lumevoq or a placebo intravitreal injection, which was administered on the same day or the following day. A total of 48 subjects were randomized to Lumevoq bilateral treatment, and 50 to Lumevoq unilateral treatment (first-affected eye treated with Lumevoq, second-affected eye treated with placebo).

At the primary time point of the analysis, 1.5 years after injection, mean best-corrected visual acuity (BCVA) in Lumevoq-treated eyes was statistically significantly better than baseline, whereas the improvement from baseline was not statistically significant in placebo eyes.

Consistent with REVERSE2 and RESCUE3, unilaterally treated subjects showed a contralateral effect in their placebo-treated eye. The contralateral effect reduced the difference in the outcomes among Lumevoq- and placebo-treated eyes, and consequently, the trial did not meet the pre-defined primary endpoint. The difference of the change from baseline in BCVA between the second affected Lumevoq- and placebo-treated eyes was -0.05 LogMAR (+3 ETDRS letters equivalent).

A dose effect, seen between bilaterally and unilaterally treated subjects, provides new evidence on Lumevoq efficacy. In each group, the BCVAs of both eyes improved from baseline in tandem, but with a higher treatment effect for bilaterally treated subjects. The mean BCVA at 1.5 years for bilaterally and unilaterally treated subjects reached 1.35 and 1.45 LogMAR, respectively, with an absolute difference between arms of +5 letters in favor of bilaterally treated subjects.

Responder analyses show that most of the subjects responded to treatment and confirm that bilateral injections provide better efficacy. Most of the subjects had on-chart BCVAs at 1.5 year (able to read letters on a screen): 85 percent of bilaterally treated subjects and 72 percent of unilaterally treated subjects.

At 1.5 years, improvement by at least 3 lines from nadir was demonstrated by 69 percent of bilaterally and 64 percent unilaterally treated subjects.

The favorable safety profile of Lumevoq was confirmed. There was no study discontinuation related to systemic or ocular adverse event. There were no serious ocular adverse events. The main ocular adverse event was intraocular inflammation, mostly mild, and responsive to conventional treatment. The good safety profile was comparable in unilaterally and bilaterally treated subjects.

GenSight said it plans to add the full results of REFLECT to the EMA clinical dossier during the ongoing review of the Lumevoq Marketing Authorisation Application and will present the analyses to the FDA later this year.

Photo: Robert Sergott, director of the neuro-ophthalmology service at Wills Eye Hospital, and founding director and CEO of the William H. Annesley EyeBrain Center at Thomas Jefferson University in Philadelphia

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