GenSight Biologics Reports Topline Results From REFLECT Phase 3 Trial, Confirming Lumevoq Efficacy

GenSight Biologics reported key efficacy and safety findings at 1.5 years (78 weeks) post-treatment in the REFLECT phase 3 clinical trial for Lumevoq. The results show better visual acuity improvements from bilateral intravitreal injections of the gene therapy compared to a unilateral injection.

“Following the rigorous guidelines of pivotal clinical trials, the data from REFLECT confirm that Lumevoq gene therapy improved best-corrected visual acuity (BCVA), also the primary outcome for REVERSE and RESCUE,” Dr. Robert Sergott, Director, Neuro-Ophthalmology Service, Wills Eye Hospital, and Founding Director and CEO, William H. Annesley EyeBrain Center, Thomas Jefferson University, Philadelphia, said in a company news release. “The surprising, ground-breaking, bilateral improvement with unilateral injection was found again, certainly not a chance event in three independent trials.”

Dr. Sergott added, “The bilateral injection of Lumevoq, showing better efficacy with no tradeoff in terms of safety or tolerability, makes the gene therapy a compelling therapeutic option. Lumevoq has changed the lives of patients with Leber Hereditary Optic Neuropathy.”

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 Leber Hereditary Optic Neuropathy (LHON) caused by a mutated ND4 mitochondrial gene; enrolled ND4 subjects 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.¹ All subjects received an intravitreal injection (IVT) of Lumevoq in their first affected eye. The second affected eye was randomized to either a second IVT of Lumevoq or a placebo IVT, which was administered on the same day or the following day. Forty-eight 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).

Significant visual acuity improvement over baseline, with better results for bilaterally injected patients

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.

Table 1: Change in Best-Corrected Visual Acuity (BCVA versus Baseline, 1.5 Years after Injection

Consistent with REVERSE² and RESCUE,³ unilaterally treated subjects showed a contralateral effect in their placebo-treated eye (Figure 1). 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; P=0.6080).

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 (Figure 2). 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% of bilaterally treated subjects and 72% of unilaterally treated subjects.

Efficacy demonstrated even more clearly in visual acuity improvement from nadir

Comparison against nadir (worst BCVA from baseline to 1.5 year) more starkly demonstrates the efficacy of Lumevoq, even for the placebo eyes that showed the contralateral effect.

Table 2: Change in Best-Corrected Visual Acuity (BCVA) versus Nadir, 1.5 Years after Injection

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

Bilateral injections have favorable safety profile

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.

Lumevoq efficacy from the three phase 3 trials – RESCUE, REVERSE and REFLECT – is highly consistent across the studies.

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

GenSight will host a KOL event on Friday, July 9, at 8:00 am EDT / 2:00 pm CEST, to present key results of REFLECT. Details will be announced at a later date.

References:

1. Newman NJ, Carelli V, Taiel M, Yu-Wai-Man P. Visual outcomes in Leber hereditary optic neuropathy subjects with the m.11778G>A (MTND4) mitochondrial dna mutation. J Neuroophthalmol. (2020) 40:547–57. doi: 10.1097/WNO.0000000000001045.
2. Yu-Wai-Man P, Newman NJ, Carelli V, Moster ML, Biousse V, Sadun AA, et al. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med. (2020) 12:eaaz7423. doi: 10.1126/scitranslmed.aaz7423
3. Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Biousse V, Vignal-Clermont C, et al. Efficacy and safety of intravitreal gene therapy for leber hereditary optic neuropathy treated within 6 months of disease onset. Ophthalmology. (2021) 128:649–60. doi: 10.1016/j.ophtha.2020.12.012.