GenSight Biologics’ LHON Gene Therapy Lumevoq Continues to Show Efficacy and Safety 4 Years Out

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The results come from the randomized, double-masked, placebo-controlled phase 3 REFLECT clinical trial (NCT03293524).

GenSight Biologics’ lenadogene nolparvovec (GS010; Lumevoq), an investigational gene therapy intended to treat Leber hereditary optic neuropathy (LHON) caused by the m.11778G>A ND4 mutation (MT-ND4), has shown sustained improvements in best corrected visual acuity (BCVA) in patients 4 years after they received the one-time treatment.1

The results come from the randomized, double-masked, placebo-controlled phase 3 REFLECT clinical trial (NCT03293524). GenSight noted that all treated participants showed sustained improvement over 4 years, but that patients treated with a bilateral injection of the gene therapy continued to have a better visual acuity than the patients treated with a unilateral injection, a disparity that had been seen in REFLECT since 1.5 years posttreatment. Furthermore, the average visual acuity for all treated eyes in REFLECT increased beyond +15 letters compared to the worst BCVA observed from baseline to 4 years posttreatment (nadir).

As of the February 20, 2024 data cutoff, patients treated bilaterally with Lumevoq showed +20 ETDRS letters (-0.40 LogMAR) improvement compared to nadir in their first affected eye (n = 48) and +17 ETDRS letters (-0.34 LogMAR) improvement compared to nadir in their second affected eye (n = 46). For patients who received a unilateral injection of Lumevoq and a placebo injection in the other eye, a +19 ETDRS letter (-0.38 LogMAR) improvement compared to nadir was seen in the first affected (Lumevoq-treated) eye (n = 50) and a +14 ETDRS letter (-0.27 LogMAR) improvement compared to nadir was seen in the placebo-treated eye (n = 50) (P < .0001 for all eye groups using linear mixed model). GenSight also pointed out that 73% of patients treated bilaterally showed a clinically meaningful improvement (+15 ETDRS letters) compared to their observed nadir and that 81% of patients treated bilaterally have the ability to read letters on a screen; the likelihood of gaining the latter ability was noted to be twice as high for patients who received the bilateral injection compared to those treated with a unilateral injection (odds ratio: 2.0 [0.7; 5.5]).

“The sustained effect on vision, as observed in the REFLECT trial, is a crucial piece of the Lumevoq story for patients, physicians and health authorities,” Laurence Rodriguez, MS, the chief executive officer of GenSight Biologics, said in a statement.1 “The durable impact from a single administration differentiates gene therapy from other treatment modalities, facilitating patient adherence and improving quality of life.”

In terms of safety, GenSight noted that patients treated bilatrally and unilaterally had comparable outcomes and that no serious ocular adverse events (AEs) were reported in REFLECT. Furthermore, no patients discontinued participation in relation to a systemic or ocular AE. Intraocular inflammation was reported to be the main ocular AE, with cases for the most part being mild and responding to conventional treatment.

“The latest REFLECT data confirms that the improvement seen with lenadogene nolparvovec is sustained 4 years after treatment has been given, including the additional benefit observed in participants receiving a bilateral intravitreal injection of the gene therapy,” principal investigator Patrick Yu-Wai-Man, MD, PhD, a professor of ophthalmology at the University of Cambridge and Moorfields Eye Hospital, added to the statement.1 “Importantly, REFLECT participants receiving a bilateral injection had a comparable safety profile to those treated unilaterally.”

The newly reported data from REFLECT adds on to data reported from other studies of Lumevoq last year at the Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting, held April 23-27, in New Orleans, Louisiana. Long-term follow-up data from the phase 3 RESTORE study (NCT03406104) presented at the meeting indicated that patients with MT-ND4 LHON had sustained improvements in BCVA in both eyes and quality of life 5 years after treatment.2 GenSight also reported real-world data from patients treated in early access programs at the meeting.3 Among 38 patients who received treatment with Lumevoq in 1 or both eyes and were evaluable at 1 year post-treatment, there was a mean change in BCVA from baseline to 1 year of -0.29 LogMAR (+14.5 EDTRS letters equivalent; standard deviation [SD], 0.67). Furthermore, among the 25 patients who received Lumevoq in both eyes, there was a mean change in BCVA from baseline to 1 year of -0.36 LogMAR (+18 ETDRS letters equivalent; SD, 0.73).

REFERENCES
1. GenSight Biologics confirms sustained efficacy and safety of bilateral LUMEVOQ® injections four years after one-time administration. News release. GenSight Biologics. March 20, 2024. Accessed April 22, 2024. https://www.gensight-biologics.com/2024/03/20/gensight-biologics-confirms-sustained-efficacy-and-safety-of-bilateral-lumevoq-injections-four-years-after-one-time-administration/
2. Yu Wai Man P, Newman NJ, Valérie B, et al. Treatment with lenadogene nolparvovec gene therapy results in sustained visual improvement in m.11778G>A MT-ND4-LHON patients: the RESTORE study. Presented at: ARVO 2023 Annual Meeting; April 23-27; New Orleans, Louisiana. Abstract 1955
3. La Morgia C, Vignal-Clermont C, Carelli V, et al. Use of lenadogene nolparvovec gene therapy for Leber hereditary optic neuropathy in early access programs. Presented at: Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting. April 23-27, 2023; New Orleans, LA. Abstract #1956
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