Investigators found that bilaterally treated participants experienced greater improvements in BCVA than unilaterally treated participants.
Lumevoq (GS010; lenadogene nolparvovec) is well-tolerated and effective in improving visual acuity in patients with vision loss due to Leber hereditary optic neuropathy (LHON) at 1.5 years post-treatment, according to topline results of the phase 3 REFLECT trial (NCT03293524) announced by GenSight Biologics.
Patients treated with GS010 had statistically significant improvements in visual acuity from baseline in the first affected eye with both unilateral (+0.15 LogMAR score [+8 ETDRS letters]; P <.05) and bilateral (+0.23 LogMAR score [+12 ETDRS letters]; P = .001) injections. A contralateral effect reduced differences between unilateral and placebo-treated eyes (P = .0680 between the second affected treated eye and placebo-treated eyes) and thus the trial did not meet its primary end point of best-corrected visual acuity (BCVA) difference between the second bilaterally-injected eye and placebo-treated eye.
“Following the rigorous guidelines of pivotal clinical trials, the data from REFLECT confirm that GS010 gene therapy improved BCVA, also the primary outcome for REVERSE and RESCUE,” Robert Sergott, MD, chief, Neuro-Ophthalmology Service, Wills Eye Hospital, and founding director and chief executive officer, William H. Annesley EyeBrain Center, Thomas Jefferson University, Philadelphia, PA, USA, said in a statement. “The surprising, ground-breaking, bilateral improvement with unilateral injection was found again, certainly not a chance event in three independent trials.”
The special protocol assessment-designated REFLECT trial is a randomized, double-blinded, placebo-controlled phase 3 trial enrolling 98 participants with vision loss due to LHON caused by a mutated ND4 mitochondrial gene. These participants had vision loss for up to 1 year from onset. All participants received an intravitreal injection of GS010 in their first affected eye and were randomized to receive either another injection of GS010 in their second affected eye (bilateral injections; n = 48) or a placebo injection (unilateral injection; n = 50).
READ MORE: Leber hereditary optic neuropathy: Outlining disease’s natural course
The trial was conducted in multiple centers across Europe, the US, and Taiwan. The first participant was treated in March 2018 and the last one in July 2019. Secondary end points of the trial include BCVA via LogMAR at 2 years post-treatment in the second affected eye compared to both placebo and the first affected, treated eye, optical coherence tomography, contrast sensitivity and quality of life scales.
GS010 uses a proprietary mitochondrial targeting sequence platform, which, when associated with the gene of interest, allows the platform to specifically address defects inside the mitochondria using an adenoviral vector. The gene of interest is delivered to the mitochondria through specific nucleotidic sequences in order to restore mitochondrial function.
Investigators saw evidence of a dose effect between bilaterally and unilaterally treated participants, with both eyes in bilaterally treated participants showing greater improvements in BCVA than the treated eye in unilaterally treated patients. 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.
Investigators also conducted responder analyses that showed most subjects responded to treatment and confirmed that bilateral injections are more efficacious than unilateral ones. Most participants had on-chart BCVAs at 1.5 year, with 85% of bilaterally treated participants able to read letters on a screen compared to 72% of unilaterally treated participants.
Comparing BCVA at 1.5 years to the BCVA nadir since baseline demonstrated clearer efficacy, with LogMAR score improving by 0.37 in bilaterally treated participants in the first eye (+19 ETDRS letters; P <.0001) and by 0.31 in the second eye (+16 ETDRS letters; P <.0001). LogMAR score improved by 0.37 (+19 ETDRS letters; P <.0001) in the first eye in unilaterally treated participants. LogMAR score also improved in the placebo-treated eye by 0.25 (+13 ETDRS letters; P <.0001). Altogether, at 1.5 years, 69% of bilaterally treated participants and 64% of unilaterally treated participants improved by at least 3 lines from nadir.
GS010 was found to be well-tolerated, with no participants discontinuing the study due to systemic or ocular adverse events (AEs). The main ocular AE was mostly mild intraocular inflammation, which was responsive to conventional treatment, and no serious ocular AEs occurred. Safety profiles were similar between unilaterally and bilaterally treated patients.
“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,” Sergott added.