Leber Hereditary Optic Neuropathy (LHON) is a rare blinding disease leading to bilateral vision loss. Lenadogene nolparvovec (rAAV2/2-ND4) is a gene therapy developed for the treatment of LHON caused by a mutation in the ND4 gene.

A unilateral intravitreal injection (IVT) of lenadogene nolparvovec was shown to significantly improve visual acuity in 76 subjects treated in the Phase III RESCUE and REVERSE trials, compared to natural history. An unexpected and sustained contralateral improvement was also reported, and vector DNA was detected in the un-injected eye of macaques injected unilaterally.

Phase III trial REFLECT included 98 MT-ND4 LHON subjects with a duration of vision loss ≤ 12 months. Each subject received an IVT of lenadogene nolparvovec in their first-affected eye, and either gene therapy or placebo in their second-affected eye.

Forty-eight subjects were treated bilaterally and 50 were treated unilaterally. At 1.5 years, the difference in best-corrected visual acuity (BCVA) improvement between second-affected eyes was equivalent to +3 ETDRS letters in favor of lenadogene nolparvovec. The eyes treated with lenadogene nolparvovec showed a significant improvement from nadir of +19 and +16 ETDRS letters for the first- and second-affected eyes respectively (p<0.0001), compared to +13 ETDRS letters in eyes treated with placebo (p<0.0001). A better average final visual acuity was reported in subjects treated bilaterally, compared to subjects treated unilaterally (+5 letters). The favorable safety profile of the gene therapy was confirmed in both unilaterally and bilaterally treated patients.

At 1.5 years post administration, a statistically significant improvement of BCVA was reported from baseline in treated eyes, and from nadir in all eyes. As in the RESCUE and REVERSE gene therapy trials, a contralateral effect was seen in the placebo-treated eyes. The results also suggest a dose effect with bilateral injection of lenadogene nolparvovec.