Objective:

To present all available updated results of lenadogene nolparvovec gene therapy (LNGT) for Leber hereditary optic neuropathy (LHON).

Background:

LNGT is an intravitreal gene therapy for LHON patients carrying the m.11778G>A MT-ND4 mutation.

Design/Methods:

LNGT clinical trials include 1 phase-1/2B study (REVEAL) and 3 randomized phase-3 studies (RESCUE, REVERSE and REFLECT), with long-term follow-up for RESCUE/REVERSE (RESTORE), and ongoing compassionate use in 63 patients. In RESCUE/REVERSE, patients received LNGT in one eye and sham injection in the other. In REFLECT, all first-affected eyes received LNGT and second eyes were randomized to LNGT or intravitreal placebo. Best-corrected visual acuity (BCVA) from phase-3 studies were indirectly compared to those of an external control group of natural history (NH) patients. Three meta-analyses assessed visual outcomes of patients with no treatment, idebenone treatment or LNGT.

Results:

Single unilateral LNGT injection improved BCVA in both eyes. Persistence of LNGT effect and a favorable safety profile were observed up to 5 years. In RESTORE, mean change in BCVA from nadir at 5 years was +22 letters for LNGT-treated eyes and +20 letters for sham-treated eyes. In REFLECT, mean improvement in BCVA from nadir to 4 years was +20 letters and +17 letters in the first- and second-affected eyes of bilaterally-treated patients, and +19 letters and +14 letters in unilaterally-treated patients. Quality-of-life VFQ25 scores meaningfully improved from baseline to last follow-up. In an indirect comparison, mean gain with LNGT was 21.5 ETDRS letters versus NH (p<0.0001). In metanalyses, clinically relevant recovery (CRR) from nadir [95%CI] at eye level was 17% [7%;30%] (n=316), 31% [24%;40%] (n=313) and 59% [54%;64%] (n=348) in untreated, idebenone-treated and LNGT-treated patients.

Conclusions:

Over 10 years, 252 MT-ND4-LHON patients have received LNGT, with good safety profile and improved BCVA and quality-of-life. A planned trial with untreated LHON patient controls (RECOVER) should allow for acceptance by regulatory agencies.