Abstract Details

Title The Latest Data from Lenadogene Nolparvovec Gene Therapy Trials for Leber Hereditary Optic Neuropathy

Topic Neuro-ophthalmology/Neuro-otology

Presentation(s) S14 - Neuro-ophthalmology/Neuro-otology (11:15 AM-11:27 AM)

Poster/Presentation
Number 001

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

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

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.

Authors/Disclosures
Nancy J. Newman, MD, FAAN (Emory University School of Medicine) PRESENTER	Dr. Newman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for GenSight. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Chiesi. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurophth. Dr. Newman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. The institution of Dr. Newman has received research support from GenSight. The institution of Dr. Newman has received research support from Santhera. The institution of Dr. Newman has received research support from NINDS/NIH. Dr. Newman has received publishing royalties from a publication relating to health care. Dr. Newman has received publishing royalties from a publication relating to health care. Dr. Newman has received publishing royalties from a publication relating to health care.
Patrick Yu-Wai-Man	Patrick Yu-Wai-Man has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for GenSight Biologics. Patrick Yu-Wai-Man has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Chiesi. Patrick Yu-Wai-Man has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke Therapeutics. Patrick Yu-Wai-Man has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PYC Therapeutics.
Valerio Carelli, MD, PhD (University of Bologna)	Dr. Carelli has received personal compensation in the range of $0-$499 for serving as a Consultant for Chiesi Farmaceutici. Dr. Carelli has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Chiesi Farmaceutici.
Valerie Biousse, MD	Dr. Biousse has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gensights Biologic. Dr. Biousse has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Topcon. Dr. Biousse has received publishing royalties from a publication relating to health care. Dr. Biousse has received publishing royalties from a publication relating to health care.
Magali Taiel	Magali Taiel has received personal compensation for serving as an employee of GenSight Biologics.
Jose-Alain Sahel	The institution of Jose-Alain Sahel has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Avista. The institution of Jose-Alain Sahel has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Tenpoint . The institution of Jose-Alain Sahel has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for THE BOARD OF GENSIGHT. The institution of Jose-Alain Sahel has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for THE BOARD OF SPARINGVISION. Jose-Alain Sahel has stock in Prophesee. Jose-Alain Sahel has stock in Tilak Healthcare. Jose-Alain Sahel has stock in Sparing Vision. Jose-Alain Sahel has stock in Chronolife. Jose-Alain Sahel has stock in VegaVect Inc.. Jose-Alain Sahel has stock in Avista. Jose-Alain Sahel has stock in Tenpoint. Jose-Alain Sahel has stock in SharpEye. Jose-Alain Sahel has stock in GenSight. The institution of Jose-Alain Sahel has received research support from LabEx LIFESENSES (ANR-10-LABX-65). The institution of Jose-Alain Sahel has received research support from IHU FOReSIGHT (ANR-18-IAHU-01). The institution of Jose-Alain Sahel has received research support from ERC Synergy "HELMHOLTZ". Jose-Alain Sahel has received intellectual property interests from a discovery or technology relating to health care.

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