Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

Abstract

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies.Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control.Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss.Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences.Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4.Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p < 0.0001).Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies.Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

Mitochondrial Retinopathies

“…This has been thought to be due to the leakage of the AAV vector into the contralateral eye, as shown experimentally in non-human primates [ 186 ]. Consistently, another two groups running similar trials with parallel gene therapy products have reported similar results [ 187 , 188 ]. In addition to this bilateral effect could be the presence of a secondary mutation in mtDNA, which could be a prompt to rethink the clinical trial design for such approaches in the future.…”

Biodistribution of intravitreal lenadogene nolparvovec gene therapy in nonhuman primates

“…An examination of these two hypotheses follows. Other less-likely explanations include an underappreciation of the natural history of visual improvement in the disease, which is not supported by recent meta-analyses, 10 , 17 , 18 involvement of inflammatory mediators or other signaling pathways triggered by the injections that activate cell survival in general, 23 , 24 or brain plasticity with plastic changes in higher visual centers to restore the original visual modality, leading to improved visual performance in both eyes. 25 , 26 , 27 …”

“…In four separate clinical trials, including one phase 1/2 study (REVEAL), two pivotal trials (REVERSE and RESCUE), and one long-term follow-up study (RESTORE), MT-ND4 LHON patients unilaterally injected with lenadogene nolparvovec demonstrated bilateral visual improvement beyond the expectations of the natural history of the disease. 8 , 9 , 10 , 11 , 17 , 18 , 19 A similar contralateral effect was reported in two other comparable gene-therapy trials developed for MT-ND4 LHON subjects in the United States 20 , 21 and in China; 12 , 13 each used a viral vector containing a cDNA coding the human wild-type mitochondrial ND4 protein (AAV2-ND4), the route of administration was IVT, and MT-ND4 subjects were injected in only one eye in all studies. This contralateral effect has not been described in gene therapies with subretinal administration targeting other ophthalmic genetic diseases, specifically in patients with RPE65 -mediated inherited retinal dystrophy who participated in a randomized, controlled, open-label, phase 3 trial.…”

“…Two randomized, double-masked, sham-controlled phase 3 clinical trials (REVERSE, ClinicalTrials.gov: NCT02652780 , and RESCUE, ClinicalTrials.gov: NCT02652767 ) and their long-term follow-up study (RESTORE, ClinicalTrials.gov: NCT03406104 ) in LHON patients harboring the m.11778G > A mutation (hereafter named MT-ND4 patients) who received a unilateral intravitreal (IVT) injection of lenadogene nolparvovec showed improvement of best-corrected visual acuity (BCVA) in both treated and untreated eyes. 8 , 9 , 10 , 11 Two other gene-therapy trials using a viral vector containing a cDNA coding the human wild-type mitochondrial ND4 protein have shown similar bilateral improvement after unilateral IVT of a similar allotopic expression-based gene therapy (AAV2-ND4) in LHON MT-ND4 patients. 12 , 13 , 14 , 15 , 16 This visual improvement is beyond what would be expected from the natural history of visual function in MT-ND4 LHON patients.…”

“… 12 , 13 , 14 , 15 , 16 This visual improvement is beyond what would be expected from the natural history of visual function in MT-ND4 LHON patients. 10 , 17 , 18…”