Keeping an eye on LHON research

GenSight Biologics announces publication of positive safety data in JAMA Ophthalmology from Phase 1/2 trial of GS010 for Leber Hereditary Optic Neuropathy

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PARIS—Today, GenSight Biologics announced publication of detailed safety data from the Phase 1/2 clinical trial of GS010 in Leber Hereditary Optic Neuropathy (LHON) patients in the Journal of the American Medical Association (JAMA) Ophthalmology. LHON is a rare maternally inherited mitochondrial genetic disease, characterized by the degeneration of retinal ganglion cells that results in brutal and irreversible vision loss that can lead to legal blindness, and mainly affects adolescents and young adults.
The publication, entitled “Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene: A Secondary Analysis of a Phase 1/2 Clinical Trial,” demonstrates that GS010 (rAAV2/2-ND4) is both safe and well tolerated 2 years after a single unilateral intravitreal administration.
The study was an open-label single-center Phase 1/2 clinical trial that included 4 dose-escalation cohorts and an extension cohort. Fifteen subjects with LHON carrying the ND4-G11778A mutation were prospectively enrolled. Each subject received a single intravitreal injection of rAAV2/2-ND4 in the worse-seeing eye. The study design included an initial follow-up period of 48 weeks, with longer-term follow-up for an additional 4 years. The primary objective was to ascertain the safety and tolerability of escalating doses of rAAV2/2-ND4. Secondary objectives included bio-dissemination and immunogenicity of rAAV2/2-ND4 and evaluation of visual functions.
“Our findings have implications for all gene therapies employing viral vectors that are administered intravitreally,” said Dr. Barrett Katz, Chief Medical Officer of GenSight. “The tolerability of our vector and safety of our drug offer further support for the application of this technology to future trials. This confirms our confidence in continuing this journey searching for answers in blinding diseases for which adequate treatment is wanting.”
The analysis included 15 patients enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum ocular inflammation score (OIS) of 9.5 was observed in a patient with history of idiopathic uveitis.
Overall, OIS was not associated with the viral dose administered. No neutralizing antibodies (NAb) against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not associated with either the dose administered or with the immune status of patients at baseline. No association was found between OIS and serum NAb titers.
“Our results are consistent with previous work in cynomolgus macaques showing that detection of NAbs in the anterior chamber and serum did not correlate with increased exposure to intravitreal AAV vectors; this finding suggests that immune responses are not specific to the gene therapy product but rather are patient driven,” says the article. “It is known that CpG-rich viral genomes, such as that of the rAAV2/2-ND4 vector, can activate Toll-like receptors and trigger an innate immune response. In our study, not every patient administered a medium or high dose developed an immune response, indicating that rAAV2/2-ND4 is not highly immunogenic when injected in the vitreous. As expected, no NAbs were detected in the aqueous humor of the patients at baseline regardless of antibody levels in the serum. However, considering that ocular inflammation was reported after vector administration, we cannot confirm that AAV vectors are completely nonimmunogenic or that the eye is an entirely immune-privileged organ. Ongoing animal studies will help determine whether antibodies against rAAV2/2-ND4 can be detected in the eye after intravitreal administration and shed light on the local immune response to gene therapy.”
The article also notes that the study was limited by the small number of patients, going on to say that “these observations should be examined along with the forthcoming results of 2 ongoing Phase 3 trials, Efficacy Study of GS010 for the Treatment of Vision Loss up to 6 Months From Onset in LHON Due to the ND4 Mutation (RESCUE) and Efficacy Study of GS010 for Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the ND4 Mutation (REVERSE), in which 76 patients with G11778A-ND4 LHON were treated with rAAV2/2-ND4 at a dose of 9 × 1010 vg per eye.”

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