Abstract
Purpose :
We investigated the safety and tolerability of RetinoStat®, a lentiviral vector-based therapy for the treatment of wet AMD, in a Phase I (GEM) study. The recombinant EIAV-based construct contains cDNAs for secretable endostatin and angiostatin to potentially inhibit angiogenesis in wet AMD subjects for whom anti-VEGF therapy is not sufficient. This is the first time in Man a lentiviral vector has been administered to the eye.
Methods :
Twenty-one patients were treated (three dose groups (n=3) and final cohort at highest tolerated dose (n=12)) with active CNV at baseline and a best-corrected visual acuity (BCVA) ≤20/200 (for dose-escalation) or ≤20/80 (final cohort). BCVA in the fellow eye was ≥20/200. All patients had advanced stage disease with central subretinal fibrosis and poor anti-VEGF response despite an initially responsive medical history, the primary endpoint was therefore safety and tolerability. Secondary endpoints to assess signs of clinical benefit were also measured, and aqueous samples, taken throughout the study, were used to quantify transgene expression.
Results :
Subretinal administration of RetinoStat® was well-tolerated at all three doses. There were no adverse events or severe adverse events related to drug or procedure. Inflammation, observed only at the highest dose, was graded mild and transient. RetinoStat® rapidly produced substantial, dose-dependent and persistent (out to >4 years so far) levels of both transgenes in the aqueous fluid. To our knowledge this is the first time a gene therapy delivered transgene product has been measured directly following administration to the eye. Vascular leakage, present in all subjects at baseline, was absent in the majority of patients at 6 and 12 months. Visual outcome showed little change across the trial in these advanced patients, potentially indicating disease stabilization.
Conclusions :
RetinoStat® met the primary endpoint of the study: it was safe and well tolerated. Patients showed signs of clinical benefit, with visual acuity stabilization and a reduction in vascular leakage consistent with the mechanism of endostatin/angiostatin function in this severe wet AMD population. The data demonstrates that the LentiVector® gene therapy platform safely and efficiently delivers genes to the retina resulting in stable, long-term expression.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.