Discovering Prodygy and Nirvana

A new gene-agnostic therapy called SPVN06 (SparingVision) has shown favourable safety and tolerability profiles in patients with retinitis pigmentosa in the Phase I/II PRODYGY clinical trial, said Daniel C Chung.

“With gene-agnostic therapy, we can probably reach a broader range of patients,” he said. “We can treat those with very rare genotypes that may not ever get any kind of clinical development done.”

He noted SPVN06 was designed to counteract cone photoreceptor degeneration in eyes with moderate to advanced retinitis pigmentosa. Using a subretinally injected adeno-associated virus (AAV) vector, SPVN06 delivers two distinct isoforms of the NXNL1 gene—rod-derived cone viability factor (RdCVF) and RdCVF long form (RdCVFL)—to the cones and retinal pigmented epithelium (RPE).

In healthy eyes, RdCVF is secreted by the rods, which initiates a metabolic pathway that increases glucose metabolism and carbohydrate synthesis when it reaches the cones, Dr Chung explained. Eyes with retinitis pigmentosa find the depletion of rods leads to an absence of RdCVF and, ultimately, cone death. RdCVFL is a potent antioxidant that protects cones against oxidative stress.

The ongoing clinical trial involves patients with retinitis pigmentosa of the alpha and beta rhodopsin phosphodiesterase genotypes. In the first dose escalation phase of the study, three dosage cohorts of three patients—each with vision of 20/200 or worse and visual fields of 20 degrees or less—will receive low, intermediate, and high dosages, respectively. The trial extension will involve three cohorts of patients with less advanced vision loss and primary and secondary endpoints of safety and efficacy at a one-year and five-year follow-up.

“We’re in the third dosing cohort right now, and if everything works out, we hope to have this fully enrolled by the end of 2024,” Dr Chung said.

He noted the first two dosage cohorts had no serious adverse events, no dose-limiting toxicities, and minimal inflammation. In the second cohort, nearly all patients developed hyperaemia—one patient had a macular hole (which resolved on its own), another patient had a reduction in visual acuity at six months (which later resolved), and one patient had a very slight reduction in visual acuity.

Dr Chung and his associates at SparingVision have developed another gene-agnostic therapy called SPVN20, designed to restore function to dormant cones with degenerated outer segments from retinal dystrophies. Like SPVN06, SPVN20 has an AAV vector but is administered intravitreally rather than subretinally, potentially in an office procedure. The treatment delivers a gene to induce membrane expression of G protein-gated inwardly rectifying potassium channel (GIRK), which creates a short transduction cascade within the dormant cones.

“In preclinical studies, once you put that in, phototransduction is restored,” he said. “So we are hoping to be able to restore function. This is restorative—a little different from RdCVF06, which is more about slowing or stopping the cone degeneration.”

SparingVision is planning a trial, which they have dubbed “NIRVANA, with SPVN20 in 2025, most likely starting with patients with no light perception,” Dr Chung said.

Dr Chung presented his paper at the 2024 Retina International Congress in Dublin.

Daniel C Chung DO, MA is Chief Medical Officer at SparingVision, Philadelphia, Pennsylvania, US. daniel.chung@sparingvision.com