A completely new drug candidate – called a small molecule ‘photoswitch’ – has moved into a Phase 2 trial after a successful first-in-human trial in Adelaide that saw one blind retinitis pigmentosa (RP) patient regain light perception for the first time in 10 years.
The experimental therapy, known as KIO-301, was evaluated in a Phase 1 clinical trial led by researchers at the Royal Adelaide Hospital and published in Nature Medicine.1
The study found the treatment was safe and produced early signs that it may restore some degree of visual function in people with advanced RP, an inherited retinal disease that progressively destroys the eye’s photoreceptors.
Unlike gene therapies that target specific genetic mutations, KIO-301 is a small molecule ‘photoswitch’ drug designed to make retinal ganglion cells responsive to light. These cells normally carry visual information from the retina to the brain but do not themselves detect light.
Professor Robert Casson, principal investigator of the Australian trial from the University of Adelaide, explained that the treatment effectively bypasses damaged photoreceptors.
The whole trick of this thing is that the KIO-301 photoswitch sits inside a retinal ganglion cell ion channel and changes shape when struck by light, and that triggers the retinal ganglion cells to fire a signal to the brain
“This small molecule can enter retinal ganglion cells with no sort of chaperone required. It’s just injected into the vitreous.
“The photoreceptors ordinarily respond to light, converting the light signal into an electrical signal, which is then transmitted to cells downstream – firstly to the bipolar cells and then to the retinal ganglion cells. And then the retinal ganglion cells fire what’s called an ‘action potential’ along the optic nerve to the brain.
“So, if the photoreceptors are completely degenerated, then the retinal ganglion cells are sort of sitting there waiting for a signal that never comes,” he told mivision.
“The whole trick of this thing is that the KIO-301 photoswitch sits inside a retinal ganglion cell ion channel and changes shape when struck by light, and that triggers the retinal ganglion cells to fire a signal to the brain.”
The open-label Phase 1 trial involved six participants with advanced RP, including some with no light perception at baseline. Participants received a single intravitreal injection of KIO-301 into each eye and were followed for 30-days.
While Prof Casson said the primary outcome was safety –the study was not designed to prove efficacy – researchers observed several signals suggesting biological activity.
Functional magnetic resonance imaging (fMRI) data showed “definite activity of visual pathways in the brain” after being treated with the drug, Prof Casson said.
“So that was particularly exciting to see. The other thing that was particularly exciting is that a patient who had no perception of light in both eyes at baseline recovered perception of light after treatment, after not seeing any light for over 10 years. I thought, ‘wow, that’s really incredible’.”
The effect lasted for weeks before wearing off, “so the drug would need to be injected probably at something like one to two monthly intervals”, similar to anti-VEGF therapy.
Safety Profile
According to the Nature Medicine paper, no serious adverse events or dose-limiting toxicities were observed and there was no drug-related intraocular inflammation. Prof Casson said the safety profile was especially encouraging given that inflammation can be a significant issue in some retinal gene therapies.
“The safety was extremely good, very reassuring,” he said. “There were no adverse events. The eyes were all completely quiet at all time points.”
Researchers believe this innovative approach may eventually have applications beyond RP, potentially including severe geographic atrophy, choroideremia, and high myopic retinopathy, provided retinal ganglion cells remain intact.
Phase 2 Underway
Because KIO-301 is gene mutation-agnostic, it may offer a treatment pathway for patients regardless of the underlying genetic mutation causing disease.
The program has already progressed into a multicentre Phase 2 study known as ABACUS-2, which will enrol 36 participants from Adelaide, Melbourne, Sydney, Brisbane, Perth, and Auckland. The trial includes a control arm designed to provide clearer evidence of efficacy.
Prof Casson said the next study would evaluate functional outcomes such as visual field changes and patients’ ability to identify objects under different lighting conditions.
If the Phase 2 data are positive, the therapy would progress to a larger Phase 3 pivotal trial focused on demonstrating clinical efficacy.
“It’s taken several years to reach the clinic,” Prof Casson said. “But it is a completely new science.”
The photoswitch technology underpinning KIO-301 was originally developed in the United States at the University of California, Berkeley, by Professor Richard Kramer and colleagues. The drug is owned by the US-based Kiora Pharmaceuticals, a clinical-stage pharmaceutical company developing small-molecule therapies to preserve and restore vision loss caused by retinal diseases.
Reference
- Casson RJ, Daniels E, Van Gelder RN, et al. Intravitreal photoswitch therapy in advanced retinitis pigmentosa: a phase 1 open-label trial. Nat Med. 2026 May;32(5):1865-1870. doi: 10.1038/s41591-026-04317-6.
