Kiora’s KIO-301 Molecular Photoswitch Evaluated for Retinitis Pigmentosa in ABACUS

Kiora Pharmaceuticals announced topline results of a phase 1/2 clinical trial demonstrating proof-of-concept that KIO-301, the company’s first-in-class intravitreal (IVT) molecular photoswitch, has the potential to meaningfully improve vision in patients with retinitis pigmentosa (RP) with ultra-low vision or complete blindness.

The ABACUS study is a first-in-human, open-label, multisite, single dose-escalating clinical trial of KIO-301. The study was directed by coprincipal investigators Professor Robert Casson, MBBS, Head of Ophthalmology & Visual Sciences, Adelaide Medical School at the University of Adelaide in Adelaide, Australia, and Russell N. Van Gelder, MD, Professor and Chair, Department of Ophthalmology, at the University of Washington School of Medicine in Seattle, Washington.

The results were presented by Dr. Gelder as a late-breaking presentation during the Retina Subspecialty Day at AAO 2023, the 127th annual meeting of American Academy of Ophthalmology held November 3-6 in San Francisco, California.

“This new technology offers hope to patients living with late-stage inherited retinal diseases,” Dr. Van Gelder said in a Kiora news release. “The mechanism of action and trial data firmly support KIO-301’s continued development, potentially filling a major unmet need in the search for treatments for these patients.”

Dr. Van Gelder added, “Based on shared pathology between RP and other inherited retinal diseases, we believe there is an opportunity to explore KIO-301 for several other indications including choroideremia and Stargardt’s disease.”

According to the company, although the study was not powered to primarily assess efficacy, the topline observations are in line with proof-of-concept for this novel class of light-restoring small molecules.

The reported observations include the following:

• Kinetic visual field (Goldmann perimetry) increased significantly from baseline at days 7 and 14 post treatment (P < .05).
• Mean improvement in visual acuity, as measured using the Berkeley Rudimentary Vision Test, of 0.30 logMAR (equivalent to three lines of visual acuity) in the high dose group (P = NS).
• Light perception, as assessed using an unprompted, binomial, back-projected letter display, improved from baseline (Odds ratio 2.1-4.2; 0.23-41.80 [80% CL]; P = NS) in patients with no or bare light perception.
• The percentage of successful navigation in the Ora-MLOM (Multiluminance Orientation & Mobility) High Contrast Room Exit—a test of mobility and functional vision under controlled lighting—trended toward improvement from 24.7 ± 15.2% at baseline to 60.0 ± 20.7% at day 28 (P = NS).
• Functional magnetic resonance imaging (MRI) demonstrated a qualitative increase in brain activity in the primary visual cortex at days 2 and 14 postinjection compared to baseline.
• Patient-reported positive impact on overall functional vision as it relates to the use of sight in everyday activities.
• Improvement in quality of life, as measured by the National Eye Institute Visual Functional Questionnaire. There was an increase of 3.3 points (an increase of 2-4 points is considered clinically meaningful).
• The duration of effect appears consistent with preclinical pharmacokinetic data, supportive of formulation as a monthly IVT injection.
• KIO-301 is safe and well tolerated with no ocular and nonocular serious adverse events, nor any signs of retinal inflammation.

In addition to the objective data, patients reported positive changes in their vision over the course of the 28-day study, advised the company.

Kiora Pharmaceutical stated that the ABACUS trial included six patients who were administered KIO-301 in each eye for a total of 12 eyes assessed. Half of the patients enrolled were the most severely affected by RP, having either no ability to perceive light or barely able to perceive light. The remaining three patients were able to perceive light but live with ultra-low vision, clinically diagnosed as being able to perceive hand motion or count fingers, but incapable of reading even the largest letter on an eye chart.

Each eye received a single IVT injection of either 7.5 (n=3), 25 (n=6), or 50 µg (n=3) of KIO-301. Assessments were performed at baseline (before KIO-301 injection) and several timepoints over 28 days post-treatment. Safety/tolerability was the primary endpoint of the trial. Visual acuity, kinetic visual field, and functional vision changes were also assessed. Additionally, functional MRI was included in the trial to understand if activity within the visual cortex of the brain changed because of treatment.

Kiora explained that KIO-301 is a small molecule, referred to as a molecular photoswitch, potentially conferring light-sensing capabilities to special types of retinal neurons called Retinal Ganglion Cells (RGCs).

In healthy eyes, light detection is performed by photoreceptors (rods and cones). In RP, mutations in any of 150 known genes lead to eventual death of photoreceptors, typically starting in the teenage years. This photoreceptor death first results in difficulty seeing in dark environments, progressing to a narrowing of one’s field of vision, and eventually leading to complete blindness.

The death of photoreceptors allows KIO-301 to selectively enter RGCs. Once inside the cell, KIO-301 localizes within specific voltage-gated ion channels involved in regulating neural signaling. When light hits these RGCs, KIO-301 alters its shape to change the flow of current, thereby activating the cell, and resulting in signaling the brain. When light is removed, KIO-301 reverts to its lower energy shape, stopping the signaling to the brain. In this way, the molecule acts as a light switch within the eye.

“I have been blind and living in complete darkness for over 10 years and was resigned to never seeing again,” commented trial patient Chris Edwards in Kiora’s press release. “During my time on this trial, under the care of Dr. Robert Casson and his team, it has changed that reality, and in fact gave me the ability to once again see light for about a month. I look forward to future clinical trials and hope this therapeutic may eventually help all of those in need.”

Eric Daniels, MD, who is Chief Development Officer of Kiora, stated in the press release, “We would like to express our sincerest gratitude to the patients, families, and caregivers for their participation in the ABACUS trial. First-in-human studies are about safety and looking for signals of efficacy. In consultation with our scientific and medical advisors, data generated in this first-in-human study strongly support Kiora continuing to a sham-controlled, multidose Phase II clinical trial in 2024. We will share the results of ABACUS and design of ABACUS II with the US FDA in the fourth quarter to ensure alignment as we look to expand our clinical development into the United States and European Union.”