KIO-301 shows promising safety results in early-stage testing

What is RP:

Inherited retinal dystrophies (IRDs), which include retinitis pigmentosa (RP) and Stargardt disease, are the most common cause of blindness in children and working aged people in the UK. Yet the conditions are rare, with only about 25,000 people affected in the UK. More than 300 genes have been linked to inherited sight loss conditions and many more are yet to be identified.

RP, one of the most common types of IRD, is associated with faults in over 100 genes, making it difficult to develop gene-specific therapies. RP causes progressive vision loss, starting peripherally, due to the loss of light-sensing photoreceptor cells in the retina. There are two types of photoreceptors, cones and rods, which differ in structure, function and location. To learn more, please watch this short animation video on Inherited Retinal Disease

Visual Pathway:

Many IRDs result in progressive vision loss due to the loss of light-sensing photoreceptors. However, even though the photoreceptors are lost, many of the other cells in the retina remain alive, such as the retinal ganglion cells (RGCs). RGCs are the output neurons of the retina that process and transfer visual information to the brain. In healthy eyes, the cycle is as follows:

Light → photoreceptors (rod/cone) → bipolar cells → retinal ganglion cells → optic nerve → brain

Due to the loss of photoreceptors in those with IRDs, researchers have been investigating ways to make the surviving cells in the retina, such as RGCs, respond to light, therefore bypassing the need for photoreceptors.

We recently published an article on the encouraging results of photoswitch drugs seen in animal models during preclinical study. In this article, however, we are pleased to share an exciting update from researchers investigating a different photoswitch drug, known as KIO-301, in early-stage clinical trials. Kiora Pharmaceuticals hope this has the potential to restore some functional vision to those with very advanced sight loss. The drug is currently being trialled in those with advanced RP, with potential to expand into choroideremia and Stargardt disease.

Photoswitch drugs:

This approach is based on photopharmacology, a technique in which drug activity can be switched on or off with light. The team created photoswitchable drugs, which are small molecules that change their behaviour when exposed to light. So, in darkness they remain inactive and when illuminated, they change shape and activate nerve cells in the retina.

Instead of repairing damaged photoreceptors, these drugs allow other retinal cells such as RGCs to detect light. This technique doesn’t change a person’s DNA or require surgery to implant a device and uses small drug molecules that could potentially be delivered more simply into the eye via injections.

KIO-301:

KIO-301 is delivered via an intravitreal injection (an injection into the jelly-like substance of the eye) to target the surviving retinal ganglion cells. Although an intravitreal injection sounds scary, the eye is numbed with anaesthetic drops before the procedure takes place and the injection only lasts a few seconds.

RGCs normally receive signals from the photoreceptors which they transmit and process to the rest of the visual pathway. However, when treated with KIO-301, these cells have the potential to respond to light. When light enters the eye, the molecules respond by changing their shape, triggering signals inside the retina in a way that mimics natural vision. These molecules can be thought of as light switches – they remain ‘off’ in dark conditions and are activated in light.

This approach will not restore full healthy vision but will provide those with advanced sight loss with some useful functional vision such as light detection.

Results from early-stage phase 1 trials supported preclinical findings and demonstrated that KIO-301 was well tolerated, with no serious adverse events or dose-limiting toxicities observed at any point. Although the main focus of this phase 1 trial was to establish safety, it also provided early insights into the efficacy of the treatment. This data will help to inform the selection and refinement of outcome measures for future, larger studies where a greater emphasis will be on the ability of KIO-301 to improve visual function and light sensitivity.

What’s next:

KIO-301 is now being evaluated in a phase 2 clinical trial known as ABACUS-2 across sites in Australia. This is a randomised, controlled, double masked and multiple dose study assessing the safety, tolerability and efficacy of intravitreal KIO-301 in patients with late-stage RP.

This means that participants are randomly allocated to receive a placebo or treatment dose and both participants and researchers are unaware of who is in which group. Participants will receive up to three doses of KIO-301 administered by intravitreal injection into both eyes every six weeks.

To learn more about this trial, please visit here.

To learn more about KIO-301 or Kiora Pharmaceuticals, please visit their website here.