Incannex Healthcare is developing IHL-42X, a novel cannabinoid pharmacotherapy, for treating obstructive sleep apnea (OSA). The phase 2/3 RePOSA study is evaluating the safety and efficacy of IHL-42X, a combination of tetrahydrocannabinol (THC) and acetazolamide, in addressing this unmet medical need.
Challenges in Developing IHL-42X
Mark Bleackley, PhD, chief scientific officer of Incannex, noted the challenges in developing IHL-42X. A primary hurdle was the absence of approved drugs for OSA, making it necessary to work closely with the FDA to determine appropriate endpoints for clinical trials. "Because it's an unmet need, we're sort of figuring it out as we go along. We don't have that roadmap to rely on," Bleackley stated.
Adverse Events and Mitigation Strategies
Clinical trials have revealed adverse events consistent with the known effects of THC, such as altered sensorium and euphoria, and acetazolamide, including paresthesia. Other common adverse events included headaches and gastrointestinal upset. To mitigate these effects, Incannex is employing a combination therapy strategy to reduce the dose of each individual component while maintaining or improving efficacy. "Looking at THC, when we ran our proof of concept study, our highest dose is where we saw the psychoactive effects of THC-related adverse events. In the next study, we're actually dropping that highest dose and focusing on the lower 2 doses to mitigate that risk of those types of adverse events," Bleackley explained.
Unexpected Dose Response
One surprising finding was the non-linear dose response observed with IHL-42X. Contrary to the expectation that higher doses would lead to greater efficacy, the study found the opposite. This phenomenon, while initially unexpected, is not uncommon with cannabinoids. "I think the one result which was initially surprising was that we didn't have a sort of standard dose response, where adding more drug led to more efficacy. We actually saw the opposite," Bleackley said. Further investigation revealed that non-linear dose responses are fairly common for cannabinoids, although the underlying mechanisms are not fully understood.
