Incannex Healthcare Inc, a pharmaceutical company developing medicinal cannabinoid pharmacotherapies and psychedelic medicine therapies, provided an update on its IHL-42X drug candidate, a cannabinoid combination product being developed for the treatment of obstructive sleep apnea (OSA).

Incannex has designed IHL-42X, a combination of dronabinol (synthetic THC) and acetazolamide, for the treatment of OSA. Both dronabinol and acetazolamide are clinically proven to reduce apnea-hypopnea index (AHI); however, both drugs have limited efficacy, as well as unwanted side effects at efficacious doses. 

Dronabinol and acetazolamide affect OSA through different pathways. Binding of dronabinol to cannabinoid receptors modulates signaling and activates muscles that dilate the airway, preventing collapse and obstruction, whereas acetazolamide induces metabolic acidosis which signals to the body that there is excess CO2 in the blood, inducing the taking of a breath.

IHL-42X is designed to combine these two activities, leading to an increase in efficacy that reduces AHI to a greater degree and/or facilitating a reduction in dose of each active pharmaceutical ingredient to minimize the side effects. 

Results from Proof-of-Concept Phase 2 Clinical Trial

To demonstrate proof-of-concept for IHL-42X in the treatment of OSA, Incannex conducted a phase 2 clinical trial comparing three dose strengths of IHL-42X, low dose (2.5 mg dronabinol + 125 mg acetazolamide), medium dose (5 mg dronabinol + 250 mg acetazolamide), and high dose (10 mg dronabinol + 500 mg acetazolamide), to placebo with regards to safety and efficacy in OSA patients.

The trial was a four-period cross-over study whereby every patient received each dose of IHL-42X and placebo for seven days. The seven-day treatment periods were separated by seven-day washout periods to minimize any lasting effect of the treatment. On night seven of each treatment period, patients completed an overnight sleep study with polysomnography to assess AHI and other sleep parameters. The results of the sleep studies were compared to baseline values, captured prior to the start of treatment. Change in AHI relative to baseline was the primary endpoint for the study.

The results of the proof-of-concept study confirmed the hypothesis that the combination of dronabinol and acetazolamide is effective at treating OSA. The average reduction in AHI compared to baseline for all three doses of IHL-42X, low (50.7 %), medium (48.1 %), and high (35.2 %), reduced AHI to a substantially greater magnitude than placebo (6.4 %).

When the difference in AHI relative to baseline was compared within each patient for the IHL-42X and placebo treatment periods the low dose was again most effective. The difference for all three doses compared to placebo was statistically significant. Further analysis of the within patient changes in AHI relative to baseline revealed that during the low-dose treatment period 62.5% of patients had a reduction in AHI of greater than 50%, and 25% of patients experienced a reduction in AHI of greater than 80%. IHL-42X also improved oxygen desaturation index, sleep efficiency, and patient reported sleep quality.

The results of the proof-of-concept phase 2 clinical trial investigating IHL-42X in patients with OSA support the hypothesis that IHL-42X would be a safe and efficacious treatment. This gave Incannex the confidence to proceed with a multisite phase 2/3 clinical trial further investigating the safety and efficacy of IHL-42X in patients with OSA.

The RePOSA Study, a Phase 2/3 Clinical Trial Investigating the Safety and Efficacy of IHL-42X

To further assess the safety and efficacy of IHL-42X in patients with OSA, Incannex is conducting a phase 2/3 clinical trial that will be conducted at 55 sites across the United States, Europe, and other countries. The study has been named RePOSA, from Revealing the Efficacy of IHL-42X use in Patients with OSA. Reposa means to rest in Spanish, Portuguese, and Italian. 

For this study, the high dose (10 mg dronabinol + 500 mg acetazolamide) of IHL-42X from the proof-of-concept study has been dropped due to the psychoactive effects of THC at the 10 mg dose. In the RePOSA study the low dose is 2.5 mg dronabinol + 125 mg acetazolamide, and the high dose is 5 mg dronabinol + 250 mg acetazolamide. The drug products being tested in the RePOSA study are representative of the to-be-marketed formulation developed by Incannex.

In preparation for the study, Incannex conducted a pre-Investigational New Drug (IND) meeting with the US Food and Drug Administration (FDA) to obtain feedback on the proposed clinical development strategy, safety, and rationale for the IHL-42X drug product. This feedback was incorporated into the RePOSA phase 2/3 study design and corresponding IND application. The IND was cleared by the FDA, and the study may proceed notification was received in August 2023.

The RePOSA study consists of two component studies. A four-week phase 2 dose-ranging study that will determine the optimal dose of IHL-42X based on safety and efficacy in OSA patients, and a 52-week phase 3 factorial study that will compare the optimal dose of IHL-42X, as identified in phase 2, to the component APIs, dronabinol and acetazolamide, at equivalent doses, as well as placebo. The study is designed to facilitate a seamless transition between phase 2 and Phase 3, reducing downtime and accelerating the development timeline.

The endpoints, inclusion/exclusion criteria, and study procedures are the same across both component studies, which streamlines the transition process from phase 2 to phase 3. The target patient population is individuals aged 18 years or older with OSA who are intolerant, non-compliant or naïve to PAP. 

The study will recruit at least 560 patients, with a total of 355 patients receiving IHL-42X over the course of the study. Start-up for the study is in progress with 22 sites selected in the US, 10 in Germany, and 1 in Finland.