The phase 3 trial, pending the FDA’s approval of new finalized protocol, will be conducted across 25 to 30 sites in the US, comparing the safety of GTX-104 with oral nimodipine.
After receiving a type C written meeting response and clarifying feedback from the FDA, Acasti Pharma plans to submit final clinical protocol that will ultimately allow it to move forward with a phase 3 clinical trial assessing its investigational agent GTX-104 in patients with subarachnoid hemorrhage (aSAH).
In the FDA’s comments toward the company’s development plan, the agency concurred that Acasti’s GTX-104-002 pharmacokinetic study may have met the criteria for a scientific bridge. The final proposed study protocol by the FDA includes patients with all grades of severity, stratified through the Hunt and Hess scale, to be randomly assigned 1:1 to either GTX-104 or oral nimodipine. Spanning across 25-30 sites in the US, the proposed study will use safety as the primary end point, measured as a percentage of significant adverse events (AEs) of hypotension related to study drugs in both arms.
GTX-104 is a clinical stage, novel formulation of nimodipine being developed as an intravenous infusion for patients with aSAH. It incorporates surfactant micelles as the drug carrier to solubilize nimodipine. This nimodipine injectable formulation is comprised of a nimodipine base, an effective amount of hydrophilic surfactant, and a pharmaceutically acceptable carrier for injection.
"We expect to move quickly to submit the final clinical protocol and all required study documentation to the FDA. Once these documents are submitted and following any final feedback and approval from the FDA, the Phase 3 safety study can be initiated. If the Phase 3 study meets the primary endpoint, an NDA filing for GTX-104 under Section 505(b)(2) is expected to follow," Prashant Kohli, chief executive officer, Acasti Pharma, said in a statement.
In May 2022, Acasti announced topline results from its PK bridging study of GTX-104, showing that the agent met all its planned study end points. Completed at a single center in Canada, the study included a 2-period crossover portion where individuals received IV GTX-104 first, followed by oral nimodipine; or oral nimodipine first, followed by IV GTX-104. The cohort included 58 individuals with aSAH who received treatment over a period of 72 hours.
The primary PK end point, maximum concentration during the first 4 hours on day 1, expressed as Cmax, was 92% (90% CI, 82-104). Total amount of nimodipine in the blood, expressed as area under the curve, was 106% (90% CI, 99-114) at day 3. The secondary end pint, Cmax measured over 24 hours on day 3, was 92% (90% CI, 85-101). All 3 end points indicated that stasticially, there was no difference in exposures between IV GXT-104 and oral nimodipine over the defined time periods for both maxium exposure and total exposure.
In terms of safety, more gastrointestinal disorders were observed with oral nimodipine (16% vs 7%), whereas more administration and sampling site related events were observed with IV GTX-104 (41% vs 11%). For both IV and oral formulations, the other most frequently observed adverse events were headache (36% and 36%), somnolence (9% and 13%), and hot flashes/flushing (10% and 11%).
Following IV administration, investigators observed significantly less variability among individuals when compared with those on oral administration of capsules. The company concluded that this is because "IV administration is not as sensitive to some of the physiological processes that affect oral administration, such as taking the drug with and without meals, variable GI transit time, variable drug uptake from the GI tract into the systemic circulation, and variable hepatic blood flow and hepatic first pass metabolism."
Additional findings from the PK study showed that the bioavailability of oral nimodipine capsules was 8% relative to IV GTX-104. Furthermore, the diurnal variation, which accounts for bodily functions such as blood flow, renal function, and hepatic metabolism, associated with IV GTX-104 was approximately half of that seen with the oral nimodipine capsules.