Acasti Pharma Inc. announced that preliminary topline results for its single-dose, pharmacokinetic (PK) bridging study to evaluate the relative bioavailability of GTX-101 compared to the reference listed drug in the U.S., bupivacaine subcutaneous injectable, met all primary outcome measures for the study. The final clinical study report is anticipated to be received by the Company in the first half of 2023. This PK study was the next step in the proposed 505(b)(2) regulatory pathway for GTX-101 and provides important information on the dose and dosing frequency in humans for future planned clinical studies. GTX-101 is a novel formulation of bupivacaine hydrochloride (HCl) for topical administration via a bio-adhesive,
film-forming polymer, for relief of pain associated with Postherpetic Neuralgia (PHN), a persistent and often debilitating neuropathic pain caused by nerve damage from the varicella zoster virus (shingles), which may persist for months and even years. The potential benefits of GTX-101 could include faster onset of action and a longer duration of pain relief as compared to the lidocaine patch. GTX-101 can be conveniently sprayed on the skin wherever the pain is located, and based on the PK profile of bupivacaine, the Company believes that GTX-101 may only need to be applied once or twice a day to the affected area for 24/7 pain relief, although this dosing schedule will need to be confirmed in future clinical studies. Based on this product profile, and assuming a successful development program, the Company believes GTX-101 has the potential to be a game-changer as a non-opioid alternative to the lidocaine patch for PHN patients who suffer from this debilitating pain. The Single Dose PK study for GTX-101 was a Phase 1, Randomized, Single-Dose, 4-Cohort, Parallel study to evaluate the pharmacokinetics, dose proportionality, safety and tolerability of GTX-101 (bupivacaine hydrochloride metered dose spray) and subcutaneous injectable bupivacaine in 48 healthy subjects. The primary objective was to assess the pharmacokinetics of 3 dose levels of GTX-101 (50, 100, and 200 mg) given as a single-dose topical application (metered spray). Details of the study design can be found on ClinicalTrials.gov [1], Identifier: NCT05517486. The study enrolled 48 healthy adult subjects (24 males/24 females, mean age = 36 years), in 12 subjects per cohort. Subjects in Cohorts 1, 2, and 3 received GTX-101 as either 5, 10, or 20ásprays (50, 100, or 200 mg, respectively). Subjects in Cohort 4 received a single 10 mg subcutaneous injection of the active control. It is important to note that one of the secondary objectives of this study was to compare the bioavailability of these two very different modes of administration. The first subject /first dose was administered on July 26th and the dosing phase of the study was completed on August 21st, 2022. GTX-101 PK Study Outcome Definitions and Preliminary Topline Findings Are as Follows: Primary outcome measures and their definitions include: + Cmax is the maximum concentration occurring at Tmax between 0 hour to 240 hours after study drug administration. Tmax is the time of maximum concentration between 0 hour to 240 hours after study drug administration. AUC last is the area under the concentration time curve from the time of last dosing to the time of last quantifiable concentration. AUC8 is the area under the concentration time curve extrapolated to infinity. Thalf is the time required for the plasma concentration to decrease by 50%. The median time to reach the maximum concentration of bupivacaine in plasma (Tmax) following GTX-101 single-dose topical applications of 50, 100 and 200 mg ranged between 18 to 24 hours depending on dose, while the median Tmax following the subcutaneous injection of 10 mg of bupivacaine was only 23 minutes. This finding suggests that the bupivacaine delivered by GTX-101 remains in the skin for a long period of time, potentially inducing prolonged analgesic effect in the sprayed area. The exposure to bupivacaine based on Cmax and AUC8 following GTX-101 topical application as a single-dose of 50, 100 and 200 mg, increased with increasing dose. This was predictable and expected. The systemic exposure to bupivacaine following a 200mg dose of GTX-101 was: Approximately 29-fold less than a single subcutaneous dose of 10mg of bupivacaine based on Cmax and,
Approximately 6-fold less than a single subcutaneous dose of 10mg of bupivacaine based on AUC 8. These results are predicted to correspond to an increased safety margin for GTX-101 with regards to toxicity risk. Postherpetic neuralgia (PHN) is neuropathic pain caused due to damage by the varicella zoster virus. After a primary varicella infection (chickenpox), the varicella zoster virus can remain persistent but clinically latent in the sensory nerve ganglia for many years before being reactivated and becoming manifest clinically as herpes zoster (shingles). Despite healing for herpes zoster, the pain may persist for months or even years and this PHN is the most common and debilitating complication of herpes zoster. Postherpetic neuralgia is associated with significant loss of function and reduced quality of life, particularly in the elderly, and is highly resistant to treatment. Since PHN is often resistant to pharmacologic treatments, a multimodal analgesic treatment strategy is often used to balance the efficacy and tolerability of the
medication regimen, the side effects of which can be limiting and can themselves compromise quality of life and patient compliance. Postherpetic neuralgia occurs most commonly in the elderly, in whom a large number of drugs are often prescribed, and so the use of a long-acting topical analgesic with minimal risk of systemic toxicity, would be advantageous.