PharmaAust’s ALS Agent Monepantel Meets Primary End Point in Phase 1 Study


Monepantel, a novel, potent, inhibitor of the mTOR pathway, was safe in patients with ALS, resulting in stabilized ALS Functional Rating Scale scores.

Michael Thurn, chief executive officer, PharmAust

Michael Thurn

Newly announced findings from a small-scale, phase 1 MEND study (NCT04894240) showed that monepantel (PharmAust), a veterinary drug, met its primary safety and tolerability end points, with slowing in disease progression, in patients with motor neuron disease (MND)/amyotrophic lateral sclerosis (ALS).1

The trial featured 12 patients with MND/ALS who were split into either cohort 1 (2 and 6 mg/kg dose levels) or cohort 2 (4 and 10 mg/kg dose levels) of monepantel for a 24-hour single-dose pharmacokinetic study, followed by a 4-week repeated escalating dose study. For all 12 patients, the estimated rate of decline was –0.74 in ALS Functional Rating Scale-Revised (ALSFRS-R) points per month or a 39% slowing in ALSFRS-R decline when compared with the PRO-ACT database, an external control cohort. All patients completed the study, with no dose limiting toxicities experienced.

From pre-dose to the end of treatment, there were no significant differences in ALSFRS-R scores for both cohort 1 (P = .41) and cohort 2 (P = .88), suggesting that treatment with the agent over 8-12 months slowed disease progression. Cohort 2 demonstrated even greater effects, demonstrated by an estimated rate of decline of –0.60 (P = .11) on ALSFRS-R, or a 58% slowing of decline. For cohort 1, the estimated rate of decline was –0.83 (P = .40) in ALSFRS-R points per month or a 23% slowing in decline.

"The release of the top-line Phase 1 MEND study results is an exciting milestone for PharmAust as we take a significant step towards helping people diagnosed with this rare and incurable disease. The 58% slowing in ALSFRS-R decline amongst Cohort 2 participants clearly demonstrates the potential to provide meaningful clinical benefit to people living with MND/ALS," Michael Thurn, chief executive officer, PharmAust, said in a statement.1 "To know that we have potentially prolonged the lives of 12 patients is extremely satisfying and humbling. We now look forward to advancing discussions with strategic partners who share our vision for monepantel."

Monepantel, a novel, potent, inhibitor of the mTOR pathway, demonstrated target engagement in the peripheral mononuclear blood cells at all dose levels. At the conclusion of the treatment period, a total of 56 treatment-emergent adverse events (TEAEs) were reported, with only 3 mild AEs considered possibly related to the study drug. After completing the study, all participants on the therapy entered into the 12-month open-label extension, where they continued with monepantel.

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Using the prognostic predictor model described in a previous 2015 study, depending on the current severity of the disease, a 0.48 slope change as calculated for all 12 patients could provide patients with an additional 13.5-56.5 months in median survival. Exploratory analyses assessing changes in slow vital capacity (P = 0.93), ALS Specific Quality of Life (P = .11), and Edinburgh Cognitive and Behavioral ALS Screen (P = .21) further supporting the therapy’s efficacy in this patient population.

Although the data was not provided, the company noted that supplemental analyses highlighted monepantel’s impact on neurofilament light, a critical biomarker of neuroaxonal damage. In terms of pharmacokinetics, concentrations of monepantel sulfane, the active metabolite of the treatment, increased proportionally with higher doses. Monepantel sulfane was found in the cerebrospinal fluid indicating that both the agent and its active metabolite have the ability to cross the blood brain barrier, according to PharmAust.

"This study has shown oral Monepantel to be safe and well tolerated by people with MND. Given the promising findings on preliminary efficacy markers, I look forward to progressing a phase 2 study as soon as possible," Susan Mathers, MD, neurologist at Monash Health, said in a statement.1

Following these positive results, PharmAust is looking to advance monepantel into a phase 2/3 trial. In January, the FDA granted the company a pre-investigational new drug meeting for the agent as a potential treatment for MND/ALS. The planned study is a multicenter, randomized, placebo-controlled, adaptive clinical trial assessing the effect of monepantel on ALSFRS-R, the primary end point, in patients with MND/ALS over a 48-week period. An interim analysis is expected to be performed at week 24 by a team of unblinded statisticians for the potential to stop the study early for either success or futility.2

1. PharmAust announces positive phase 1 MEND study top-line results in MND/ALS. PharmAust. February 28, 2024. Accessed March 12, 2024.
2. FDA grants PharmAust pre-IND meeting. PharmAust. January 2, 2024. Accessed March 12, 2024.
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