FDA, PharmAust to meet over plans for Phase 2/3 trial of monepantel

Widely used veterinary drug may help to protect motor neurons with ALS/MND

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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PharmAust announced that it soon will engage with U.S. Food and Drug Administration (FDA) regulators regarding development plans for monepantel, its investigational therapy for amyotrophic lateral sclerosis (ALS) and motor neuron disease (MND).

If the pre-investigational new drug meeting goes well, the company intends to file a request to open a Phase 2/3 clinical trial of monepantel in ALS/MND patients by mid-year, PharmAust stated in a company press release. A widely used veterinary medicine, a repurposed version of monepantel was tested in these patients in a recently completed Phase 1 clinical study.

In addition to the therapy’s further development, discussions will cover clinical and nonclinical studies and manufacturing protocols, and the possibility of monepantel being considered by the FDA under accelerated approval.

Written feedback from reviewers at the FDA’s Office of Neuroscience is expected by Feb. 13.

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“We are looking forward to receiving feedback from the FDA,” said Michael Thurn, PhD, PharmAust’s CEO. “Receiving feedback … in February positions us well to achieve our near-term milestone of opening an [investigative new drug filing] in Q2 2024 with the goal of initiating the planned adaptive Phase 2/3 clinical study in patients shortly after that.”

ALS is characterized by the progressive death of motor neurons — the specialized nerve cells that control muscle movements — leading to disease symptoms of overall muscle weakness.

While approved ALS therapies aim to slow its progression, none can stop its advance or reverse accrued damage.

Monepantel is used as a deworming agent (anthelmintic) in animals. PharmAust reports that it also showed off-target effects in studies, indicating it was a potent inhibitor the mTOR signaling pathway.

This pathway is involved in regulating cell growth, proliferation and autophagy, a process cells use to recycle abnormal or defective components or molecules. mTOR inhibitors have shown a potential in treating cancer, and PharmAust expects that monepantel will help to clear the misfolded proteins that build over time in the motor neurons of ALS/MND patients, damaging and killing these cells.

Early Phase 1 trial data suggest more stable disease in ALS/MND patients

The recently completed Phase 1 clinical trial, called MEND (NCT04894240), evaluated oral monepantel in 12 adults, ages 18 to 75, with ALS or MND at two sites in Australia. Participants were treated once daily, with tablets taken after meals for 28 days at a starting dose estimated to be five times lower than that deemed safe and effective in cancer patients. Up to three higher doses then could be given, each in 28-day cycles, until an optimal dose was reached and tested for at least six months.

An interim trial analysis showed stable blood levels of neurofilament light chain (NfL), a marker of nerve cell damage, in 11 of the 12 patients, suggesting “stabilized MND progression,” the company reported in August.

Updated study data is expected in the coming months, and should support the selection of an optimal Phase 2/3 trial dose. The company also opened a long-term extension study (NCT06177431) of monepantel for Phase 1 trial patients, where all will be treated daily at a 10 mg/kg dose, that trial’s highest dose, for one year.

The planned and multicenter Phase 2/3 study aims to evaluate the safety and efficacy of monepantel in MND/ALS patients randomly assigned to treatment or a placebo for 48 weeks (almost one year).

Its primary goal is changes in disease severity from the study’s start, as assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) total score, and patients’ survival.

As an adaptive study, an interim analysis will be performed after six months to determine if the trial should be stopped early due to a strong showing of treatment efficacy, or stopped for futility because positive effects are unlikely with further treatment.