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<a href="https://www.pharmaust.com/" rel="nofollow">PharmAust</a> announced that it soon will engage with U.S. Food and Drug Administration (FDA) regulators regarding development plans for monepantel, its investigational therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (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 <a href="https://www.marketindex.com.au/asx/paa/announcements/fda-grants-pharmaust-preind-meeting-6A1188539">company press release</a>. 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&#8217;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&#8217;s Office of Neuroscience is expected by Feb. 13.
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<h3>Monepantel shows potential to be potent inhibitor of mTOR signaling pathway</h3>
“We are looking forward to receiving feedback from the FDA,&#8221; said Michael Thurn, PhD, PharmAust’s CEO. &#8220;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.&#8221;
<a href="https://alsnewstoday.com/causes-of-als/">ALS is characterized</a> by the progressive death of motor neurons — the specialized nerve cells that control muscle movements — leading to <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a> of overall muscle weakness.
While approved <a href="https://alsnewstoday.com/approved-treatments-for-als/">ALS therapies</a> 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 <a href="https://www.pharmaust.com/therapeutic-pipeline/" rel="nofollow">potent inhibitor the mTOR signaling pathway</a>.
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 <a href="https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-020-00396-1">potential in treating cancer</a>, 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.
<h3>Early Phase 1 trial data suggest more stable disease in ALS/MND patients</h3>
The recently completed Phase 1 clinical trial, called <a href="https://clinicaltrials.gov/study/NCT04894240?term=monepantel&amp;rank=1">MEND (NCT04894240)</a>, 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 <a href="https://www.pharmaust.com/additional-phase-1-data-suggest-mpl-may-inhibit-mnd/">interim trial analysis</a> showed stable blood levels of <a href="https://alsnewstoday.com/news/blood-neurofilament-light-chain-levels-able-marker-of-als-progression-study-says/">neurofilament light chain</a> (NfL), a marker of nerve cell damage, in 11 of the 12 patients, suggesting &#8220;stabilized MND progression,&#8221; 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 (<a href="https://classic.clinicaltrials.gov/ct2/show/NCT06177431">NCT06177431</a>) of monepantel for Phase 1 trial patients, where all will be treated daily at a 10 mg/kg dose, that trial&#8217;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&#8217;s start, as assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) total score, and patients&#8217; 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.

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

<a href="https://www.lifearc.org/">LifeArc</a>, a U.K.-based independent medical research charity, is offering £5 million (about $6 million) to scientists around the world as part of a <a href="https://www.lifearc.org/strategy/neurodegeneration/motor-neuron-disease-translational-challenge/mnd-drug-repurposing-programme/">grant program</a> to tackle motor neuron disease (MND) using repurposed or combined medicines.
The program is part of the <a href="https://www.lifearc.org/strategy/neurodegeneration/motor-neuron-disease-translational-challenge/">Motor Neuron Disease Translational Challenge</a>, which seeks to make MND treatable by 2030 and to find a cure. It will award up to £750,000 ($954,000) to five projects from international research teams in academia or at small and medium-sized enterprises.
MND is the name for a group of progressive neurological conditions that includes <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
To be eligible, applicants must have previously identified a new repurposed therapy or a drug initially developed and sometimes approved for other indications with proven potential to treat MND in preliminary preclinical studies.
Proposals should also focus on validating available biomarkers that demonstrate the repurposed treatment is engaging with its target and modifying the course of MND as intended, or should include plans to identify and validate new biomarkers that may be translatable from preclinical models to patients.
“Improving confidence in drug repurposing requires more robust preclinical research, meaning that repurposed drug candidates are progressed into trials with sufficient evidence to predict they could benefit someone living with MND,” Paul Wright, PhD, head of LifeArc’s MND Translational Challenge, said in a <a href="https://www.globenewswire.com/news-release/2023/12/06/2791467/0/en/LifeArc-announces-5-million-drug-repurposing-programme-for-motor-neuron-disease.html">press release</a>. “To achieve our ambition of making MND treatable by 2030, we need to start with better decision-making at the preclinical stage to demonstrate as early as possible that a repurposed drug candidate has the potential to deliver improvements for patients.&#8221;
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<h3>Making repurposed therapies work for MND</h3>
Existing treatment candidates for MND, including repurposed therapies, haven&#8217;t been shown to benefit patients and the failure rate in MND clinical studies remains high, according to LifeArc.
Awarded proposals are expected to generate high-quality preclinical data and independent replication of data that provide compelling evidence the repurposed drug can treat MND. These are &#8220;two areas that have been historically underfunded in academia, but are critical for drug discovery,&#8221; LifeArc said in a page that announced the grant details.
The findings should contribute to evidence-based decision-making about which repurposed therapies should enter into biomarker-guided MND trial platforms, including the UK’s <a href="https://www.experts-als.uk/">EXPERTS-ALS clinical trial</a> and the ongoing <a href="https://clinicaltrials.gov/study/NCT04302870">MND-SMART trial (NCT04302870)</a>, which is recruiting adult ALS patients at sites in the U.K.
LifeArc recommends that applicants review the white paper “<a href="https://www.myname5doddie.co.uk/assets/media/Guiding%20principles%20for%20drug%20discovery%20and%20development%20in%20amyotrophic%20lateral%20sclerosis_Final.pdf">Guiding Principles for Drug Discovery and Development in Amyotrophic Lateral Sclerosis</a>,” the result of a yearlong project by MND experts and patients to outline a consensus approach for improving preclinical research to increase the chance of success in clinical studies of new treatments.
&#8220;Repurposing of existing licenced medicines is one way of speeding up the process of finding effective treatments. It’s been tried very successfully in cancer, where it has delivered many new treatments for patients, so it is important that MND researchers learn from their successes,&#8221; Jane Hadley, director of research at <a href="https://mndscotland.org.uk/">MND Scotland</a>. &#8220;We welcome LifeArc’s £5 million investment in this area — it is about time there was a world without MND, and this can only be achieved through research.&#8221;
Dates will be announced later, but the call for expressions of interest opens in February 2024 and closes in May. A workshop for shortlisted applicants will be held the following month. A <a href="https://forms.office.com/pages/responsepage.aspx?id=ghBZGYkvSUSWvSND96nl8960RWz4IvlEkkFAU2XThhJUODJJRUYzUTY4VlVPM1pFU01VNkUzQU00TC4u">webinar</a> on the program will also happen in February. More information on it or the program is available by emailing MND@lifearc.org.
The full application deadline is in October, followed by a panel review in November. Final decisions on applications will be made in December and projects would start within three months of receiving an award.
“This exciting new funding call will provide a shot in the arm for the research community, catalysing the translation of the vast new knowledge gained about MND in recent years and feeding the pipeline of repurposed drug candidates available for clinical trials,” said Brian Dickie, director of research development at the U.K.&#8217;s <a href="https://www.mndassociation.org/">MND Association</a>.
As part of the program, LifeArc is also offering to fund a maximum of five bioinformatic projects that use MND datasets at up to £100,000 ($127,000) each over 12 months. The aim is to support data science, artificial intelligence, and machine learning approaches to repurpose treatments in MND.

Tag: repurposed therapies

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

LifeArc grant to fund research into repurposing therapies for MND