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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.
[recommended-reading id=88296]
<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

The biotechnology company <a href="https://projenx.com/">ProJenX</a> recently received $15 million in funding to advance its experimental oral treatment <a href="https://projectals.org/project-als-introduces-prosetin/">prosetin</a> for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
This Series A financing round is essentially the next round of funding after seed money was used to rapidly develop the investigational treatment.
Both rounds were led by Medical Excellence Capital, which <a href="https://alsnewstoday.com/news/projenx-develop-als-therapy-prosetin-brain-disease/">created ProJenX</a> last year in collaboration with Columbia University researchers and <a href="https://projectals.org/">Project ALS</a>, an organization that identifies and funds research for potential <a href="https://alsnewstoday.com/als-treatment/">ALS therapies</a>.
&#8220;We are focused on accelerating the development of prosetin to meet the critical need for new treatments for people <a href="https://alsnewstoday.com/living-with-als-2/">living with ALS</a>,&#8221; Stan Abel, ProJenX president and CEO, said in a <a href="https://www.prnewswire.com/news-releases/projenx-announces-initial-closing-of-15m-series-a-financing-and-appoints-rick-hartz-to-board-of-directors-301975260.html">company press release</a>.
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<h3>Oral prosetin designed to reach brain and reverse stress in nerve cells</h3>
In ALS, certain proteins abnormally fold and form toxic clumps in nerve cells. This causes stress in certain cellular compartments, including in the endoplasmic reticulum (ER), a cell organelle involved in protein production, modification, and transport, and ultimately results in nerve cell damage and death.
ProJenX&#8217;s lead compound, prosetin, is a first-in-class oral therapy designed to reach the brain and reverse ER stress in nerve cells. It works by inhibiting the function of a protein called mitogen-activated protein kinase kinase kinase kinase (MAP4K).
Project ALS and Columbia University researchers developed the therapy candidate, which was found to <a href="https://www.projectals.org/wp-content/uploads/2019/10/Development-of-MAP4-Kinase-Inhibitors-as-Motor-Neuron-Protecting-Agents.pdf">potently block MAP4K</a> in an ALS animal model, lower inflammation, and improve nerve cell survival.
Soon after ProJenX&#8217;s launch, a first-in-human <a href="https://clinicaltrials.gov/study/NCT05279755">Phase 1 clinical trial (NCT05279755)</a> began <a href="https://alsnewstoday.com/news/dosing-begins-phase-1-clinical-trial-prosetin-als/">testing prosetin</a> in people with ALS and in healthy volunteers. In the trial&#8217;s initial two parts, researchers are assessing the safety, tolerability, and pharmacokinetics of single and ascending doses of the compound versus a placebo in healthy participants. Pharmacokinetics refers to the movement of drug into, through, and out of the body.
After those portions are completed, the same measures will be evaluated in ALS patients. The company is planning to launch this third portion in people with ALS early next year.
&#8220;We are encouraged by the therapeutic window emerging from our phase 1 trial and ongoing nonclinical studies and are looking forward to advancing prosetin to people living with ALS in early 2024,&#8221; Abel said.
The overall aim of the study is to establish the optimal prosetin dose and gather biomarker data that help inform the design of upcoming trials.
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<h3>Prosetin named orphan drug by FDA in 2020</h3>
Prosetin was <a href="https://alsnewstoday.com/news/prosetin-granted-orphan-drug-designation-for-als/">granted orphan drug designation</a> by the U.S. Food and Drug Administration for ALS in 2020. Such a designation offers a range of incentives to developers of medications for rare disorders, including seven years of market exclusivity if an approval is ultimately granted.
ProJenX also announced the board appointment of Rick Hartz, senior vice president, global pharma and human health business development at Merck (known as MSD outside North America).
&#8220;I am excited to join the ProJenX Board and contribute to its mission to advance promising therapies for ALS and other neurodegenerative diseases,&#8221; Hartz said. &#8220;With an orphan drug designation, prosetin is poised to advance toward a global pivotal trial next year and I look forward to working with my fellow board members and the ProJenX team to help guide the growth of the company.&#8221;

ProJenX receives $15M in funding to further develop prosetin for ALS

A first healthy volunteer has been dosed in a Phase 1 clinical study evaluating how safe and well tolerated is CVN293, a treatment candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer’s disease</a>, the therapy&#8217;s developer, <a href="https://www.cerevance.com" rel="nofollow">Cerevance</a>, announced.
The treatment, given orally, is designed to block a protein called KCNK13 on microglia, a type of immune cell that resides in the brain and is thought to play a role in ALS and other diseases.
Single ascending doses (SAD) and multiple ascending doses (MAD) are being tested in the study, with ascending doses of CVN293 administered once or repeatedly and compared with a placebo.
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<h3>Problems in microglia function may promote brain inflammation in ALS</h3>
A total of 64 healthy men and women, ages 18 to 55, will be randomly assigned in a 6:2 ratio to either CVN293 or a placebo. Five groups of eight people will be in the study&#8217;s SAD part; three groups of eight will enter its MAD portion.
In addition to therapy safety and tolerability, the study will evaluate CVN293&#8217;s pharmacokinetics, or how the drug moves into, through, and out of the body.
“We are very pleased to advance CVN293, a selective small-molecule inhibitor of the novel target KCNK13 into Phase 1 clinical development,” Craig Thompson, Cerevance’s CEO, said in a <a href="https://www.globenewswire.com/news-release/2023/09/19/2745619/0/en/Cerevance-Doses-First-Subject-in-Phase-1-Clinical-Study-of-CVN293-a-Selective-Inhibitor-of-KCNK13-Designed-to-Selectively-Modulate-Neuroinflammation-for-the-Treatment-of-ALS-and-Al.html">company press release</a>.
ALS occurs when motor neurons — the nerve cells that control muscle movement — become damaged and die over time. This results in <a href="https://alsnewstoday.com/symptoms-of-als/">muscle weakness</a>, leading to problems that include breathing, speaking, and eating.
What exactly <a href="https://alsnewstoday.com/causes-of-als/">causes ALS</a> is not known, but immune cells like microglia are believed to be involved. Like macrophages, the pathogen-engulfing immune cells that reside in tissues outside the brain, microglia eat bacteria, viruses, and debris.
It is thought that microglia, which normally protect the brain from harmful invaders, may go awry in ALS and allow a long-lasting cycle of inflammation that further damages motor neurons.
CVN293 was developed using the company’s proprietary <a href="https://www.cerevance.com/netsseq" rel="nofollow">Nuclear Enriched Transcript Sort sequencing (NETSseq) platform</a>, which lets researchers scan the molecular signature of specific types of cells within the brain and identify potential targets for neurological conditions.
It is designed to block KCNK13, also known as THIK-1, a channel protein that allows potassium ions to flow out of microglia. Earlier <a href="https://www.pnas.org/doi/10.1073/pnas.2106294118">work in mice</a> found that ion efflux (outflow) regulates the release of inflammatory signals from microglia, limiting communication between nerve cells.
By targeting the ion channel and preventing potassium release by microglia, CVN293 aims to lower inflammation in the brain without dampening immune cells working outside the central nervous system (brain and spinal cord).
Unlike other proteins, KCNK13 is almost exclusive to microglia and present only at very low levels in macrophages. As such, CVN293 may target microglia while leaving macrophages — needed for a healthy immune response — unharmed.
“KCNK13, an important modulator of neuroinflammation, was selectively identified using NETSseq and represents the power of the Cerevance platform in discovering precision neuroscience targets,” Thompson said.
“This [trial] is an important milestone as we continue to translate scientific discoveries into potential therapeutic options to address neuroinflammatory conditions,” he added.

Dosing of healthy adults begins in Phase 1 study of oral CVN293

VRG50635, an experimental oral therapy being developed by <a href="https://www.vergegenomics.com">Verge Genomics</a> for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), was found to be safe and well-tolerated in healthy volunteers, new Phase 1 trial data show.
Top-line data from the <a href="https://www.isrctn.com/ISRCTN14792372">trial (ISRCTN14792372)</a> also showed a promising tolerability and pharmacological profile supporting once-daily dosing.
The company is now planning to advance the treatment into a proof-of-concept study in people with <a href="https://alsnewstoday.com/sporadic-als/">sporadic</a> and <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a> that’s expected to start in the final months of 2023.
“We are extremely encouraged by these initial results which highlight the favorable safety and tolerability profile of VRG50635,” Diego Cadavid, MD, chief medical officer of Verge, said in a <a href="https://www.businesswire.com/news/home/20230615018038/en/Verge-Genomics-Announces-Positive-Safety-and-Tolerability-Data-from-the-Phase-1-Clinical-Trial-of-VRG50635-a-Potential-Best-in-Class-Therapeutic-for-All-Forms-of-ALS">company press release</a>.
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<h3>VRG50635 works to block PIKfyve, identified by AI as therapeutic target</h3>
VRG50635 is a small molecule designed to block the PIKfyve protein, a potential therapeutic target in ALS. PIKfyve was identified by the company’s artificial intelligence (AI) platform after sorting a large amount of biological data stemming from brain and spinal cord samples of ALS patients.
The protein is thought to play a role in the endolysosomal pathway, a kind of recycling system inside cells that helps break down faulty or unneeded molecules to keep the cells clean and functioning properly.
In ALS patients, this recycling system is usually not working as needed, leading to the buildup of toxic protein clumps — a hallmark of the disease known to contribute to the death of motor neurons and the progression of <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a>. Motor neurons are the nerve cells that control muscle movement and are progressively lost in ALS.
VRG50635 <a href="https://alsnewstoday.com/news/verge-starts-first-human-trial-pikfyve-inhibitor-als/">advanced from discovery</a> to a first-in-human trial in four years. In the lab, it extended survival of nerve cells from ALS patients and models of motor neuron degeneration.
“The lack of predictive animal models is one of the greatest challenges to developing effective ALS therapies today,” said Alice Zhang, CEO and co-founder of Verge. “This is why we’re excited to advance VRG50635, a drug derived directly from human data, into trials in people with ALS.”
The Phase 1 trial tested VRG50635 versus a placebo in 80 healthy adult volunteers. The therapy was given at different doses once or multiple times over one week, starting with a low dose of 60 mg and gradually increasing it up to 1,800 mg in subsequent groups.
There were no serious side effects, and VRG50635 was considered safe. The therapy was also deemed well-tolerated at the highest planned dose.
Data also showed the maximum concentration of VRG50635 in the body and the total exposure to the drug increased in proportion to the dose. Its active metabolite had a half-life (the time taken for its concentration to reduce by half) of about 37 hours, suggesting that VRG50635 may be taken by mouth once daily.
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<h3>Data to be presented at upcoming European conference in Barcelona</h3>
More detailed data will be presented at the upcoming European Network to Cure ALS (ENCALS) 2023 meeting, which will be held July 12-14 in Barcelona, Spain.
“We look forward to sharing additional information at the ENCALS meeting in Barcelona next month and anticipate progressing to a proof-of-concept study in patients with sporadic and familial ALS later this year,” Cadavid said.
According to Zhang, the study is “designed to overcome historical challenges in ALS clinical trials by using state of the art technology, such as digital at-home devices and blood-based biomarkers, that can capture richer, higher-fidelity patient data and have the potential to detect efficacy with greater sensitivity.”

Tag: Phase 1 trial

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

ProJenX receives $15M in funding to further develop prosetin for ALS

Dosing of healthy adults begins in Phase 1 study of oral CVN293

Potential ALS therapy, VRG50635, found to be safe in healthy adults