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<a href="https://www.axoltis.com/">Axoltis Pharma</a>&#8216;s new treatment candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and other neurodegenerative diseases was deemed safe and well tolerated at multiple doses in healthy volunteers who participated in a Phase 1b trial.
Findings from the trial and preclinical studies also indicate NX210c is working as intended, boosting neuroprotection and neuronal communication and repairing the blood-brain barrier (BBB), the highly selective membrane that prevents microbes and other harmful molecules in circulation from entering the brain and spinal cord.
“This trial confirms the excellent safety and tolerability profile of NX210c. Moreover, we are excited to observe significant pharmacodynamic effects on blood and [spinal] fluid biomarkers, especially those important for BBB integrity, neuroprotection and neurotransmission,” Annette Janus, MD, neurologist and chief medical officer at Axoltis, said in a <a href="https://www.axoltis.com/wp-content/uploads/2023/12/231212-Axoltis-results-EN.pdf">company press release</a>. Pharmacodynamic effects are the effects of a compound on the body.
The company plans to launch two clinical trials in 2024 to study NX210c in people with neurodegenerative conditions — a Phase 2 trial in ALS and a Phase 1b trial in <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s disease</a>.
“The results are very promising and provide a strong foundation to build on the NX210c drug development strategy,” Janus said.
A hallmark feature of aging and many neurodegenerative conditions is a loss of integrity of the BBB. This lets unwanted compounds in the blood reach the brain and spinal cord and contribute to inflammation and nerve damage. In ALS, damage to this barrier is believed to occur <a href="https://journals.sagepub.com/doi/10.1177/0271678X231153281">in the earliest stages of disease</a>, possibly before overt clinical signs are evident.
Neuronal inflammation and impaired nerve communication are also features of the disease, leading to <a href="https://alsnewstoday.com/als-symptoms/">symptoms</a> such as trouble walking and speaking, and breathing difficulties.
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<h3>What is NX210c and how does it work?</h3>
NX210c is a small protein fragment derived from SCO-spondin, a protein important for processes such as nerve cell survival, maturation, and growth during embryonic development. It is mostly lost in later developmental stages.
By providing patients with the functional part of SCO-spondin, NX210c should exert neuroprotective effects, boost the communication between nerve cells, and promote the integrity of the BBB.
The molecule was tested in a <a href="https://clinicaltrials.gov/study/NCT05827653?intr=NCT05827653&amp;rank=1">Phase 1b clinical trial (NCT05827653)</a> in 29 healthy participants, ages 55 and older, who were randomly assigned to one of two doses of NX210c — 5 mg/kg or 10mg/kg — or a placebo, given as a 10-minute intravenous (into-the-vein) infusion, three times a week for four weeks.
The trial was conducted at the Center for Human Drug Research in the Netherlands. Its main goal was to evaluate the compound&#8217;s safety and tolerability, and a secondary measure examined its pharmacokinetics, or movement into, through, and out of the body.
A number of disease biomarkers were also examined, including MRI biomarkers to assess BBB integrity and cerebral blood flow, along with blood and spinal fluid biomarkers of BBB integrity and neuroinflammation.
NX210c was safe and well tolerated at both doses, with only mild side effects reported. The most common treatment-emergent side effects were headache and somnolence. Its neurologic safety profile was also validated using <a href="https://chdr.nl/clinical-studies-development/methods-biomarkers/central-nervous-system/neurocart">NeuroCart</a>, which can conduct a battery of nervous system tests.
The findings follow <a href="https://alsnewstoday.com/news/potential-als-therapy-nx210c-be-tested-insilico-axoltis-teamup/">positive tolerability findings</a> from a Phase 1 trial with 39 healthy people who received single ascending doses.
“We are very pleased with our preclinical and clinical studies, which strengthen Axoltis’ position to become a key leader in BBB repair. Among our target applications is the initiation of a Phase 2 trial for NX210c in patients living with amyotrophic lateral sclerosis, as BBB deterioration may be a trigger in the progression of this terrible disease,” said Yann Godfrin, PhD, CEO of Axoltis.
Under a partnership with InSilicoTrials, Axoltis will conduct further virtual modeling to evaluate and optimize NX210c for other neurodegenerative diseases.

Promising findings seen in healthy volunteer study of Axoltis’ NX210c

<a href="https://akavatx.com/">Akava Therapeutics</a> will soon launch a Phase 1 clinical trial to test AKV9, its investigational therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), in healthy people.
The trial follows the clearance of Akava&#8217;s investigational new drug (IND) application by the U.S. Food and Drug Administration (FDA). It will be AKV9&#8217;s first-in-human study and is designed to evaluate the therapy&#8217;s safety, tolerability, and pharmacological properties of single and multiple ascending doses.
&#8220;The FDA&#8217;s IND approval of AKV9 is a testament to our team&#8217;s dedication and the remarkable potential of our approach. We are thrilled to take this important step forward in the development of a groundbreaking therapy for ALS patients,&#8221; Richard Silverman, PhD, founder of Akava Therapeutics, said in a <a href="https://www.businesswire.com/news/home/20230816654411/en/Akava-Therapeutics-Inc.-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-the-Treatment-of-Amyotrophic-Lateral-Sclerosis">company press release</a>.
ALS is caused by the loss of motor neurons, the nerve cells that control voluntary movements, leading to muscle atrophy and the loss of control over vital functions. The disease affects both upper motor neurons, which send messages from the brain to the spinal cord, and lower motor neurons, the nerve cells that connect the spinal cord to the muscles.
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<h3>What does AKV9 do in ALS?</h3>
Most ALS cases are marked by the toxic buildup of proteins, such as SOD-1 and TDP-43, as well as problems in the function of mitochondria and the endoplasmic reticulum (ER) inside motor neurons. Mitochondria are organelles responsible for generating the cells’ energy. The ER is essential for protein production, modification, and transport.
Some <a href="https://alsnewstoday.com/approved-treatments-for-als/">treatments</a> can help manage the disease and extend survival by a few months. There is no cure is available for ALS, however, but an unmet medical need remains for treatments that can meaningfully slow disease progression.
AKV9 inhibits protein aggregation and has been shown to improve the health of upper motor neurons <a href="https://akavatx.com/science-behind-the-discoveries/#protein-aggregation-is-the-hallmark-of-neurodegenerative-diseases-including-als-protein-aggregation-is-one-of-the-common-causes-of-neuronal-vulnerability-and-degeneration,details-ornithine-aminotransferase-inactivators">via multiple mechanisms</a>. Along with lowering protein clumps, the therapy resulted in increased nerve fiber lengthening and branching, improved mitochondrial and ER integrity, and better motor function <a href="https://alsnewstoday.com/news/novel-compound-reverses-motor-neuron-damage-als-mouse-models/">in an animal model of ALS</a> carrying SOD1 mutations.
Combining AKV9 with the approved ALS therapies riluzole (sold as Rilutek, among others) and edaravone (sold as Radicava and Radicava ORS) <a href="https://alsnewstoday.com/news/experimental-als-treatment-akv9-nu-9-fares-well-mouse-study/">led to even greater improvements</a> in upper motor neuron health in additional experiments in a similar mouse model.
The therapy can also cross the blood-brain barrier, a highly selective membrane that regulates which substances can access the brain and spinal cord from the bloodstream.
“Our goal is to make a meaningful difference in the lives of those affected by neurodegenerative diseases and we are excited about the potential impact of AKV9 in addressing this devastating disease,&#8221; Silverman said.

FDA clears first-in-human clinical trial of AKV9 in healthy volunteers

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.”

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

The first healthy volunteer has been dosed in a Phase 1 clinical trial evaluating VTX3232, <a href="https://ventyxbio.com/">Ventyx Biosciences</a>’ investigational oral therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and other neurodegenerative conditions.
Top-line data from the trial are expected in the first half of 2024.
“VTX3232 is our fourth internally discovered compound to enter the clinic and an exciting addition to our broad, wholly-owned clinical-stage pipeline of orally delivered small molecules targeting large disease populations with high unmet need,” Raju Mohan, PhD, CEO at Ventyx, said in a <a href="https://www.globenewswire.com/news-release/2023/06/14/2687919/0/en/Ventyx-Biosciences-Announces-Initiation-of-Dosing-in-a-Phase-1-Trial-of-VTX3232-a-Novel-CNS-Penetrant-NLRP3-Inhibitor.html">company press release</a>.
ALS is a progressive neurological disorder that damages motor neurons, the nerve cells that control voluntary movements, causing them to degenerate and die. This results in a loss of control over muscle movements and patients lose the ability to perform everyday tasks.
Although <a href="https://alsnewstoday.com/causes-of-als/">genetic causes</a> have been linked with developing ALS, other biological changes, like inflammation, are thought to contribute.
VTX3232 works by blocking the NLRP3 inflammasome, a protein complex within cells that drives inflammation in response to certain triggers. This inflammatory response involves the release of pro-inflammatory molecules such as interleukin-1 beta (IL-1 beta) and IL-18 and the induction of an inflammatory form of cell death.
The activation of NLRP3 inflammasome is thought to be implicated in the progressive nerve cell damage that occurs in neurodegenerative diseases like ALS.
Given that VTX3232 can reach the central nervous system (CNS; the brain and spinal cord), it may have therapeutic potential in a range of neuroinflammatory diseases with high unmet medical needs, including ALS, <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson’s disease</a>, and <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer’s disease</a>.
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<h3>About the Phase 1 trial of VTX3232</h3>
The Phase 1 trial is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending doses of VTX3232 against a placebo in adult healthy volunteers. Pharmacokinetics refers to the therapy’s movement into, through, and out of the body, and pharmacodynamics comprises its effects on the body.
The trial will include a serial sampling of cerebrospinal fluid (CSF) — the fluid that bathes the brain and the spinal cord — to assess brain exposure to the compound.
The company is also developing another oral NLRP3 inhibitor, VTX2735, for treating systemic inflammatory diseases, that’s now in clinical trials.
“We believe we are well positioned to explore the therapeutic potential of NLRP3 inhibition and its effect on [IL-1 beta] biology across both systemic [whole-body] and neuroinflammatory diseases with VTX2735, which is peripherally restricted, and VTX3232, a novel CNS-penetrant NLRP3 inhibitor,” Mohan said.

1st healthy volunteer dosed in trial of potential ALS therapy VTX3232

A new formulation of MediciNova&#8217;s investigational <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> treatment <a href="https://alsnewstoday.com/mn-166/">ibudilast</a> (MN-166) given via an intravenous (into the vein) infusion was found to be safe and well tolerated in healthy volunteers.
That’s according to data from a recently completed Phase 1 clinical trial that tested the safety and tolerability of a 10 mg dose of it. All side effects were mild and none were unexpected.
The formulation is being developed mainly for people with life-threatening inflammatory disorders that require immediate treatment, such as acute respiratory distress syndrome, sepsis, and cytokine release syndrome. But it could also be an option for people with ALS or other conditions who can&#8217;t swallow the oral capsules.
“We are pleased with the results from this Phase I trial and are excited to evaluate the potential of the MN-166 [intravenous] formulation in acute and severe clinical settings that require fast bioavailability,” said Kazuko Matsuda, MD, PhD, <a href="https://medicinova.com">MediciNova</a>’s chief medical officer, in a <a href="https://www.globenewswire.com/news-release/2023/01/05/2584169/7767/en/MediciNova-to-Meet-with-U-S-FDA-to-Discuss-Clinical-Development-of-a-Parenteral-Formulation-of-MN-166-ibudilast.html">company press release</a>.
This &#8220;formulation will expand the clinical utility of MN-166 by enabling the treatment of indications for which the oral formulation is not suitable,” Matsuda said.
In ALS, the nerve cells responsible for controlling voluntary movements become progressively damaged over time. The exact <a href="https://alsnewstoday.com/causes-of-als/">causes behind this damage</a> are unclear, but inflammation is thought to play a role.
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Ibudilast is a small molecule designed to block the action of three proteins — PDE4, PDE10, and MIF — that are released by white blood cells into the bloodstream to set off an immune response. By blocking these molecules, the medication is expected to turn off the production of inflammatory molecules and switch on the production of protective, anti-inflammatory molecules.
It also reduces the activity of glial cells, a type of supporting cell in the brain that&#8217;s overly active and causes damage in ALS. These actions combined are expected to ease the <a href="https://alsnewstoday.com/symptoms-of-als-2/">symptoms of ALS</a>.
Data from a <a href="https://clinicaltrials.gov/ct2/show/NCT02238626">Phase 2 clinical trial (NCT02238626)</a> showed ibudilast, when given in combination with the approved therapy <a href="https://alsnewstoday.com/als-treatment/rilutek-riluzole/">Rilutek</a> (riluzole), significantly <a href="https://alsnewstoday.com/news/phase-2-als-trial-shows-ibudilast-rilutek-improves-function/">increased the proportion of patients</a> who had no functional decline over six months of treatment compared with Rilutek alone. It also helped patients <a href="https://alsnewstoday.com/news/als-treatment-candidate-mn-166-delays-disease-worsening-improves-survival-trial/">live longer</a>.
The company is now investigating ibudilast in a Phase 2b/3 trial, dubbed <a href="https://clinicaltrials.gov/ct2/show/NCT04057898">COMBAT-ALS (NCT04057898)</a>, which is enrolling up to 230 participants at more than 20 clinical sites in the U.S. and Canada. Participants will receive ibudilast twice daily (up to 100 mg a day) or a placebo along with their standard ALS medications.
The trial will last a year, after which participants will be able to enter an open-label extension part where all will receive ibudilast for another six months.
Ibudilast was granted <a href="https://alsnewstoday.com/news/fda-grants-fast-track-designation-for-medicinovas-mn-166-ibudilast-for-the-treatment-of-amyotrophic-lateral-sclerosis/">fast track</a> and <a href="https://alsnewstoday.com/news/ibudilast-mn-166-named-orphan-drug-for-amyotrophic-lateral-sclerosis-by-fda/">orphan drug</a> designations from the U.S. Food and Drug Administration (FDA), and <a href="https://alsnewstoday.com/news/eu-panel-recommends-orphan-drug-status-for-als-therapy-ibudilast/">orphan drug status</a> in Europe for treating ALS.
Matsuda said the company will ask the FDA for guidance in developing a plan that would lead to the therapy&#8217;s approval.

Tag: healthy volunteers

Promising findings seen in healthy volunteer study of Axoltis’ NX210c

FDA clears first-in-human clinical trial of AKV9 in healthy volunteers

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

1st healthy volunteer dosed in trial of potential ALS therapy VTX3232

Intravenous Ibudilast Safe, Tolerated Well Among Healthy Volunteers