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The U.S. Food and Drug Administration (FDA) has signed off on the chemistry, manufacturing, and controls (CMC) clinical development plan for <a href="https://www.neurosense-tx.com/">NeuroSense Therapeutics</a>&#8216; lead candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) ahead of a planned Phase 3 study.
The Phase 3 trial of PrimeC is <a href="https://alsnewstoday.com/news/primec-potential-als-therapy-earns-patents-in-europe-japan-israel/">due to start in 2024</a> pending positive results from the company&#8217;s ongoing <a href="https://classic.clinicaltrials.gov/ct2/show/NCT05357950">PARADIGM Phase 2b clinical trial (NCT05357950)</a>, whose results are <a href="https://alsnewstoday.com/news/results-paradigm-trial-primec-als-expected-years-end/">expected in December</a>. CMC refers to the manufacturing practices and product specifications that must be followed and met to ensure product safety and consistency between batches.
&#8220;This confirmation from the FDA of our CMC strategy for a future pivotal Phase 3 clinical trial and commercial launch of PrimeC in the treatment of ALS marks a critical milestone in our drug development program,” Alon Ben-Noon, CEO of NeuroSense, said in a <a href="https://www.prnewswire.com/news-releases/neurosense-receives-us-fda-confirmation-of-cmc-strategy-for-primec-in-preparation-for-pivotal-phase-3-in-als-and-commercial-readiness-301986040.html">company press release</a>. “It sets the stage for a smooth transition, particularly as we anticipate clinical efficacy top-line results (secondary endpoints) from our Phase 2b trial very soon.&#8221;
<a href="https://www.neurosense-tx.com/primec/">PrimeC</a> is an oral, fixed-dose combination of ciprofloxacin, an antibiotic, and celecoxib, an anti-inflammatory. Both are approved in the U.S. for other indications. The compound&#8217;s combined action would block key mechanisms in ALS to slow <a href="https://alsnewstoday.com/stages-of-als/">disease progression</a>.
[recommended-reading id=86968]
<h3>What is PARADIGM trial assessing?</h3>
An initial formulation of PrimeC was deemed <a href="https://alsnewstoday.com/news/primec-safe-lowers-als-disease-biomarkers-phase-2-clinical-study/">safe and well tolerated</a>, in a <a href="https://clinicaltrials.gov/study/NCT04165850">Phase 2a clinical trial (NCT04165850)</a> with 15 ALS patients. After treatment, patients saw a slower decline in their functional and respiratory abilities over a historical group of untreated patients. Key ALS blood biomarkers, particularly TDP-43, also were reduced.
PARADIGM is assessing the safety and effectiveness of a longer-acting formulation of PrimeC, which would release the medications over time, requiring less frequent dosing.
A total of 69 ALS patients from Canada, Italy, and Israel were randomly assigned to a placebo or PrimeC for six months, while continuing with their standard <a href="https://alsnewstoday.com/als-treatment/">ALS treatments</a>. PrimeC was given at a total daily dose of 1,496 mg, taken as two tablets twice daily.
The trial will also measure PrimeC&#8217;s impact on key ALS blood biomarkers, TDP-43 and prostaglandin J2. Changes in functional disability, assessed by the ALS Functional Rating Scale-Revised (ALSFRS-R), as well as lung health, quality of life, and survival will also be assessed.
After completing six months of treatment in the trial&#8217;s randomized part, most patients (96%) joined an open label extension, where they are receiving PrimeC for a year.
The company plans to announce safety results and data from the trial&#8217;s secondary measures in December. Biomarker analyses, including those conducted in collaboration with Roche, are due in the first half of 2024.
PrimeC has received <a href="https://alsnewstoday.com/news/als-combination-therapy-primec-receives-fdas-orphan-drug-designation-enters-clinical-trials/">orphan drug status in the U.S.</a> and <a href="https://alsnewstoday.com/news/primec-orphan-drug-designation-europe-treatment-als/">the European Union</a>. The designation is meant to accelerate the development and regulatory review of rare disease therapies.

NeuroSense’s CMC earn FDA OK ahead of PrimeC Phase 3 trial

<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.
[recommended-reading id=77460]
<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

<a href="https://www.cognixion.com/">Cognixion</a>’s flagship device <a href="https://one.cognixion.com/">Cognixion ONE Axon</a>, a product designed to improve communication in people with severe motor impairments, has beed granted breakthrough device designation by the U.S. Food and Drug Administration (FDA).
The wireless device is specifically designed for people with people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and other paralyzing conditions in advanced disease stages who no longer can communicate using standard eye-tracking devices due to loss of eye muscle function. No device is currently available for these advanced disease patients, according to Cognixion.
The designation is awarded to new medical technologies that could potentially help those with life-threatening or debilitating diseases, such as ALS, for whom there are no alternatives. It allows manufacturers to work more closely with the FDA and grants prioritized review to subsequent submissions to speed up a product&#8217;s development.
&#8220;This FDA Breakthrough Device designation is a significant milestone, and we are thrilled to receive it for our Cognixion ONE device,&#8221; Andreas Forsland, CEO and founder of Cognixion, said in a <a href="https://www.prnewswire.com/news-releases/cognixion-receives-fda-breakthrough-device-designation-for-its-brain-computer-interface-with-augmented-reality-for-assistive-communication-301815743.html">company press release</a>.
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<h3>Communicating and interacting</h3>
Cognixion ONE is an assisted reality device that combines artificial intelligence, augmented reality, and natural user interface technology to help people with severe motor impairments communicate independently and interact with their surroundings.
It&#8217;s powered by electroencephalogram (EEG) technology, which measures the electrical impulses generated by nerve cells to communicate with each other to create a brain-computer interface that lets patients &#8220;speak&#8221; with their thoughts.
By integrating AI-powered large language models that allow for contextual predictions, Cognixion ONE provides suggestions of words in agreement with users&#8217; intentions and desired outcomes. These suggestions can be quickly selected and communicated via sound and visibly on the visor.
The device doesn&#8217;t require surgery or multiple training sessions, providing more independence and autonomy than other devices.
The FDA’s decision &#8220;validates the potential of our technology to make a real difference in the lives of individuals with severe motor impairments and underscores the importance of how AI can be used to assist people in everyday situations,&#8221; Forsland said. We are excited to continue our work to bring this life-changing technology to those who need it most.”

Wearable Cognixion ONE Axon named FDA breakthrough device

The U.S. Food and Drug Administration (FDA) will hold an advisory committee meeting to discuss <a href="https://brainstorm-cell.com/">BrainStorm Cell Therapeutics</a>&#8216; application to approve <a href="https://alsnewstoday.com/nurown/">NurOwn</a> for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
Such a meeting, called an ADCOM, is normally for when a therapy is under regulatory review so experts can discuss its potential merits. The meeting is an independent review and the regulatory agency may or may not follow the committee&#8217;s recommendation.
While BrainStorm filed a biologics license application (BLA) in September for NurOwn&#8217;s approval, the FDA <a href="https://alsnewstoday.com/news/fda-declines-considering-nurown-als/">refused</a> to review it due to insufficient evidence of its benefits.
With the BLA seemingly shut down, it wasn&#8217;t clear if an ADCOM would be scheduled. BrainStorm has utilized a &#8220;file over protest&#8221; procedure, however, meaning it will proceed with the application over the FDA&#8217;s objection, making an ADCOM attainable.
The application, which the company says has been amended to address most of the agency&#8217;s concerns, will be before the FDA&#8217;s Center for Biologics Evaluation and Research.
&#8220;The FDA provided us with more than one path to an ADCOM for NurOwn,&#8221; Chaim Lebovits, president and CEO of BrainStorm, said in a <a href="https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-announces-fda-advisory-committee-meeting-to-review-biologics-license-application-for-nurown-for-the-treatment-of-als-301781735.html">company press release</a>. &#8220;Our goal has always been to make NurOwn available to people living with ALS as quickly as possible, therefore we chose the File Over Protest pathway since this offered the fastest path to an ADCOM and regulatory decision relative to other pathways provided by the FDA &#8230; we firmly believe our data support regulatory approval of NurOwn.&#8221;
The stem cell-based therapy was evaluated in a <a href="https://clinicaltrials.gov/ct2/show/NCT03280056">Phase 3 trial (NCT03280056)</a> of 189 adults with rapidly progressing ALS, but it <a href="https://alsnewstoday.com/news/nurown-fails-to-slow-disease-progression-in-als-patients-top-line-data-show/">failed</a> to meet its main efficacy goal of slowing disease progression relative to a placebo.
At that time, the FDA said there <a href="https://alsnewstoday.com/news/nurown-showed-no-benefit-over-placebo-in-als-clinical-trial-fda-states/">wasn&#8217;t enough data</a> to support a regulatory application.
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<h3>Brainstorm: Efficacy results skewed by advanced disease patients</h3>
BrainStorm later argued the trial contained a large number of patients with advanced disease, which may have obscured NurOwn&#8217;s benefits.
These advanced patients often had some of the lowest possible scores on subscales of the ALS Functional Rating Scale-Revised (ALSFRS-R) when they enrolled, meaning there was no room to detect meaningful disease progression changes.
That assertion was supported by <a href="https://alsnewstoday.com/news/nurown-continues-show-benefit-rapidly-advancing-als/">additional analyses</a> that showed NurOwn could meaningfully and significantly <a href="https://alsnewstoday.com/news/nurown-benefits-patients-less-severe-als-analyses-show/">slow disease progression</a> when the severely affected participants were excluded.
With that data in hand, BrainStorm filed a new application, but the FDA declined to review it, citing a lack of “substantial evidence” of efficacy, in addition to <a href="https://alsnewstoday.com/news/fda-grants-jan-11-meeting-discuss-nurown-future-als-brainstorm/">concerns related to chemistry, manufacturing and quality control</a>.
BrainStorm then <a href="https://alsnewstoday.com/news/brainstorm-files-fda-meeting-new-bid-nurown-approval/">requested</a> a Type A meeting with the FDA, with a main goal of securing an ADCOM as quickly as possible. That meeting was held in January.
&#8220;Securing an ADCOM represents an important step towards our goal of making NurOwn broadly available to individuals living with ALS who are in urgent need of new, effective therapies,&#8221; said Stacy Lindborg, PhD, Brainstorm&#8217;s co-CEO.
The ADCOM meeting would serve as &#8220;an open forum for BrainStorm and the FDA, together with medical experts, statisticians, and the ALS community, to thoughtfully review all available evidence supporting NurOwn,&#8221; Lindborg said.
The FDA&#8217;s resistance to reviewing NurOwn was criticized by the ALS community, with two separate patient groups <a href="https://alsnewstoday.com/news/veterans-als-seek-fda-meeting-discuss-nurown-therapy-benefits/">calling</a> for an ADCOM within weeks of the FDA&#8217;s refusal to file.
&#8220;It is critical for all ALS treatments that they be given the chance to proceed to an ADCOM,&#8221; said Brian Wallach, a patient advocate and founder of nonprofit <a href="https://iamals.org/">I AM ALS</a>. &#8220;The ALS community has waited years for this ADCOM. It is time to let the science have a full, fair, and transparent hearing so that we can get this treatment to people who are living with and dying from ALS as soon as possible.&#8221;
A date for the ADCOM has not been set.

BrainStorm nets NurOwn ADCOM meeting over FDA objections

<a href="https://www.kadimastem.com/">Kadimastem</a> is planning a Phase 2a clinical trial to test if repeat dosing of AstroRx, its investigational therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), can continuously delay the disease&#8217;s progression.
The study will investigate every three-month dosing after findings from an earlier <a href="https://clinicaltrials.gov/ct2/show/NCT03482050">Phase 1/2 trial (NCT03482050)</a> showed a single infusion led to a clinically meaningful <a href="https://alsnewstoday.com/news/astrorx-safe-slows-als-progression-phase-1-2-clinical-trial/">decline in disease progression</a> over the first three months, but lost effectiveness later on.
The company recently submitted an investigational new drug (IND) application asking the U.S. Food and Drug Administration (FDA) to clear the trial.
“The submission of an IND to the FDA is a major milestone. It is very exciting to have arrived at this juncture. We eagerly await the approval to start this trial and wanting to help ALS patients as soon as possible,” said Michel Revel, MD, PhD, founder and chief scientific officer at Kadimastem, in a <a href="https://www.kadimastem.com/post/kadimastem-submits-ind-application-to-the-fda-for-its-phase-iia-clinical-trial-with-astrorx-for-als">company press release</a>.
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AstroRx is an off-the-shelf, investigational cell therapy composed of healthy astrocytes derived from human embryonic stem cells. Astrocytes are star-shaped cells that support nerve cells in the brain and spinal cord, but are believed to go awry in ALS and contribute to disease progression.
Injected directly into the spinal canal (intrathecal administration), it&#8217;s expected to make up for the faulty astrocytes, preventing further damage to nerve cells and slowing disease progression.
AstroRx&#8217;s safety and preliminary signs of efficacy were investigated in the Phase 1/2 study in Israel, which enrolled 10 patients who&#8217;d been diagnosed with ALS in the past two years.
After an initial monitoring period of three months, patients were equally divided to receive a single dose of 100 million AstroRx cells (low dose) or 250 million AstroRx cells (high dose) and were monitored for up to a year.
Results from the open-label trial showed both doses induced a significant decrease in the rate of disease progression over the first three months — a 53% reduction. However, no benefits were observed in either group after six and 12 months&#8217; follow-up, suggesting repeat dosing is necessary to maintain its efficacy.
“For the last year, we’ve reported our plans to submit an IND to the FDA with AstroRx for the treatment of ALS. The submission of the IND marks a significant milestone for the company, and subject to the approval of the FDA we hope to commence this very important multi-site trial and to bring this potential life enhancing therapy to the market and to patients as soon as possible,” said Ronen Twito, Kadimastem’s board executive chairman.
The investigational cell therapy was granted a U.S. patent <a href="https://alsnewstoday.com/news/als-cell-therapy-maker-kadimastem-awarded-patent-astrorx/">in August 2022</a> for treating ALS and other neurodegenerative diseases. Patents are also in place in Japan and Israel. The company also continues to advance its diabetes program, according to Kadimastem CEO Asaf Shiloni.

Tag: U.S. Food and Drug Administration (FDA)

NeuroSense’s CMC earn FDA OK ahead of PrimeC Phase 3 trial

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

Wearable Cognixion ONE Axon named FDA breakthrough device

BrainStorm nets NurOwn ADCOM meeting over FDA objections

Kadimastem asks for FDA to clear new AstroRx clinical trial