A SUPER-powered WP Engine Atlas Test Site

Joe&#039;s Atlas Experimentation Site

NeuroSense Therapeutics&#8217; investigational therapy <a href="https://www.neurosense-tx.com/primec/">PrimeC</a> tends to reduce blood levels of neurofilament light chain (NfL), a biomarker of nerve damage, in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — especially when given earlier in the course of the disease.
That&#8217;s according to data from the <a href="https://clinicaltrials.gov/study/NCT05357950">PARADIGM Phase 2b trial (NCT05357950)</a>, in which the oral treatment — also found in this study to be well tolerated — was able to <a href="https://alsnewstoday.com/news/primec-safe-shows-trends-slowing-als-progression-paradigm-trial/">significantly slow disease progression</a> among patients who adhered to the study&#8217;s protocol.
<a href="https://www.neurosense-tx.com/">NeuroSense</a> had previously <a href="https://alsnewstoday.com/news/primec-potential-als-therapy-earns-patents-in-europe-japan-israel/">indicated plans</a> to launch a Phase 3 trial in 2024 should the Phase 2 findings be positive.
“We feel strongly that this is now ready to go forward to another … Phase 3 trial,” Merit E. Cudkowicz, MD, the director of the Sean M. Healey &amp; AMG Center for ALS, said in a talk titled “<a href="https://www.aan.com/msa/Public/Events/AbstractDetails/57911">PrimeC Meets Primary and Secondary Endpoints in a Phase 2b Trial</a>.”
Cudkowicz gave the presentation at the American Academy of Neurology (AAN) 2024 Annual Meeting, held this past week in Colorado, and virtually. 
[recommended-reading id=87909]
<h3>PARADIGM trial tested PrimeC in patients within 2.5 years of symptom onset</h3>
PrimeC is a fixed-dose combination of two medications individually approved in the U.S. — the anti-inflammatory drug celecoxib and ciprofloxacin, an antibiotic. Together, they are thought to slow ALS progression by targeting key cellular processes implicated in the degeneration of motor nerve cells that characterizes the disease.
In PARADIGM, 68 adults with ALS were randomly assigned to receive a long-acting formulation of PrimeC or a placebo for six months, while remaining on their standard <a href="https://alsnewstoday.com/als-treatment/">ALS therapy regimen</a>. Treatment was given twice daily, with a total of four tablets per day.
About 90% of the participants were being treated with riluzole (e.g. <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a>, <a href="https://alsnewstoday.com/tiglutik-for-als/">Tiglutik</a>) during the trial, according to Cudkowicz. All participants also were within 30 months, or 2.5 years, of <a href="https://alsnewstoday.com/symptoms-of-als/">ALS symptom</a> onset.
The study&#8217;s main goals were to evaluate PrimeC’s safety and tolerability, as well as its effects on certain disease-associated biomarkers. Secondary efficacy endpoints included measures of disease progression, lung function, quality of life, and survival.
As reported late last year, top-line data showed that the therapy was tolerated well by patients, meeting one of the study’s main goals. Side effects, all of which were mild and temporary, were all “expected based on what’s known about the two drugs,” Cudkowicz said.
Across the full study population, PrimeC also led to a meaningful — although not statistically significant — 29.2% slower disease progression relative to the placebo, as assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R).
Analyses that focused solely on the trial’s so-called per protocol population — the 62 people who complied with the trial’s initial rules — indicated that PrimeC was associated with a significant, 37.4% reduction in functional declines compared with the placebo. A per protocol population is thought to more accurately reflect how a treatment works when used exactly as intended.
In this population, the data showed a mean difference of 3.22 ALSFRS-R points between the PrimeC and placebo groups after six months, indicating less advanced disease in the treated group.
Across both groups, benefits of PrimeC tended to be observed across ALSFRS-R subdomains, although statistical significance was only observed in the per protocol population for the respiratory domain, according to Cudkowicz.
Previous trial analyses have also indicated that PrimeC is associated with non-significant slowing of lung function declines, <a href="https://alsnewstoday.com/news/primec-shown-extend-complication-free-survival-als-patients/">improved life quality, and prolonged complication-free survival</a>.
“We saw a consistently positive effect in all clinical outcomes,” said Cudkowicz, who also is chief of the department of neurology at Massachusetts General Hospital, and professor of neurology at Harvard Medical School.
[recommended-reading id=87331]
<h3>New data analyses focus on blood biomarker levels over study&#8217;s course</h3>
Blood levels of NfL were evaluated in an exploratory manner. Across the entire study population, PrimeC was associated with a small, 4.3% reduction in NfL levels after six months relative to the placebo, without statistical significance.
The reductions in NfL were greatest in patients who were earlier in the disease course, and grew increasingly smaller with longer ALS duration. Individuals within nine months of symptom onset experienced an average 29.1% NfL drop relative to the placebo. That compared with an average decline of 17.1% for patients within a year of symptom onset, and 5.1% for those within 1.5 years. An average decline of 3.6% was seen for patients within two years of the start of symptoms.
“What we can learn from this is that, particularly in the people who started the drug earlier in their illness, that’s where we saw the largest difference,&#8221; Cudkowicz said, noting &#8220;this is still a work in progress.”
Analyses of additional biomarkers — one of the study&#8217;s main outcome measures — are ongoing, with results expected in the coming months.
[quote=&#8221;center&#8221;]What we can learn from this is that, particularly in the people who started the drug earlier in their illness, that’s where we saw the largest difference.[/quote]
After the main trial, participants were enrolled in an ongoing open-label extension study, where all are receiving PrimeC.
“We’re very thankful for the trial participants, their family, and caregivers for being part of the study and all the site investigators and their coordinators … that enrolled these patients,“ Cudkowicz concluded.

AAN 2024: PrimeC found to lower nerve damage biomarker in trial

Treatment with NeuroSense Therapeutics’ <a href="https://www.neurosense-tx.com/primec/">PrimeC</a> was found to extend patients&#8217; time without complications or death, and to lead to clinically meaningful effects on quality of life, among those with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The new data comes from the <a href="https://clinicaltrials.gov/study/NCT05357950">PARADIGM Phase 2b study (NCT05357950)</a>, a <a href="https://alsnewstoday.com/news/neurosense-paradigm-trial-primec-als-completes-enrollment-patients/">fully enrolled</a> clinical trial that’s testing oral PrimeC against a placebo in 68 adults with ALS. Participants had experienced their first symptoms within the prior 30 months and could continue to receive their standard <a href="https://alsnewstoday.com/als-treatment/">ALS medications</a>.
These findings come shortly after positive top-line data from the PARADIGM trial that was announced late last year. In that report, the therapy <a href="https://alsnewstoday.com/news/primec-safe-shows-trends-slowing-als-progression-paradigm-trial/">was seen to be safe and well tolerated</a> by patients — and to <a href="https://alsnewstoday.com/news/primec-showed-significant-clinical-efficacy-paradigm-trial-new-data/">significantly slow disease progression</a> in the group of participants who complied with the trial&#8217;s protocol.
&#8220;PrimeC&#8217;s demonstrated positive effect on quality of life and survival, aligned with the already positive clinical outcome measures, in a relatively small Phase 2b clinical trial truly demonstrates its potential to deliver a meaningful benefit,&#8221; Ferenc Tracik, MD, <a href="https://www.neurosense-tx.com/">NeuroSense</a>&#8216;s chief medical officer, said in a <a href="https://www.prnewswire.com/news-releases/neurosense-reports-additional-positive-results-from-its-als-phase-2b-paradigm-trial-302067299.html">company press release</a>.
&#8220;From a clinical perspective,&#8221; Tracik said, speaking of the therapy&#8217;s performance in the trial, &#8220;these parameters are crucial to neurologists, but more importantly to people living with ALS.&#8221;
[recommended-reading id=84549]
<h3>Patients on PrimeC had fewer hospitalizations than those on placebo</h3>
PrimeC is a fixed-dose combination of ciprofloxacin, an antibiotic used to treat bacterial infections, and celecoxib, an anti-inflammatory agent. Both therapies are approved in the U.S. and have well-established safety profiles; together, they are expected to slow ALS progression by key mechanisms thought to drive nerve cell degeneration.
The PARADIGM trial is testing a long-acting formulation of PrimeC, given at a total daily dose of 1,496 mg, in 68 ALS patients, ages 18 to 75. The participants were randomly assigned to receive either PrimeC (45 patients) or a placebo (23 patients), taken as two tablets twice daily for six months, on top of their standard ALS treatments.
The study&#8217;s primary goals are to assess the treatment&#8217;s safety and tolerability, and whether it can reduce the levels of certain ALS blood biomarkers. Secondary measures — the focus of this data — include changes in the rate of disease progression, assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R), as well as changes in lung function, quality of life, and survival.
NeuroSense in December reported that the therapy was generally safe and well tolerated — and that 96% of patients were joining an open-label extension in which they would continue to receive PrimeC after the initial six months. In the open-label part, both participants and researchers know the exact medication being given.
In the overall patient population, participants given PrimeC had a 29% slower disease progression and a 13% slower lung function decline than those on the placebo, but the differences failed to reach statistical significance. However, an analysis of the trial’s per-protocol population, covering 62 participants who complied with the trial’s established protocol or rules, showed a significant slowing of disease progression compared with a placebo, by 37.4%.
The company now reported that PrimeC also exerted positive effects in other clinical outcomes, including in the physical and mental aspects of quality of life. The therapy also extended complication-free survival compared with a placebo.
[quote=&#8221;center&#8221;]The positive impact of PrimeC on quality of life and complication-free survival, together with its demonstrated ability to meaningfully slow down disease progression, is of great value, as we see that we have the potential to profoundly affect patients&#8217; lives across the board.[/quote]
Complications were defined as respiratory failure — the need for a breathing tube or noninvasive ventilation for more than 22 hours per day over at least 10 consecutive days — hospitalization due to ALS complications, or advances in <a href="https://alsnewstoday.com/stages-of-als/">ALS disease stages</a>. Complication-free survival, a measure of the time to death from any cause or any of those complications, was reduced with PrimeC by 53%.
&#8220;The positive impact of PrimeC on quality of life and complication-free survival, together with its demonstrated ability to meaningfully slow down disease progression, is of great value, as we see that we have the potential to profoundly affect patients&#8217; lives across the board,” said Alon Ben-Noon, NeuroSense&#8217;s CEO.
The company now is examining how PrimeC impacts the levels of neurofilaments, biomarkers of nerve cell damage, as well as the ALS blood biomarkers TDP-43 and prostaglandin J2. The neurofilament analysis is being done in collaboration with <a href="https://www.biogen.com/">Biogen</a> and is expected until the end of March. Meanwhile, TDP-43 and prostaglandin analyses are expected in the first half of the year.
“We are in great anticipation to soon report on the status of our collaboration on neurofilaments and how this may contribute to expediting the development of PrimeC,&#8221; Ben-Noon said.

PrimeC in ALS patients shown to extend complication-free survival

People with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) given PrimeC in the PARADIGM Phase 2b trial — and who did not diverge in major ways from the trial&#8217;s rules — experienced a significant slowing in disease progression compared with a placebo, the treatment&#8217;s developer, <a href="https://www.neurosense-tx.com/" rel="nofollow">NeuroSense Therapeutics</a>, announced.
This finding comes from the trial’s per protocol population, an analysis covering 62 of the 68 patients randomly assigned to PrimeC or to a placebo, who adhered well to what is called a trial’s established protocol (its rules).
Recent top-line trial results, covering all 68 patients, showed a meaningful <a href="https://alsnewstoday.com/news/primec-safe-shows-trends-slowing-als-progression-paradigm-trial/">trend toward slower disease progression</a>, with a lesser <a href="https://alsnewstoday.com/symptoms-of-als/#Muscular_symptoms">decline in the muscle strength</a> needed for daily life activities, and a lesser decline in lung function and the known <a href="https://alsnewstoday.com/symptoms-of-als/#Muscular_symptoms">breathing difficulties with ALS</a>. These treatment differences relative to a placebo, however, were not statistically significant.
[recommended-reading id=88541]
<h3>PrimeC showing potential to render &#8216;significant and meaningful clinic benefit&#8217;</h3>
The new analysis in the trial&#8217;s per protocol population — focusing on the 62 patients who complied with its rules or protocol — showed a significant 37.4% reduction in functional decline, as assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R).
&#8220;As we analyze the PARADIGM trial results, we continue to gain a better understanding of PrimeC&#8217;s potential to render a significant and meaningful clinical benefit to people living with ALS,” Alon Ben-Noon, NeuroSense&#8217;s CEO, said in a <a href="https://www.prnewswire.com/news-releases/neurosense-reports-new-data-statistically-significant-clinical-efficacy-in-phase-2b-als-trial-302015639.html">company press release</a>.
&#8220;Today we are eager to share these new data with the ALS community, as we believe the PP [per protocol] analysis, demonstrating a statistically significant 37.4% difference in ALSFRS-R in patients treated with PrimeC vs. placebo, is an exceptional result,&#8221; Ben-Noon added.
PrimeC is an oral fixed-dose combination of ciprofloxacin, an antibiotic used to treat bacterial infections, and celecoxib, an anti-inflammatory agent. Both have well-established safety profiles and are approved in the U.S.
The combination is thought to slow <a href="https://alsnewstoday.com/stages-of-als/">ALS progression</a> by easing inflammation and iron accumulation while improving RNA processing. These are key mechanisms known to be involved in ALS motor degeneration.
The <a href="https://clinicaltrials.gov/study/NCT05357950">PARADIGM trial (NCT05357950)</a> is testing a long-acting formulation of PrimeC, given at a total daily dose of 1,496 mg, taken as two tablets twice daily. A total of 68 adult patients were randomly assigned to either PrimeC (45 people) or a placebo (23 people) for six months, while maintaining their standard <a href="https://alsnewstoday.com/approved-treatments-for-als/">ALS treatments</a>.
The study, due to fully conclude in late 2024, set evaluations of the treatment&#8217;s safety and tolerability, and whether it can lower certain ALS biomarkers in the blood, as its primary goals. Secondary measures include changes in the patient’s ability to perform daily tasks — assessed with the ALSFRS-R — along with changes in lung function, quality of life, and survival.
<h3>Many of ALS trial&#8217;s patients continuing with PrimeC in study extensions</h3>
Top-line data shared earlier this month, covering all 68 trial participants, showed that six months of this PrimeC formulation was safe and well tolerated, with 96% of patients choosing to be treated in a one-year open-label extension. To date, all who completed these 1.5 trial years are continuing with PrimeC in an ongoing, investigator-initiated study, NeuroSense reported, without specifying the number of patients involved.
Six months of PrimeC&#8217;s use also reduced the rate of ALSFRS-R decline by 29%, and slowed the decline in lung function by 13%, compared with those receiving a placebo, top-line data showed. But these differences did not reach statistical significance.
For a better sense of the treatment&#8217;s effectiveness, a pre-specified analysis focused specifically on the per protocol group of 62 adherent patients, allowing for an assessment of treatment efficacy under optimal conditions. This is thought to provide a fair understanding of how a treatment works when used as intended.
Of these 62 patients, 43 had been randomized to treatment with PrimeC and 19 were given a placebo.
Now, six months of PrimeC use was seen to significantly slow the decline in ALSFRS-R scores by 37.4% compared with a placebo. A 17.2% reduction in lung function decline also was reported, but this difference again failed to reach statistical significance.
Results of treatment biomarker analyses are expected in the first half of 2024, NeuroSense stated. These include changes over six months in the ALS blood biomarkers TDP-43 and prostaglandin J2, as well as changes in nerve cell damage biomarkers called neurofilaments, an analysis being done in collaboration with Biogen.
&#8220;This data, in conjunction with hopefully correlative neurofilament readouts, will create a regulatory opportunity to advance PrimeC&#8217;s development in a breakthrough manner toward the market,&#8221; said Ben-Noon.
NeuroSense also announced plans for an end-of-Phase 2 meeting with the U.S. Food and Drug Administration, as well as a scientific advice meeting with the European Medicines Agency, both in the first half of 2024.
These meetings aim to discuss trial results and best approaches for PrimeC&#8217;s continued development, which is expected to include a pivotal and global <a href="https://alsnewstoday.com/news/primec-potential-als-therapy-earns-patents-in-europe-japan-israel/">Phase 3 trial of PrimeC</a> that could launch next year.

PrimeC can significantly slow ALS progression, PARADIGM trial finds

NeuroSense Therapeutics’ PrimeC was found to be safe and well tolerated in a Phase 2b trial, and use of the oral therapy for six months led to &#8220;meaningful slowing of disease progression&#8221; in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), the company said in a <a href="https://www.prnewswire.com/news-releases/neurosenses-phase-2b-als-trial-achieves-primary-safety-and-tolerability--secondary-clinical-efficacy-endpoints-302005837.html">press release</a> announcing top-line results.
The new data comes from <a href="https://clinicaltrials.gov/study/NCT05357950">PARADIGM (NCT05357950)</a>, a <a href="https://alsnewstoday.com/news/neurosense-paradigm-trial-primec-als-completes-enrollment-patients/">fully enrolled</a> clinical trial that&#8217;s testing PrimeC against a placebo in 69 adults with a <a href="https://alsnewstoday.com/als-diagnosis/">diagnosis of ALS</a>.
The positive findings will now support the launch of a pivotal and global Phase 3 trial that&#8217;s <a href="https://alsnewstoday.com/news/primec-potential-als-therapy-earns-patents-in-europe-japan-israel/">planned for 2024</a>. The U.S. Food and Drug Administration (FDA) already has <a href="https://alsnewstoday.com/news/fda-oks-neurosenses-cmc-primec-ahead-phase-3-trial/">agreed to the manufacturing practices</a> and product specifications set in place ahead of the trial.
“The release of this portion of the top-line results of the PARADIGM trial marks an exciting milestone for NeuroSense as we take another step toward helping people suffering from this dire disease,” said Alon Ben-Noon, <a href="https://www.neurosense-tx.com">NeuroSense</a>’s CEO.
According to the release, PrimeC &#8220;achieved primary safety and tolerability endpoints [goals] with a safety and tolerability profile comparable to [a] placebo.&#8221;
[recommended-reading id=87331]
<h3>Use of PrimeC in PARADIGM leads to 29% slower disease progression</h3>
NeuroSense also is planning to report the results of biomarker analyses from the PARADIGM trial in the first half of 2024.
These include changes in ALS blood biomarkers TDP-43 and prostaglandin J2 after six months — one of the trial&#8217;s main goal. The company also expects to share its findings on changes in neurofilament blood levels, a biomarker of nerve cell damage. That analysis is being done in collaboration with <a href="https://www.biogen.com/">Biogen</a>.
“We look forward to meeting with the FDA to determine the best path forward and to advancing discussions with strategic partners who share our vision for PrimeC to benefit people living with ALS,” Ben-Noon said.
PrimeC contains a fixed-dose combination of two FDA-approved medications: ciprofloxacin, an antibiotic used to treat bacterial infection, and celecoxib, a medicine for relieving pain and inflammation. It is expected to slow <a href="https://alsnewstoday.com/stages-of-als/">disease progression</a> by blocking key mechanisms behind ALS.
PARADIGM, slated for completion in fall of 2024, is testing a long-acting formulation of PrimeC, which releases the medications in the body over time. In the trial, PrimeC was given at a total daily dose of 1,496 mg, taken as two tablets twice daily.
A total of 69 adults with ALS — taking part in the study at sites in Canada, Italy, and Israel — were randomly assigned to receive the medication or a placebo for six months. Data was gathered from 68 patients, due to one misdiagnosis.
The trial&#8217;s main goals are to determine if PrimeC is safe and well tolerated in ALS patients, and whether it reduces the amount of ALS biomarkers in circulation, indicating a potential effect on disease processes.
Secondary measures include changes in the ability to perform daily tasks, as assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R), as well as changes in lung function, quality of life, and survival.
Over the trial&#8217;s six months, safety and tolerability profile of PrimeC was comparable to that of the placebo.
[quote=&#8221;center&#8221;]In addition to the safety and tolerability profile observed, we believe the 29% difference observed in ALSFRS-R in favor of PrimeC as well as the 13% decline in [lung function] compared to the placebo arm, illustrate PrimeC&#8217;s potential to render a meaningful clinical benefit to people living with ALS.[/quote]
Also, patients treated with PrimeC experienced a 29% slower disease progression on the ALSFRS-R scale, as well as a 13% slower decline in lung function, compared with those given a placebo. These differences failed to reach statistical significance, but the company noted that this trial was not powered to detect such significant difference.
&#8220;In addition to the safety and tolerability profile observed, we believe the 29% difference observed in ALSFRS-R in favor of PrimeC as well as the 13% decline in [lung function] compared to the placebo arm, illustrate PrimeC&#8217;s potential to render a meaningful clinical benefit to people living with ALS,&#8221; said Ferenc Tracik, MD, NeuroSense’s chief medical officer.
After completing the six months of dosing, most participants (96%) chose to enter an open-label extension, in which all are being treated with PrimeC for up to one year. So far, all who completed 1.5 years of treatment have opted to continue taking PrimeC by joining an ongoing investigator-initiated trial.
“I am excited by the top-line clinical data from PARADIGM, as this is an important milestone for the patients I care for and for the entire ALS community,” said Merit Cudkowicz, MD, chair of neurology at the Massachusetts General Hospital and director of the Healey &amp; AMG Center for ALS in Boston.
“The positive results support moving forward to a Phase 3 pivotal trial. The biomarker data will also be very informative, and I look forward to seeing those results in early 2024,” added Cudkowicz, who is also a member of NeuroSense’s scientific advisory board.

PrimeC safe, shows trends toward slowing ALS progression: Trial data

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://www.neurosense-tx.com/" rel="nofollow">NeuroSense Therapeutics</a> is planning to soon announce top-line safety and efficacy results from its PARADIGM trial, which is testing PrimeC in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
News of trial findings being expected in December follows the dosing of a final patient in the randomized portion of the <a href="https://clinicaltrials.gov/study/NCT05357950">Phase 2b trial (NCT05357950)</a>. A total of 69 people have received the experimental therapy or a placebo for six months, and most (96%) have chosen to enter an open-label extension where all are being treated with PrimeC for up to one year.
The company also plans to report findings across a number of PARADIGM biomarker analyses in the first half of 2024.
&#8220;We are excited to soon begin sharing the results of the double-blind segment of our Phase 2b trial,&#8221; Alon Ben Noon, NeuroSense’s CEO, said in a <a href="https://www.prnewswire.com/il/news-releases/neurosense-completes-dosing-of-last-patient-in-the-double-blind-segment-of-phase-2b-als-trial-topline-clinical-efficacy-results-expected-december-2023-301978417.html">company press release</a>.
[recommended-reading id=87783]
<h3>PARADIGM trial assessing a longer-acting formulation of PrimeC</h3>
&#8220;We would like to thank the trial participants, their caregivers and families, as well as the sites&#8217; Principal Investigators and study coordinators for their tremendous contribution to PARADIGM,&#8221; Ben Noon added.
PrimeC is an oral, fixed-dose combination of two medications approved in the U.S. for other indications, with established safety profiles. One is ciprofloxacin, an antibiotic, and the other is celecoxib, an anti-inflammatory.
Together, these compounds are designed to target several key mechanisms that contribute to the nerve cell degeneration that <a href="https://alsnewstoday.com/causes-of-als/">causes ALS</a>. Specifically, it aims to block inflammation, iron accumulation, and impaired RNA regulation to slow <a href="https://alsnewstoday.com/stages-of-als/">disease progression</a>.
In a previous <a href="https://clinicaltrials.gov/study/NCT04165850">Phase 2a clinical trial (NCT04165850)</a> in Israel, an initial formulation of PrimeC was found to be <a href="https://alsnewstoday.com/news/primec-safe-lowers-als-disease-biomarkers-phase-2-clinical-study/">safe and well tolerated</a> in 15 ALS patients. The therapy also slowed functional and respiratory decline compared with an historical group of untreated patients, and lowered ALS biomarkers, particularly TDP-43.
PARADIGM is testing a longer-acting formulation of PrimeC that releases the medications over an extended period of time, requiring less frequent dosing.
Participants, whose symptoms of muscle weakness began less than 30 months before screening, were randomly assigned to either PrimeC or a placebo for six months. The active medication was given at a total daily dose of 1,496 mg, taken as two tablets twice daily, and patients were allowed to continue their standard <a href="https://alsnewstoday.com/als-treatment/">ALS therapies</a>.
<h3>Efficacy measured by changes in disability, lung health with treatment</h3>
The study&#8217;s primary goals are to determine PrimeC&#8217;s safety and its effects on key ALS blood biomarkers, TDP-43 and prostaglandin J2. Secondary goals include changes in the ALS Functional Rating Scale-Revised (ALSFRS-R), a measure of functional disability, changes in lung health and quality of life, and survival outcomes.
Data covering these secondary efficacy measures, as well as safety results, are expected to be announced in December, and the biomarker findings by June. NeuroSense also expects to report, by the close of March, results of a blood biomarker analysis being conducted under a collaboration with Biogen.
This analysis is looking at changes in plasma levels of neurofilaments, established markers of nerve damage, among people treated with PrimeC. Biogen is conducting the analysis, and under the agreement has a right of first refusal to co-develop and co-commercialize PrimeC depending on the results.
PrimeC has been <a href="https://alsnewstoday.com/news/als-combination-therapy-primec-receives-fdas-orphan-drug-designation-enters-clinical-trials/">designated an orphan drug in the U.S.</a> and <a href="https://alsnewstoday.com/news/primec-orphan-drug-designation-europe-treatment-als/">the European Union</a>, a status meant to accelerate the development and regulatory review of therapies for rare diseases.

Top-line results of PARADIGM trial into PrimeC expected by year’s end

PrimeC, <a href="https://www.neurosense-tx.com/" rel="nofollow">NeuroSense Therapeutics</a>&#8216; investigational, fixed-dose combination therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), significantly boosted the survival of patient-derived motor neurons to levels similar to healthy controls in a lab study.
The independent study was led by Justin Ichida, PhD, a professor of stem cell biology and regenerative medicine at the University of Southern California (USC).
&#8220;Dr. Ichida has been described as being beyond the cutting edge in his field and we are honored that he and his lab chose to evaluate PrimeC in this non-sponsored study,&#8221; Alon Ben Noon, founder and CEO of NeuroSense, said in a <a href="https://www.prnewswire.com/news-releases/neurosenses-primec-demonstrates-outstanding-effect-on-als-survival-in-innovative-ipsc-model-301946965.html">company press release</a>.
[recommended-reading id=86465]
<h3>PrimeC combines the antibiotic ciprofloxacin with anti-inflammatory celecoxib</h3>
Findings were presented by Shiran Zimri, PhD, NeuroSense&#8217;s vice-president of research and development, at the recent Northeast Amyotrophic Lateral Sclerosis (NEALS) annual meeting in Florida.
&#8220;These results further bolster our confidence that PrimeC may offer a much-needed therapy for this debilitating disease,&#8221; Noon said.
<a href="https://www.neurosense-tx.com/primec/" rel="nofollow">PrimeC</a> is an oral, fixed-dose combination of two approved compounds with well-established safety profiles: the antibiotic ciprofloxacin and the anti-inflammatory celecoxib.
Together, the medications are expected to prevent ALS progression by targeting inflammation and other mechanisms that damage motor neurons, the nerve cells in the brain and spinal cord that coordinate movement by sending commands to muscle cells.
Ichida and his team at USC&#8217;s Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research examined the efficacy of PrimeC in patient-derived motor neurons.
These cells were generated from blood cells using a kind of cellular programming. First, the scientists collected blood cells from ALS patients and healthy people. Then, through a series of biochemical manipulations, the blood cells were reprogrammed into induced pluripotent stem cells, or iPSCs, which are lab-made stem cells able to grow into other types of cells.
Because the iPSCs retain the genetic code of the person that the blood cells were collected from, they enable the creation of nerve cells that recapitulate the same features of diseased motor neurons. iPCS also provide an almost unlimited source of patient-derived motor neurons, which can be used for large screenings of potential therapies.
&#8220;At our lab, we screen thousands of compounds in search of one that may be effective in ALS, and we were very impressed by the data resulting from our iPCS in vitro study of PrimeC,&#8221; Ichida said. “We chose to evaluate PrimeC based on the growing body of clinical, pre-clinical, and biomarker data on its efficacy in ALS.&#8221;
<h3>PrimeC protected motor neurons more effectively than its components alone</h3>
In a previous study, Ichida found PrimeC to be among the best at improving motor neuron survival in a list that included multiple approved and <a href="https://alsnewstoday.com/experimental-treatments-for-als/">experimental ALS therapies</a>, NeuroSense reported, adding that PrimeC outperformed <a class="waffle-rich-text-link" href="https://alsnewstoday.com/amx0035/">Relyvrio</a> (sodium phenylbutyrate and taurursodiol) and <a class="waffle-rich-text-link" href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone) in that study&#8217;s model.
In the current study, researchers compared survival rates of ALS motor neurons with PrimeC versus each of its components. They also tested each of those treatments against motor neurons derived from healthy individuals.
Data showed that, while both ciprofloxacin and celecoxib led to significantly better survival rates than no treatment, the combination therapy was better than either drug alone at improving cell survival.
Notably, ALS motor neurons treated with PrimeC had survival rates similar to those seen in healthy motor neurons, NeuroSense reported.
&#8220;These findings present a new opportunity to potentially screen super responder patients using iPSCs, a non-invasive method which only requires a blood draw from the patient. Using this screening model may result in higher efficacy in people living with ALS who are most likely to benefit from PrimeC,” Zimri said.
In a <a href="https://classic.clinicaltrials.gov/ct2/show/NCT04165850">Phase 2a clinical trial (NCT04165850)</a> that concluded in 2021, an early formulation of PrimeC showed a potential to <a href="https://alsnewstoday.com/news/primec-safe-lowers-als-disease-biomarkers-phase-2-clinical-study/">safely slow overall disease progression</a> and lung function decline compared with an historical group of patients.
A new, extended-release formulation of PrimeC is being investigated in a Phase 2b clinical trial, called <a href="https://classic.clinicaltrials.gov/ct2/show/NCT05357950">PARADIGM (NCT05357950)</a>. There, 69 adults were randomly assigned to the experimental medicine or a placebo, given twice daily for six months alongside standard ALS medications. <a href="https://alsnewstoday.com/news/neurosense-paradigm-trial-primec-als-completes-enrollment-patients/">Top-line trial findings are expected</a> in the coming months.

PrimeC boosts survival of motor neurons derived from ALS patients

A Phase 2b trial of PrimeC for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) has completed patient enrollment, according to <a href="https://www.neurosense-tx.com/">NeuroSense Therapeutics</a>, the therapy&#8217;s developer.
Called <a href="https://clinicaltrials.gov/ct2/show/NCT05357950">PARADIGM (NCT05357950)</a>, the study enrolled 69 adults <a href="https://alsnewstoday.com/als-diagnosis/">diagnosed with ALS</a>, ages 18-75, at sites in Israel, Italy, and Canada. The company anticipates top-line results late this year.
The trial is testing an extended-release formulation of PrimeC, designed to require less frequent dosing for patients.
“Based on the new formulation, we are aiming for efficacy and safety results that will meet and exceed the results achieved in the Phase 2a study,” Vivian Drory, MD, principal investigator of the PARADIGM trial at Tel Aviv Sourasky Medical Center, in Israel, said in a <a href="https://www.prnewswire.com/news-releases/neurosense-completes-enrollment-in-phase-2b-als-clinical-trial-301824559.html">company press release</a>.
Results from this study will inform the design of a future pivotal Phase 3 clinical trial of PrimeC, the company said.
[recommended-reading id=78033]
<h3>PARADIGM trial testing 17 outcome measures for Prime C</h3>
PrimeC is an oral, fixed-dose combination of two medications approved in the U.S. that both have well-established safety profiles. One, ciprofloxacin, is an antibiotic, while the other, celecoxib, is an anti-inflammatory agent.
The combination is thought to potentially inhibit disease progression by targeting key mechanisms in ALS motor degeneration. Specifically, the therapy aims to block inflammation, iron accumulation, and impaired RNA processing.
An initial formulation of PrimeC was found to be <a href="https://alsnewstoday.com/news/primec-safe-lowers-als-disease-biomarkers-phase-2-clinical-study/">safe and well tolerated</a>, and showed some promising trends toward less functional and respiratory decline, in a previous <a href="https://clinicaltrials.gov/ct2/show/NCT04165850">Phase 2a trial (NCT04165850)</a>. That trial involved 15 ALS patients.
The PARADIGM trial was designed to test a longer-acting formulation of PrimeC, which may be administered less frequently because it releases the two medications over an extended period of time.
The trial enrolled ALS patients whose symptoms of muscle weakness began less then 30 months (about 2.5 years) before screening. All participants were randomly assigned to receive Prime C, at a total daily dose of 1,496 mg — two tablets twice daily — or a placebo, for six months. All patients maintained their standard <a href="https://alsnewstoday.com/als-treatment/">ALS medication</a> regimen during the trial.
The study primarily aims to evaluate the treatment&#8217;s safety and tolerability, as well as changes in ALS biomarkers associated with PrimeC treatment. Secondary measures include changes in patients&#8217; functional disability, lung function, quality of life, and survival.
“PARADIGM is tracking 17 different outcome measures while the primary endpoint remains focused on biomarkers,“ said Ferenc Tracik, MD, chief medical officer at NeuroSense.
“This wealth of outcome data will not only be used to optimize the design of a future pivotal Phase 3 study for PrimeC, but we believe it will provide greater insight into the mechanisms of ALS for the scientific community as we advance toward a day when ALS will become a highly treatable disease,&#8221; Tracik said.
After completing the trial’s randomized phase, patients will have the option to enter an open-label extension phase, during which all participants will receive PrimeC for one year. To date, 26 participants completed the randomized phase, and 25 chose to continue into the extension part.
&#8220;It is highly encouraging that nearly all participants who completed the study have elected to continue in the [open label extension] phase with the treatment of PrimeC,&#8221; Drory said.
&#8220;We look forward to seeing the topline data from this study,&#8221; Drory added, noting the trial is testing the &#8220;optimized formulation of PrimeC.&#8221;
PrimeC has been granted orphan drug status in both the U.S. and the European Union. This designation is awarded to therapies that aim to treat rare diseases.
&#8220;We are pleased to share this milestone for the PARADIGM clinical trial,&#8221; said Alon Ben-Noon, CEO of NeuroSense, adding, &#8220;We are grateful to the participants living with ALS, their families, and the study investigators for their commitment to the PARADIGM trial and for taking part in our mission to develop an effective therapy for ALS.&#8221;

PARADIGM trial of PrimeC for ALS now fully enrolled with 69 adults

A Phase 2b trial that&#8217;s testing PrimeC in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) has reached 80% enrollment and is on track to complete patient recruitment by June, <a href="https://www.neurosense-tx.com/" rel="nofollow">NeuroSense Therapeutics</a> announced in a quarterly update.
Called <a href="https://clinicaltrials.gov/ct2/show/NCT05357950">PARADIGM (NCT05357950)</a>, the study began <a href="https://alsnewstoday.com/news/first-als-patient-enrolled-phase-2b-study-neurosenses-primec/">enrolling ALS patients in mid-2022</a>, and it plans to include up to 69 adults recently diagnosed with ALS, ages 18-75, at sites in Israel, Italy, Germany, and Canada. Top-line results are expected later this year. For those interested in possibly taking part, <a href="https://clinicaltrials.gov/ct2/show/NCT05357950#contactlocation">contact information</a> is available.
“We are … well on our way to completing patient enrollment in our Phase 2b ALS study,&#8221; Alon Ben-Noon, CEO of NeuroSense Therapeutics, said in a <a href="https://www.prnewswire.com/news-releases/neurosense-ceo-provides-q1-2023-update-phase-2b-als-trial-achieves-80-enrollment-301798875.html">company press release</a>.
[recommended-reading id=83732]
<h3>PrimeC is fixed-dose combination of an antibiotic and anti-inflammatory</h3>
PrimeC is composed of a fixed-dose combination ciprofloxacin, an antibiotic, and celecoxib, an anti-inflammatory agent. Both medications are individually approved in the U.S. and have an established safety profile.
The combination is thought to lower inflammation in the nervous system, improve RNA processing, and normalize iron accumulation. Problems in these areas help to drive disease progression.
In an ALS fish model, PrimeC was reported to significantly outperform standard ALS treatments, improving motor abilities and the function of motor neurons, the cells damaged in ALS. It also helped restore neuromuscular junctions, the regions where nerves and muscles communicate.
In a previous <a href="https://clinicaltrials.gov/ct2/show/NCT04165850">Phase 2a trial (NCT04165850)</a> in 15 ALS patients, oral PrimeC was found to be <a href="https://alsnewstoday.com/news/primec-safe-lowers-als-disease-biomarkers-phase-2-clinical-study/">safe and well tolerated</a>, and to lower disease biomarkers. Findings also suggested a slowing of disease progression compared with an historical group of patients.
The PARADIGM trial now is testing an extended-release formulation of PrimeC in ALS patients with disease onset less than 30 months, about 2.5 years, before a screening for the study.
Participants are being randomly assigned to PrimeC — given as two extended-release tablets twice daily, for a total daily 1,496 mg dose — or to placebo tablets for six months, while continuing on their standard <a href="https://alsnewstoday.com/als-treatment/">ALS medications</a>.
The study&#8217;s primary goals are to determine treatment safety, and changes in ALS biomarkers with treatment. Secondary measures include changes in functional disability, lung function, and quality of life.
After completing the trial&#8217;s randomized phase, patients will have the option to join an open-label extension phase, in which all will be treated with PrimeC for up to one year.
Of note, patients in the U.S. were expected to enroll in PARADIGM, but the company <a href="https://alsnewstoday.com/news/paradigm-trial-testing-als-therapy-primec-drops-u-s-sites/">decided against opening sites</a> there after the U.S. Food and Drug Administration requested more data to support the trial’s duration.
Should PARADIGM conclude successfully, NeuroSense plans to meet with the regulatory agency to include U.S. sites in a pivotal Phase 3 trial.
Under a collaboration with researchers at Massachusetts General Hospital, the company also aims to study <a href="https://alsnewstoday.com/news/primecs-impacts-key-als-disease-mechanisms-be-studied/">PrimeC&#8217;s effects on key ALS processes</a>. Particularly, it is looking into the buildup of TDP-43, a protein that’s abnormal in most disease cases; cellular recycling; and oxidative stress, the imbalance between the production of oxygen-containing molecules and the body’s ability to clear them.
&#8220;We continue to form collaborations with leading institutions and innovative companies to advance the science of biomarkers in the diagnosis and treatment of neurological diseases,&#8221; Ben-Noon said.
PrimeC has received orphan drug status from the FDA and European Medicines Agency (EMA), a designation meant to support and accelerate the development of potentially life-saving treatments for rare diseases.

Tag: PrimeC