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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;
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<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

<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>.
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<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

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.
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<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>.
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<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.

PARADIGM trial of PrimeC in treating ALS nears full enrollment

The Phase 2b trial testing PrimeC in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) will no longer enroll patients in the U.S., its maker <a href="https://www.neurosense-tx.com/">NeuroSense Therapeutics</a> has announced.
Meanwhile, the company has been given the green light from regulatory agencies in <a href="https://www.prnewswire.com/news-releases/neurosense-receives-approval-in-germany-to-enroll-patients-in-its-phase-2b-als-trial-301741859.html">Germany</a> and Canada to enroll new participants, joining earlier approvals in Israel and <a href="https://alsnewstoday.com/news/phase-2b-clinical-trial-als-test-primec-sites-us-italy/">Italy</a>.
The <a href="https://clinicaltrials.gov/ct2/show/NCT05357950">PARADIGM Phase 2b trial (NCT05357950)</a>, which <a href="https://alsnewstoday.com/news/first-als-patient-enrolled-phase-2b-study-neurosenses-primec/">began enrolling last June</a>, seeks to <a href="https://clinicaltrials.gov/ct2/show/NCT05357950#contacts">recruit about 69 adults</a> with ALS, ages 18-75. It&#8217;s currently about 50% enrolled, with top-line data expected in the second half of the year.
&#8220;In the interest of treating and completing dosing of people living with ALS in an expedient and safe manner through PARADIGM, we&#8217;ve focused our North American recruitment in Canada,&#8221; said Alon Ben-Noon, NeuroSense CEO, in a <a href="https://www.prnewswire.com/news-releases/neurosense-expands-its-phase-2b-als-paradigm-trial-to-canada-and-withdraws-protocol-from-us-ind-to-align-its-clinical-strategy-with-the-fda-for-a-potential-pivotal-phase-3-study-301739360.html">company press release</a>.
NeuroSense intends to meet with the U.S. Food and Drug Administration (FDA) about a pivotal Phase 3 trial that would include U.S. sites should PARADIGM conclude successfully.
The decision to drop U.S. sites was agreed upon by NeuroSense and the FDA after the agency requested additional nonclinical data to support the trial&#8217;s duration.
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The request was made because PrimeC is intended as a long-term treatment. The PARADIGM trial currently involves a six-month placebo-controlled part followed by an open-label extension wherein all patients will receive PrimeC for an additional year.
&#8220;We expect to enroll the first study participant in Germany in the next few weeks, and we are very pleased to receive regulatory clearance to enroll and dose people living with ALS also in Germany for our PARADIGM study,&#8221; Ferenc Tracik, MD, NeuroSense&#8217;s chief medical officer, said in a <a href="https://www.prnewswire.com/news-releases/neurosense-receives-approval-in-germany-to-enroll-patients-in-its-phase-2b-als-trial-301741859.html">separate press release</a>.
Participants in PARADIGM are being randomly assigned to receive PrimeC as two <a href="https://alsnewstoday.com/news/primec-als-safety-good-profile-extended-release-tablet/">extended-release</a> oral tablets twice daily — 1,496 mg a day — or a placebo for six months in addition to standard therapies.
The study&#8217;s main goals are safety and the impact of PrimeC on disease biomarkers. Secondary goals include measures of disease severity, lung function, quality of life, and survival.
Although PARADIGM won&#8217;t include U.S. sites, NeuroSense still intends for a future trial to take place in the U.S., which would support a potential regulatory application for PrimeC&#8217;s U.S. approval if it&#8217;s successful.
&#8220;We look forward to working with the FDA on a path that includes clinical sites in the U.S. in a future Phase 3 pivotal study of PrimeC to address the dire unmet need of the U.S. ALS community who are eager to receive PrimeC for long-term use,&#8221; Ben-Noon said.
PrimeC is made up of a fixed dose combination of the antibiotic ciproflaxin and celecoxib, an anti-inflammatory medication, both of which are individually approved by the FDA and with established safety profiles.
It&#8217;s thought the combination may target key ALS disease processes, including reducing inflammation, improving RNA processing, and normalizing iron accumulation. Its original formulation showed promise on <a href="https://alsnewstoday.com/news/primec-safe-lowers-als-disease-biomarkers-phase-2-clinical-study/">disease progression</a> in a previous <a href="https://clinicaltrials.gov/ct2/show/NCT04165850">Phase 2 trial (NCT04165850)</a>.
PrimeC holds orphan drug status in the <a href="https://alsnewstoday.com/news/als-combination-therapy-primec-receives-fdas-orphan-drug-designation-enters-clinical-trials/">U.S.</a> and <a href="https://alsnewstoday.com/news/primec-orphan-drug-designation-europe-treatment-als/">Europe</a>, a designation given to accelerate the development of potentially life-saving treatments for rare diseases.

Tag: PARADIGM trial

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

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

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

PARADIGM trial of PrimeC in treating ALS nears full enrollment

PrimeC PARADIGM trial drops U.S. sites, adds Canada, Germany