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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

Treatment with <a href="https://alsnewstoday.com/cnm-au8/">CNM-Au8</a> was shown to significantly prolong survival — relative to the natural history of the disease — among people with advanced <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) who took part in two expanded access programs (EAP), also known as compassionate use programs.
The findings from these EAPs, which allow an experimental therapy&#8217;s use in patients outside of clinical trials, are consistent with previous observations in Phase 2 studies that tested the oral therapy in less severely affected individuals with ALS.
“These EAP results help us better understand how people living with more advanced disease respond to treatment,” Richard S. Bedlack Jr., MD, PhD, a professor at the Duke University School of Medicine, in North Carolina, and a member of the steering committee for one of the EAP studies, said in a <a href="https://www.globenewswire.com/news-release/2024/02/22/2833653/0/en/Clene-Reports-Significant-Survival-Benefit-With-CNM-Au8-Treatment-in-ALS-EAP-Compassionate-Use-Programs.html">press release announcing the results</a>.
The data support developer <a href="https://clene.com/">Clene Nanomedicine</a>’s plans to advance CNM-Au8 to Phase 3 clinical testing, which the company has previously noted is expected to begin this year.
Clene last October also was awarded a four-year, $45.1 million grant from the National Institutes of Health to <a href="https://alsnewstoday.com/news/new-eap-makes-cnm-au8-available-als-patients-outside-trials/">support the launch of a third EAP</a>. That compassionate use program will particularly seek to reach U.S. patients in rural and remote areas virtually via a telemedicine platform. It&#8217;s expected to start enrolling in all 50 states during the first half of this year.
“Collecting data of peoples’ experience beyond clinical trials is extremely important in rare diseases like ALS,&#8221; Bedlack said, adding that the EAP data &#8220;warrant consideration to be included in Clene’s discussions about CNM-Au8 with regulatory agencies.”
[recommended-reading id=88296]
<h3>Compassionate use programs allow patients to get treatment outside trials</h3>
CNM-Au8 is an oral liquid suspension of gold nanoparticles. It aims to slow ALS progression by supporting nerve cells’ energy needs and protecting against types of cellular damage that are implicated in the neurodegenerative disease.
Phase 2 clinical trials of the therapy candidate are wrapping up, among them the <a href="https://clinicaltrials.gov/ct2/show/NCT04098406">RESCUE-ALS study (NCT04098406)</a> and its <a href="https://clinicaltrials.gov/ct2/show/NCT05299658">open-label extension (NCT05299658)</a>, as well as an arm of the <a href="https://clinicaltrials.gov/study/NCT04297683">HEALEY ALS platform trial (NCT04297683)</a>. RESCUE-ALS tested CNM-Au8 against a placebo in 45 patients, while its extension involved an estimated 40 individuals. In that open-label part, both researchers and participants know the exact medication that&#8217;s being given. The HEALEY ALS trial, meanwhile, is a multicenter, multi-regimen clinical trial evaluating several treatment candidates at the same time.
For their part, EAPs are regulated pathways that intend to offer access to an investigational therapy outside of clinical trial settings for patients with serious or life-threatening diseases for whom no satisfactory treatment is available.
The CNM-Au8 EAPs, both of which are still active, include patients in the U.S. who were not eligible for CNM-Au8 clinical trials — usually because their disease was too advanced.
The first <a href="https://clinicaltrials.gov/study/NCT04081714?cond=ALS&amp;intr=CNM-Au8&amp;rank=2">EAP (NCT04081714)</a> was launched in 2019 at the Sean M. Healey &amp; AMG Center for ALS at Massachusetts General Hospital, where the HEALEY ALS platform trial is also being led. A second <a href="https://clinicaltrials.gov/study/NCT05281484?cond=ALS&amp;intr=CNM-Au8&amp;rank=3">EAP (NCT05281484</a>) was launched in 2021, and is available to patients at 16 U.S. sites associated with the Northeast ALS Consortium.
In addition to expanding patient access to the therapy, the EAPs are expected to provide additional safety and efficacy data for regulators to review when deciding on the treatment’s possible approval.
[recommended-reading id=41328]
<h3>Comparing use of CNM-Au8 to natural history, or no treatment</h3>
Clene’s recent update concerned pooled data from the EAPs, through which more than 250 patients have been treated with CNM-Au8 at a daily oral dose of 30 mg.
Survival analyses were conducted to compare outcomes from a total of 220 EAP participants — who had been treated for up to four years — with data from matched untreated ALS patients in either of two databases.
The first was PRO-ACT, a large database containing information from more than 12,000 ALS patients who participated in previous clinical trials. The other was the ALS/MND Natural History Consortium, a study that has collected real-world data from about 1,700 ALS patients.
The results indicated that CNM-Au8 was associated with a significant, 68% decreased risk of death compared with people in PRO-ACT, and a significant, 57% lower risk relative to the ALS/MND Consortium, according to the company.
[quote=&#8221;center&#8221;]The long-term safety and survival data from the CNM-Au8 expanded access programs add to the available data supporting CNM-Au8 moving rapidly to Phase 3 testing in ALS. &#8230; This is one of a few therapies with positive Phase 2 data that must go forward to Phase 3 trials.[/quote]
CNM-Au8 was well tolerated, with no serious adverse events deemed related to treatment. Also, no significant safety findings were identified.
Overall, the findings are consistent with <a href="https://alsnewstoday.com/news/cnm-au8-seen-to-extend-survival-by-more-than-1-5-years-in-als-trial/">previous analyses</a> from the RESCUE and HEALEY-ALS trials, in which treatment with CNM-Au8 <a href="https://alsnewstoday.com/news/long-term-survival-benefit-seen-cnm-au8-healey-als-analyses-trial/">prolonged survival</a> and <a href="https://alsnewstoday.com/news/cnm-au8-delayed-clinical-worsening-als-patients-healey-trial/">delayed clinical worsening</a> in ALS patients.
“The long-term safety and survival data from the CNM-Au8 expanded access programs add to the available data supporting CNM-Au8 moving rapidly to Phase 3 testing in ALS,” said Merit Cudkowicz, MD, chair of neurology and director of the Healey &amp; AMG Center at Mass General Hospital, a principal investigator of the EAP being conducted at Healey &amp; AMG Center, and a professor at Harvard Medical School.
“This is one of a few therapies with positive Phase 2 data that must go forward to Phase 3 trials,&#8221; Cudkowicz added.

CNM-Au8 extends patient survival in 2 ALS compassionate use studies

Treatment with <a href="https://alsnewstoday.com/cnm-au8/">CNM-Au8</a> was found to significantly delay disease progression and prolong survival, by more than 1.5 years, among adults with early-stage <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in the RESCUE-ALS trial and its open-label extension phase.
That&#8217;s according to two different statistical analyses, which overall showed that patients who received CNM-Au8 had a 70% lower risk of death over two years of follow-up compared with those never given the medication.
Indeed, the new analyses revealed a &#8220;19.3 month significant survival difference for CNM-Au8 treated participants versus [those on a] placebo,&#8221; <a href="https://clene.com/">Clene Nanomedicine</a>, the company developing CNM-Au8, stated in a <a href="https://www.globenewswire.com/news-release/2023/08/29/2733238/0/en/Clene-Reports-Significantly-Improved-Survival-Benefit-of-19-3-Months-and-Significantly-Delayed-Clinical-Worsening-in-Rescue-Als-Open-Label-Extension-Two-Year-Follow-Up.html">press release</a>.
“The data that continues to be received from the RESCUE-ALS open label extension study is truly impressive, and now shows consistently significant decreased risk of death greater than 70% using two different long-term analysis models,” said Matthew Kiernan, PhD, of the University of Sydney, one of the trial&#8217;s clinical advisors.
“The survival benefit across treatment arms is linked to less worsening of disease, as experienced by ALS patients. At the same time, the further safety data confirms that CNM-Au8 is well tolerated in ALS patients,” Kiernan added.
[recommended-reading id=84096]
<h3>Main trial of CNM-Au8 failed to meet primary, secondary goals</h3>
The oral therapy is a suspension of gold nanoparticles that&#8217;s intended to slow ALS progression by preventing the death of the motor nerve cells that are progressively lost in the disease.
CNM-Au8 is believed to promote nerve cell survival by boosting energy production and protecting against a type of cellular damage, called oxidative stress, that&#8217;s implicated in ALS .
The Phase 2 <a href="https://clinicaltrials.gov/ct2/show/NCT04098406">RESCUE-ALS trial (NCT04098406)</a>, sponsored by Clene and launched in late 2019, enrolled 45 adults with early ALS at two sites in Australia. All had developed their first symptoms of the progressive disorder in the prior two years.
The participants were randomly assigned to receive CNM-Au8, at a dose of 30 mg, or a placebo, given as a liquid suspension once daily for 36 weeks, or about eight months. The therapy was given in addition to <a href="https://alsnewstoday.com/als-treatment/">standard ALS medications</a>.
Following the main trial, most participants (90%) entered into an <a href="https://clinicaltrials.gov/ct2/show/NCT05299658">open-label extension (NCT05299658)</a>, in which all would be given CNM-Au8 for up to 120 weeks, or more than two years.
The main trial had <a href="https://alsnewstoday.com/news/cnm-au8-failed-primary-rescue-als-goals-top-line-trial-data/">failed to meet its primary and key secondary goals</a> of improving motor nerve cell health and slowing lung function declines after 36 weeks.
However, additional analyses spanning the trial and its extension have indicated a <a href="https://alsnewstoday.com/news/early-cnm-au8-treatment-als-continues-show-survival-benefits/">survival benefit</a> and <a href="https://alsnewstoday.com/news/slower-progression-experimental-als-treatment-cnm-au8/">slower disease progression</a> among patients who started the therapy eight months earlier relative to those who switched from the placebo in the extension phase.
[recommended-reading id=84549]
<h3>Survival benefits with CNM-Au8 still being seen in extension trial</h3>
Now, Clene has reported that the survival benefits of CNM-Au8 are still being observed as of July 2023 — after two years in the extension trial.
Specifically, patients who started CNM-Au8 eight months earlier had a median survival of 34.2 months, or almost three years, compared with 24.1 months, or about two years, among those who switched from placebo. That&#8217;s a survival benefit of 10.1 months, and it amounts to a 46% lower risk of death among those originally assigned to CNM-Au8.
Investigators also conducted another survival analysis wherein the data were adjusted to subtract the potential survival benefits received by those who started on a placebo and then switched to CNM-Au8.
Essentially, the analysis estimated survival in this group if the patients had remained on a placebo and never switched over. That survival was determined to be 14.9 months, or about 1.2 years.
Here, the survival benefits of those always on CNM-Au8 were even more pronounced, with patients living about 19.3 months longer relative to those on a placebo. This was associated with a 75% lower risk of death in participants on continuous CNM-Au8.
[quote=&#8221;center&#8221;]A median survival improvement of 19.3 months provides people living with ALS, their families, and caregivers more time that is so invaluable, and adds to the totality of data we are seeing in our ALS clinical program.[/quote]
The researchers then compared the survival of individuals treated with CNM-Au8 with historical placebo-treated patients — controls whose data were contained in the PRO-ACT ALS patient database. In that analysis, treatment with CNM-Aug was associated with a 70% lower risk of death.
Patients initially assigned the experimental therapy in the main trial also were found to be at a 52% lower risk of clinical worsening compared with those who started treatment eight months later. Clinical worsening was defined as the occurrence of one of several outcomes: death, breathing tube placement, assisted ventilation, or feeding tube placement.
Among open-label participants treated with CNM-Au8, 42% are still alive up to 3.5 years after their enrollment in RESCUE-ALS — and up to 6.6 years after their ALS symptom onset — according to Benjamin Greenberg, MD, head of medical at Clene.
Greenberg called this finding &#8220;a profoundly meaningful milestone for people living with this devastating disease.&#8221;
“A median survival improvement of 19.3 months provides people living with ALS, their families, and caregivers more time that is so invaluable, and adds to the totality of data we are seeing in our ALS clinical program,” Greenberg said.
[recommended-reading id=83732]
<h3>CNM-Au8 also shows benefit in ALS platform trial</h3>
Similar findings also were observed in the CNM-Au8 arm of <a href="https://clinicaltrials.gov/ct2/show/NCT04297683">HEALEY ALS (NCT04297683)</a>, a platform trial that is investigating multiple ALS therapies simultaneously as a way to reduce costs and accelerate treatment development.
In that platform trial arm, treatment with 30 mg CNM-Au8 for six months lowered the risk of death by <a href="https://alsnewstoday.com/news/cnm-au8-found-lower-risk-death-als-healey-platform-trial/">more than 90%</a>. Moreover, <a href="https://alsnewstoday.com/news/cnm-au8-delayed-clinical-worsening-als-patients-healey-trial/">significant reductions also were observed</a> in the risk of needing a feeding tube, assisted ventilatory support, or being hospitalized.
Additionally, in more than 475 collective years of CNM-Au8 exposure in patients with several neurodegenerative disorders — ALS, <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a>, and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s disease</a> — no safety signals have been identified, according to researchers. Most reported side effects have been mild to moderate in severity, and temporary.
Side effects reported in RESCUE-ALS include nausea, bruising, abdominal discomfort, and aspiration pneumonia, or inflammation caused by food or liquids inhaled into the airways.
Clene has reported plans to launch a Phase 3 trial of CNM-Au8 called RESTORE-ALS. Should results be positive, the data may support regulatory applications for the therapy&#8217;s approval.

Tag: prolonged survival

PrimeC in ALS patients shown to extend complication-free survival

CNM-Au8 extends patient survival in 2 ALS compassionate use studies

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