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<a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava </a>(edaravone) significantly prolongs long-term survival for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to an analysis of nearly 3,000 patients. It didn&#8217;t significantly slow the progression of disease symptoms, as assessed by scores on the ALS Functional Rating Scale-Revised (ALSFRS-R), however.
The results were presented at last week&#8217;s American Academy of Neurology (AAN) 2023 annual meeting in the poster, “<a href="https://www.aan.com/MSA/Public/Events/AbstractDetails/54324">Survival in Amyotrophic Lateral Sclerosis Patients Treated with Edaravone &#8211; a Pooled Analysis of 2845 Patients</a>.”
Radicava is an approved <a href="https://alsnewstoday.com/als-treatment/">treatment for ALS</a> that&#8217;s thought to reduce oxidative stress — a type of cell damage that plays a major role in driving the disease. It&#8217;s available as an intravenous (into the vein) infusion or in a newer oral formulation called Radicava ORS. Both are sold by <a href="https://www.mt-pharma.co.jp/e/">Mitsubishi Tanabe Pharma</a>, which was not involved with this analysis.
Despite Radicava&#8217;s approval in <a href="https://alsnewstoday.com/news/fda-approves-radicava-first-new-als-therapy-in-20-years-and-cause-for-hope/">the U.S.</a>, <a href="https://alsnewstoday.com/news-posts/2018/10/09/radicava-now-approved-to-treat-als-patients-in-canada/">Canada</a>, Switzerland, and a number of other countries, evidence on its effectiveness <a href="https://alsnewstoday.com/news/radicava-suggests-more-real-world-data-needed-to-determine-efficacy-of-edaravone-in-als/">isn&#8217;t settled</a>, leading scientists at Al-Azhar University, Egypt to analyze pooled data from 12 previously published studies to assess its effect on disease progression and survival.
[recommended-reading id=82936]
The analysis included data on 2,845 patients, among whom, 1,141 were treated with Radicava, sometimes in combination with the older ALS therapy riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek </a>and other formulations). The other 1,704 were given a control treatment, either a placebo or riluzole alone.
After 18 months (1.5 years) of follow-up, the chances of survival were significantly higher, by about 13%, for patients given Radicava. Later analyses also showed a significant survival benefit with Radicava — by 22% at 24 months (two years) and by 17% at 30 months (2.5 years).
At earlier timepoints (six or 12 months), survival tended to be slightly better in the Radicava group, but the difference with the control group was not statistically significant. That means it&#8217;s mathematically plausible the difference could be due to random chance.
Rates of symptom progression, as measured by the change in ALSFRS-R scores, tended to slightly favor Radicava, but weren&#8217;t significantly different from controls. Rates of side effects and other safety issues were comparable in the two groups, leading the scientists to conclude that Radicava “improves long-term survival with no effect on the ALSFRS-R score&#8221; and with a similar rate of adverse events between the groups.

AAN 2023: Radicava leads to better long-term survival in ALS

Daily oral treatment with memantine did not slow disease progression nor did it reduce biomarker changes among people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) enrolled in a Phase 2b trial.
Approved under the brand name <a href="https://alzheimersnewstoday.com/alzheimers-disease-treatment/approved-drugs/namenda-memantine/">Namenda</a> to treat cognitive problems in people with <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer&#8217;s disease</a>, memantine has also been shown to help people with <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s disease</a>, but evidence for the therapy&#8217;s benefits in ALS has been conflicting.
Researchers discussed the data in a poster presentation at the American Academy of Neurology (AAN) 2023 Annual Meeting, held April 22-27 in Boston and virtually.
The poster was titled “<a href="https://www.aan.com/MSA/Public/Events/AbstractDetails/54463">A 40-week Phase 2B Randomized, Multicenter, Double-blind, Placebo-controlled Study Evaluating the Safety and Efficacy of Memantine in Amyotrophic Lateral Sclerosis</a>.”
[recommended-reading id=73830]
<h3>Memantine designed to prevent toxic effects of excitotoxicity</h3>
Excitotoxicity, a type of cell death driven by the excessive activity of glutamate — a chemical signaling molecule — in the brain has been implicated in ALS and other neurodegenerative diseases. Glutamate exerts its effects in several ways, one of which involves binding to N-methyl-D-aspartate (NMDA) receptors.
Memantine is a small molecule that blocks NMDA receptors, thereby working to prevent the toxic effects of excessive glutamate signaling.
Consequently, the drug has been associated with reductions in inflammation, prevention of protein misfolding, and reduced production of toxic oxidative molecules, all of which are implicated in ALS.
Preclinical studies have indicated that memantine may prolong survival in a mouse model of ALS. A few small clinical studies testing memantine in ALS patients have been conducted, but yielded conflicting results, according to the scientists.
For example, a <a href="https://clinicaltrials.gov/ct2/show/NCT01020331">pilot open-label study (NCT01020331)</a> involving 19 ALS patients found the treatment reduced the rate of clinical decline by 38% compared with a historical untreated control group. However, another <a href="https://clinicaltrials.gov/ct2/show/NCT00353665">placebo-controlled study (NCT00353665)</a> involving 60 patients did not see any slowing of disease progression.
[quote=&#8221;center&#8221;]Memantine did not slow the progression of ALS nor did it ameliorate the neurocognitive or behavioral effects of ALS.[/quote]
<h3>Phase 2b trial tested memantine&#8217;s safety and efficacy in 89 adults with ALS</h3>
To learn more, the researchers conducted a larger <a href="https://clinicaltrials.gov/ct2/show/NCT02118727">Phase 2b trial (NCT02118727)</a>, called TAME, evaluating memantine&#8217;s safety and efficacy among 89 adults with ALS, ages 18-85, who had started experiencing <a href="https://alsnewstoday.com/als-symptoms/">symptoms</a> of the neurodegenerative disease in the last three years.
In the trial, which took place from December 2018 to September 2020, participants were randomly assigned to receive oral memantine (58 people) or a placebo (31 people) for 40 weeks, or about nine months. The dose of memantine was increased to a maximum of 20 mg twice daily (40 mg total) or to the highest dose tolerated by each patient.
Patients were allowed to continue treatment with approved ALS therapies <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone) and riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a> among others) if they had been stable on treatment for more than a month.
The trial’s main goal was to assess changes in disease progression, as assessed by the Revised ALS Functional Rating Scale (ALSFRS-R), over 36 weeks. Secondary outcomes included changes in disease biomarkers and behavioral measures.
Results showed that monthly rates of functional decline were similar in the two groups, with those given memantine seeing a 1.26-point monthly drop in ALSFRS-R scores, compared with a 1.23-point monthly decline among those in the placebo group.
Likewise, scores on the ALS Cognitive Behavioral Screen and the Neuropsychiatric Inventory Questionnaire, two measures of cognitive and neuropsychiatric function, did not differ between the two groups.
[recommended-reading id=83732]
<h3>No differences found in blood levels of ALS-associated biomarkers</h3>
There also were no differences in blood levels of neurofilament light chain, a biomarker of nerve damage, or other disease-associated biomarkers.
&#8220;Memantine did not slow the progression of ALS nor did it ameliorate the neurocognitive or behavioral effects of ALS,&#8221; the researchers wrote.
The most frequently reported side effects among those treated with memantine included falls (26%), dizziness (26%), confusion (17%), and constipation (14%). Three deaths occurred in each group and were attributed to disease progression.
While the findings overall do not support the use of memantine in ALS, the researchers noted that the study, which allowed remote enrollment because of the COVID-19 pandemic, &#8220;demonstrated the feasibility of an almost entirely remote clinical trial that can be used for future trials.&#8221;
Memantine, taken as an oral solution, is also being examined in the ongoing multi-arm Phase 2/3 <a href="https://clinicaltrials.gov/ct2/show/NCT04302870">MND-SMART clinical trial (NCT04302870)</a>, which is recruiting adults with ALS at sites in the U.K. Its main goals are to assess changes in ALSFRS-R scores and survival with daily memantine compared with a placebo over 18 months, or about 1.5 years.

AAN 2023: Memantine fails to slow disease progression in Phase 2b trial

It&#8217;s been nearly three years since the HEALEY platform clinical trial started and, so far, two promising experimental treatments for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) have been identified.
Both potential medications — <a href="https://alsnewstoday.com/cnm-au8/">CNM-Au8</a> and <a href="https://alsnewstoday.com/pridopidine-experimental-treatment-als/">pridopidine</a> — are headed toward Phase 3 clinical testing, while testing has been ruled out for two others.
&#8220;Since we launched in the summer of 2020, we&#8217;ve had two no-go decisions and moved two drugs to Phase 3 testing,&#8221; said Sabrina Paganoni, MD, PhD, a physician-scientist at Massachusetts General Hospital (MGH) and the trial&#8217;s co-lead investigator.
Paganoni discussed the findings at this week&#8217;s American Academy of Neurology (AAN) 2023 Annual Meeting in the oral presentation, &#8220;Results from the First Four Regimens of the HEALEY ALS Platform Trial.&#8221;
The <a href="https://clinicaltrials.gov/ct2/show/NCT04297683?term=HEALEY+ALS&amp;draw=2&amp;rank=1">HEALEY platform trial (NCT04297683)</a>, led by the Sean M. Healey &amp; AMG Center for ALS at MGH, intends to test multiple potential <a href="https://alsnewstoday.com/als-treatment/">ALS therapies</a> at once, an approach that may help reduce the cost and time associated with drug development.
&#8220;A platform trial is a novel approach to trial design. The goal of platform trials is to develop new drugs faster and more efficiently, and we do so by using a common infrastructure or platform,&#8221; Paganoni said, noting the platform approach hasn&#8217;t been tried before in ALS, but has led to &#8220;savings across the board,&#8221; including in time, money, and patient resources in cancer studies.
&#8220;This is the perfect time for a platform trial in ALS, because like never before we have a very robust and growing drug pipeline and companies are looking for ways to develop their drugs most efficiently,&#8221; Paganoni said.
HEALEY encountered obstacles soon after its launch that arose from the COVID-19 pandemic. &#8220;As you can imagine, this was challenging because this was at the very beginning of the pandemic, but COVID did not stop ALS trials,&#8221; Paganoni said. &#8220;In fact, we continued to grow and experienced great enrollment rates.&#8221;
[recommended-reading id=83742]
<h3>Participation in HEALEY trial</h3>
Enrollment has been completed for five potential therapies, including zilucoplan, verdiperstat, CNM-Au8, pridopidine, and <a href="https://seelostherapeutics.com/sls-005-trehalose/">SLS-005</a>. The sixth trial arm testing ABBV-CLS-7262 started <a href="https://www.massgeneral.org/news/press-release/the-healey-als-platform-trial-enrolls-first-participants-for-the-investigational-product-abbv-cls-72-from-calico-life-sciences">enrolling last month</a> and the DNL343 arm is expected to begin <a href="https://alsnewstoday.com/news/aan-2023-dnl343-safe-appears-work-intended-phase-1-trial/">later this year</a>.
Patients enrolling in the trial don&#8217;t choose which treatment arm they&#8217;ll enter. They&#8217;re randomly assigned to one of the arms that&#8217;s enrolling at the time they join.
&#8220;When we started the trial, people asked us: &#8216;Will patients want to enroll in a new type of trial, a platform trial, where they cannot choose the drug they are assigned to?&#8217; And the answer to that is a resounding yes. Patients are eager to learn about and participate in innovative research,&#8221; Paganoni said, adding trial sites have also been eager to join. More than 70 clinics across the U.S. are participating in HEALEY.
Paganoni&#8217;s presentation covered data from the first four treatment arms, testing the experimental therapies zilucoplan, verdiperstat, CNM-Au8, and pridopidine, respectively.
In each treatment arm, most participants were given the investigational drug while a few were given a placebo. Because each treatment arm uses the same eligibility criteria, data from patients given each treatment can be compared with data from those given a placebo across all arms of the study.
The main goal of each treatment arm is to compare the effect on survival and disease progression, as measured by the ALS Functional Rating Scale Revised (ALSFRS-R), after six months.
Researchers also regularly carried out interim analyses to test for futility — in other words, statistical tests based on available data to check if there was a reasonable likelihood the therapy may provide a benefit for patients.
<h3>Disappointment with zilucoplan, verdiperstat</h3>
The first treatment arm for zilucoplan ended early after futility analyses showed it was <a href="https://alsnewstoday.com/news/ucb-stops-zilucoplan-arm-early-healey-trial-als-lack-of-efficacy/">unlikely to be beneficial</a>.
&#8220;While this was disappointing, it actually in a way met the goals of the trial, which is really to screen out drugs rapidly. So we were able to end this regimen early, saving months of operational activities,&#8221; Paganoni said.
Data from the second arm showed <a href="https://alsnewstoday.com/news/als-therapy-verdiperstat-fails-healey-trial-efficacy-goals/">verdiperstat failed to significantly slow ALS progression</a> and that arm has also been discontinued.
Findings from the third and fourth trial arms have been more promising, however.
[recommended-reading id=83515]
<h3>CNM0Au8, pridopidine move toward Phase 3 testing</h3>
Data from the third arm suggested CNM-Au8, at a daily dosage of 30 mg, <a href="https://alsnewstoday.com/news/cnm-au8-found-lower-risk-death-als-healey-platform-trial/">significantly reduced the risk of death</a> and the combined risk of death or permanent assisted ventilation by more than 90%. Recent analyses also suggested CNM-Au8 <a href="https://alsnewstoday.com/news/cnm-au8-delayed-clinical-worsening-als-patients-healey-trial/">delayed clinical worsening</a>. The treatment is designed to boost energy production in the nervous system.
Long-term data from a separate Phase 2 trial, <a href="https://clinicaltrials.gov/ct2/show/NCT04098406">RESCUE-ALS (NCT04098406)</a> and its <a href="https://clinicaltrials.gov/ct2/show/NCT05299658">open-label extension (NCT05299658)</a>, indicated early CNM-Au8 treatment may <a href="https://alsnewstoday.com/news/slower-progression-experimental-als-treatment-cnm-au8/">slow disease progression</a> and <a href="https://alsnewstoday.com/news/early-cnm-au8-treatment-als-continues-show-survival-benefits/">reduce the risk of death</a>. Findings from early clinical trials of CNM-Au8 in <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a> (MS) have <a href="https://multiplesclerosisnewstoday.com/news-posts/2023/03/01/actrims-2023-cnm-au8-bound-phase-3-testing-after-positive-data/">also been promising</a>.
&#8220;With this growing body of evidence, we are increasingly confident that CNM-Au8 has an effect across neurodegenerative diseases, such as ALS and MS, providing a potential treatment option with a novel and complementary mechanism of action for the patient community,&#8221; Rob Etherington, president and CEO of CNM-Au8&#8217;s developer <a href="https://clene.com/">Clene Nanomedicine</a>, said in a <a href="https://invest.clene.com/news-releases/news-release-details/als-and-ms-clinical-data-clenes-cnm-au8r-featured-multiple">company press release</a>.
In the fourth arm, pridopidine failed to show an effect on ALSFRS-R scores or survival outcomes in the overall group, but <a href="https://alsnewstoday.com/news/pridopidine-shows-some-potential-in-healey-trial-but-misses-main-goal/">promising trends</a> were seen for patients with early, rapidly progressing disease.
Pridopidine also significantly improved objective measures of speech function in a pre-specified analysis.
&#8220;This was of great interest to us because of the mechanism of action of pridopidine,&#8221; Paganoni said, noting the therapy is thought to act on a type of protein involved in regulating mouth and throat functions.
Pridopidine&#8217;s developer <a href="https://www.prilenia.com/">Prilenia Therapeutics</a> recently announced positive data from a Phase 3 study testing pridopidine in Huntington’s disease (HD).
&#8220;Pridopidine showed encouraging results for the potential treatment of ALS that deserve further exploration,&#8221; Merit Cudkowicz, MD, the HEALEY trial lead investigator, said in a <a href="https://www.businesswire.com/news/home/20230424006021/en/Prilenia-Shares-Preliminary-Topline-Results-from-Phase-3-PROOF-HD-Clinical-Trial-in-Huntington">press release from Prilenia</a>.
&#8220;The impact of pridopidine on rater-independent speech measures was especially notable &#8230; Speech is a highly clinically relevant endpoint in ALS studies and more than 80 percent of ALS patients become speech impaired, which significantly impacts their quality of life,&#8221; said Cudkowicz, the director of the Healey &amp; AMG Center and chief of the department of neurology at MGH.
The CNM-Au8 and pridopidine arms are still collecting more long-term data. Clene is working to launch a Phase 3 study of CNM-Au8 and Prilenia is exploring Phase 3 ALS testing of pridopidine.
&#8220;Clene now awaits important new biomarker data from both the double-blind and open label periods of the HEALEY ALS Platform Trial &#8230; These data will help determine our regulatory filing strategy,&#8221; Etherington said. &#8220;In parallel, Clene plans to meet with the FDA in an end of Phase 2 meeting during the third quarter of 2023 to discuss the regulatory path forward for CNM-Au8 in ALS.&#8221;

Category: AAN 2023

AAN 2023: Radicava leads to better long-term survival in ALS

AAN 2023: Memantine fails to slow disease progression in Phase 2b trial

AAN 2023: ALS treatments ID’d in HEALEY head toward Phase 3 tests