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On the heels of promising HEALEY-ALS Phase 2 trial data, <a href="https://www.prilenia.com/">Prilenia Therapeutics</a> plans to launch a pivotal Phase 3 study of <a href="https://alsnewstoday.com/pridopidine-experimental-treatment-als/">pridopidine</a>, its candidate <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) treatment, in the second half of this year.
Relative to a placebo, pridopidine was associated with slower disease progression, a better life quality, and a potential to prolong survival in patients in early disease stages. These recently<a href="https://alsnewstoday.com/als-diagnosis/"> diagnosed ALS</a> patients with rapidly progressing symptoms saw particular benefit in terms of respiratory health and speech, although better speech was evident across all treated patients.
Prilenia reports it has completed discussions with global regulatory agencies regarding the next stage of pridopidine’s development.
“Based on the clinical data generated to date, pridopidine has the potential to become a meaningful treatment for ALS,” Michael R. Hayden, PhD, a physician, and CEO and founder of Prilenia, said in a <a href="https://www.businesswire.com/news/home/20240118053094/en/Prilenia-Announces-Clinical-Data-in-Support-of-its-Plans-to-Initiate-Global-Phase-3-Study-in-ALS">company press release</a>.
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<h3>&#8216;Active planning&#8217; underway for global clinical trial in ALS patients</h3>
“We believe it is important for Prilenia to advance our clinical program in ALS, and we are actively planning a single, global, pivotal Phase 3 clinical trial,” Hayden said.
Pridopidine is an oral small molecule designed to selectively bind to and activate the sigma-1 receptor (S1R), a protein involved in several processes critical to the function and survival of nerve cells.
Essentially, pridopidine aims to slow ALS progression by boosting the clearance of toxic molecules, increasing energy production, reducing cellular stress, and limiting inflammation.
The <a href="https://clinicaltrials.gov/ct2/show/NCT04297683">HEALEY ALS (NCT04297683)</a> platform trial is designed to simultaneously evaluate multiple experimental ALS treatments against a shared placebo group. It is being led by researchers at the Sean M. Healey &amp; AMG Center for ALS at Massachusetts General Hospital in Boston.
The <a href="https://clinicaltrials.gov/ct2/show/NCT04615923">Phase 2/3 pridopidine arm (NCT04615923)</a> enrolled 163 adults with clinically possible, probable, or definite ALS, whose symptoms had started within the last three years.
Participants were randomly assigned to oral pridopidine (45 mg) or a matched placebo taken twice daily for 24 weeks, or about six months. This was followed by an open-label extension study, where all participants received pridopidine.
The <a href="https://alsnewstoday.com/news/pridopidine-shows-some-potential-in-healey-trial-but-misses-main-goal/">pridopidine trial failed to meet its main goal</a> of demonstrating that treatment could slow functional decline relative to a placebo, reflected by changes in ALS Functional Rating Scale-Revised (ALSFRS-R) scores. Secondary goals related to muscle strength, respiratory function, and survival also were not met.
However, pridopidine led to significant improvements in certain speech measures, including speaking rate (how fast a person can speak) and articulation rate, or how quickly and clearly someone pronounces a word, after six months.
Additional analyses indicated that pridopidine&#8217;s use slowed ALSFRS-R declines in a subgroup of patients with definite ALS who were in an early disease course — within 1.5 years of symptom onset.
These patients experienced a significant, 2.4-point slower decline in ALSFRS-R scores compared with those given a placebo. Pridopidine was particularly effective at slowing changes on the ALSFRS-R respiratory domain, mainly on questions related to <a href="https://alsnewstoday.com/symptoms-of-als/#Breathing_difficulties">shortness of breath</a> (dyspnea).
Early ALS patients also experienced significantly slower declines in overall life quality compared with a placebo, with particular benefits in the eating/drinking and communication domains.
<h3>Particular benefit seen in HEALEY trial for those with fast progression</h3>
Even greater benefits were observed in the subset of probable or definite ALS patients who were early in the disease course but also considered to have fast-progressing disease. In this group, pridopidine was associated with a significant slowing of ALSFRS-R declines starting at week eight of treatment, and with a 5.2-point difference from a placebo after 24 weeks, corresponding to a 41% slower decline.
This subgroup of early, fast-progressing patients also showed the greatest improvements relative to a placebo in terms of changes on the ALSFRS-R respiratory domain, dyspnea, and speech.
Survival analyses spanning the main trial and its extension phase showed that pridopidine may increase survival time for those with definite or probable ALS in early disease phases.
Specifically, participants treated with pridopidine from the main trial&#8217;s start experienced a median survival of about 600 days (around 1.5 years), compared with a 300-day median survival for patients first randomized to a placebo, amounting to a 57% lower risk of death.
Pridopidine also was well tolerated with no serious treatment-related side effects reported.
Support for pridopidine’s continued development also may come from an <a href="https://alsnewstoday.com/news/nih-grant-supports-als-expanded-access-program-pridopidine/">ongoing expanded access program</a>. This study, <a href="https://clinicaltrials.gov/study/NCT06069934?term=pridopidine&amp;rank=1">(NCT06069934)</a>, is enrolling about 200 ALS patients in the U.S. who are not eligible to participate in clinical trials of pridopidine, all of whom will receive the therapy for up to two years.
&#8220;Our sincere appreciation to the many ALS patients, caregivers and healthcare providers who have contributed so much to our clinical studies as well as to those who will participate in future trials,&#8221; Hayden said.
Pridopidine has been designated an orphan drug in the U.S. and Europe for the treatment of ALS, a status that intends to help speed its clinical development. Prilenia is also developing pridopidine for <a href="https://huntingtonsdiseasenews.com/what-is-huntingtons-disease">Huntington’s disease</a>.

Phase 3 trial of oral pridopidine in treating ALS likely this year

<a href="https://alsnewstoday.com/what-is-als/">Amyotrophic lateral sclerosis</a> (ALS) patients not eligible to participate in clinical trials of <a href="https://alsnewstoday.com/pridopidine-experimental-treatment-als/">pridopidine</a> — a small molecule developed by <a href="https://www.prilenia.com/">Prilenia Therapeutics</a> to slow disease progression in ALS — will soon be able to receive the experimental therapy via an expanded access program (EAP).
EAPs, also known as compassionate-use programs, are aimed at people with serious or life-threatening conditions that have few or no adequate treatments. Such programs allow patients to access investigational therapies available outside of a clinical trial. They typically run in parallel with late-stage clinical trials and provide additional clinical data that may support an approval of the given treatment by regulatory agencies.
Led by researchers at the Sean M. Healey &amp; AMG Center for ALS at Massachusetts General Hospital in collaboration with Prilenia, this EAP will enroll about 200 patients at as many as 45 centers across the U.S. Participants will receive the medication for up to two years.
The program is being launched thanks to a grant from the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), and is supported by the Accelerating Access to Critical Therapies (ACT) for ALS act.
“Prilenia is proud to work together with The Sean M. Healey &amp; AMG Center for ALS at Massachusetts General Hospital to make this important EAP possible for the many people living with more advanced stages of ALS,” Michael R. Hayden, Prilenia’s founder and CEO, said in a <a href="https://www.massgeneral.org/neurology/als/news/healeyamg-awarded-ninds-grant-for-eap-pridopidine">press release</a>, adding, &#8220;We share the great appreciation for the NIH and NINDS for supporting this work through the Act for ALS.&#8221;
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<h3>EAP for pridopidine expected to provide real world data</h3>
In the release, the Healey &amp; AMG Center staff said the expanded access program &#8220;will provide real world safety, biomarker, and clinical data in two hundred (200) ALS individuals treated with pridopidine for up to two (2) years, thus contributing to our understanding of the effects of pridopidine in a broad population.&#8221;
The EAP&#8217;s lead investigators are Suma Babu, an assistant professor of neurology at Harvard Medical School, James Berry, MD, director of Massachusetts General Hospital&#8217;s Neurological Clinical Research Institute, and Sabrina Paganoni, MD, PhD, a physician-scientist at the Healey Center and co-director of the Neurological Clinical Research Institute.
“We are grateful to the NIH for this award, and the opportunity to launch the pridopidine EAP,&#8221; Babu, Berry, and Paganoni said, adding, &#8220;Programs like this help advance research and innovation in ALS.”
Pridopidine is an orally available small molecule designed to bind and activate the sigma-1 receptor (S1R), a protein that&#8217;s broadly produced in the brain and spinal cord and <a href="https://www.prilenia.com/about-pridopidine/">regulates a number of processes</a> needed for nerve cell function and survival.
By activating S1R, the therapy boosts the clearance of toxic molecules, increases energy production, and limits inflammation and cellular stress — all known hallmarks of ALS. In doing so, the therapy is expected to ease certain disease mechanisms, thereby slowing disease progression.
[quote=&#8221;center&#8221;]We are grateful to the NIH for this award, and the opportunity to launch the pridopidine EAP. &#8230; Programs like this help advance research and innovation in ALS.[/quote]
The candidate therapy was the focus of one arm of the <a href="https://clinicaltrials.gov/ct2/show/NCT04297683">HEALEY ALS Platform trial (NCT04297683)</a> — a study testing multiple potential <a href="https://alsnewstoday.com/als-treatment/">ALS therapies</a> at the same time against a shared placebo group. The study was led by the Healey Center.
Pridopidine&#8217;s <a href="https://clinicaltrials.gov/ct2/show/NCT04615923">Phase 2/3 trial arm (NCT04615923)</a> enrolled 163 adults with ALS, whose symptoms had started less than three years before screening. Each was randomly assigned to receive either oral pridopidine, at a dose of 45 mg, or a placebo, twice daily for 24 weeks, or about six months.
The trial ultimately <a href="https://alsnewstoday.com/news/pridopidine-shows-some-potential-in-healey-trial-but-misses-main-goal/">failed to meet its primary goal</a> of showing that pridopidine could significantly slow disease progression, as measured by changes in the ALS Functional Rating Scale-Revised (ALSFRS-R), a standardized measure that assesses a patient&#8217;s ability to perform daily activities.
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<h3>Pridopidine fails primary trial goal, but shows some benefits</h3>
There were significant benefits seen in certain speech measures in participants given pridopidine, however, as well as positive trends in respiratory function for these patients.
The medication also showed <a href="https://alsnewstoday.com/news/pridopidine-shows-some-potential-in-healey-trial-but-misses-main-goal/">promising trends</a> in a subgroup of patients with rapidly progressing disease, all of whom were enrolled less than 18 months after symptom onset.
In this group, pridopidine-treated patients had a significantly smaller decline in ALSFRS-R scores than those given the placebo (7.5 vs. 12.7). These patients also had an average 40% reduction in neurofilament light chain (NfL) levels, a marker or nerve damage, compared with patients given the placebo.
Based on these findings, Prilenia has decided to <a href="https://alsnewstoday.com/aan-2023/aan-2023-als-treatments-idd-healey-trial-move-toward-phase-3-tests/">move pridopidine into</a> Phase 3 clinical trials.
Participants also are being followed in the trial&#8217;s open-label extension, in which all are receiving the experimental therapy. Data from this open-label part and from the upcoming EAP may help to better understand the effects of pridopidine in ALS patients.
“We &#8230; want to express our gratitude to the participants and their families as well as the site healthcare providers and staff who will make this EAP possible, further advancing our understanding of pridopidine as a potential therapy for ALS,” Hayden said.
Pridopidine has been granted orphan drug designation for ALS in both the U.S. and Europe. This designation aims to encourage therapies for rare and serious diseases, through benefits such as market exclusivity and exemption from certain fees.

New EAP will allow pridopidine use for ALS patients not in trial

<a href="https://alsnewstoday.com/pridopidine-experimental-treatment-als/">Pridopidine</a>, an oral small molecule, failed to meet its primary goal of improving physical function across <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) patients who took part in a Phase 2/3 clinical trial.
Changes in secondary endpoints measuring muscle strength and respiratory function also did not significantly differ between people taking pridopidine and those on a placebo, <a href="https://www.prilenia.com">Prilenia Therapeutics</a>, the therapy&#8217;s developer, reported in a <a href="https://www.businesswire.com/news/home/20230222005679/en/Prilenia-Announces-Topline-Results-for-Pridopidine-in-Phase-2-ALS-Study">press release</a>.
But significant physical benefits were reported in a subset of recently diagnosed patients — within 18 months or 1.5 years — whose <a href="https://alsnewstoday.com/symptoms-of-als/">ALS</a> <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a> indicated rapidly progressing disease. And all treated patients showed “trends” toward better respiratory health, with significant gains seen in two measures of speech.
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<h3>&#8216;Encouraging results&#8217; seen with pridopidine &#8216;deserve further exploration&#8217;</h3>
The Phase 2/3 study (<a href="https://clinicaltrials.gov/ct2/show/NCT04615923">NCT04615923</a>) is an arm of <a href="https://clinicaltrials.gov/ct2/show/NCT04297683">HEALEY ALS (NCT04297683)</a>, a platform trial where multiple experimental treatments are being tested at the same time against a shared placebo (control) group. It is being led by researchers at the Sean M. Healey &amp; AMG Center for ALS at Massachusetts General Hospital in Boston.
“Pridopidine showed encouraging results for the potential treatment of ALS that deserve further exploration,” said Merit Cudkowicz, MD, principal investigator for HEALEY ALS, director of the ALS center, and chief of neurology at Massachusetts General.
The trial&#8217;s open-label extension is ongoing, and Prilenia will share full study data at upcoming scientific meetings.
Cudkowicz particularly saw as “notable” pridopidine&#8217;s impact on speech measures. “Speech is a highly clinically relevant endpoint in ALS studies, and more than 80 percent of ALS patients become <a href="https://alsnewstoday.com/symptoms-of-als/#Speech_problems">speech impaired</a>, which significantly impacts their quality of life,” she said.
Pridopidine is designed to act as an agonist, binding to and activating the sigma-1 receptor (S1R). S1R is a protein present at high levels in the brain and spinal cord that, among many roles, is thought to help <a href="https://www.prilenia.com/about-pridopidine">keep nerve cells healthy</a>.
As an S1R agonist, pridopidine aims to prevent nerve cell loss and improve the connections between these cells that are commonly impaired in neurodegenerative diseases such as ALS.
“Pre-clinical data in mice and other species strongly indicated that S1R activity can mitigate the features of ALS,” said Michael R. Hayden, PhD, CEO and founder of Prilenia. “This study showed for the first time in humans that S1R agonism with pridopidine has the potential to impact ALS.”
The trial enrolled 163 adults with ALS who were randomized to either oral pridopidine at 45 mg or a matching placebo taken twice daily.
Its primary goal was a change in overall physical function, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), from baseline or study start through 24 weeks. Higher scores on this scale reflect better function, indicating slower disease progression. However, changes between treatment and control patients failed to reach significance.
<h3>Physical function gains reach significance in recently diagnosed patient group</h3>
Among the prespecified group of people recently diagnosed with rapidly progressing and &#8220;probable or definitive&#8221; ALS, as per <a href="https://alsnewstoday.com/als-diagnosis/#El_Escorial_criteria">El Escorial criteria</a>, patients taking pridopidine showed a significantly lesser decline in physical function (minus 7.51 points for total ALSFRS-R score) than those on a placebo (minus 12.71 points) in post-hoc analyses.
Significant benefits were also seen in speech measures across all treated patients, namely in terms of speaking rate (how fast someone talks) and articulation rate (how quickly and clearly someone sounds out each word), and positive &#8220;trends&#8221; in respiratory function were evident.
An analysis of neurofilament light (NfL) levels in the recently diagnosed patient group also found an average 40% reduction in the levels of this biomarker of nerve cell loss among treated patients relative to controls at 24 weeks.
Pridopidine was well tolerated, with a safety profile similar to that of the placebo, Prilenia reported.
“This study adds to the growing body of evidence that S1R activation has beneficial neuroprotective effects, and this gives us a compelling rationale for further development of pridopidine in ALS,” Hayden said. “Prilenia intends to continue its evaluation of pridopidine in ALS, and our future clinical program will build on the important learnings from the HEALEY ALS Platform Trial.”
The company holds orphan drug designations for pridopidine in ALS in both the U.S. and Europe, and is exploring next steps for its clinical development.

Tag: pridopidine

Phase 3 trial of oral pridopidine in treating ALS likely this year

New EAP will allow pridopidine use for ALS patients not in trial

Pridopidine shows some potential in HEALEY trial, but misses main goal