A SUPER-powered WP Engine Atlas Test Site

Joe&#039;s Atlas Experimentation Site

<a href="https://seelostherapeutics.com/sls-005-trehalose/">SLS-005</a> did not significantly slow <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) progression compared with a placebo in the HEALEY platform trial, according to top-line data showing that the experimental therapy did not ease functional declines nor extend patient survival.
The therapy, developed by <a href="https://seelostherapeutics.com/">Seelos Therapeutics</a>, also failed to slow declines in muscle strength and lung function, which, overall, means the trial failed to meet its primary and key secondary measures.
“Though we did not achieve success with this trial, we remain committed to using the data to advance ALS science, and our experience with the trial to understand ALS,&#8221; Merit Cudkowicz, MD, principal investigator and sponsor of the HEALEY ALS Platform Trial, said in a <a href="https://www.massgeneral.org/neurology/als/news/healeyamg-announces-platform-trial-update">press release</a>.
“We are thankful to the many people who participated in this study. We will learn from these results and continue to use this data to inform future advances in ALS trial design,” added Cudkowicz, who is also director of the Sean M. Healey &amp; AMG Center for ALS, chief of the Department of Neurology at Massachusetts General Hospital (MGH), and the Julieanne Dorn Professor of Neurology at Harvard Medical School.
[recommended-reading id=83732]
<h3>SLS-005 aims to slow ALS progression by breaking down toxic protein clumps</h3>
SLS-005 contains trehalose, a natural sugar molecule that promotes autophagy, which is a cellular recycling process that helps break down old and faulty proteins. In so doing, it prevents them from toxically accumulating in cells.
The therapy was designed to slow ALS progression by entering the brain and breaking down these toxic protein clumps. Such clumps, or aggregates, contribute to nerve cell death in the neurodegenerative disease.
SLS-005 was assessed in the <a href="https://clinicaltrials.gov/ct2/show/NCT04297683?term=HEALEY+ALS&amp;draw=2&amp;rank=1">HEALEY platform trial (NCT04297683)</a> — a novel approach to drug testing in which multiple ALS therapy candidates are investigated simultaneously against a shared placebo group. Dubbed a perpetual trial, HEALEY continues to <a href="https://clinicaltrials.gov/ct2/show/NCT04297683?term=HEALEY+ALS&amp;draw=2&amp;rank=1#contacts">enroll adults</a> with ALS whose first symptoms occurred within the last three years.
The trial is ongoing at dozens of U.S. sites. Once a participant is deemed eligible through the trial’s master protocol, he or she can be randomly assigned to any active treatment arm.
The <a href="https://clinicaltrials.gov/ct2/show/NCT05136885">SLS-005 arm (NCT05136885)</a> enrolled 161 patients: Among them, 120 received weekly SLS-005 infusions into the bloodstream, and the rest, a placebo.
The participants also could continue to use a stable regimen of <a href="https://alsnewstoday.com/approved-treatments-for-als/">approved ALS therapies</a>, consisting of <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone) or riluzole (e.g., Rilutek, Tiglutik, Exservan). <a href="https://alsnewstoday.com/amx0035/">Relyvrio</a> (sodium phenylbutyrate and taurursodiol) was approved about eight months after the SLS-005 trial arm began enrollment, and some participants also ended up receiving that newly approved medication along with their assigned treatment.
As with all arms of the platform trial, the main goal was to evaluate whether SLS-005 could significantly slow disease progression relative to the placebo over 24 weeks, or about six months.
Progression was assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R), which measures a person&#8217;s ability to perform activities of daily living, such as turning in bed, gripping a pen, climbing stairs, speaking, and breathing.
[recommended-reading id=41326]
<h3>Monthly declines in ALSFRS-R scores seen in SLS-005, placebo groups</h3>
Seelos now has reported that the trial’s goal was not met, with patients in the SLS-005 arm and the shared placebo group seeing similar monthly declines in ALSFRS-R scores.
In an analysis accounting for functional declines and mortality, SLS-005 was associated with a 13% delay in disease progression or death; however, these differences failed to reach statistical significance. Similarly to the primary goal, other key secondary endpoints, such as muscle strength and respiratory function, also were not met.
[quote=&#8221;center&#8221;]Even though the trial results were negative, participants&#8217; involvement in the trial contributed greatly to ALS research by providing substantial clinical and biomarker data that will help us better understand ALS disease mechanisms and the role of the cellular catalysts in people living with ALS and may help unlock keys to the next ALS treatment.[/quote]
“We would like to extend our sincere gratitude to participants in the trehalose regimen who committed their invaluable time and energy in the trial as well as the NEALS investigators and study staff for their dedicated effort and expertise,&#8221; said Shafeeq Ladha, MD, Barrow Neurological Institute and co-lead investigator of the trehalose regimen.
“Even though the trial results were negative, participants&#8217; involvement in the trial contributed greatly to ALS research by providing substantial clinical and biomarker data that will help us better understand ALS disease mechanisms and the role of the cellular catalysts in people living with ALS and may help unlock keys to the next ALS treatment,” Ladha added.
Seelos, however, shared some data suggesting that SLS-005 may have benefited a subset of patients who did not simultaneously receive Relyvrio while in the trial. Relyvrio was <a class="c-link" href="https://alsnewstoday.com/news/relyvrio-amx0035-approved-us-als-treatment/" target="_blank" rel="noopener noreferrer" data-stringify-link="https://alsnewstoday.com/news/relyvrio-amx0035-approved-us-als-treatment/" data-sk="tooltip_parent">approved in the U.S.</a> in 2022, but now is being withdrawn after it failed to show efficacy in a clinical trial.
During the SLS-005 trial, while it wasn&#8217;t initially planned for, some participants ultimately started using Relvvrio. Seelos believes this mid-trial addition could confound the results, and noted that, by removing those individuals, the analysis is cleaner and more in line with how the data appeared originally.
For its part, SLS-005 was generally well tolerated. More deaths occurred in the SLS-005 group, but none were considered related to treatment. Seelos notes that it plans to run additional analyses, including those related to biomarkers and patient subgroups, as the data become available.
The company now is also planning to meet with the U.S. Food and Drug Administration (FDA) to discuss the next steps for SLS-005&#8217;s development.
“We believe the observed signal and success probability is competitive to other recently FDA-approved therapies for ALS,&#8221; Raj Mehra, PhD, chairman and CEO of Seelos said in a <a href="https://www.prnewswire.com/news-releases/seelos-therapeutics-provides-update-on-top-line-results-from-its-amyotrophic-lateral-sclerosis-als-study-with-sls-005-iv-trehalose-302092918.html">company press release</a>. &#8220;We plan to request a meeting with the FDA to discuss potential next steps for the program.”

Infusion therapy SLS-005 fails to slow ALS progression in 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;

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

<a href="https://seelostherapeutics.com/">Seelos Therapeutics</a> has finished enrolling patients in its Phase 2/3 clinical trial of <a href="https://seelostherapeutics.com/sls-005-trehalose/">SLS-005</a> to treat <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), the company announced.
The <a href="https://clinicaltrials.gov/ct2/show/NCT05136885">ongoing trial (NCT05136885)</a> recruited 160 patients with <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial</a> and <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic ALS</a>, and top-line results are expected by the second half of 2023.
This is the fifth arm of the <a href="https://clinicaltrials.gov/ct2/show/NCT04297683?term=HEALEY+ALS&amp;draw=2&amp;rank=1">HEALEY platform trial (NCT04297683)</a>, which is being led by researchers at the Sean M. Healey &amp; AMG Center for ALS at Massachusetts General Hospital (MGH), Boston to investigate several ALS therapies simultaneously against a shared placebo group.
The company also expects to launch an <a href="https://alsnewstoday.com/news/funding-expands-access-seelos-investigational-als-therapy-sls-005/">expanded access program</a> (EAP) in the coming months to give people with ALS who aren&#8217;t eligible for clinical trials the opportunity to access SLS-005. The EAP will include 70 participants who&#8217;ll receive the experimental therapy for 24 weeks. <a href="https://seelostherapeutics.com/patients-and-caregivers/">More information</a> is available at Seelos&#8217; website.
&#8220;The full enrollment of this study is a significant milestone for Seelos. We look forward to releasing the top-line data later this year and initiating the Expanded Access Program later this quarter,&#8221; said Raj Mehra, PhD, Seelos’ chairman and CEO, in a <a href="https://www.prnewswire.com/news-releases/seelos-therapeutics-announces-completion-of-enrollment-of-its-phase-iiiii-trial-of-sls-005-in-amyotrophic-lateral-sclerosis-on-the-healey-als-platform-301744494.html">company press release</a>.
EAP will be funded by a grant from the National Institute of Neurological Disorders and Stroke (NINDS) under the <a href="https://alsnewstoday.com/news/landmark-act-for-als-act-president-biden/">Accelerating Access to Critical Therapies for ALS Act</a> (ACT for ALS).
&#8220;We would like to offer our gratitude to the ALS community for its support and to the team at Healey &amp; AMG Center for ALS at Mass General and the clinical trial sites in the Northeast ALS Consortium for their hard work and commitment in running this innovative platform trial. We also thank the NINDS for the financial support of the Expanded Access Program grant under the ACT for ALS,&#8221; Mehra said.
[recommended-reading id=81946]
<h3>SLS-005 promotes protein clearance</h3>
SLS-005 is made of a natural sugar molecule called trehalose that can enter the brain and promote autophagy, the process by which cells break down and recycle old or faulty proteins they no longer need, preventing their toxic buildup.
Administered directly into the bloodstream, SLS-005 has been shown to lower faulty proteins&#8217; aggregation and reduce the accumulation of toxic clumps in animal models of neurodegenerative conditions.
In ALS models, it promoted the clearance of TDP-43 and SOD1 proteins, which are known to accumulate to toxic levels and contribute to nerve cell death. By doing so, the treatment was able to prevent nerve cell loss and delay disease progression in these models.
SLS-005 received orphan drug status — a designation that&#8217;s intended to speed the development and review of therapies for life-threatening rare diseases — in both <a href="https://alsnewstoday.com/news-posts/2020/11/20/fda-grants-orphan-drug-designation-to-seelos-sls-005-for-treating-als/">the U.S.</a> and the <a href="https://alsnewstoday.com/news-posts/2021/06/04/ema-orphan-drug-designation-sls-005-als/">European Union</a>.
In the SLS-005 arm of the HEALEY ALS platform trial, participants were randomly assigned to weekly intravenous (into-the-vein) injections of SLS-005 or a placebo for 24 weeks (about six months). The patients were randomized in a 3:1 ratio, meaning for each patient assigned a placebo, three were given SLS-005.
The trial’s main goal is to evaluate whether SLS-005 slows disease progression, as measured with the ALS Functional Rating Scale Revised (ALSFRS-R). Secondary goals include changes in lung function, muscle strength, and quality of life, as well as symptoms of disease progression.
Other treatments being investigated in the HEALEY trial include Prilenia Therapeutic’s pridopidine <a href="https://clinicaltrials.gov/ct2/show/NCT04615923">(NCT04615923)</a> and Clene Nanomedicine‘s CNM-Au8 <a href="https://clinicaltrials.gov/ct2/show/NCT04414345">(NCT04414345)</a>.
Another regimen, UCB’s zilucoplan <a href="https://clinicaltrials.gov/ct2/show/NCT04436497">(NCT04436497)</a>, was <a href="https://alsnewstoday.com/news/ucb-stops-zilucoplan-arm-early-healey-trial-als-lack-of-efficacy/">discontinued in March 2022</a> due to a lack of effectiveness in an interim analysis. Biohaven Pharmaceuticals’ verdiperstat <a href="https://clinicaltrials.gov/ct2/show/NCT04436510">(NCT04436510)</a> also <a href="https://alsnewstoday.com/news/als-therapy-verdiperstat-fails-healey-trial-efficacy-goals/">failed to meet</a> its primary and secondary goals.

Tag: HEALEY platform trial

Infusion therapy SLS-005 fails to slow ALS progression in trial

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

Enrollment complete in HEALEY Phase 2/3 trial arm of SLS-005