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A double-blind Phase 2 clinical trial that will test Corcept Therapeutics&#8217; oral <a href="https://corcept.com/cortisolmodulation/">cortisol modulator</a> dazucorilant against a placebo in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) is now fully enrolled, the company announced in a <a href="https://www.globenewswire.com/news-release/2024/04/15/2862710/0/en/Corcept-Completes-Enrollment-in-Phase-2-DAZALS-Trial-in-Patients-With-Amyotrophic-Lateral-Sclerosis-ALS.html">press release</a>.
Called <a href="https://clinicaltrials.gov/study/NCT05407324">DAZALS (NCT05407324)</a>, the trial involves 249 adults with <a href="https://alsnewstoday.com/forms-of-als/">sporadic or familial ALS</a> across multiple sites in the U.S. and Canada, and in Europe.
Participants are randomly assigned to receive one of two dazucorilant doses (150 or 300 mg), or a placebo, with neither researchers nor patients knowing who gets which one. Treatment is given as four softgel capsules once daily for 24 weeks, or about six months, in addition to standard <a href="https://alsnewstoday.com/als-treatment/">ALS treatments</a>.
The trial&#8217;s main goals are to assess dazucorilant&#8217;s safety and tolerability, as well as changes in ALS Functional Rating Scale-Revised (ALSFRS-R) scores, which measure a person&#8217;s ability to perform everyday tasks. The researchers also will evaluate changes in muscle strength, lung function, and quality of life after 24 weeks.
“Fully enrolling DAZALS is an important step toward understanding dazucorilant&#8217;s potential for significantly improving outcomes for people living with this devastating disease,”  said Bill Guyer, <a href="https://corcept.com/">Corcept</a>’s chief development officer. Early data from the trial is expected later this year, Guyer said.
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<h3>Fully enrolled human trial follows positive results in animal study</h3>
People with ALS often show signs of having overactive adrenal glands. These small glands, located atop the kidneys, are responsible for producing cortisol and other hormones.
Cortisol is a steroid hormone that is released into circulation in the body to help manage stressful conditions. However, prolonged elevations in cortisol levels can promote inflammation and nerve cell death, which is thought to drive ALS progression.
Consistently, high levels of cortisol seem to be particularly present in ALS patients with rapid <a href="https://alsnewstoday.com/stages-of-als/">disease progression</a>.
Dazucorilant is a cortisol modulator that binds to glucocorticoid receptors to prevent their interaction with cortisol, preventing the cascade of events that cause neuronal inflammation and death. This is expected to reduce the negative effects of excessive cortisol in ALS patients.
In <a href="https://www.sciencedirect.com/science/article/abs/pii/S0006899319306055">preclinical studies</a> using animal models of ALS, the scientists found that daily treatment with dazucorilant eased inflammation and nerve cell death. Mice also had better motor function and less muscle wasting, as compared with untreated mice.
Now, Corcept aims to see if the therapy is safe and effective in humans at either of two doses.
[quote=&#8221;center&#8221;]Better treatments for ALS are urgently needed. &#8230; Dazucorilant showed great promise in an animal model of ALS – improving motor performance and reducing neuroinflammation and muscular atrophy.[/quote]
The Phase 2 trial, now fully enrolled, has study sites in four U.S. states and eight European countries, as well as locations in Ontario and Quebec. Participants who complete the trial will then be eligible to enter an open-label extension study, in which they can receive a 300 mg daily dose of the active treatment for an additional 132 weeks, or about 2.5 years.
“Better treatments for ALS are urgently needed,” Guyer said, noting that “dazucorilant showed great promise in an animal model of ALS – improving motor performance and reducing neuroinflammation and muscular atrophy.”

Phase 2 trial testing dazucorilant in ALS patients now fully enrolled

Denali Therapeutics&#8217; SAR443820 (DNL788) treatment candidate — now in late-stage clinical testing for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), per the <a href="https://www.denalitherapeutics.com/pipeline">company&#8217;s website</a> — has failed to significantly slow disease progression in adults in a Phase 2 trial.
The experimental therapy &#8220;did not meet the primary endpoint of change&#8221; in outcomes measures relative to a placebo in trial, <a href="https://www.denalitherapeutics.com/">Denali</a> reported in a Securities and Exchange Commission (SEC) <a href="https://www.sec.gov/ixviewer/ix.html?doc=/Archives/edgar/data/0001714899/000171489924000065/dnli-20240216.htm">filing</a>. That means that the HIMALAYA study, which had been testing SAR443820 versus the placebo in more than 300 ALS patients, has failed to meet its primary goal.
Detailed study results were not disclosed in the filing, but co-developer <a href="https://www.sanofi.com/en">Sanofi</a>, which is running the trial, plans to present additional safety and efficacy data at an upcoming scientific conference, Denali noted.
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<h3>Slowing ALS progression was main goal of HIMALAYA trial</h3>
SAR443820 is an oral inhibitor of RIPK1, an enzyme that plays an important role in inflammation and cell death within the central nervous system (CNS), which is comprised of the brain and spinal cord. Both inflammation and cell death are key features of many neurodegenerative diseases, including ALS and <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a> (MS), for which SAR443820 also was being developed.
RIPK1 levels are found to be <a href="https://pubmed.ncbi.nlm.nih.gov/27493188/">increased in the spinal cord</a> of ALS patients.
The molecule is designed to be brain-penetrant, meaning it can cross the selective blood-brain barrier that normally prevents substances circulating in the bloodstream from entering the CNS. This barrier can pose a significant challenge to developing treatments for brain disorders.
By blocking RIPK1, SAR443820 is intended to ease neuroinflammation and cell death, thereby slowing the progression of neurodegeneration. It was awarded fast track designation from the U.S. Food and Drug Administration in 2021 for the treatment of ALS. That designation aims to speed a therapy&#8217;s clinical development.
The global <a href="https://clinicaltrials.gov/study/NCT05237284">Phase 2 HIMALAYA trial (NCT05237284)</a> enrolled 305 adults with ALS, ages 18-80, whose symptoms had emerged within the prior two years. The participants were randomly assigned to receive SAR443820 or a placebo, taken as oral tablets twice daily for 24 weeks, or about six months.
After that, all participants could enter an open-label treatment period and receive SAR443820 for about 1.5 more years (80 weeks). In an open-label study, both participants and researchers know the exact treatment patients are given.
During the trial, participants could remain on stable regimens of other ALS therapies, such as <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone), <a href="https://alsnewstoday.com/amx0035/">Relyvrio</a> (sodium phenylbutyrate and taurursodiol), or riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a>, <a href="https://alsnewstoday.com/tiglutik-for-als/">Tiglutik</a>, and <a href="https://alsnewstoday.com/exservan-riluzole-oral-film/">Exservan</a>). Patient <a href="https://alsnewstoday.com/news/patient-dosing-starts-phase-2-trial-oral-sar443820-als/">dosing began</a> in May 2022.
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<h3>Developers still testing SAR443820 as MS therapy</h3>
The trial&#8217;s main goal was to evaluate whether SAR443820 could slow disease progression, as assessed by changes in scores on the revised ALS Functional Rating Scale (ALSFRS-R), a commonly used measure in ALS, after 24 weeks.
While the SEC filing reported that this primary goal was not met, no information was provided regarding any secondary endpoints. Specifically, the trial was testing SAR443820 for secondary outcomes that included survival, respiratory function, muscle strength, and safety.
Sanofi acquired certain clinical development rights to SAR443820 in a <a href="https://alsnewstoday.com/news/denali-sanofi-to-develop-small-molecules-that-might-treat-als-other-diseases/">2018 collaboration agreement</a> with Denali, which also covered a number of other molecules originally developed by Denali.
One of them was a RIPK1 inhibitor called DNL747, which was being developed for ALS and <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer&#8217;s disease</a>. The companies <a href="https://alsnewstoday.com/news/denali-sanofi-pause-dnl747-studies-favor-advancing-dnl788/">paused its development in 2020</a>, and decided to shift their focus to SAR443820.
It is unclear how these findings will impact the companies&#8217; plans for SAR443820 in ALS, but the compound is still being developed as a possible treatment for MS, Denali noted in the SEC filing. In MS, the therapy also is in Phase 2 clinical testing.
&#8220;Sanofi intends to present the detailed efficacy and safety results of the ALS Phase 2 HIMALAYA study at a future scientific forum,&#8221; Denali stated in the SEC filing.

Denali therapy candidate fails to slow ALS progression in trial

Enrollment is complete in a Phase 2 trial testing <a href="https://inflectisbioscience.com/">InFlectis BioScience</a>’s oral candidate IFB-088 (icerguastat) in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), the company has announced.
The <a href="https://clinicaltrials.gov/study/NCT05508074">trial (NCT05508074)</a> enrolled a total of 50 adults with bulbar-onset ALS, a form of the disease that first affects the muscles in the head and neck, leading to swallowing, chewing, and speech difficulties.
Participants were randomly assigned to receive IFB-088 or a placebo, given as an add-on to <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">riluzole</a>, an approved ALS therapy sold as Rilutek, Tiglutik, or Exservan. Treatment will be given twice a daily for six months, and early results might be presented later this year.
“We dosed the first patient in December 2022 and randomized the last patient on January 30, 2024,” Anne Visbecq, MD, InFlectis’ chief medical officer, said in a <a href="https://inflectisbioscience.reportablenews.com/pr/inflectis-completes-enrollment-phase-2-trial-of-ifb-088-in-als">company press release</a>. “Following the six-month treatment period, we look forward to reporting our initial findings as early as the end of this year.”
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<h3>Phase 2 trial results will determine timing, scope of potential global study</h3>
“These results will determine the timing and scope of a potential global registration study in the overall ALS population,” Visbecq added.
ALS is characterized by the progressive dysfunction and death of motor neurons, the nerve cells that control voluntary movements. About one-third of patients have <a href="https://alsnewstoday.com/forms-of-als/">bulbar-onset ALS</a>, which is more aggressive and has a shorter life expectancy than limb-onset ALS, in which first symptoms are associated with weakness in the muscles of the arms and hands, or legs and feet.
IFB-088 is an orally available small molecule capable of crossing the blood-brain barrier, a cell layer that protects the brain from disease-causing agents and toxins that may be present in the blood.
The medication inhibits the PPP1R15A/PP1c protein complex to keep a natural cellular stress-response mechanism active. This is thought to give stressed cells additional time to correct their protein imbalances and eliminate protein clumps, a hallmark of ALS that contributes to neurodegeneration.
IFB-088 also serves as an inhibitor of certain glutamate receptors. These receptors are involved in a process called excitotoxicity, in which neurons are over-stimulated and fire much more than needed, leading to nerve damage.
An earlier <a href="https://clinicaltrials.gov/study/NCT03610334">Phase 1 trial (NCT03610334)</a> involving healthy volunteers showed the investigational therapy is generally safe and well tolerated. The therapy was given at doses ranging from 2.5 mg to 60 mg daily, and no reports of serious adverse events or dose-limiting toxicities were reported.
The ongoing Phase 2 trial enrolled 50 patients at sites in France and Italy who are receiving 50 mg daily of IFB-088 — given as two oral 25 mg capsules 12 hours apart and 30 minutes before a meal — or a placebo, for 26 weeks. All are also taking riluzole in the form of tablets (Rilutek and generics) or a suspension formulation (<a href="https://alsnewstoday.com/tiglutik-for-als/">Tiglutik</a>) at a daily dose of 100 mg, given as two 50 mg doses every 12 hours.
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<h3>Trial to examine IFB-088&#8217;s safety, ability to slow functional decline in patients</h3>
The trial’s main goal is to assess the treatment&#8217;s safety and tolerability, but researchers will also examine if the therapy can slow patients’ functional decline, reflected by changes in the ALS Functional Rating Scale-Revised.
Two <a href="https://alsnewstoday.com/stages-of-als/">staging systems</a> — the King’s College and the Milano-Torino systems — will also be used to assess changes in patients&#8217; clinical progression and treatment response. The therapy’s effect on the patient&#8217;s quality of life and disease-related blood biomarkers will also be assessed.
“This trial reflects our commitment to bring a novel molecule with a unique mode of action to ALS patients, starting with patients suffering from bulbar-onset ALS, the most aggressive form of the disease,” Visbecq said.
IFB-088&#8217;s development and the Phase 2 trial were financially supported by the <a href="https://www.als.org/">ALS Association</a>, AFM-Téléthon (a French patient organization fighting rare neuromuscular diseases), and Bpifrance (the French public bank of investment). The <a href="https://alsnewstoday.com/news/inflectis-okd-to-start-phase-2-trial-of-ifb-088-for-bulbar-onset-als/">trial was approved</a> in 2022 by the French health authority ANSM.
Also in 2022, IFB-088 was granted <a href="https://alsnewstoday.com/news/inflectis-ifb-088-orphan-drug-status-fda-als-treatment/">orphan drug designation</a> by the U.S. Food and Drug Administration. The designation is meant to accelerate IFB-088’s clinical development and review by providing regulatory support and financial benefits, and a seven-year marketing exclusivity if the therapy is ultimately approved.

Phase 2 trial of oral IFB-088 for bulbar-onset ALS now fully enrolled

CL2020, a stem cell-based therapy that was being developed by the Life Science Institute, part of <a href="https://www.m-chemical.co.jp/en/index.html">Mitsubishi Chemical</a>, was found to be safe and  tolerated well by five people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) who took part in a Phase 2 clinical study.
The investigational therapy, which involved repeated injections of a special type of stress-enduring stem cells, known as Muse cells, directly into the bloodstream, also tended to improve physical function for these patients, but not significantly so.
Because the study included only a small number of patients, “a double-blinded study including a larger number of ALS patients with a longer observation period should be conducted,” the researchers wrote.
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In February 2023, however, Mitsubishi had already decided to discontinue the development of CL2020 “after comprehensive and careful consideration of the latest clinical developments, timelines for commercialization, and its pharmaceutical business strategy going forward,” the company stated in a <a href="https://www.mcgc.com/english/news_release/01489.html">news release</a>.
The study, “<a href="https://journals.sagepub.com/doi/10.1177/09636897231214370">Safety and Clinical Effects of a Muse Cell-Based Product in Patients With Amyotrophic Lateral Sclerosis: Results of a Phase 2 Clinical Trial,</a>” was published in <a href="https://journals.sagepub.com/home/CLL">Cell Transplantation.</a>
ALS is a progressive disease that causes the loss of motor neurons, the nerve cells that control voluntary muscles in the body, leading to muscle weakness and atrophy (shrinkage) and a range of <a href="https://alsnewstoday.com/symptoms-of-als/">other symptoms</a>.
The exact <a href="https://alsnewstoday.com/causes-of-als/">causes of ALS</a> are unclear, but inflammation triggered by astrocytes is believed to contribute to disease progression. Astrocytes are star-shaped cells found in the brain and spinal cord that are needed to maintain healthy motor neurons.
<h3>Stem cells&#8217; roles in treating ALS</h3>
Stem cells may have a role to play in treating ALS, either by delivering growth factors to motor neurons, by replacing lost motor neurons with new ones derived from stem cells, or by providing a source of healthy astrocytes to support motor neurons.
Unlike other types of stem cells, it is believed that Muse cells, when injected into the bloodstream, tend to travel to damaged tissue, survive in hostile environments, and naturally develop into any type of cells compatible with the surrounding tissue.
They can be found in the connective tissue of nearly every organ, and <a href="https://www.nature.com/articles/nprot.2013.076">do not take very long to collect</a>. A <a href="https://alsnewstoday.com/news/specific-stem-cells-motor-neuron-survival-muscle-strength-als-mouse-study/">preclinical study</a> in a mouse model of ALS showed that Muse cells can turn into astrocytes, help motor neurons survive, and prevent muscle atrophy.
Now, a team of researchers in Japan led an open-label <a href="https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2063200047">clinical study (jRCT2063200047)</a> testing the safety and efficacy of Life Science Institute’s CL2020, a Muse cell-based product derived from bone marrow human mesenchymal stem cells. These cells have the ability to transform into various cell types, such as bone, fat, and cartilage cells, and play a crucial role in tissue repair and regeneration.
The study included three men and two women, ages 45 to 68 years, with a <a href="https://alsnewstoday.com/als-diagnosis/">diagnosis of ALS</a>. Three were receiving treatment with riluzole, sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a> among others.
As part of the study, they received a total of six intravenous (into-the-vein) injections of clinical-grade CL2020 administered at one-month intervals. Each dose of CL2020 contained 15 million Muse cells.
<h3>Study goals</h3>
The study’s main goal was to assess the treatment&#8217;s safety and tolerability. Over 12 months (one year) following the first dose, a total of 28 side effects were reported. The most common side effects were headache (four cases) and fatigue (three cases).
However, there were no treatment-related serious side effects and no changes in the patients’ vital signs or lab test results. “Treatment was highly tolerated without serious side effects,” the researchers wrote.
As a secondary goal, physical function was measured using the ALS Functional Rating Scale Revised (ALSFRS-R), where lower scores indicate more impaired physical function.
While ALSFRS-R scores were a mean three points lower at 12 months than at the beginning of the study (37.6 vs. 40.6 points), the rate of change over the 12-month window showed only a trend toward improvement.
“The difference was not statistically significant,” the researchers wrote. “Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change.”
<h3>Neurofilament light chain (NfL) levels</h3>
Blood levels of interleukin-6 and tumor necrosis factor-alpha, two inflammatory molecules, increased over the course of the study. Neurofilament light chain (NfL), a marker of nerve cell damage, increased in cerebrospinal fluid, the liquid that surrounds the brain and spinal cord.
However, the levels of NfL “were relatively lower than those of ALS natural history patients,” indicating that patients in the study possibly had “a relatively slow rate of disease progression.”
Blood levels of sphingosine 1-phosphate (S1P), a molecule that guides immune cells to sites of inflammation, decreased over the course of the study. Targeting S1P signaling with <a href="https://alsnewstoday.com/gilenya-fingolimod/">Gilenya</a> (fingolimod), a medication approved for <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a>, is being tested in ALS.
“Considering the results of clinical scores, including the ALSFRS-R, and the biomarker findings mentioned above, it can be concluded that CL2020 treatment alone may have slowed down ALS progression but was not fully capable of halting it,” the researchers wrote.

Stem cell-based therapy deemed safe in Phase 2 study

Colchicine, an anti-inflammatory medication used to treat gout, was safe, but did not significantly slow the progression of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in a small Phase 2 clinical trial.
While some clinical measures suggested a possible benefit of a low dose of colchicine in slowing disease progression and extending survival, most efficacy and biomarker outcomes failed to reach statistical significance. Researchers believe more clinical trials will be needed to establish the possible efficacy of the medication in ALS and to understand responses to different doses of colchicine.
&#8220;The absence of statistically significant results in most outcome measures &#8230; does not indicate a clinical efficacy of colchicine in this context,&#8221; Jessica Mandrioli, MD, of the University of Modena and Reggio Emilia in Italy, said in an oral presentation at the 34th International Symposium on ALS/MND, being held Dec. 6-8 in Basel, Switzerland, and virtually.
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&#8220;In this moment, we have to deepen the knowledge of this drug before going on,&#8221; Mandrioli added.
The presentation was titled &#8220;<a href="https://www.tandfonline.com/doi/pdf/10.1080/21678421.2023.2260189">Safety profile, biological and clinical effects of colchicine in ALS: results from a phase 2 multicenter, randomized, controlled, double-blind clinical trial.</a>&#8221; (C61 in the symposium abstract book.)
In nearly all cases of ALS, a misfolded version of the TDP-43 protein toxically accumulates in nerve cells, driving cell damage and death. That&#8217;s why therapeutic strategies to target this abnormal protein — including ones that would enable its proper folding or clear it altogether — are of interest for treating ALS.
Colchicine is an approved medication — sold in the U.S. under distinct brand names and generics —used to prevent and treat gout attacks, to treat a rare condition known as familial Mediterranean fever, and to lower the risk of cardiovascular conditions. It works to ease inflammation and reduce the buildup of uric acid in the joints, which causes the painful symptoms of gout.
Among its effects, colchicine induces the activity of certain proteins involved in autophagy, a cellular process by which old, damaged, or faulty proteins are engulfed and recycled. Some evidence suggests that <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694295/#:~:text=Increasing%20evidence%20suggests%20that%20ALS,and%20Alzheimer%27s%20diseases%20%5B85%5D.">a failure of the autophagy process</a> could contribute to the accumulation of misfolded proteins in ALS and related conditions.
Previously, the scientists found that colchicine <a href="https://www.nature.com/articles/srep22827">boosted the activity of HSPB8</a>, an autophagy protein that&#8217;s been shown to promote the removal of misfolded proteins implicated in ALS.
As such, the researchers are exploring it as a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549675/#R13">possible therapeutic option</a> for enhancing autophagy-mediated clearance of TDP-43. The scientists also believe the medication&#8217;s anti-inflammatory effects could be of benefit in ALS.
<h3>Reasons for choosing colchicine</h3>
&#8220;We chose to study colchicine in ALS because colchicine is an inexpensive drug and immediately available and it has two mechanisms of action that can be useful for ALS,&#8221; Mandrioli said.
The <a href="https://clinicaltrials.gov/study/NCT03693781?cond=Amyotrophic%20Lateral%20Sclerosis&amp;term=Colchicine&amp;rank=1">Phase 2 Co-ALS clinical trial (NCT03693781)</a> was designed to evaluate the effects of oral colchicine treatment in ALS patients.
A total of 54 participants, ages 18-80, were enrolled across several sites in Italy and assigned randomly to receive colchicine at a dose of 0.01 or 0.005 mg/kg, or a placebo. Treatment was taken orally once a day for 30 weeks (about seven months), and patients were followed for up to week 54, or about one year. All could continue to receive a stable dose of riluzole (i.e., <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a>, <a href="https://alsnewstoday.com/tiglutik-for-als/">Tiglutek</a>) throughout the trial.
<h3>Evaluating ALS progression was main goal of trial</h3>
The trial&#8217;s main goal was to evaluate changes in disability progression, as assessed by the ALS Functional Rating Scale-Revised (ALSFRS-R), where a lower score indicates greater disability. Specifically, researchers were looking for the proportion of patients who achieved a positive treatment response, or no more than a 4-point decline in ALSFRS-R scores after 30 weeks.
Among patients treated with colchicine at its 0.005 mg/kg dose, about a third (33.3%) achieved this endpoint, compared compared with 13.3% who achieved that in the placebo group. This indicated a slower disability progression with this colchicine dose, but the difference did not reach statistical significance. Among those given colchicine at its higher dose, 7.1% achieved a positive response.
While positive responses were not significantly more frequent with either colchicine dose, monthly ALSFRS-R scores declined significantly slower for those receiving low dose colchicine than those on a placebo, and this significant difference was maintained throughout the post-treatment follow-up.
A trend toward prolonged survival and preserved respiratory function for patients on the lower dose also was observed, although not statistically significant. Secondary outcomes related to biomarkers of neurodegeneration, inflammation, or autophagy, were generally not different between groups.
Blood levels of a toxic version of TDP-43 increased in the placebo group, and generally decreased with colchicine, with a significant difference observed between the placebo and the combined colchicine groups at 30 weeks.
<h3>Interpret results cautiously, researcher says</h3>
&#8220;I would like to underline that the numbers are very, very small, so we have to be very cautious in interpretation,&#8221; Mandrioli noted.
Rates of side effects were similar between groups. Gastrointestinal side effects were more common in patients receiving colchicine, consistent with its known safety profile.
&#8220;Colchicine treatment was safe, but further trials are necessary to evaluate efficacy of this commercial drug in ALS,&#8221; the researchers concluded in the presentation&#8217;s abstract.

ALS/MND 2023: Gout med fails to show efficacy in small trial

<a href="https://www.zyduslife.com/zyduslife/">Zydus Lifesciences</a> has launched a Phase 2 clinical trial to evaluate the safety and effectiveness of its experimental anti-inflammatory therapy ZYIL1 in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The company announced it has received clearance for the <a href="https://classic.clinicaltrials.gov/ct2/show/NCT05981040">clinical trial (NCT05981040)</a> from India&#8217;s Central Drugs Standard Control Organization (CDSCO). The study is not recruiting patients yet, and the site(s) where it will be conducted have not been announced.
“Zydus has always aimed at improving the quality of life of patients through its life changing discoveries,” Pankaj R. Patel, chairman of Zydus, said in a <a href="https://www.zyduslife.com/investor/admin/uploads/21/83/Zydus-Lifesciences-initiates-Phase-II-clinical-trial-of-ZYIL1--a-novel-oral-NLRP3-inflammasome-inhibitor-in-patients-with-Amyotrophic-Lateral-Sclerosis-(ALS).pdf">press release</a>. “This study is a positive step in this direction to address very high unmet medical needs of patients suffering with ALS.”
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ALS is characterized by the progressive death and dysfunction of motor neurons, the specialized nerve cells that control voluntary movements. Although the exact biological mechanisms that drive <a href="https://alsnewstoday.com/causes-of-als/">motor neuron dysfunction in ALS</a> aren&#8217;t completely understood, it&#8217;s thought that inflammation plays a central role.
Under normal circumstances, the body produces an inflammatory response to fend off infections, but in neurological diseases like ALS it&#8217;s thought that out-of-control inflammation drives nerve damage.
ZYIL1 is an oral medication designed to reduce inflammation by blocking the activity of the NLRP3 inflammasome, a complex of inflammation-driving proteins that normally helps the body fight off viruses.
Preclinical studies have indicated the therapy is able to get into the brain and spinal cord of several animal models and to show beneficial effects in validated models of neuroinflammation and neurodegeneration, according to Zydus.
“By targeting neuroinflammation and neurodegeneration with ZYIL1, we hope to open up new possibilities in treating ALS,” Patel said.
<h3>Previous trials of anti-inflammatory therapy candidate ZYIL1</h3>
Two previous Phase 1 trials conducted in India tested single (<a href="https://clinicaltrials.gov/study/NCT04731324">NCT04731324</a>) and multiple (<a href="https://clinicaltrials.gov/study/NCT04972188">NCT04972188</a>) doses of ZYIL1 in a total of 48 healthy volunteers. Data showed the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087697/">therapy was safe and well tolerated</a> up to a single 400‐mg dose and a 100-mg dose twice daily for 14 days.
ZYIL1 also was found to have a favorable pharmacological profile and to effectively suppress the NLRP3 inflammasome pathway.
The newly launched Phase 2 trial will evaluate the therapy’s safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy in up to 24 adults, ages 18 to 80, who experienced the first ALS symptoms within nine months before enrollment.
Pharmacokinetics refers to the therapy’s movement into, through, and out of the body. while pharmacodynamics concerns the therapy’s effects on the body.
Participants will be assigned randomly to take receive either one of three doses of ZYIL1 (25, 50, or 75 mg) or a placebo, twice daily for 12 weeks (about three months).
<h3>Main and secondary goals of the Phase 2 trial</h3>
The study’s main goal is to assess the impact of ZYIL1 treatment on scores of the Amyotrophic Lateral Sclerosis Functional Rating Scale, a standardized measure of how much motor function is affected by ALS.
Key secondary goals include changes in a measure of lung function called slow vital capacity, as well as on blood levels of a nerve damage marker called neurofilament light chain.
ZYIL1 also is being evaluated as a potential treatment for a rare hereditary inflammatory condition called cryopyrin associated periodic syndrome and for which it received orphan drug status in the U.S. Such designation is meant to speed the therapy’s clinical development and regulatory review.

Zydus launches Phase 2 trial of anti-inflammatory ZYIL1

<a href="https://www.neurosense-tx.com/" rel="nofollow">NeuroSense Therapeutics</a> has received key patents in Europe, Japan, and Israel covering the use of PrimeC, its investigational, fixed-dose combination therapy, in treating neurological diseases such as <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
These patents are valid through 2038 and join others covering Prime C&#8217;s use in the <a href="https://alsnewstoday.com/news/primec-safe-well-tolerated-us-patent-allowance-als/">U.S.</a>, Canada, and Australia. Additional patents relating to PrimeC are pending.
PrimeC is being tested in a Phase 2b clinical trial, called <a href="https://classic.clinicaltrials.gov/ct2/show/NCT05357950">PARADIGM (NCT05357950)</a>, which <a href="https://alsnewstoday.com/news/neurosense-paradigm-trial-primec-als-completes-enrollment-patients/">enrolled 69 adults with ALS</a> at sites in Israel, Italy, and Canada. The company expects to present top-line trial data in the coming months.
Should results be promising, a pivotal and global Phase 3 clinical trial in ALS patients is planned for 2024.
[recommended-reading id=83127]
<h3>PrimeC showed safety and potential efficacy in earlier ALS clinical trial</h3>
&#8220;We are pleased to receive this most recent patent grant in Europe, Japan, and Israel which adds to our growing [intellectual property] estate as we expect the clinical read-out from our PARADIGM Phase 2b study towards year&#8217;s end,” Alon Ben-Noon, NeuroSense’s CEO and co-founder, said in a <a href="https://www.prnewswire.com/news-releases/neurosense-granted-patents-in-europe-japan-and-israel-for-its-als-drug-primec-301931701.html">press release</a>.
“ALS remains a pressing unmet need, and our unwavering commitment to advancing our program, supported by robust intellectual property, underscores our dedication to delivering an effective therapy for individuals battling ALS,&#8221; Ben-Noon added.
The company also was given Small and Medium-Sized Enterprise (SME) status by the European Medicines Agency (EMA) and opened an office in Germany, NeuroSense reported in a <a href="https://www.prnewswire.com/news-releases/european-medicines-agency-grants-neurosense-sme-status-301933411.html">separate press release</a>. The designation offers multiple benefits, including regulatory guidance throughout clinical development, financial benefits, and facility inspections, as well as fee exemption in the first years should the therapy be approved.
<a href="https://www.neurosense-tx.com/primec/" rel="nofollow">PrimeC</a> is an oral, fixed-dose combination of ciprofloxacin, an antibiotic, and celecoxib, an anti-inflammatory medication. The two compounds have well-established safety profiles and are approved in the U.S.
Used together, these medicines may have the potential to prevent disease progression by targeting key mechanisms that contribute to the degeneration of motor neurons, the nerve cells affected in ALS. Specifically, PrimeC is designed to reduce inflammation and iron accumulation, and to improve RNA processing.
In a previous <a href="https://classic.clinicaltrials.gov/ct2/show/NCT04165850">Phase 2a clinical trial (NCT04165850)</a> in Israel, an initial formulation of PrimeC taken three times daily was found to be <a href="https://alsnewstoday.com/news/primec-safe-lowers-als-disease-biomarkers-phase-2-clinical-study/">safe and well tolerated in ALS patients</a>. It also was seen to slow declines in the ability to perform daily activities and in lung function compared with an historical group of patients.
<h3>Phase 2b clinical trial of PrimeC to be followed by open-label extension</h3>
A new, extended-release formulation of PrimeC then was developed to be longer acting, requiring twice daily dosing. That formulation is being tested in the PARADIGM trial, with Prime C or a placebo given patients twice a day for six months.
Participants, ages 18 to 75 and whose symptoms of muscle weakness started less than 2.5 years before enrollment, also are continuing on their standard <a href="https://alsnewstoday.com/als-treatment/">ALS medications</a>.
The trial’s main goals are to evaluate PrimeC’s safety and tolerability, as well as changes in ALS biomarkers. Secondary goals will investigate the treatment&#8217;s efficacy on motor abilities, lung health, quality of life, and survival.
After completing the trial, patients can join an open-label extension phase, where all will be treated for up to one year.
PrimeC was designated an <a href="https://alsnewstoday.com/news/als-combination-therapy-primec-receives-fdas-orphan-drug-designation-enters-clinical-trials/">orphan drug in the U.S.</a> and the <a href="https://alsnewstoday.com/news/primec-orphan-drug-designation-europe-treatment-als/">European Union</a>. This status is given to therapies that aim to treat rare diseases and provides several benefits, including exemption from regulatory fees, assistance with clinical trial protocols, and several years of market exclusivity upon approval.

PrimeC, potential ALS therapy, earns patents in Europe, Japan, Israel

<a href="https://coyatherapeutics.com/">Coya Therapeutics</a> is planning to file a request with the U.S. Food and Drug Administration (FDA) to continue testing its investigational therapy COYA 302 for the treatment of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in a Phase 2 clinical trial.
The company is preparing a meeting with the regulatory agency to discuss its development plans and ensure they align with FDA expectations and requirements before submitting the investigational new drug (IND) application.
The pre-IND meeting will take place this fall, and the company is hoping to have the application cleared early next year, with plans to initiate the clinical trial soon thereafter.
“We are preparing for a pre-IND meeting with the FDA in the fall of 2023,” Howard Berman, PhD, CEO of Coya, said in a <a href="https://www.businesswire.com/news/home/20230808949580/en/Coya-Therapeutics-Inc.-Provides-Business-Update-and-Reports-Q2-2023-Unaudited-Financial-Results">company press release</a>. “We hope to have our IND application for a phase 2 trial accepted by the FDA early next year and are optimistic the trial can begin soon thereafter.”
ALS is marked by the <a href="https://alsnewstoday.com/symptoms-of-als/">progressive damage and death of motor neurons</a>, the nerve cells that control voluntary movements. With the loss of these neurons, the brain becomes less and less able to control muscle movement.
COYA 302 is a combination of the immune signaling molecule interleukin-2 (IL-2) and a fusion protein named CTLA4-Ig or abatacept. It is administered via a subcutaneous (under-the-skin) injection.
[recommended-reading id=85814]
<h3>Reducing inflammation, decreasing activity of damaging immune cells</h3>
The low-dose IL-2 in the combination is intended to reduce inflammation by increasing the activity of anti-inflammatory immune cells called regulatory T-cells (Tregs). CTLA4-Ig, in turn, is designed to decrease the activity of immune cells that promote inflammation and damage in ALS.
The therapy was tested in a small proof-of-concept trial involving four people with ALS. Participants were treated with COYA 302 for 48 weeks and were followed for eight more weeks after stopping the medication.
Results showed that COYA 302 resulted in a <a href="https://alsnewstoday.com/news/mda-2023-coya-302-therapy-slows-als-progression-early-trial/">considerable slowing of disease progression</a>. While participants were losing about 1.1 points per month in the ALS Functional Rating Scale (ALSFRS-R) — a measure of functional ability — before starting on COYA 302, they lost an average of 1.5 points in the whole trial duration.
However, once patients stopped the treatment, disease progression rates went back to those observed before treatment.
Analysis of immune cell function showed similar findings, with Treg activity increasing during treatment as expected, but decreasing once patients stopped treatment. Other markers of inflammation and oxidative stress, a type of cell damage associated with inflammation, also decreased with COYA 302.
The therapy was generally well tolerated, with no serious side effects described. The most common side effects were injection site reactions, which were mostly mild in severity.
Coya now expects to release data from biomarker analyses, and also publish full results from the trial in a peer-reviewed journal, before year&#8217;s end.

Coya to meet with FDA about a Phase 2 trial of COYA 302 for ALS

Enrollment is still ongoing for a Phase 2 clinical trial testing the safety and efficacy of <a href="https://www.corcept.com">Corcept Therapeutics</a>&#8216; cortisol modulator, called dazucorilant, in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The <a href="https://clinicaltrials.gov/ct2/show/NCT05407324">DAZALS trial (NCT05407324)</a>, launched in November 2022, is expected to enroll an estimated 198 adults with <a href="https://alsnewstoday.com/forms-of-als/">sporadic or familial ALS</a> across multiple sites in the U.S. and Europe. Recruitment is <a href="https://clinicaltrials.gov/ct2/show/NCT05407324#contactlocation">now underway</a> at three locations in the Netherlands and Poland, with more sites expected to open soon.
The study is being conducted in partnership with the <a href="https://www.tricals.org/en/">Treatment Research Initiative to Cure ALS</a> (TRICALS), a European network focused on finding new treatments for the progressive neurodegenerative disease.
“The 55,000 patients in the United States and Europe with ALS have an urgent need for better treatment,” Bill Guyer, Corcept’s chief development officer, said in a <a href="https://www.globenewswire.com/news-release/2023/02/28/2617676/0/en/Corcept-Therapeutics-Announces-Fourth-Quarter-and-Full-Year-2022-Audited-Financial-Results-and-Provides-Corporate-Update.html">company press release</a>.
“We are conducting this important study in collaboration with TRICALS, the leading ALS academic consortium in Europe, to investigate dazucorilant’s potential to significantly improve the lives of patients with ALS,” Guyer added.
[recommended-reading id=79333]
<h3>Up to 198 adults needed for DAZALS trial</h3>
Many people with ALS show symptoms of overactive adrenal glands, which are the small glands that sit atop the kidneys. Such signs can include high levels of the stress hormone cortisol and irregular circadian rhythms, commonly known as one&#8217;s biological clock.
Cortisol is a steroid hormone that is released into circulation to help the body manage stressful conditions. However, sustained elevations in cortisol levels can promote inflammation and nerve cell death, which is thought to contribute to the <a href="https://alsnewstoday.com/causes-of-als/">development of ALS</a>.
Dazucorilant is an antagonist of the glucocorticoid receptors, meaning it prevents cortisol from binding its natural receptors in the body and initiating the cascade of events leading to neuronal inflammation and death. It use is expected to ease the harmful effects of excess cortisol.
In preclinical studies, daily treatment with dazucorilant was found to reduce inflammation and <a href="https://www.sciencedirect.com/science/article/abs/pii/S0006899319306055">protect against nerve cell death</a> in animal models of ALS. Mice on the therapy also had better motor function and less muscle wasting than untreated mice.
“Dazucorilant showed great promise in animal models of ALS — improving motor performance and reducing neuroinflammation and muscular atrophy,” Guyer said.
The ongoing DAZALS trial is designed to test dazucorilant&#8217;s safety and efficacy in adults, 18 and older, with moderate rates of ALS disease progression.
[quote align=&#8221;center&#8221;]We are conducting this important study in collaboration with TRICALS, the leading ALS academic consortium in Europe, to investigate dazucorilant’s potential to significantly improve the lives of patients with ALS.[/quote]
To determine <a href="https://alsnewstoday.com/news/corcept-therapeutics-phase-2-trial-dazucorilant-als/">whether patients are eligible</a>, their overall prognosis will be estimated using a tool called the European Network to Cure ALS (ENCALS) risk profile score, whose scores ranges from about -12 to zero. Scores closer to zero indicate patients with very fast progression and short survival times, while those closer to minus 12 are given to those with very slow progression with good prognosis and survival rates.
The DAZALS trial is including patients with scores raging from –6 to –3, a range that includes nearly 60% of the overall ALS population and selects patients with similar disease progression rates.
Participants will be assigned randomly to one of two dazucorilant doses (150 mg or 300 mg) or a placebo, given as softgel capsules once daily for 24 weeks, or about six months.
The trial&#8217;s main goals are to determine the treatment&#8217;s safety, as well as changes in the ability to perform day-to-day tasks, as assessed with the ALS Functional Rating Scale Revised (ALSFRS-R). Researchers also will investigate changes in muscle strength, lung function, and quality of life as secondary outcome measures.
After completing the clinical trial, patients will have the option for enrollment in an open-label extension part, in which all will receive the 300 mg dose for an additional 24 weeks.

Tag: Phase 2 clinical trial