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<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

Inhibiting the NLRP3 inflammasome — an immune system protein complex believed to contribute to the inflammation that drives <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — alone was not sufficient to ease spinal cord inflammation in a mouse model of the disease, according to recent research.
NLRP3 is overactive in ALS and has been a focus of therapeutic development, but there are other inflammasome complexes that could be involved.
<a href="https://www.zyversa.com/">ZyVersa Therapeutics</a> believes the study findings support its development of inflammasome inhibitors that target multiple pathways — not just NLRP3 — to control inflammation in ALS and other inflammatory diseases.
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“The research &#8230; reinforces the need to inhibit more than the NLRP3 inflammasome pathway to control inflammation associated with activation of multiple inflammasomes,” Stephen C. Glover, co-founder, chairman, CEO and president of ZyVersa, said in a <a href="https://www.globenewswire.com/news-release/2023/09/12/2741445/0/en/ZyVersa-Therapeutics-Announces-Research-Published-in-Frontiers-in-Immunology-Reinforcing-IC-100-s-Rationale-for-Inhibiting-Multiple-Inflammasomes-to-Control-Inflammation-in-Various.html">press release</a>.
The study, &#8220;<a href="https://www.frontiersin.org/articles/10.3389/fimmu.2023.1190219/full">Divergent functional outcomes of NLRP3 blockade downstream of multi-inflammasome activation: therapeutic implications for ALS</a>,&#8221; was published in <a href="https://www.frontiersin.org/journals/immunology">Frontiers in Immunology</a>. It was funded by <a href="https://www.ucb.com/">UCB BioPharma</a> and all study authors are UCB employees.
Inflammasomes are protein complexes that sense threats (i.e., microbes or other foreign molecules) and respond by inducing inflammatory attacks against them. Their excessive activation can contribute to the chronic inflammation that&#8217;s involved in a wide range of diseases.
<h3>Understanding inflammasomes</h3>
There are several types of <a href="https://www.zyversa.com/inflammasomes">inflammasomes</a> in the body. Each contains a unique sensor molecule that responds to different environmental threats.
That sensor binds to ASC, a protein that recruits caspase-1, which initiates the production of pro-inflammatory molecules called cytokines and inflammatory cell death, or pyroptosis. Additional ASC molecules gather and form structures called specks that are critical for perpetuating cytokine release.
The most widely studied inflammasome in the context of neurological diseases is the type that contains the NOD-Like Receptor Family Pyrin Domain Containing 3  (NLRP3) sensor molecule.
Indeed, a growing body of evidence indicates that activation of NLRP3 contributes to inflammation and nerve cell death in ALS. As such, it is <a href="https://alsnewstoday.com/news/trial-potential-als-therapy-vtx3232-sees-1st-healthy-volunteer-dosed/">being investigated</a> as a potential therapeutic target for the neurodegenerative disease.
Yet, evidence suggests that other inflammasome types also are dysregulated in ALS and other neurological diseases. As such, ZyVersa believes that targeting NLRP3 alone may not be enough to dampen inflammation in these conditions.
<h3>Investigational antibody IC 1oo inhibits the ASC protein</h3>
The company is developing IC 1oo, an investigational antibody that inhibits the ASC protein. Because ASC is integral to the formation and function of multiple inflammasome types, including NLRP3, its blockade could inhibit the initiation of inflammatory signaling across multiple disease-associated complexes.
“ZyVersa’s Inflammasome ASC inhibitor IC 100 is designed to inhibit formation of multiple types of inflammasomes to attenuate initiation of the inflammatory cascade, and to inhibit ASC specks to attenuate perpetuation of damaging inflammation,” Glover explained.
IC 100 has been found to <a href="https://investors.zyversa.com/static-files/64964310-ab95-4a06-bc47-dd44c63dc5c7">suppress inflammation</a> in preclinical studies, including in models of <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a>, age-related inflammation, <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer&#8217;s disease</a>, traumatic brain injury, and spinal cord injury.
In the study, scientists examined the impacts of specific NLRP3 inhibition in various cell and animal models of ALS. Various immune cell types from healthy people and ALS patients were exposed to inflammatory stimuli meant to activate the NLRP3 inflammasome.
Genetic or pharmacological NLRP3 inhibition in these cells led to reduced release of cytokines and less pyroptosis. However, in cells stimulated to activate other inflammasome complexes, the NLRP3 inhibitor, called MCC950, led to variable responses in terms of cytokine release or pyroptosis.
In healthy mice and an ALS mouse model, MCC950 also was able to block NLRP3-induced pyroptosis, but it failed to prevent cell death induced by other types of inflammasomes.
Notably, in a mouse model of ALS, NLRP3 inhibition alone was not sufficient to ease spinal cord inflammation.
<h3>Limitations of NLRP3 inhibition</h3>
&#8220;Our study highlights potential limitations of NLRP3 inhibition in attenuating cytokine release and inflammatory cell death when other inflammasomes are active,&#8221; the researchers wrote.
&#8220;As such we suggest future therapeutic focus in neurological indications with multi-inflammasome activation should be on converging executer nodes downstream of inflammasomes, rather than single inflammasome-inhibiting approaches,&#8221; they added.

Tag: NLRP3 inflammasome

Zydus launches Phase 2 trial of anti-inflammatory ZYIL1

NLRP3 inhibition alone does not ease ALS inflammation: Study