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Troriluzole, a new formulation of the approved <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) treatment riluzole, can be taken with or without food and appears to have better pharmacological properties than approved versions of the medication that allow once daily administration.
That&#8217;s according to data from three studies in healthy volunteers presented by Heather Sevinsky, executive director of clinical pharmacology and pharmacometrics at <a href="https://www.biohaven.com/">Biohaven Pharmaceuticals</a>, which is developing troriluzole.
Sevinsky&#8217;s talk, &#8220;<a href="https://www.aan.com/msa/Public/Events/AbstractDetails/55596">Next Generation Prodrug Troriluzole: Increased Bioavailability of Riluzole with No Food Effect in Healthy Subjects</a>,&#8221; took place at the American Academy of Neurology (AAN) 2024 Annual Meeting held April 13-18 in Denver, Colorado, and online.
Riluzole was approved in the 1990s as the first treatment for ALS. An oral therapy thought to reduce nerve damage by altering neurological signaling, it was originally authorized under the brand name <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a>, which is sold as tablets. Other formulations taken as an oral suspension (<a href="https://alsnewstoday.com/tiglutik-for-als/">Tiglutik</a>) or an oral film (<a href="https://alsnewstoday.com/exservan-riluzole-oral-film/">Exservan</a>) have also been approved in more recent years.
Although riluzole has been proven to slow the <a href="https://alsnewstoday.com/stages-of-als/">progression of ALS</a>, the therapy has some notable drawbacks. It can cause liver damage, requires twice daily administration, and has to be taken on an empty stomach because food can prevent the medication from being absorbed properly.
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<h3>Aim is safer, easier formulation</h3>
Troriluzole is a prodrug, an inactive agent that is converted into therapeutic riluzole once inside the body. Biohaven is developing the therapy with the goal of creating a new riluzole formulation that&#8217;s safer and easier to take.
&#8220;Trorilulozole is a novel prodrug that was designed to overcome the shortcomings of oral riluzole,&#8221; Sevinsky said.
Biohaven has conducted three, single-center studies to test the safety and pharmacological effects of a single dose of troriluzole in healthy volunteers.
The first study, which involved 24 participants, compared the bioavailability of troriluzole, at a dose of 100 or 280 mg, against that of oral riluzole at the approved dose of 50 mg. Bioavailability refers to how much of the drug is absorbed into the body.
Results showed that the maximum concentration of active riluzole in the bloodstream was similar for oral riluzole compared with any of the troriluzole doses tested. However, levels stayed higher for longer with troriluzole, such that the total amount of active riluzole in the blood over time was 40% to 50% higher with troriluzole.
Sevinsky noted that troriluzole also led to markedly less variability in levels of riluzole in the bloodstream. Levels varied by about 40% with troriluzole, compared with more than 50% with oral riluzole.
The other two studies, which collectively involved 26 volunteers, tested whether taking troriluzole with food alters how the body absorbs the drug.
Results indicated that, when the 280 mg dose of troriluzole was taken with a fatty meal, the time it took for blood riluzole levels to reach a peak was delayed by about two hours, and the maximum concentration was 20% lower compared with taking the therapy on an empty stomach.
Nonetheless, when considering the total amount of the medication in the bloodstream over time, &#8220;the overall riluzole absorption &#8230; was unaffected by food,&#8221; Sevinsky said.
To put those results in perspective, Sevinsky said that when oral riluzole is taken with a fatty meal, the total amount of drug in the bloodstream over time is reduced by about 20%.
Collectively, these three studies &#8220;confirm higher bioavailability of riluzole when administered as troriluzole and demonstrate troriluzole may be taken without regard to food,&#8221; Sevinsky said.
&#8220;Additionally, results show lower variability of riluzole, representing an optimized profile allowing once daily administration,&#8221; she added, noting that the findings support further development of the new treatment formulation.

AAN 2024: Troriluzole may be taken with food, data suggest

<a href="https://braintrustbio.com/">Brain Trust Bio</a> (BTB) has been cleared to launch Phase 1 clinical trials in Australia to test the efficacy of its patented method for delivering therapeutics directly into the spinal canal, with a focus on the <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) therapy riluzole.
The approach is intended to further enhance riluzole&#8217;s therapeutic benefits, which have been associated with slightly extending survival of ALS patients when taken orally.
The trials will be conducted in Australia, but they’ll meet American standards so when its time for Phase 2 trials, the Phase 1 findings will be accepted by U.S. regulators without needing to be repeated, the company said.
&#8220;The approval to conduct these trials signifies a pivotal moment in advancing our mission,&#8221; Chen Benkler, PhD, co-founder and CEO of BTB, said in a <a href="https://braintrustbio.com/brain-trust-bio-receives-approval-for-patient-trials-targeting-als-and-other-cns-diseases-with-continuous-intrathecal-drug-delivery-method/">company press release</a>.
The central nervous system (CNS), that is, the brain and spinal cord, is protected from harmful circulating substances by a tight-knit cellular layer that lines the blood vessels called the blood brain barrier (BBB).
While the BBB protects CNS health, it can pose a challenge for treating neurological diseases. Many medications that are systemically delivered, that is, by swallowing a pill or by being infused into the bloodstream, can&#8217;t breach the BBB effectively and therefore can’t reach the tissues where they need to exert their effects.
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<h3>Benefit of intrathecal delivery in ALS</h3>
Intrathecal delivery, where medicine is directly infused into the spinal canal, can get around this problem, because that space is filled with cerebrospinal fluid (CSF), which surrounds the brain and spinal cord. This lets a therapy bypass the BBB and access the CNS, potentially enhancing its therapeutic effects at smaller doses while avoiding off-target side effects elsewhere.
BTB’s patented intrathecal delivery method is designed for continuous infusion of medications. Its early focus is on administering riluzole to ALS patients.
A few versions of riluzole are approved in the U.S. for ALS, but all are delivered systemically. <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a> is an oral tablet, <a href="https://alsnewstoday.com/tiglutik-for-als/">Tiglutek</a> is a liquid oral suspension, and <a href="https://alsnewstoday.com/exservan-riluzole-oral-film/">Exservan</a> is an oral film that dissolves on the tongue.
Riluzole is the only approved ALS therapy known to extend survival, but does so by only about three months, according to BTB. Oral doses can’t be increased to boost its effectiveness because they can cause liver toxicity. The oral medication can also result in cognitive issues and weakness.
BTB believes it can enhance the survival benefits of riluzole without increasing its side effects by administering low daily doses via the intrathecal route. It developed and patented a formulation for this delivery method, which it called IT-riluzole.
The approach has already demonstrated early signs of efficacy, said BTB, with two patients treated for more than two years without any observed side effects.
Preliminary data indicate IT-riluzole may be about five times more effective than existing delivery modes, according to the company. While other methods extend survival by a few months, IT-riluzole may offer another year or more.
The planned Phase 1 trials will involve 10 patients treated with IT-riluzole over six months at two sites in Australia.
The intrathecal approach also lets researchers take CSF samples from patients to look for disease biomarkers.
“Our proposed treatment offers unprecedented access to CSF sampling, enabling us to provide CSF biomarker results to an extent never seen before, further enhancing our understanding and ability to treat CNS diseases,” Benkler said.
The company plans to evaluate the potential of its delivery method in <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a> and spinal cord cancer, other CNS diseases.

Tag: riluzole

AAN 2024: Troriluzole may be taken with food, data suggest

Efficacy of riluzole given by intrathecal delivery OK’d for study