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Note: This story was updated Jan 24, 2024, to correct that Radicava and Radicava Oral Suspension are available in Switzerland but not in other European countries.
FAB122, an oral formulation of edaravone developed by <a href="https://www.ferrer.com/en">Ferrer</a>, failed to slow disease progression or extend survival in adults with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) who took part in a Phase 3 clinical trial.
The <a href="https://www.clinicaltrials.gov/study/NCT05178810">ADORE trial (NCT05178810)</a>, running across dozens of sites in Europe, was testing the formulation against a placebo, given as a daily dose of 100 mg for 48 weeks, on top of the standard of care for ALS.
“We are disappointed with this outcome and would like to thank the people with ALS, caregivers, investigators, and clinical trial staff for their participation in [the] ADORE clinical trial,” Tatjana Naranda, PhD, Ferrer’s chief research and development officer, said in a <a href="https://www.ferrer.com/en/results-study-ADORE-ALS">company press release</a>.
The company will terminate <a href="https://clinicaltrials.gov/study/NCT05866926">ADOREXT (NCT05866926)</a>, an open-label extension to the ADORE trial that was testing the long-term safety of FAB122 <a href="https://alsnewstoday.com/news/fnp122-oral-formulation-edaravone-enters-phase-3-extension/">for up to three years</a>.
“Although the results are not what we hoped for, our work to advance potentially transformative therapies in areas of high unmet need for people living with ALS will not stop,” Naranda said.
Edaravone protects nerve cells by neutralizing unstable molecules produced during metabolism called reactive oxygen species. When those unstable molecules build up in excess, they can damage nerve cells and contribute to the neurodegeneration seen in ALS.
The medication is available in the U.S. as <a class="c-link" href="https://alsnewstoday.com/radicava-edaravone-for-als/" target="_blank" rel="noopener noreferrer" data-stringify-link="https://alsnewstoday.com/radicava-edaravone-for-als/" data-sk="tooltip_parent">Radicava</a>, which is infused into the bloodstream, and as Radicava ORS, an oral suspension taken by mouth or via a feeding tube. Except for Switzerland, no European countries have approved either of these therapies.
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<h3>What were the goals of the ADORE trial?</h3>
FAB122, also called FNP122 and TWoo1, is a distinct formulation of edaravone that&#8217;s made of granules packaged in sachets to be dissolved in water. It was developed by the Dutch company <a href="https://treeway.nl/">Treeway</a>, who <a href="https://treeway.nl/ferrer-and-treeway-enter-into-licence-agreement-for-the-development-and-commercialisation-of-tw001-fnp122-for-amyotrophic-lateral-sclerosis/">licensed it to Ferrer</a> for clinical testing in Europe and some Asian countries.
ADORE recruited about 300 adults, ages 18-80, who&#8217;d had their first ALS symptoms within the last two years. It was conducted with the support of <a href="https://www.tricals.org/en/">Treatment Research Initiative to Cure ALS</a> (TRICALS), an European research initiative.
The trial&#8217;s main goal was to determine if adding FAB122 to standard ALS treatment could significantly slow disease progression, as assessed with the Revised ALS Functional Rating Scale (ALSFRS-R). Safety and the treatment&#8217;s impact on the Combined Assessment of Function and Survival (CAFS) were secondary measures. CAFS is a composite measure that ranks clinical outcomes based on survival and the rate of ALSFRS-R decline.
The treatment was safe and well tolerated, but failed to slow disease progression at 48 weeks compared with a placebo and didn&#8217;t improve CAFS outcomes at 48 and 72 weeks.
“At TRICALS, we had hoped for a different outcome of the ADORE study and are disappointed that this is not the positive result we all wanted,” said Leonard van den Berg, MD, PhD, chair of TRICALS. “We will continue to do our utmost to find a treatment for ALS as soon as possible.” Van den Berg is also professor of neurology at the University Medical Centre Utrecht in the Netherlands and was the trial’s principal investigator.
<a href="https://www.mt-pharma-america.com/">Mitsubishi Tanabe Pharma America</a>, the developer of Radicava and Radicava ORS, said FAB122 contains a distinct formulation of edaravone than that found in its products.
The clinical trial also had &#8220;many significant differences&#8221; from the Phase 3 trial that supported Radicava&#8217;s approval, so &#8220;any data and/or conclusions relative to FNP122 (FAB122) cannot be directly compared to [Radicava] or Radicava ORS,&#8221; the company said in a <a href="https://www.mt-pharma-america.com/media/news/press-releases/2024/01/17/mitsubishi-tanabe-pharma-america-inc-mtpa-statement-on-ferrers-phase-3-adore-clinical-trial-of-fnp122-fab122">press release</a>.

Edaravone formulation FAB122 fails to slow ALS progression

An into-the-nose (intranasal) formulation of edaravone — the active ingredient in the <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) medication <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> — may enhance the medication&#8217;s ability to reach brain tissue, according to a recent study.
The formulation, which was made by packaging edaravone into tiny carriers called nanoparticles, was found to ease toxicity in cell cultures, and showed good brain distribution with limited accumulation in other organs when delivered via the intranasal route in mice.
Researchers believe this approach might eventually offer patients an alternate mode of delivery for edaravone with fewer side effects, but could also be used to formulate other <a href="https://alsnewstoday.com/als-treatment/">ALS medications</a> that have a hard time getting into the brain.
&#8220;This study is the first of its kind to develop an ALS drug in a nanoparticulate formulation for nose-to-brain delivery raising hope to ALS patients where currently treatment options are limited,&#8221; researchers wrote.
The study, &#8220;<a href="https://www.sciencedirect.com/science/article/pii/S0168365923003711">Intranasal administration of edaravone nanoparticles improves its stability and brain bioavailability</a>,&#8221; was published in the <a href="https://www.sciencedirect.com/journal/journal-of-controlled-release">Journal of Controlled Release</a>.
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<h3>Radicava designed to combat oxidative stress</h3>
Radicava works to slow functional decline in ALS by combating oxidative stress, a type of cellular damage that&#8217;s implicated in the nerve cell death that characterizes the disease.
It is available to patients in a number of countries as an into-the-vein (intravenous) infusion, but an oral formulation called Radicava ORS is also approved in the <a href="https://alsnewstoday.com/news/fda-approves-radicava-ors-oral-suspension-edaravone-als/">U.S.</a> and <a href="https://alsnewstoday.com/news/radicava-oral-suspension-approved-canada-treat-als/">Canada</a>. Neither formulation has been cleared in the European Union.
Intranasal formulations of medications are thought to offer certain advantages for treating neurological conditions, but such a formulation of Radicava does not currently exist.
With this approach, medications are often packaged into nanoparticles, which have characteristics that help to bypass the selective blood-brain barrier (BBB) and efficiently reach the brain tissue when inhaled through the nose. The BBB is a tight-knit collection of cells that works to keep unwanted molecules out of the brain. A consequence of this is that certain medications, when delivered into the bloodstream, have a hard time getting in.
In addition to helping medications reach the brain in higher concentrations, intranasal therapies are thought to help avoid side effects that arise when a medication accumulates in various organs after a systemic mode of delivery.
[quote=&#8221;center&#8221;]This study is the first of its kind to develop an ALS drug in a nanoparticulate formulation for nose-to-brain delivery raising hope to ALS patients where currently treatment options are limited.[/quote]
<h3>Researchers develop new nanoparticle-encapsulated version of edaravone</h3>
As such, researchers in the U.K. and China developed a new nanoparticle-encapsulated version of edaravone, referred to as NP-EDV and examined its properties in cell cultures and mice.
Results indicated that edaravone could be efficiently loaded into the nanoparticles and had better shelf-life stability than the molecule normally has on its own.
Moreover, NP-EDV exhibited favorable pharmacological properties and reduced signs of oxidative stress and associated cellular toxicity in an oxidative stress cell culture model.
The encapsulated treatment was then tagged with a fluorescent marker and administered to healthy mice via intranasal or intravenous delivery. The fluorescent marker can be imaged to look at the distribution of the medication throughout the body.
While both modes of delivery enabled NP-EDV to reach the brain, similar concentrations were reached with a much lower dose of the intranasal treatment, suggesting &#8220;smaller drug doses can be given without compromising drug concentrations in the brain,&#8221; the researchers wrote.
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<h3>Intranasal route limited uptake of medication largely to brain, GI tract</h3>
On the other hand, distribution of NP-EDV was more widespread throughout the body with the intravenous infusion, showing accumulation in several organs including the liver, whereas the intranasal route limited uptake of the medication largely to the brain and gastrointestinal tract.
&#8220;Altogether the imaging study &#8230; suggested that the [intranasal] route offers a more ‘brain targeting’ approach with relative lower accumulation in the rest of the body,&#8221; the researchers wrote.
Avoiding accumulation in these other organs might help to prevent side effects.
In addition to supporting the potential benefits of an intranasal edaravone formulation, the scientists believe the study&#8217;s findings have broader applications. The nanoparticles they developed could also be used to package other potential ALS therapies that have a limited ability to reach the brain on their own.
&#8220;The current approach also opens up new opportunities for repurposed drugs for treatment of ALS which could otherwise be limited due to poor BBB crossing and brain bioavailability,&#8221; the team concluded.

Tag: Edaravone

Edaravone formulation FAB122 fails to slow ALS progression

Intranasal formulation helps edaravone reach brain: Early study