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Early treatment with <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone), an approved therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), significantly reduced the risk of hospitalization, need for ventilatory support, or death compared with delaying treatment for six months.
That&#8217;s according to analyses of data from <a href="https://clinicaltrials.gov/ct2/show/NCT01492686">Study 19 (NCT01492686)</a>, the Phase 3 clinical trial that supported Radicava&#8217;s approval, and its open-label extension.
Patients initially assigned to Radicava in the Phase 3 trial tended to have better survival outcomes as well as a lower risk of death or need for ventilation than those who started it in the extension. These results failed to reach statistical significance, however.
“This analysis illustrates the importance of earlier and continued treatment with [Radicava] for patients with ALS in the clinical setting,” the researchers wrote in “<a href="https://onlinelibrary.wiley.com/doi/10.1002/mus.27946">The effects of intervention with intravenous edaravone in Study 19 on hospitalization, tracheostomy, ventilation, and death in patients with amyotrophic lateral sclerosis</a>,” which was published in <a href="https://onlinelibrary.wiley.com/journal/10974598">Muscle &amp; Nerve</a>.
Radicava, infused directly into the bloodstream, was <a href="https://alsnewstoday.com/news/fda-approves-radicava-first-new-als-therapy-in-20-years-and-cause-for-hope/">approved in the U.S.</a> for ALS in 2017. It&#8217;s designed to decrease oxidative stress, a type of cellular damage that&#8217;s believed to contribute to nerve cell death in the disease. More recently, the treatment became available as an oral suspension formulation called <a href="https://www.radicava.com/patient/taking-radicava-ors/">Radicava ORS</a>.
Radicava&#8217;s approval was based on data from Study 19, a clinical trial in Japan that enrolled 137 people with ALS and randomly assigned them to Radicava or a placebo for 24 weeks. The patients who started Radicava earlier continued to have a slower disease progression than those who transitioned from a placebo.
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<h3>Slow disease progression seen with early Radicava treatment</h3>
After six months, those given Radicava saw a significantly slower decline in their ability to perform everyday activities, by 33%, over the placebo group.
After completing the randomized part, patients could join an <a href="https://pubmed.ncbi.nlm.nih.gov/28872920/">open-label extension (OLE)</a>, where all received Radicava for 24 weeks to assess its long-term effectiveness. Those who started it earlier continued to have a slower disease progression than those who transitioned from a placebo.
A team led by researchers at <a href="https://www.mt-pharma-america.com/">Mitsubishi Tanabe Pharma</a>, the developer of Radicava formulations, conducted a post hoc analysis — or one done after the trial is over and all the results have been gathered — to examine survival and other disease milestones with participants in Study 19 and its OLE.
The analysis included 65 patients who were always on Radicava and 58 who initially received a placebo for 24 weeks and then switched to Radicava until week 48. Almost a third (23%) of those assigned first to Radicava and 41% originally on a placebo discontinued treatment over the 48 weeks.
While no deaths were registered in the 24-week period, two patients always on Radicava and four who started on a placebo died during the OLE. The risk of death was lowered by 52% in the continuous Radicava group, but the findings were not significant, the analyses suggested.
Similarly, starting Radicava earlier tended to extend the time to death, the need for a tube in the neck to help with breathing, or tracheostomy, or the need for permanent assisted ventilation, but that also failed to reach significance.
<h3>A lower combined risk with Radicava</h3>
When the researchers examined the combined risk of events such as death, tracheostomy, permanent assisted ventilation, or hospitalization, there was a significant difference, however. Those continuously on Radicava were 53% less likely to have any of those events over those who started it six months later.
This difference in risk was mainly driven by hospitalizations, the researchers noted. Hospitalizations occurred in 38.2% of those first given a placebo, compared with 27.5% with those always on Radicava.
The findings show into-the-vein Radicava is “associated with a lower rate of death, tracheostomy, PAV [permanent assisted ventilation], or hospitalization during the 48-week trial,&#8221; the researchers said, noting more research was recommended to confirm the results.

Early Radicava lowers ventilation, hospitalization, mortality risk

<a href="https://www.mt-pharma-ca.com/">Mitsubishi Tanabe Pharma Canada</a> (MTP-CA) is teaming up with the <a href="https://cndr.org/">Canadian Neuromuscular Disease Registry</a> (CNDR) in Canada&#8217;s first real-world, evidence-generating study of <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone) in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
Data are expected to provide real-life insights into the survival benefits of Radicava in the progressive neurodegenerative disorder, thought to affect about 3,000 Canadians.
When Radicava was approved in Canada in 2018, it became the first new ALS treatment in that country in nearly two decades. The treatment is infused into the bloodstream and an oral formulation called Radicava Oral Suspension was approved Canada last year. The effect of edaravone — the active ingredient in both formulations — on real-world survival in ALS hasn&#8217;t been established, however.
&#8220;Edaravone has previously been shown to slow disease progression in people with ALS over six months; however, further real-world effectiveness evidence is needed,&#8221; Agessandro Abrahao, MD, CNDR&#8217;s co-principal investigator, said in a <a href="https://www.newswire.ca/news-releases/mitsubishi-tanabe-pharma-canada-announces-collaboration-with-the-cndr-on-first-canadian-real-world-evidence-study-of-radicava-r-iv-edaravone-survival-benefits-in-als-864837565.html">press release</a>.
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<h3>What does the real-world Radicava study seek to accomplish?</h3>
Edaravone is known as a free radical scavenger, meaning it extracts the reactive molecules that contribute to oxidative stress, a type of cellular damage implicated in ALS. Neurons are especially <a href="https://www.hindawi.com/journals/omcl/2019/2105607/">sensitive to oxidative stress</a>. By removing them, the therapy should mitigate nerve damage and slow disease progression.
While Radicava is approved in Canada, the U.S., and some other countries, the evidence showing its effectiveness isn&#8217;t settled and regulators in Europe and other regions have declined to approve it.
&#8220;The objective of this study is to describe real-world survival effectiveness over a longer time frame,&#8221; said Abrahao, a neurologist and associate scientist with the Sunnybrook Health Sciences Centre in Toronto who is co-leading the study.
&#8220;This collaboration with the CNDR is part of our legacy in Canada and ongoing commitment to benefit patients, caregivers, and loved ones touched by rare diseases, including ALS,&#8221; said Andy Zylak, president of Mitsubishi Tanabe Pharma Canada.
The study is enrolling ALS patients across Canada whose symptoms started in the past three years. So far, about 182 patients on Radicava for at least six months between 2017-2022 and 860 controls on other medications have signed on, Abrahao announced in a poster presentation in June at the 2023 Canadian Neurological Sciences Federation Congress.
Its main goal is to see if Radicava can extend the time until a tracheostomy, or a tube in the neck to help with breathing, is needed. This outcome is known as tracheostomy-free survival.
&#8220;Real-world data provides additional insight into treatment for rare diseases like ALS, which can sometimes be challenging to research and evaluate in clinical trials,&#8221; said Dung Pham, medical affairs director, Mitsubishi Tanabe Pharma Canada. &#8220;Through our collaboration with the CNDR, we hope to gain important real-life insights into the role of Radicava in the treatment of ALS — insights that will ultimately benefit people living with this progressive, life-threatening disease and their families.&#8221;
&#8220;Access to innovative therapies is an urgent issue for people living with ALS,&#8221; said Tammy Moore, president of <a href="https://als.ca/">ALS Canada</a>. &#8220;Understanding how innovative treatments perform in a real-world setting can assist stakeholders from across the healthcare system with decision making and potentially lead to faster access for people living with ALS and improved health outcomes.&#8221;
The Canadian Neuromuscular Disease Registry is an independent registry of people — more than 4,500 to date — with a neuromuscular disease. It works to improve understanding of such disorders and accelerate the development  of treatments.

ALS survival benefits with Radicava to be studied as part of collaboration

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>.
[recommended-reading id=85260]
<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.

Intranasal formulation helps edaravone reach brain: Early study

<a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava </a>(edaravone) significantly prolongs long-term survival for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to an analysis of nearly 3,000 patients. It didn&#8217;t significantly slow the progression of disease symptoms, as assessed by scores on the ALS Functional Rating Scale-Revised (ALSFRS-R), however.
The results were presented at last week&#8217;s American Academy of Neurology (AAN) 2023 annual meeting in the poster, “<a href="https://www.aan.com/MSA/Public/Events/AbstractDetails/54324">Survival in Amyotrophic Lateral Sclerosis Patients Treated with Edaravone &#8211; a Pooled Analysis of 2845 Patients</a>.”
Radicava is an approved <a href="https://alsnewstoday.com/als-treatment/">treatment for ALS</a> that&#8217;s thought to reduce oxidative stress — a type of cell damage that plays a major role in driving the disease. It&#8217;s available as an intravenous (into the vein) infusion or in a newer oral formulation called Radicava ORS. Both are sold by <a href="https://www.mt-pharma.co.jp/e/">Mitsubishi Tanabe Pharma</a>, which was not involved with this analysis.
Despite Radicava&#8217;s approval in <a href="https://alsnewstoday.com/news/fda-approves-radicava-first-new-als-therapy-in-20-years-and-cause-for-hope/">the U.S.</a>, <a href="https://alsnewstoday.com/news-posts/2018/10/09/radicava-now-approved-to-treat-als-patients-in-canada/">Canada</a>, Switzerland, and a number of other countries, evidence on its effectiveness <a href="https://alsnewstoday.com/news/radicava-suggests-more-real-world-data-needed-to-determine-efficacy-of-edaravone-in-als/">isn&#8217;t settled</a>, leading scientists at Al-Azhar University, Egypt to analyze pooled data from 12 previously published studies to assess its effect on disease progression and survival.
[recommended-reading id=82936]
The analysis included data on 2,845 patients, among whom, 1,141 were treated with Radicava, sometimes in combination with the older ALS therapy riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek </a>and other formulations). The other 1,704 were given a control treatment, either a placebo or riluzole alone.
After 18 months (1.5 years) of follow-up, the chances of survival were significantly higher, by about 13%, for patients given Radicava. Later analyses also showed a significant survival benefit with Radicava — by 22% at 24 months (two years) and by 17% at 30 months (2.5 years).
At earlier timepoints (six or 12 months), survival tended to be slightly better in the Radicava group, but the difference with the control group was not statistically significant. That means it&#8217;s mathematically plausible the difference could be due to random chance.
Rates of symptom progression, as measured by the change in ALSFRS-R scores, tended to slightly favor Radicava, but weren&#8217;t significantly different from controls. Rates of side effects and other safety issues were comparable in the two groups, leading the scientists to conclude that Radicava “improves long-term survival with no effect on the ALSFRS-R score&#8221; and with a similar rate of adverse events between the groups.

AAN 2023: Radicava leads to better long-term survival in ALS

<a href="https://alsnewstoday.com/what-is-als/">Amyotrophic lateral sclerosis</a> (ALS) patients treated with <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone) tend to go longer before reaching disease milestones such as needing a walking aid or breathing support, according to an analysis of insurance data.
The findings were presented at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference in the poster, &#8220;<a href="https://www.mdaconference.org/abstract-library/longer-milestone-free-time-in-iv-edaravone-treated-vs-iv-edaravone-naive-amyotrophic-lateral-sclerosis-patients-an-administrative-claims-analysis/">Longer Milestone-free Time in IV Edaravone-treated vs IV Edaravone-naïve Amyotrophic Lateral Sclerosis Patients: An Administrative Claims Analysis</a>.&#8221; The work was funded by <a href="https://www.mt-pharma-america.com/">Mitsubishi Tanabe Pharma America</a> (MTPA), which markets Radicava in the U.S.
Radicava is an <a href="https://alsnewstoday.com/als-treatment/">approved treatment</a> for ALS that&#8217;s thought to work by decreasing oxidative stress, a type of cellular damage that contributes to nerve cell death. It&#8217;s administered via infusion into the bloodstream, but an oral formulation called Radicava ORS has been approved in the U.S. MTPA <a href="https://www.prnewswire.com/news-releases/mitsubishi-tanabe-pharma-america-announces-more-than-10-000-people-with-als-treated-with-radicava-ors-edaravone-andor-radicava-edaravone-301773547.html">recently announced</a> that more than 10,000 people in the U.S. have received one of the two formulations.
A team of scientists at MTPA and other institutions analyzed data from a large U.S. insurance database between 2017-2021. The analysis only included patients with commercial insurance or Medicare Advantage plans, so it may not represent all ALS patients, the researchers noted.
The researchers examined 360 patients treated with Radicava for a median of 9.1 months and an equal number of patients who weren&#8217;t given Radicava. The two groups were matched based on available data so they were comparable for age, race, gender, and disease duration.
[recommended-reading id=82739]
<h3>Comparing outcomes of Radicava treatment</h3>
To compare outcomes between them, the researchers calculated a statistical measure called restricted mean time lost (RMTL), which represents the average amount of time lost due to a certain milestone. For instance, a lower RMTL for death would suggest longer survival times. The researchers specifically assessed the first year after patients were entered into the database.
Results showed, for both commercially insured and Medicare Advantage patients, the RMTL for requiring a walking aid (such as a cane, walker, or wheelchair) was lower for those given Radicava, suggesting treated patients retained their ability to walk independently longer.
Radicava-treated patients also had lower RMTLs for noninvasive ventilation, using artificial nutrition, and hospice care. RMTLs were significantly higher among Radicava-treated patients for invasive ventilation or speech-generating devices, however.
The researchers also compared survival outcomes in the first and second year after patients were enrolled in the database. Results showed, for those who didn&#8217;t receive Radicava, mortality rates were 69.9% in the first year and 77.3% in the second. By contrast, mortality rates were 40.4% and 47% in the first and second years respectively for patients on Radicava.
These results &#8220;provide an example of real-world impact of [Radicava] in patients with ALS,&#8221; the scientists said, adding the findings &#8220;may be useful to payers and clinicians in evaluating the use of [Radicava].&#8221;
Both Radicava and Radicava ORS are administered in 28-day cycles of 14 days on treatment, followed by 14 days off. MTPA is currently running a Phase 3 clinical trial called <a href="https://clinicaltrials.gov/ct2/show/NCT04569084">MT-1186-A02 (NCT04569084)</a> to compare alternative dosing regimes of Radicava ORS.
Results are expected later this year. Scientists at MTPA and other institutions shared details of the trial&#8217;s design at the MDA conference in the poster, &#8220;<a href="https://www.mdaconference.org/abstract-library/phase-3b-study-to-evaluate-efficacy-and-safety-of-oral-edaravone-over-48-weeks-in-patients-with-amyotrophic-lateral-sclerosis-mt-1186-a02/">Phase 3b Study to Evaluate Efficacy and Safety of Oral Edaravone Over 48 Weeks in Patients with Amyotrophic Lateral Sclerosis (MT-1186-A02)</a>.&#8221;
The trial intends to enroll about 380 adults with ALS whose disease began within two years of enrollment. Participants will be randomly assigned to one of two groups and treated for about a year.
In one group, participants will be treated with Radicava ORS (105 mg) every day, rather than taking 14 days off treatment in each 28-day cycle. In the second group, participants will first get Radicava ORS for 14 days, then a placebo for 14 days (mimicking the currently approved schedule) for one 28-day-cycle. For the next 11 cycles, participants will take the therapy for 10 days and a placebo for 18 days.
The main goal is to compare outcomes on the ALS Functional Rating Scale Revised (ALSFRS-R), a standardized measure of ALS symptom severity. Secondary measures include changes in lung function, survival, and quality of life.
After completing the main trial, participants will be able to enter an open-label extension and receive Radicava ORS for an extended period.
&#8220;This study will provide important information on the safety, efficacy, and tolerability of 2 dosing regimens for [Radicava ORS] in patients with ALS,&#8221; the researchers concluded in their poster.
&#8220;These presentations reflect our determination to not only broaden our expertise in ALS, but to continue sharing key insights that have a meaningful impact on the patient and medical communities,&#8221; Gustavo A. Suarez Zambrano, MD, vice president of medical affairs at MTPA, said in a <a href="https://www.prnewswire.com/news-releases/mitsubishi-tanabe-pharma-america-announces-presentations-in-als-at-2023-mda-clinical--scientific-conference-301774776.html">company press release</a>.

Tag: Radicava (edaravone)

Early Radicava lowers ventilation, hospitalization, mortality risk

ALS survival benefits with Radicava to be studied as part of collaboration

Intranasal formulation helps edaravone reach brain: Early study

AAN 2023: Radicava leads to better long-term survival in ALS

MDA 2023: Walking, other functions retained longer on Radicava