Life Med: Continuous antioxidant treatment for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease that affects motor neurons, resulting in muscle weakness and atrophy, with a median survival of only about 2 to 4 years
after symptom onset.
The annual incidence of ALS worldwide is about 1.
5-2.
4 per 100,000.

There is currently a lack of effective disease-modifying therapies
.
Riluzole is the only drug approved by all drug regulatory agencies for the treatment of ALS, but it can only prolong survival by about 3-5 months, and new drug development is imminent
.

Oxidative stress is an important pathophysiological mechanism and potential therapeutic target of
ALS.
Antioxidant drugs have been used in pilot studies
for the treatment of ALS.
Edaravone, a clinical treatment for acute ischemic stroke, has been tried for the treatment of ALS
due to its antioxidant effects.
In two phase 3 randomized controlled trials (RCTs), edaravone treatment for 24 weeks delayed functional decline in patients with early ALS by 30%, and was approved by the US FDA as the second disease-modifying drug
for the treatment of ALS in 2017.
RCTs were conducted
in critically selected participants who met ideal conditions.
A recent observational study in Germany re-evaluated the efficacy of edaravone in the real world, and no benefit was observed in any ALS patients or early-stage patients, including rate of disease progression, survival, and time without mechanical ventilation
.

Why are the effects observed in an ideal world not reproduced in the real world? A plausible explanation is that the therapeutic effects of edaravone are overshadowed
by the influence of numerous confounding factors in the real world.
A key factor is the short
duration of exposure to edaravone in existing treatment regimens.
At present, edaravone on the market is an intravenous preparation, in the above test, the use of edaravone is 60mg/day intravenous drip, every 28 days for 1 course of treatment, each course of treatment is only the first 10 days of medication (the first course of treatment is the first 14 days of medication).

As a result, patients are completely drug-free for 18 days of each session; During the 10-day period, the plasma concentration of edaravone 60 mg intravenously was almost undetectable after 8 hours, and the blood concentration was insufficient for at least 16 hours per day.

This means that patients are exposed to less than 20% of the effective concentration of edaravone (Figure 1).

ALS is a chronic, progressive disease in which oxidative stress persists and gradually worsens, and maintaining a stable and adequate blood concentration is necessary to break through the masking of real-world confounding factors and effectively treat the disease
.

Long-term intravenous fluids can lead to infusion-related adverse events, poor compliance, and oral formulations are more suitable for long-term, multiple-dose administration
.
Recently, several oral formulations of edaravone have been available, such as edaravone solid dispersible tablets, which have good
bioavailability.
Oral edaravone suspension (Radicava ORS) was recently approved by the FDA at a recommended dose of 105 mg/day
.
The pharmacokinetics at this dose is similar to that of 60 mg intravenous preparation, and the dosing regimen is the same
.
Under these conditions, the adequate drug exposure time for Radicava ORS is still less than 20%.

Whether long-term, multiple-dose administration of edaravone is effective in treating ALS remains to be answered
.

Other antioxidant stress drugs are also expected
.
Sodium phenylbutyric acid-taurine diol (PB-TURSO) slowed ALS patient functional decline by 25% and extended survival by 18 months in a Phase 2 clinical trial, and was recently conditionally approved by Health Canada for a Phase 3 trial that is being recruited
.
Verdiperstat has been granted orphan drug and Fast Track designation by the FDA and the European Food and Drug Agency for the treatment of multisystem atrophy, and the Phase 2/3 clinical trial of the drug for ALS is ongoing
.

In summary, maintaining sufficient and stable blood concentrations of antioxidant drugs may be a necessary condition for effective treatment of ALS, which is a bridge between the ideal world and the real world.
Oral reagents offer hope for effective treatment of diseases to achieve this condition, as well as opportunities
for the treatment of other chronic neurodegenerative diseases such as Alzheimer's disease.

References

1.
Ferrante RJ, Browne SE, Shinobu LA, et al.
Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis.
J Neurochem.
Nov 1997; 69(5):2064-74.
doi:10.
1046/j.
1471-4159.
1997.
69052064.
x

2.
Abe K, Itoyama Y, Sobue G, et al.
Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients.
Amyotroph Lateral Scler Frontotemporal Degener.
Dec 2014; 15(7-8):610-7.
doi:10.
3109/21678421.
2014.
959024

3.
Writing G, Edaravone ALSSG.
Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.
Lancet neurology.
Jul 2017; 16(7):505-512.
doi:10.
1016/S1474-4422(17)30115-1

4.
Witzel S, Maier A, Steinbach R, et al.
Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis.
JAMA Neurol.
Feb 1 2022; 79(2):121-130.
doi:10.
1001/jamaneurol.
2021.
4893

5.
Jiao SS, Yao XQ, Liu YH, et al.
Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits.
Proc Natl Acad Sci U S A.
Apr 21 2015; 112(16):5225-30.
doi:10.
1073/pnas.
1422998112

About the author

Wang Jun, Daping Hospital, Army Medical University

Jun Wang is an associate professor
of neurology at Daping Hospital, Army Medical University.
Selected as Chongqing Talents and Young Top Talents
.
His research interests include the mechanism of Alzheimer's disease from a systematic perspective, the search for peripheral diagnostic biomarkers and new prevention and treatment strategies
.
As the first/corresponding author, he has published 18 SCI papers in journals such as Nature Reviews Neurology and Science Advances
.

Wang Yanjiang, Daping Hospital, Army Medical University

Wang Yanjiang, Director, Chief Physician and Professor
of the Department of Neurology, Daping Hospital, Army Medical University.
He was awarded the National Science Foundation for Outstanding Young Scholars and was selected as a "Changjiang Scholar" Distinguished Professor
of the Ministry of Education.
He is a member of the Standing Committee of the Neurology Branch of the Chinese Medical Association, an associate editor of Neuroscience Bulletin Journal, and a director of
Vas-Cog Asia.
The scientific research direction is cognitive impairment-related diseases, and the corresponding author has published more than 80 papers in Nature Reviews Neurology, Lancet Infectious Disease, JAMA Neurology, PNAS and other journals, and won 1 second prize of National Science and Technology Progress Award and 3 first prizes of
military and provincial and ministerial levels.

Xinfu Zhou, University of Flinders, Australia, University of South Australia

Xinfu Zhou is a senior researcher and professor at the University of Flinders and the University of South Australia, and an associate editor
of the journal Neurotoxicity Research.
He has long been engaged in the research of neurotrophic factors and their receptors, focusing on their biological functions and their role
in nerve damage and neurodegenerative diseases.
In recent years, the role of neuroprotective agents in cerebral ischemia, Alzheimer's disease, multiple sclerosis and peripheral immune diseases and their drug development
have been explored.
Won the Australian Talent Research Fund several times; He has published more than 240 SCI papers, which have been cited more than 11300 times, H-index 59
.