Edaravone, sold under brands such as Radicava and Radicut, is an intravenous drug used to help recover from stroke and treat amyotrophic lateral sclerosis (ALS). Adverse reactions to this product include bruises, gait disorders, headache, skin inflammation, eczema, dyspnea, excessive sugar in the urine, and skin fungal infection. But the US Food and Drug Administration (FDA) considers it a first-class drug.
The mechanism by which edaravone may be effective is unclear. However, it is known that this product is an antioxidant. It is speculated that oxidative stress is part of the process of killing neurons in patients with ALS.
What is amyotrophic lateral sclerosis?
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a fatal degenerative disease that affects the motor neurons connecting the brain and spinal cord, leading to eventual paralysis and death. Approximately 5,600 individuals are diagnosed with ALS annually in the United States, and as many as 30,000 Americans are currently affected. Although rare, ALS is the most common motor neuron disease; it affects people of all races and ethnicities but has a higher prevalence among Caucasians.
In patients with ALS, the brain loses the ability to control muscle movement when the neurons controlling mobility begin to die, resulting in complete paralysis in its latter stages. Early symptoms of the disease include muscle twitching, cramping, stiffness, weakness, and eventually slurred speech and difficulty chewing or swallowing. Psychological and cognitive difficulties are also seen in patients with ALS, including involuntary laughing or crying, depression, impaired executive functions, and maladaptive social behavior. Advanced stages of the disease feature symptoms such as muscle atrophy, spasticity, cramps, and weakness, all of which progressively worsen. The average life expectancy of a person with ALS is two to five years from the time of diagnosis, with death resulting from respiratory failure (e.g., aspiration pneumonia) and medical conditions related to immobility. About half of patients with ALS live at least three years or more after diagnosis; 20% live five years or more, and up to 10% survive for more than 10 years.
ALS was first described in 1869 by the French neurologist Jean-Martin Charcot. The disease gained wide recognition in the United States after baseball player Lou Gehrig announced his ALS diagnosis in 1939. The disorder causes “amyotrophy”—the atrophy of muscle fibers—and “lateral sclerosis”—the changes were seen in the lateral columns of the spinal cord when upper motor neuron axons in these areas degenerate and are replaced by fibrous astrocytes. Although the cause of ALS is unknown, about 5% of patients have a family history of the disease. Studies conducted on twins show a genetic contribution with a heritability of about 61%.
Although there is no cure for ALS, available treatments can extend the length of quality of life in most patients. As the mainstay of ALS therapy, the American Academy of Neurology recommends adaptive treatments directed at the clinical manifestations of the disease, which include enteral nutrition via percutaneous endoscopic gastrostomy to stabilize body weight in patients with impaired oral intake, noninvasive ventilation to treat respiratory insufficiency to prolong survival and slow the decline of forced vital capacity (FVC), and mechanical insufflation/insufflation to clear secretions in patients with reduced peak cough flow, particularly during an acute respiratory infection. The first drug approved by the Food and Drug Administration (FDA) for the treatment of ALS was riluzole, which should be offered to all patients with ALS to slow disease progression. In May 2017, the FDA approved edaravone (Radicava, Mitsubishi Tanabe Pharma America), a novel neuroprotective agent indicated to slow the advance of ALS.
What is the pharmacology of edaravone?
The mechanism by which edaravone might be effective in ALS is unknown. The drug is known to be an antioxidant, and oxidative stress has been hypothesized to be part of the process that kills neurons in people with ALS.
The half-life of edaravone is 4.5 to 6 hours and the half-lives of its metabolites are 2 to 3 hours. It is metabolized to a sulfate conjugate and a glucuronide conjugate, neither of which are active. It is primarily excreted in urine as the glucuronide conjugate form.
Clinical trials on Radicava
The Radicava™ clinical development program included multiple phase III clinical trials. FDA approval was based on a pivotal phase III clinical trial known as MCI186-19, which was a double-blind, placebo-controlled study that evaluated the efficacy and safety of Radicava™.
The study enrolled 137 patients with ALS, who were randomized in a 1:1 ratio to receive Radicava™ 60mg intravenously for 60 minutes or a placebo for six months. The primary endpoint of the study was a change in the ALS functional rating scale-revised (ALSFRS-R) score from baseline to six months. The revised ALSFRS was used to measure disease status and levels of disability in patients with amyotrophic lateral sclerosis.
Results of the study demonstrated that patients treated with Radicava™ exhibited less decline in physical function by 33% compared to placebo, at week 24. The study showed that patients treated with Radicava™ witnessed less decline in physical function by 2.49 ALSFRS-R points compared to those in the placebo group.
The most common adverse reactions found in patients treated with Radicava were bruising, gait disturbance, and headache.
Radicava™’s efficacy with long-term patients and its effect on survival is yet to be evaluated.