Breakthroughs in ALS Treatment

Amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease after the famed 1920s and 30s baseball player, is a disease most have heard of but do not know much about. The disease received an uptick in recognition over the last few years in connection to the “ice bucket challenge” popular on social media which was started to help raise awareness for research against this disease. It is a neurodegenerative disorder with symptoms stemming from damaged motor neurons causing muscle weakness, muscle wasting, weight loss, progressive disability, and eventual death. Most patients do not experience sensory loss and most remain mentally sharp only experiencing the continually progressing loss of muscle control. The average life span after diagnosis is 3 years although a small number of patients may live 20 years or more with the disease

According to the amyotrophic lateral sclerosis association (alsa.org) as many as 20,000 Americans currently suffer from this disease with about 6,000 new diagnoses per year. The total annual costs of treatment and care for those suffering from ALS are not well defined but have been estimated to be about $63,693 per patient per year. With 20,000 currently affected, this could represent a annual cost of $1.2 billion per year in the United States alone

The causes of ALS are unclear which has limited the treatment options for patients. Until very recently the only FDA approved drug for the treatment of disease progression was oral riluzole, a glutamate antagonist, approved under the trade name Rilutek in 1995. Generic forms of riluzole were first available in the US in 2013. Today riluzole is relatively inexpensive hovering about $150 to $200 per patient per month. The American Academy of Neurology published a 2009 update to its ALS practice parameters, which included strengthened language for the use of riluzole in patients with ALS. Their review of the research revealed that the use of riluzole may extend patients’ lives by about 6 months which is twice as long as the 3 months originally seen in clinical trials. Other drug treatments commonly used in patients with ALS are for symptom management only including: stimulants for fatigue, anticonvulsants/muscle relaxants for muscle spasms, anticholinergics for drooling, opioids/NSAIDs for pain, sedatives for sleep, and antidepressants for mood.  Other non-drug treatments commonly used include noninvasive ventilation and percutaneous endoscopic gastrostomy.

A new drug for the treatment of ALS called Radicava (edaravone) was approved for use in the United States by the FDA under an orphan disease designation in May 2017. Radicava was approved for use in Japan in 2015 which caught the attention of the FDA who then requested the manufacturer to file an application in the US. It is an IV infused drug given over 60 minutes daily for 14 days then off for 14 days. For continuation, it is given a minimum of 10 days within a 14 day window then off for 14 days. It is unclear how the drug works to treat ALS, but it is thought to be related to the scavenging of free radicals and protecting nerves from further damage.

The FDA approval of Radicava is based on a phase 3, randomized, placebo-controlled, double-blind study which included Japanese subjects who had a diagnosis of ALS for 2 years, retained the ability to perform most activities of daily living, and had normal respiratory function (Radicava package insert). The primary endpoint was a change in ALSFRS-R score which is calculated from a 12 point questionnaire to assess symptom severity with a maximum score of 48 (higher means more function). At 24 weeks, Radicava showed superiority to placebo with a mean change in score of −5.01±0.64 compared to a mean change of −7.50±0.66 for placebo (p = 0.0013). No large safety concerns were seen in clinical trials, though Radicava did have a higher incidence of contusion, gait disturbance, headache, dermatitis, eczema, respiratory failure, respiratory disorder, hypoxia, glycosuria, and tinea infection than placebo. To help alleviate concerns that may arise from a complete Japanese study population, a pharmacokinetics study was undertaken and showed no difference in kinetics between Japanese and Caucasian subjects.

A search on clinicaltrials.gov shows no further studies currently underway for Radicava in the treatment of ALS. Further research into Radicava’s ability to decrease disease progression long term and to see if it provides any benefit for mortality would help solidify its place in ALS treatment. As may be expected with a drug tied to an orphan disease, the cost of Radicava is high. It currently has an AWP price of $1,303.20 per dose or about $169,416 per patient per year. Considering this is more than twice the estimates provided above of the annual treatment costs of ALS, this has potential to represent a significant financial burden for payers and patients.

As there were more than 20 years between riluzole and Radicava, it is hard to predict when the next drug to treat ALS might be approved. There is currently one drug in phase 3 trials from manufacturer Cytokinetics called tirasemtiv that is being studied with endpoints centered around respiratory decline. Results from the first tirasemtiv study may be available as early as the end of 2017. A number of drugs are in phase 2 studies including familiar drugs like rasagiline, mexiletine, and tocilizumab (brand name Actemra). Much of the research in ALS is focused on understanding the cause of the disease and finding biomarkers that could be used to identify patients earlier before noticeable disease progression. With the awakened social awareness of this disease, and the excitement surrounding the approval of Radicava, there is likely more to come over the next few years in the treatment of ALS.