Adult bronchiectasis, asthma therapy, frailty in ILD

Home-Based Mechanical Ventilation and Neuromuscular Disease

Update on two recent FDA-approved therapies for ALS and SMA

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neuromuscular diseases often deteriorating to progressive respiratory failure. Two medications received recent FDA approval and are now available in clinical practice – edaravone for ALS and nusinersen for SMA. We present a balanced overview of the favorable data along with realistic challenges.

Edaravone (Radicava) is the second FDA-approved medication for management of ALS (Riluzole was approved over 20 years ago). Edaravone is a free radical scavenger that reduces oxidative stress, resulting in a protective effect on neuronal cells. It originally showed promise in acute ischemic stroke in Japan and was subsequently studied for ALS. A phase 3 randomized, double-blind placebo-controlled study performed in Japan (Lancet Neurol. 2017;16[7]:505) compared ALSFRS-R scores of a specific subset of ALS patients receiving edaravone vs placebo. This study revealed that patients with early ALS (2 years duration or less) with rapid progression (ALSFRS-R score of 7.5 in 6 months) had a 33% decrease in their degree of progression (reducing their ALSFRS-R score to 5) in the edaravone group. Of note, there was also slowing in the decline of FVC, though not clinically significant. Although the drug was rapidly approved by the FDA, there are obvious challenges that must be recognized. First, it is unclear if patients will discern such a mild degree of slowing of disease progression. In addition, the annual cost may be prohibitive, and lifelong IV administration of the medication for 10 days every month may pose logistical barriers.

Nusinersen (Spinraza) is the first FDA-approved therapeutic medication for spinal muscular atrophy (SMA). SMA is a hereditary neuromuscular disorder leading to degeneration of motor neuron cells and ultimately diffuse muscle weakness and often respiratory failure. Nusinersen is an antisense oligonucleotide that modifies splicing of the SMN-2 gene to increase production of normal, full-length SMN protein, which is deficient in SMA. The ENDEAR trial (Finkel RS, et al. N Engl J Med. 2017;377[18]:1723) was a phase 3, multicenter, double-blind study that enrolled SMA infants to receive nusinersen vs sham. Infants who received treatment had improvements in motor milestones (41% vs 0%) and less permanent-assisted ventilation or death in the nusinersen group (39% vs 68%), a 47% reduction in risk of death. The therapy is safe and tolerable, although there is reported risk of bleeding abnormalities, renal toxicity, and constipation. Administered intrathecally, there is a series of four loading doses, followed by maintenance doses every 4 months – presumably lifelong. Although FDA approved all three SMA subtypes, the eventual impact is uncertain, especially in cases of advanced muscle weakness. There are realistic challenges: the high cost ($125,000/dose), limited longitudinal evidence, technical administration, and limited access.

Pulmonologists should be aware of both medications as new therapeutic options for ALS and SMA; however, the long-term impact is yet to be determined.

Ashraf Elsayegh, MD, FCCP
Steering Committee Member

Won Y. Lee, MD
Steering Committee Member