Approval of Spinraza (nusinersen), the first disease-modifying therapy for spinal muscular atrophy (SMA), has brought not only hope, but also some challenges for both patients and researchers, according to a recent review.
The study, “Advances in therapy for spinal muscular atrophy: promises and challenges,” was published in the journal Nature Reviews Neurology.
SMA is a neurodegenerative disease caused by mutations in the SMN1 gene, which provides instructions to make the survival motor neuron (SMN) protein. It is classified into four categories based on age of onset and severity.
Spinraza, developed by Biogen, is currently the only approved treatment for all types of SMA in the U.S., Europe, Canada, and Japan. It takes advantage of the existence of a second survival motor neuron gene called SMN2. This gene can also produce SMN protein, but due to a slight difference in its DNA sequence, 90 percent of the resulting protein is shorter and nonfunctional.
Spinraza increases the ability of the SMN2 gene to produce a full-length SMN protein, restoring its levels and function. However, its effects can vary among patients, and to achieve the best results, it should be delivered as soon as possible.
Clinicians hope that data from ongoing and future clinical trials assessing the efficacy of Spinraza in presymptomatic SMA patients and in older patients with milder types of SMA will help determine its effectiveness in these patient groups.
Recently, the results of the Phase 3 CHERISH clinical trial (NCT02292537), published in The New England Journal of Medicine, showed that treatment with Spinraza significantly improved motor function in children with later-onset SMA, defined as after 6 months of age and likely corresponding to types 2 and 3.
One of the main challenges of Spinraza is patient access to the therapy. Besides being very expensive, which will likely change only when new treatments are approved to compete with it, the delivery method — injections into the spinal canal — has to be administered by qualified personnel in a proper clinical setting.
This delivery method also limits the therapy’s distribution throughout the body, and the initial therapy involves repeated injections, which increases the patient’s burden. Researchers are working on, and testing, more efficient and less invasive treatment options, with similar modes of action.
Designed to deliver a functional copy of the SMN1 gene to motor nerve cells, it showed promising results in its initial, dose-finding Phase 1 clinical trial (NCT02122952) in 15 infants with type 1 SMA who were given a one-time injection of either a high or low dose of AVXs-101.
All responded, but those in the high-dose group showed the greatest improvements in motor control, strength, and independence — responses unheard of in the natural history of this disease.
AveXis will now launch clinical trials in a broader range of SMA patients, reflecting the company’s belief that the treatment may also benefit those with milder forms of the disease. The planned studies include one that will enroll presymptomatic patients with SMA type 1, 2, and 3; another will recruit patients with these same disease subtypes who do not qualify for other trials.
In the future, these treatments could help reduce problems related to muscle fatigue and weakness in SMA patients.
Preclinical data has also highlighted the potential of combining therapies that target SMN and other genes that influence SMN.
“SMN restoration alone — whether via an ASO, gene therapy and/or small-molecule-based approach — does not represent a therapy that is sufficient to ameliorate all symptoms in every patient with SMA,” the authors suggest in the review.
In fact, the authors believe that “additional non-SMN-targeted therapies will probably be required to deliver effective therapy that is capable of covering the whole lifespan. Thus, the next generation of therapies for SMA are expected to be of a primarily combinatorial SMN-plus nature.”
This combined approach could lead to significant improvements in SMA symptoms. However, finding patients who have not previously been treated to participate in new clinical trials is likely to become more difficult, as most qualified patients will already be benefiting from SMN-targeted therapies like Spinraza, or possibly AVXS-101, in the near future.
It is crucial that patients, advocacy groups, researchers, as well as industry and regulatory agencies “continue to work together to ensure that the exciting and promising therapies emerging from research pipelines are successfully translated into accessible and effective treatments for all patients,” the authors concluded.