The SMA and DMD Therapeutic Landscape

The SMA and DMD Therapeutic Landscape

Patients with spinal muscular atrophy (SMA) stand to benefit from recent improvements in the current landscape of SMA treatment. Newborn screening is becoming more widely available, and with it, we can expect earlier diagnosis and access to treatment to slow progression of the condition.

Zolgensma (onasemnogene abeparvovec-xioi), a gene-replacement therapy for SMA in pediatric patients, is one of such promising treatments. Marketed globally by Novartis, Zolgensma was approved by the FDA in 2019 for treatment in patients less than 2 years old with mutations in SMN1 – a specific gene involved in SMA. Notably, its approval includes treatment before symptoms appear, which fits well with increased access to newborn screening.

Data from the STR1VE phase III trial of Zolgensma supported use of the therapy in a pediatric patient population, especially over current alternatives, such as Spinraza. Some providers may prefer to use Zolgensma in the youngest group of patients unless there’s a strong reason not to do so, such as the very rare development of neutralizing antibodies. More data would be necessary to determine the duration of action and if the antibodies fade over time.

Biogen’s Spinraza (nusinersen) and risdiplam, developed by Roche, are other agents for the treatment of SMA. Current practice is monotherapy with one of these agents for a number of reasons. Patients need to be observed closely to help determine the effectiveness of each therapy. Additionally, insurance would not support concurrent treatment with both Spinraza and Zolgensma.

 In the case of Zolgensma, early signals from clinical trial data show more benefit for younger patients. Older patients seeking treatment may experience less benefit because they’ve lost motor neurons through the course of the disease. Preliminary data from STRONG suggests that there is some drop-off of benefit from age two to five (and patients older than five years old were not studied). This is different from Spinraza, or even risdiplam, where benefit can be seen in older patients.

Frequency of Treatment

Spinraza’s biggest issue is the frequency of treatment (every four months), especially in patients who need radiologic guidance to administer the drug directly into the intrathecal space. In addition to repeated exposure to harmful X-rays, younger patients may need sedation. We are starting to see type I patients, who previously would not have survived past a few years without treatment, develop scoliosis and thus need radiologic guidance as well.

As you can imagine, COVID-19 poses a problem because of the frequency of treatments involved with drugs such as Spinraza. Follow-up physicals can be completed remotely, but in-person treatment visits are necessary, and a dedicated space is required for an interventional radiologist. Because of the increased risk of infection, parents may be reluctant to complete their visits.

Treatment Routes

Risdiplam is an oral drug that received priority review designation from the FDA. Current data shows it may be better than Spinraza in certain SMA populations, even approaching what we’re seeing with Zolgensma. Additionally, its route of administration may be a big differentiator here. Risdiplam’s SUNFISH trial went up to age 24 years, but it did not seem superior to Spinraza for ages 2 to 12 years. But because only risdiplam has prospective data for SMA 2 and 3 patients older than 12 years, it’s a good option for this population. For newborns with type 1 disease, Zolgensma is still a strong choice.

Options for Duchenne Muscular Dystrophy

A lack of dystrophin is the core issue in Duchenne muscular dystrophy (DMD), therefore assessing the current options for DMD warrants a look at dystrophin production. Unfortunately, none of the current options lead to significant dystrophin production, but that could change.

A majority of DMD patients are given steroid medications, such as prednisone. A smaller number are on Emflaza, which is challenging to get approval for treatment despite retrospective data showing fewer side effects. The benefits for Exondys have to be substantial, because of problems encountered with infusions, such as infections and blood clots. Exondys only slows progression and increases dystrophin to 1% of normal, so the benefit is modest at best.

Viltolarsen, by NS Pharma, is showing a higher increase in dystrophin from phase II data (up to 6%). This is higher than other exon-skipping products such as Vyondys, by Sarepta. Again, looking at dystrophin levels, we don’t know the threshold required for significant benefit. In terms of approval odds for agents with exon-skipping technology, the precedents, Vyondys and Exondys, seemed to have weak data but received approval. Exon-skipping agents also target specific mutations, so they’re limited to specific parts of the overall population.

Beyond Exon Skipping

The phase II data from the study of Antisense Therapeutics’ ATL1102 looks promising, showing improvement in multiple areas. However, the CD47d is located on T cells, so this drug’s mechanism targets the immune system. Clinicians must decide if adding this for patients, a majority of whom are already on steroids, is a good option or if it may worsen immunosuppression.

With the majority of DMD patients having cardiomyopathy, prevention of that complication is critical. This is where CAP-1002, from Capricor, comes in. Alternatives such as the exon-skipping drugs don’t work well for cardiac muscles. So a therapy that’s targeted for cardiac muscles is extremely important, since cardiac function is strongly linked to mortality. The preliminary data for CAP-1002 shows both improvement in cardiac function and benefit in other outcomes, such as grip strength.

 Edasalonexent, an oral agent that targets NF-kappa B and is not specific to an underlying mutation, is easy to take and can possibly be combined with other similar agents.

Gene Therapy in DMD

It’s still early to tell how effective CRISPR technology can be in DMD because current drugs don’t make a lot of dystrophin, which is critical for clinical improvement in Duchenne. In microdystrophin, by Solid, safety issues with aberrant complement activation cannot be ignored. There’s no guarantee that gene therapy will be more effective or durable, but there is some optimism about the Sarepta products.


About Dr. Yaacov Anziska

 Dr. Yaacov Anziska is the Director of the SUNY Downstate Medical Center, Muscular Dystrophy Association Neuromuscular Care Center, and an Associate Professor in the Department of Neurology at SUNY Downstate. He also runs the Botulinum Toxin Clinic and the neuro-immunology group at SUNY Downstate. Dr. Anziska specializes in the treatment of neuromuscular diseases and has experience with peripheral neuropathies, myasthenia gravis, and muscular dystrophies. His research interests include quality of life and pain in neuromuscular patients, as well as assessing clinical and daily functioning, especially in those with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). Dr. Anziska focuses on bringing new drugs and treatments from the lab into clinical practice, including for DMD and SMA, as well as pursuing the latest genetic testing available in neuromuscular diseases.


This article is adapted from the May 6, 2020, GLG teleconference “SMA and DMD Therapeutic Landscape.” If you would like access to this teleconference or would like to speak with Dr. Anziska or any of our more than 700,000 experts, contact us.