Understanding the Treatment Challenges and Unmet Needs of Spinal Muscular Atrophy

^{By Julie Gould} 

Wildon R Farwell, MD, MPH, global medical head of Neuromuscular Diseases, Biogen, breaks down the treatment challenges and unmet needs in spinal muscular atrophy (SMA), and reviews a recent SMA clinical trial. 

What are the challenges in treating spinal muscular atrophy (SMA)?

SMA is a rare, genetic neuromuscular disorder. It is characterized by a loss of motor neurons that results in progressive muscle atrophy and weakness. The disease impacts individuals of all ages, from infants and children to teens and adults, with a spectrum of disease severity. 

The clinical course of SMA is highly variable; however, progressive muscle weakness, motor function impairment and disability affect all individuals with SMA regardless of disease type. Without treatment, the majority of children born with the most severe form of the disease usually die before they turn 2 years of age without nutritional and respiratory support.

Until just a few years ago, no disease modifying treatments existed for SMA. Fortunately, there are three approved treatments now available—with SPINRAZA being the first treatment approved in 2016—offering different dosing and administration options. These medicines have demonstrated unprecedented survival and improvement in motor function in patients with SMA.

Can you identify some of the unmet needs of this patient population?

People with SMA do not produce enough survival motor neuron (SMN) protein, which is critical for the maintenance of motor neurons that support sitting, walking and the basic functions of life, including breathing and swallowing. Once motor neurons are lost, they cannot be replaced.  

In clinical practice, there is a sense of urgency to address motor neuron loss in SMA from the earliest sign of symptoms, or even prior to symptoms, to prevent additional disease progression. As we continue to pursue improved outcomes for children with SMA, the need for additional benefit in some patients treated with the gene therapy Zolgensma® (onasemnogene abeparvovec) has been observed.  

It has been reported that to-date, four out of 10 patients in the long-term study of Zolgensma have subsequently been treated with SPINRAZA, in addition to real-world experience with SPINRAZA treatment following Zolgensma.^1-4 We believe that, for certain SMA patients, motor neurons may be insufficiently treated by this gene therapy. Preclinical data also show that not all motor neurons are transduced by gene therapy, leaving some untreated.^5,6 

Why is Biogen conducting the RESPOND trial? Has the SMA community asked for more information supporting the use of SPINRAZA following Zolgensma?

We have heard from the SMA patient community, as well as from health care providers, that additional data is needed from a clinical trial setting to better inform treatment decisions. 

SPINRAZA has demonstrated clinically significant, sustained benefit for a broad range of patients with SMA, and there is compelling clinical rationale for the potential of additional efficacy with SPINRAZA following treatment with gene therapy.

To support the needs of the SMA community, the RESPOND study aims to understand the extent to which SPINRAZA could potentially improve outcomes for patients previously treated with gene therapy. The study will enroll children who are determined by the investigator to have the potential for additional clinical improvement after receiving Zolgensma. Physicians will use criteria that may include one or more of the following: suboptimal motor function (eg, a score lower than 50 on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders); the need for respiratory support; abnormal swallowing or feeding ability; or other factors deemed relevant by the investigator.

For more information about the RESPOND study and updates on available clinical trial sites, visit clinicaltrials.gov.

What do you hope the clinical community can learn from this study?

The RESPOND study seeks to understand if the proven efficacy of SPINRAZA and its continuous production of SMN protein may also benefit patients previously treated with gene therapy who have had a suboptimal clinical response.   

We expect that the RESPOND study will generate valuable data to help inform future treatment decisions for our youngest SMA patients and their families. 

Is there anything else you would like to add? 

There is still no cure for SMA, and unmet needs remain for many people living with the disease. At Biogen, we are committed to furthering research to expand the understanding of SMA and explore the potential of SPINRAZA to offer meaningful outcomes for patients.

About Dr Farwell

In his role as the Global Medical Head of Neuromuscular Diseases at Biogen, he helps lead the generation of clinical evidence about the efficacy of SPINRAZA® (nusinersen) and has led clinical development efforts to develop and advance treatments for spinal muscular atrophy (SMA) and other neuromuscular diseases.

References: 

1. Zolgensma EU Summary of Product Characteristics (SmPC). Available at: https://www.ema.europa.eu/en/documents/product-information/zolgensma-epar-product-information_en.pdf. Accessed: December 2020.
2. Finkel R, et al. Presented at the Muscular Dystrophy Association (MDA) 2020 Clinical & Scientific Conference.
3. Harada Y, et al. Presented at the Muscular Dystrophy Association (MDA) 2020 Clinical & Scientific Conference.
4. Finkel R, et al. Presented at the World Muscle Society’s (WMS) 2020 Virtual Congress.
5. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009 Jan;27(1):59-65. doi: 10.1038/nbt.1515. Epub 2008 Dec 21. 
6. Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH, Kaspar BK. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010 Mar;28(3):271-4. doi: 10.1038/nbt.1610. Epub 2010 Feb 28.