Deconstructing SMA Types and Treatments

Over the past decade, medical and scientific advances have increased overall health and life expectancy in people with spinal muscular atrophy (SMA). SMA causes progressive muscle weakness in affected individuals and without treatment, can lead to premature death before the age of two in severe cases. A disease-modifying therapy for SMA (Spinraza) was approved in 2016 and two more therapies (Zolgensma and Evrysdi) have been approved since then. These therapies have been shown to slow, stop, or reverse SMA symptoms, but they do not cure the disease. New therapies are still needed to help address disease symptoms for many people with SMA.

What Causes SMA?

In most cases, SMA is caused by loss of or mutation in the survival motor neuron 1 (SMN1) gene, which leads to reduced production of SMN protein. This protein is required to maintain healthy, functional motor neurons (muscle-controlling nerve cells). Without SMN protein, motor neurons degenerate and stop working. They are no longer able to send signals to muscles, causing the muscles to weaken and become smaller because of inactivity.

In some people with SMA, a gene located next to SMN1, known as SMN2, can partially compensate for the SMN1 defect by making some SMN protein. Only a small percentage of the SMN protein produced from the SMN2 gene is full-length and functional, however. As a result, affected people with more copies of the SMN2 gene are able to produce more functional SMN protein, and typically experience a milder SMA disease course.

Addressing the Different Types of SMA

SMA has traditionally been classified into types (1-4) based on the age at which symptoms begin and the level of physical function achieved by the person with the disease. With the availability of new therapies and earlier diagnosis, however, the typical progression of SMA is changing and SMA is beginning to be seen more as a disease continuum.

Consensus-based care recommendations were developed in 2007 by healthcare and patient experts in SMA to guide physicians in evidence-based treatment of people living with the different types of SMA. These guidelines were published as the “International Standards of Care for SMA,” and were later updated in November 2017 (Part 1 and Part 2). These guidelines classify people with SMA into three functional groups to help streamline disease and symptom management:

Non-sitters (historical SMA type 1): In this group, the onset of weakness occurs at less than 6 months of age. This is the most common form of SMA, representing about 50% of all cases. Non-sitters are unable to sit or roll. They have the most severe loss of muscle tone (hypotonia), and usually experience death or the need for permanent breathing assistance within 2 years.

Sitters (historical SMA type 2): In this group, the onset of weakness occurs between 6 to 18 months of age. Sitters are able to sit up, but not stand or walk independently. They have weakness in the muscles closest to the center of the body (proximal), but often survive into adulthood.

Walkers (historical SMA types 3 and 4): In this group, the onset of weakness occurs after 18 months of age. Walkers usually retain the ability to walk, but demonstrate a range of mild to moderate motor impairments. Affected children in this group are most likely to have a normal life span.

Though there is currently no cure for SMA, multidisciplinary care of affected individuals can help manage symptoms and improve quality of life. Treatment is based on each person’s symptoms and may include, but is not limited to, pulmonary, nutritional and orthopedic care, in combination with administration of disease-modifying treatments.

Status of Approved Therapies

There are currently three disease-modifying therapies approved by the US Food and Drug Administration (FDA) for treatment of SMA. These therapies use different strategies to address the deficiency of the SMN protein that causes SMA.

In December 2016, the FDA approved nusinersen (brand name Spinraza) for the treatment of all types (1-4) of SMA in children and adults. Spinraza works by increasing the amount of full-length SMN protein that is available in the body. Across all clinical trials of Spinraza, treated participants showed clinically significant improvements in achieving motor milestones and overall stabilization of motor function. The final report from the open-label phase 2 study of Spinraza treatment in participants with SMA demonstrated improvements in motor function for up to 3 years.

In May 2019, the FDA approved onasemnogene abeparvovec-xioi (brand name Zolgensma) for treatment of children under 2 years of age with an SMA diagnosis (types 1-4) confirmed by genetic testing. Zolgensma is a gene therapy, given by a one-time injection, that enables long-term production of full-length SMN protein within motor neurons. After FDA approval, two follow-up studies of Zolgensma treatment, LT-001 (NCT03421977) and LT-002 (NCT04042025), have shown long-term durability and efficacy of the gene therapy. Data from LT-001 demonstrated efficacy up to 7.5 years after treatment of children with SMA symptoms. All treated children maintained their previously achieved motor milestones without further deterioration and three treated children even achieved a new milestone, specifically standing with assistance. In an interim analysis of the 15-year LT-002 study, pre-symptomatic and symptomatic children treated with Zolgensma also demonstrated maintenance of motor milestones.

In August 2020, the FDA approved risdiplam (brand name Evrysdi) for the treatment of SMA in infants, children, and adults two months of age or older. Evrysdi is designed to enhance overall production of SMN protein from the SMN2 gene, thereby increasing the amount of functional SMN protein available in the body. Treatment with Evrysdi was approved based on demonstrated improvements in motor function and ventilator-free survival in infants with SMA type 1 and in motor function in children with later-onset SMA after 12 months of treatment. A long-term follow-up study (up to five years) of participants treated with Evrysdi is currently underway.

Investigational therapies

While availability of Spinraza, Zolgensma, and Evrysdi has significantly improved the lives of many people with SMA, these therapies do not cure the disease. They cannot reverse the muscle damage that occurred before treatment was given, so for many people with SMA, there remains a significant disease burden.

One strategy that is currently being tested to improve the outcomes of people receiving therapy is the combination of the SMN-modifying therapies with a myostatin inhibitor. Myostatin is a protein that normally inhibits muscle growth. Blocking this protein in animal models has been shown to increase muscle mass and function. Anti-myostatin therapies being explored to help preserve or restore muscle tissue in SMA include:

RO7204239 (Hoffmann-La Roche) – RO7204239 is an investigational anti-myostatin antibody that is designed to target myostatin. It is being studied in a phase 2/3 clinical trial (MANATEE) in combination with risdiplam.

Apitegromab (Scholar Rock, Inc.) – Apitegromab is a human monoclonal antibody that binds to and blocks the activity of various forms of myostatin. It is being studied in a phase 3 clinical trial (SAPPHIRE) in people with type 2 or type 3 SMA who are already being treated with Spinraza or Evrysdi.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about spinal muscular atrophy (SMA), open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.