Our understanding of spinal muscular atrophy (SMA) has come a long way, especially in the past few decades. Researchers in the 1990s first identified the altered SMN1 gene that leads to motor neuron loss and muscle weakness in people with SMA. We now know a lot about the genetics and causes of SMA. We also have drugs that treat SMA by making up for the loss of functional SMN1 genes.
Even still, there is a lot left to understand about SMA. Currently approved treatments are being tested in different situations and people. New drugs in clinical trials work in different ways to treat SMA. Basic research also continues to uncover details about SMA that may lead to new treatments.
What research is being done on approved treatments?
As of early 2021, 3 drugs are approved by the U.S. Food and Drug Administration (FDA) to treat people with SMA:
Clinical research is continuing to understand the best way to use them in different situations. For example, clinical trials with Spinraza are testing:1-5
- Treatment in pre-symptomatic infants with type 1 or 2 SMA (Nurture trial)
- Long-term safety and efficacy (Shine and Onward trials)
- Whether higher dosing can safely provide more benefits (Devote trial)
- Outcomes in people previously treated with Zolgensma (Respond trial)
Early results from the Nurture trial show that starting treatment earlier improves health outcomes. At 3 years old, all infants treated with Spinraza before showing symptoms were alive. Nearly 90 percent could walk independently.1
Ongoing clinical trials with Zolgensma are testing:6-8
- Treatment in symptomatic infants with type 1 SMA (Str1ve trial)
- Treatment in pre-symptomatic infants (Spr1nt trial)
- Long-term safety and efficacy (Start Long-Term Follow-Up trial)
- Intrathecal (into the spine) administration in type 2 SMA (Strong trial)
Early results from the Str1ve trial show that Zolgensma increases chances of survival and unsupported sitting.9
Ongoing clinical trials with Evrysdi are testing:7
- Treatment in people who received other SMA treatments (Jewelfish trial)
- Treatment in pre-symptomatic infants (Rainbowfish trial)
What new drugs are in clinical trials?
As of early 2021, a few new drugs are in clinical trials. Some of them work by increasing the amount of “survival of motor neuron” (SMN) protein. Others work in new ways to treat SMA.10,11
Reldesemtiv may improve muscle function in people with SMA. It works by activating a protein called troponin. Troponin is important for muscles to contract after receiving signals from motor neurons. Reldesemtiv helps skeletal muscles contract, even without signals from motor neurons.7,12
A phase 2 clinical trial showed that Reldesemtiv improves lung and motor function in SMA types 2, 3, and 4.13
Branaplam works by increasing the ability of cells to use the SMN2 gene to make the SMN protein. A phase 1/2 clinical trial is testing Branaplam in children with type 1 SMA.12,14
Apitegromab may improve muscle strength and motor function in people with SMA. It is a protein designed in the lab to block myostatin. Myostatin is a protein that limits muscle growth. Blocking myostatin in people with SMA may help increase muscle mass.7,12
A phase 2 clinical trial (Topaz) is testing safety and efficacy in type 2 and 3 SMA.15
What other SMA research is happening?
New research is exploring why the SMN protein is so important for motor neurons. We know that the SMN protein helps assemble the cellular machinery that processes our genes. Without SMN, certain genes cannot be processed. This prevents our cells from using those genes to make important proteins.16,17
Think of our genes as recipes in a large cookbook for our cells. But the instructions in each recipe are jumbled and need to be put in order. The SMN protein is part of a system that acts like scissors and glue to make each recipe readable by cells. It helps process genes so they can be used to make proteins. Without it, certain proteins cannot be prepared. We do not yet know which proteins are impacted by a lack of SMN and how they lead to SMA.16,17
New research is also identifying proteins affected by a loss of SMN. For example, a lack of SMN causes low levels of a protein called “Stasimon.” A lack of Stasimon triggers a complex pathway that leads to motor neuron death. Drugs that act on this pathway prevent motor neuron death in animal models of SMA.18,19
Other research is exploring potential drugs in the preclinical “discovery” phase. This includes E1v1.11, which works like Spinraza to increase SMN protein production. It increases motor function in mouse models of SMA.20,21
Researchers are also studying other ways to treat SMA that do not involve SMN. Other cellular processes are abnormal in motor neurons of people with SMA. Drugs that interfere with these processes improve motor function in animal models of SMA.7