Spinal Muscular Atrophy Research

Understanding of spinal muscular atrophy (SMA) has come a long way, especially in the past few decades. Researchers in the 1990s found that changes to the SMN1 gene leads to motor neuron loss and muscle weakness in people with SMA. We know a lot about the genetics and causes of SMA. We also have drugs that can treat SMA by making up for the loss of working SMN1 genes.^1,2

However, there is a lot left to understand about SMA. Researchers are testing currently approved treatments in different situations. They are testing new drugs that work in different ways to treat SMA. And research continues to uncover details about SMA that may lead to new treatments.¹

What research is being done on approved treatments?

As of July 2024, 3 drugs are approved by the U.S. Food and Drug Administration (FDA) to treat people with SMA:^1,2

• SpinrazaⓇ (nusinersen)
• ZolgensmaⓇ (onasemnogene abeparvovec-xioi)
• Evrysdi™ (risdiplam)

Spinraza

Clinical trials with Spinraza are testing:^3-7

• 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. All infants treated with Spinraza before showing symptoms were alive at 3 years old. Nearly 90 percent could walk independently.³

Early results from the Respond trial also show promising results. Nearly all participants showed lower levels of neurofilament in the blood. This suggests that the treatment reduces neuron loss. Most participants also showed improved motor function.^8,9

Zolgensma

Ongoing or completed clinical trials with Zolgensma have tested:^10-14

• Treatment in symptomatic infants with type 1 SMA (Str1ve trial)
• Treatment in pre-symptomatic infants with a genetic SMA diagnosis (Spr1nt trial)
• Long-term safety and efficacy (Start Long-Term Follow-Up trial)
• Intrathecal (into the spine) administration in type 2 SMA (Steer trial)

The Str1ve and Spr1nt trials have shown that Zolgensma increases chances of survival and unsupported sitting. These results show the importance of newborn screening programs. The Start trial has shown long-term safety and efficacy more than 7 years after treatment.^12,13,15-17

Evrysdi

Ongoing or completed clinical trials with Evrysdi have tested:^10,18

• Treatment in people who received other SMA treatments (Jewelfish trial)
• Treatment in pre-symptomatic infants (Rainbowfish trial)
• Treatment in infants with type 1 SMA (Firefish trial)

Early results from the Rainbowfish and Firefish trials show that most infants achieve sitting without support. The Jewelfish trial results are also showing improved or maintained motor function.^18-20

What new drugs are in clinical trials?

As of July 2024, several new drugs are in clinical trials. They work in new ways to treat SMA.

Apitegromab (SRK-015)

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.^10,21

A phase 2 clinical trial (Topaz) tested apitegromab in people with type 2 and 3 SMA. Results have shown improved motor function when the drug is taken alone or in combination with Spinraza. Phase 3 clinical trials are now testing:^22-24

• Treatment of people with type 2 or type 3 SMA, in combination with Spinraza or Evrysdi (Sapphire trial)
• Long-term safety and efficacy in people who have completed Topaz or Sapphire (Onyx trial)

Taldefgrobep alfa

Taldefgrobep alfa is another protein designed to block myostatin. A phase 3 trial (Resilient) is testing it in people with SMA who have been given other treatments.²⁵

GYM329

GYM329 is another protein designed to block myostatin. It may increase muscle size and growth. A phase 2/3 clinical trial (Manatee) is testing GYM329 in combination with Evrysdi.²⁶

NMD670

NMD670 is a chemical that blocks a protein called ClC-1. This protein prevents muscles from becoming overstimulated. Blocking ClC-1 can increase how easily muscles can contract. A phase 2 clinical trial (Synapse) is testing NMD670 in people with type 3 SMA.²⁷

What other SMA research is happening?

New research is exploring why the SMN protein is important for motor neurons. The SMN protein helps put together 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.^1,2

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. It helps process genes so they can be used to make proteins.¹

Researchers are starting to identify the effects of a lack of SMN. They are trying to understand how those effects can lead to SMA. This may help find new ways for treatments to improve motor function.^1,2

Other research is exploring potential drugs in preclinical or discovery phases. Some of these drugs work by increasing SMN production, like current treatments. Others work in new ways that do not involve the SMN protein.^1,2