People with spinal muscular atrophy (SMA) have mutated SMN1 genes. This leads to low levels of the “survival of motor neuron” (SMN) protein. Without the SMN protein, motor neurons eventually die. Muscles that depend on signals from motor neurons go unused, causing them to weaken and waste away.1,2
Researchers are exploring different approaches to treat SMA. The most common way is to increase production of the SMN protein. This is how the drugs for SMA that have been approved by the U.S. Food and Drug Administration (FDA) work. However, other approaches may be effective and are being tested in clinical trials with emerging drugs.1,2
What treatment approaches are possible for SMA?
The most direct way to treat SMA is to increase the amount of the SMN protein. This helps make up for the inability of the SMN1 gene to be used to make the SMN protein. These methods are called “SMN-based” approaches.1,2
As of early 2021, the 3 FDA-approved treatments are SMN-based. Some SMN-based approaches include:1,2
- Replacing or correcting the faulty SMN1 gene – ZolgensmaⓇ (onasemnogene abeparvovec-xioi)
- Improving how the SMN2 “back-up” gene can be used to make SMN protein – Evrysdi™ (risdiplam) and SpinrazaⓇ (nusinersen)
- Preventing the SMN protein from getting broken down.
Other ways to treat SMA do not involve SMN. The loss of SMN protein impacts other processes. Treatments that target these processes are called “non-SMN” approaches. Some of these approaches include:1-3
- Protecting muscle or improving muscle mass
- Improving neuron survival (neuroprotection)
- Increasing communication between motor neurons and muscles
- Newer approaches targeting other processes
Non-SMN approaches do not address the genetic cause of SMA. However, they may slow or stop the progression of SMA. A combination of SMN-based and non-SMN approaches may be even more effective. This could mean taking 2 drugs together or at different stages of SMA. Current research is exploring these approaches.3
What emerging drugs are in clinical trials for SMA?
Dozens of drugs to treat SMA have been tested in pre-clinical and clinical studies. Many have not performed well in clinical trials. However, some have shown benefits for people with SMA in clinical trials. These drugs are in later stages of clinical trials, and include:
Reldesemtiv may improve muscle function and motor abilities in SMA. It works by increasing the ability of muscles to contract with less signaling from motor neurons.1
Muscle cells contract when signals from motor neurons cause calcium levels to increase. Some of this calcium attaches to a protein called troponin. This causes troponin to change how it interacts with other muscle proteins, leading to muscle contraction. Reldesemtiv increases the attraction between calcium and troponin. This makes muscle cells more sensitive to calcium and allows them to contract with less motor neuron signaling.1
A phase 2 trial tested Reldesemtiv in people with SMA types 2, 3, and 4. It is administered twice a day by mouth. The group taking a higher dose showed more improvement in motor function and lung function tests. The next steps of development are being discussed.4,5
Branaplam works the same way as Evrysdi. It is also taken by mouth. It increases the ability of cells to use the SMN2 “back-up” gene to make the SMN protein. In animal models of SMA, Branaplam increases the amount of SMN protein and improves body weight and survival.2,6
A phase 1/2 trial is testing Branaplam in infants with type 1 SMA. The trial was paused for 2 years because of unexpected side effects in animal studies. In 2017, the trial resumed after confirming the safety of Branaplam.7,8
Apitegromab may improve muscle strength and physical function in people with SMA. It is a protein designed to block myostatin. Myostatin is a protein that maintains a healthy muscle mass by limiting muscle growth. By blocking myostatin, Apitegromab increases muscle mass and function in animal models of SMA.1
A phase 2 trial (Topaz) is testing Apitegromab in people with type 2 and 3 SMA. It is given as an intravenous (into the vein) infusion once every 4 weeks. Early results show improvements in motor functioning in two-thirds of participants. People receiving a higher dose showed larger improvements in motor function.9,10