The Shift in SMA Treatment
For over a century, SMA, a progressive genetic disease that causes muscle weakness and wasting, was primarily managed through supportive care, focusing on respiratory support and physical therapy. However, the discovery of the underlying genetic cause—mutations in the survival motor neuron 1 (SMN1) gene—paved the way for a new era of disease-modifying therapies. This led to the development of groundbreaking treatments that address the core problem by increasing the amount of functional SMN protein, which is critical for motor neuron health. Since the first FDA approval in 2016, the prognosis for SMA patients has dramatically improved, especially with early intervention.
FDA-Approved Medications for SMA
Nusinersen (Spinraza)
Nusinersen, sold under the brand name Spinraza, was the first drug approved for SMA and has been cleared for use in all ages. It is an antisense oligonucleotide (ASO) therapy that targets the SMN2 gene, often referred to as the "backup" gene for SMN1. A single nucleotide difference typically causes the SMN2 gene to produce a shortened, less functional SMN protein. Nusinersen modifies the splicing of the SMN2 gene to promote the production of more full-length, functional SMN protein, which helps improve motor neuron health.
- Administration: Nusinersen is administered via an intrathecal (IT) injection, which delivers the medication directly into the fluid surrounding the spinal cord.
- Dosing Schedule: Treatment begins with four "loading doses" over the first two months, followed by maintenance doses every four months for life.
- Considerations: Because it is delivered to the spinal fluid, the medication may be less accessible for individuals with severe scoliosis or spinal fusion.
Onasemnogene abeparvovec (Zolgensma)
Onasemnogene abeparvovec (Zolgensma) is a one-time gene replacement therapy approved for pediatric patients with SMA under two years of age. This treatment addresses the genetic root cause by replacing the missing or nonworking SMN1 gene.
- Mechanism: Zolgensma uses a modified, harmless virus called adeno-associated virus serotype 9 (AAV9) as a vector to deliver a new, working copy of the SMN1 gene to the body's motor neuron cells. This enables the cells to produce sufficient SMN protein.
- Administration: The treatment is delivered through a single intravenous (IV) infusion that takes about an hour.
- Monitoring: Patients require close monitoring for at least three months, including lab tests for liver function and platelet counts. Prophylactic corticosteroid treatment is given to help prevent liver inflammation, a serious potential side effect.
Risdiplam (Evrysdi)
Risdiplam (Evrysdi) is the first oral medication approved for SMA patients, aged two months and older. Like nusinersen, it is an SMN2 splicing modifier, but its oral administration offers systemic distribution.
- Mechanism: As a small molecule, risdiplam binds to the SMN2 messenger RNA (mRNA), increasing the production of full-length, functional SMN protein throughout the body. This systemic effect may also benefit non-motor symptoms associated with the disease.
- Administration: Risdiplam is taken daily by mouth as a liquid.
- Side Effects: Common side effects include fever, diarrhea, and rash. Liver toxicity is not a concern with risdiplam.
Key Differences in SMA Therapies
| Feature | Nusinersen (Spinraza) | Onasemnogene abeparvovec (Zolgensma) | Risdiplam (Evrysdi) |
|---|---|---|---|
| Mechanism | SMN2 splicing modifier (ASO) | SMN1 gene replacement (AAV9 vector) | SMN2 splicing modifier (Small molecule) |
| Administration | Intrathecal (spinal) injection | Single intravenous (IV) infusion | Oral liquid (daily) |
| Frequency | 4 loading doses, then every 4 months for life | Single, one-time treatment | Once daily, for life |
| Age/SMA Type | All ages and types | Under 2 years of age | 2 months and older, all types |
| Coverage | Primarily CNS | Systemic (replaces gene in motor neuron cells body-wide) | Systemic (increases SMN protein body-wide) |
| Side Effects | Headaches, back pain, respiratory infections, kidney issues, bleeding risk. | Elevated liver enzymes, vomiting, risk of liver injury, thrombocytopenia. | Fever, diarrhea, rash, mouth ulcers, joint pain, UTIs. |
The Importance of Early Intervention
Multiple clinical studies and real-world observations demonstrate that the earlier SMA treatment is initiated, the better the outcomes. Newborn screening programs for SMA have become increasingly crucial for early diagnosis, allowing for pre-symptomatic treatment before motor neuron loss occurs. Infants treated pre-symptomatically have shown remarkable motor development, with some achieving near-normal milestones like independent sitting and walking. This highlights the importance of timely diagnosis and treatment, which can significantly alter the disease's course.
The Future of SMA Treatment
The progress made in SMA therapy in recent years is a testament to dedicated research and development. The therapeutic landscape continues to evolve, with multiple new therapies and novel formulations on the horizon. Researchers are exploring additional approaches that could complement existing therapies, such as:
- Higher-Dose Spinraza: Biogen is investigating a higher-dose regimen of Spinraza for potentially enhanced clinical benefits.
- Muscle-Targeting Therapies: Medications like Scholar Rock's apitegromab directly target muscles, which could be beneficial for patients with pre-existing muscular weakness. These treatments inhibit myostatin, a protein that limits muscle growth.
- Alternative Delivery: Novartis is working on an intrathecal version of Zolgensma (OAV101 IT) for older children and adolescents, potentially expanding eligibility for gene therapy.
These ongoing efforts hold promise for further improving the quality of life and long-term outcomes for individuals living with SMA. For more information, visit Cure SMA.
Conclusion
In just a few years, medications for SMA have transformed a devastating diagnosis into a treatable condition. By addressing the fundamental genetic flaw, Nusinersen, Risdiplam, and Onasemnogene abeparvovec have enabled patients to gain motor function, improve survival, and enjoy a higher quality of life. The choice of therapy depends on factors such as age, disease type, and individual circumstances, and should be discussed with a healthcare team. As research continues to advance, the future of SMA treatment appears brighter than ever, with novel therapies promising even more effective solutions for patients. The rapid development and approval of these treatments underscore the vital importance of continued scientific investigation in rare diseases.
