Revolutions in Spinal Muscular Atrophy Treatment

Spinal muscular atrophy (SMA) is a rare, debilitating genetic disease marked by the progressive loss of motor neurons in the spinal cord, causing muscle weakness that can impair basic vital functions (eg, walking, swallowing, and breathing).¹ Disease progression varies, but before disease-modifying treatments became available, most babies with severe symptoms died before age 2. Others with less severe symptoms lived into adulthood.²

An estimated 1 in 50 people are carriers for SMA,³ which is caused by an autosomal recessive variation in the survival of motor neuron 1 (SMN1) gene. SMA can be passed on to children if this variation in SMN1 is inherited from both parents.⁴ Approximately 10,000 to 25,000 people in the US are living with SMA.⁵

SMA has historically been sorted into different types based on severity of symptoms and age of onset.⁶ Type 0 is the most severe form of the disease, with symptoms appearing prenatally, and Type 4 is the least severe, with symptoms appearing in adulthood.

Before the advent of disease-modifying treatments to slow the progression of SMA, physicians could only offer symptom management, such as physical therapy and palliative care, while motor neurons continued to be lost and muscles continued to weaken.⁴

Treating SMA Today

In 2020, Evrysdi® (risdiplam) was approved by the US Food and Drug Administration (FDA) for the treatment of SMA in patients 2 months of age and older as the first oral, at-home treatment option (see important safety information on Evrysdi below).⁷ In May 2022, Evrysdi was approved for children and adults of all ages.⁸

However, there are still adults with SMA who have not received medical care for their disease. They may have left their neurologist prior to the approval of disease-modifying treatments, or never sought neurologic care in the first place, thinking that the medical field had little to offer for SMA.

Now, it’s critical to engage, or in some cases re-engage, with patients to help them explore their treatment options. It’s important to invite them back in and explain that there are ways to treat SMA.

Dr. Ramos notes, “When discussing treatment options with patients and their families, I find it’s helpful to explain in simple terms how current treatments can address the cause of SMA. It’s also critical to be up front about the benefits and risks of each treatment option and give space for questions. One question that has come up recently with adult patients is whether heavier people are getting a strong enough dose with Evrysdi. I reassure these patients that the Evrysdi clinical trials included a wide range of weights, up to about 250 pounds, with no indication that the FDA-approved adult dose was less effective in larger people.”

Two Genes and a Fortunate Natural Experiment

In 1995, researchers discovered that variations in the SMN1 gene on chromosome 5, when inherited from both parents, cause SMA.⁹ The SMN protein, produced by SMN1, protects spinal motor neurons against cell death via a mechanism that is not yet fully understood.¹⁰ Variations or deletions in SMN1 result in inadequate production of SMN, leading to death of α-motor neurons in the spinal cord.

A related gene, SMN2, provides something of a “backup system,” although it is far from perfect. SMN1 and SMN2 are almost identical, differing in only a single nucleotide.¹¹ That small difference, however, has a large effect by excluding exon 7 from 85% to 90% of the messenger RNA (mRNA) transcripts of SMN2. Because exon 7 is necessary to produce functional, full-length SMN, the result is that SMN2 produces only 10% to 15% as much SMN.⁴ These low levels of SMN produced by SMN2 are not enough to fully compensate for disease-causing variations and deletions in SMN1.

What SMN2 does provide is a therapeutic target and an explanation for why changing a single nucleotide can result in such a broad spectrum of disease. The number of SMN2 copies naturally varies from person to person. People with SMA who have relatively more copies of SMN2 usually have milder disease. For instance, people with SMA Type 1 tend to have 2 or fewer copies of SMN2, whereas those with SMA Type 4 tend to have 4 or more copies.¹²

Harnessing Genetics to Replace Missing Protein

Gene therapy for SMA can directly replace SMN1, and 1 such product is approved for use in children under 2 years of age.¹³

Therapies targeting SMN2 are designed to modify mRNA splicing such that exon 7 is included in mRNA transcripts more frequently, which should increase production of full length SMN protein.¹⁴ One SMN2-targeting therapy, which is approved for use among SMA patients of all ages, employs antisense oligonucleotides, injected into the cerebrospinal fluid.⁴

Small molecules targeting SMN2 have also been developed, such as Evrysdi, which is the only oral, at-home SMA medication approved by the FDA.¹⁵ Evrysdi is  approved for SMA patients of all ages.

“SMA treatment has undergone nothing short of a revolution in recent years,” said Dr. Ramos. “In less than 30 years, we’ve gone from discovering the smoking gun gene to administering drugs that offer real hope to people with SMA.”

Now, neurologists can focus their efforts on ensuring greater access to disease-modifying therapies, with a particular emphasis on older people with SMA who may have given up on treatment when there was none to offer. Today, the SMA treatment landscape is entirely different than decades past. With these new options available, it’s time to start managing disease progression.

Important Safety Information & Indication

Indication

Evrysdi is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.

Important Safety Information

Interactions with Substrates of MATE Transporters

• Based on in vitro data, Evrysdi may increase plasma concentrations of drugs eliminated via MATE1 or MATE2-K, such as metformin.
• Avoid coadministration of Evrysdi with MATE (multidrug and toxin extrusion) substrates. If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction of the coadministered drug if needed.

Pregnancy & Breastfeeding

• Evrysdi may cause embryofetal harm when administered to a pregnant woman. In animal studies, administration of Evrysdi during pregnancy and/or lactation resulted in adverse effects on development. Advise pregnant women of the potential risk to the fetus
• Pregnancy testing is recommended prior to initiating Evrysdi. Advise female patients to use contraception during treatment with Evrysdi and for at least 1 month after the last dose
• The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Evrysdi and any potential adverse effects on the breastfed infant

Potential Effects on Male Fertility

• Counsel male patients that fertility may be compromised by treatment with Evrysdi. Male patients may consider sperm preservation prior to treatment

Most Common Adverse Reactions

• The most common adverse reactions in later-onset SMA (incidence in at least 10% of patients treated with Evrysdi and more frequent than control) were fever, diarrhea, and rash.
• The most common adverse reactions in infantile-onset SMA were similar to those observed in later-onset SMA patients. Additionally, adverse reactions with an incidence of at least 10% were upper respiratory tract infection (including nasopharyngitis, rhinitis), lower respiratory tract infection (including pneumonia, bronchitis), constipation, vomiting, and cough
• The safety profile for presymptomatic patients is consistent with the safety profile for symptomatic SMA patients treated with Evrysdi in clinical trials

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see full Prescribing Information for additional Important Safety Information.