Introduction

Spinal muscular atrophy (SMA) is a rare genetic disorder that affects approximately one in 6,000 to 10,000 live births globally, causing progressive muscle weakness and atrophy. SMA is caused by mutations in the SMN1 gene, responsible for producing the survival motor neuron (SMN) protein, which is crucial for the function of motor neurons that control muscle movement. Without sufficient levels of this protein, motor neurons degenerate, leading to muscle wasting and weakness. In severe cases, SMA can result in early death.

For many years, treatment options for SMA were limited to supportive care, such as physical therapy, respiratory support, and nutritional assistance. However, in recent years, groundbreaking advancements in gene therapies and small molecule drugs have revolutionized the management of SMA. One of the most prominent drugs developed for SMA treatment is Risdiplam, marketed under the brand name Evrysdi. Approved by the U.S. Food and Drug Administration (FDA) in August 2020, Risdiplam represents a significant milestone in SMA therapy, offering an oral treatment option that can be administered at home.

Risdiplam (Evrysdi) is an innovative treatment for spinal muscular atrophy (SMA), a genetic disorder caused by mutations in the SMN1 gene, which leads to motor neuron degeneration and progressive muscle weakness. As an oral SMA medication, Risdiplam works by modifying SMN2 splicing to increase the production of the SMN protein. This revolutionary drug, approved by the FDA, offers an alternative to gene therapy for SMA. In clinical trials like FIREFISH, it demonstrated significant improvements in patients’ motor functions. Compared to Spinraza and the expensive Zolgensma, Risdiplam provides a more convenient and accessible treatment option for individuals suffering from neuromuscular disorders.

This article delves into the development, mechanism of action, clinical efficacy, and real-world impact of Risdiplam (Evrysdi), highlighting its significance as a high-profile drug in the treatment of SMA.

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Overview of Spinal Muscular Atrophy (SMA)

SMA is an autosomal recessive neuromuscular disorder characterized by the loss of motor neurons in the spinal cord, leading to progressive muscle weakness and atrophy. There are several types of SMA, classified based on the age of onset and severity of symptoms:

1. Type 0 (Prenatal SMA): This is the most severe form, and affected infants show symptoms in utero. Unfortunately, it is usually fatal shortly after birth.

2. Type 1 (Werdnig-Hoffmann Disease): The most common and severe form of SMA in infants. Symptoms typically present within the first six months of life, and without intervention, children with Type 1 SMA have a life expectancy of less than two years.

3. Type 2 (Intermediate SMA): This type presents between 6 and 18 months of age. Children can sit but cannot stand or walk independently. Life expectancy is variable, depending on the severity of respiratory involvement.

4. Type 3 (Kugelberg-Welander Disease): This is a milder form of SMA that presents after 18 months of age. Individuals with Type 3 SMA can stand and walk, though they may lose these abilities over time.

5. Type 4 (Adult-Onset SMA): This is the mildest form of SMA, with symptoms typically appearing in adulthood. It generally leads to mild muscle weakness.

The underlying cause of SMA is a deficiency of the SMN protein, which is essential for the survival of motor neurons. In most cases of SMA, the SMN1 gene, responsible for producing this protein, is either deleted or mutated. However, humans have a backup gene called SMN2, which produces small amounts of SMN protein. Risdiplam works by modifying the splicing of SMN2 mRNA to increase the production of functional SMN protein, thereby alleviating the symptoms of SMA.

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Development of Risdiplam (Evrysdi)

Risdiplam was developed by Roche and its subsidiary Genentech in collaboration with PTC Therapeutics and the SMA Foundation. The goal of Risdiplam’s development was to create an effective, safe, and convenient oral therapy for SMA that could be administered at home. Unlike other SMA treatments, which are delivered via injection or infusion, Risdiplam is a liquid medication taken once daily by mouth, making it particularly appealing for individuals who require long-term treatment.

Risdiplam was granted FDA approval in August 2020 for the treatment of SMA in adults and children two months of age and older. This approval was based on data from two pivotal clinical trials—FIREFISH and SUNFISH—which demonstrated Risdiplam’s ability to improve motor function and increase SMN protein levels in patients with SMA. Risdiplam has also received approval from regulatory authorities in several other countries, including the European Union, Japan, and Canada.

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Mechanism of Action

Risdiplam is a small molecule SMN2 splicing modifier. As mentioned earlier, the SMN1 gene is the primary source of functional SMN protein, but in individuals with SMA, SMN1 is mutated or deleted. However, humans possess a backup gene, SMN2, which can produce the SMN protein, albeit in insufficient quantities. The challenge with SMN2 is that it predominantly produces a truncated, non-functional version of the SMN protein due to alternative splicing that excludes exon 7.

Risdiplam acts by modifying the splicing of SMN2 pre-mRNA, promoting the inclusion of exon 7 and thereby increasing the production of full-length, functional SMN protein. This increased production of the SMN protein helps to maintain motor neurons, slow disease progression, and improve motor function in individuals with SMA.

One of the key advantages of Risdiplam is that it distributes evenly throughout the body, including the central nervous system (CNS) and peripheral tissues, which is essential for addressing the widespread effects of SMA on both motor neurons and muscles.

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Clinical Trials and Efficacy

The clinical development of Risdiplam was supported by several trials, with FIREFISH and SUNFISH being the most prominent.

FIREFISH Trial (Infantile-Onset SMA – Type 1)

FIREFISH was a two-part clinical study designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of Risdiplam in infants aged 1 to 7 months with Type 1 SMA, the most severe form of the disease.

• Part 1 was an exploratory, dose-escalation study aimed at determining the optimal dose of Risdiplam for infants with SMA.
• Part 2 was a pivotal study that evaluated the efficacy of the selected dose in 41 infants with Type 1 SMA.

The primary endpoint of FIREFISH Part 2 was the proportion of infants who were able to sit without support for at least five seconds after 12 months of treatment. The study found that 29% of infants achieved this milestone, a significant improvement considering that untreated infants with Type 1 SMA typically do not achieve motor milestones like sitting independently.

Additionally, 90% of the infants were alive and did not require permanent ventilation at 12 months, a remarkable outcome given the typically poor prognosis for infants with Type 1 SMA.

SUNFISH Trial (Type 2 and Type 3 SMA)

SUNFISH was a two-part clinical study focused on individuals aged 2 to 25 years with Type 2 or Type 3 SMA.

• Part 1 was an exploratory study designed to determine the appropriate dose of Risdiplam.
• Part 2 was a randomized, double-blind, placebo-controlled trial that evaluated the efficacy of Risdiplam in improving motor function in individuals with Type 2 and Type 3 SMA.

The primary endpoint of SUNFISH Part 2 was the change from baseline in the Motor Function Measure-32 (MFM-32) score at 12 months. The results showed that patients treated with Risdiplam had a significant improvement in motor function compared to those receiving placebo. Moreover, the safety profile of Risdiplam was favorable, with no significant adverse events reported.

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Safety and Side Effects

Risdiplam has been shown to have a generally favorable safety profile. In clinical trials, the most common side effects observed were mild and included fever, diarrhea, rash, and respiratory infections. Serious adverse events were rare, and the overall incidence of side effects was comparable to that of patients receiving placebo.

One of the key advantages of Risdiplam is its ability to be administered orally, making it a less invasive option than other treatments like gene therapy or intrathecal injections, which carry higher risks of complications. This also makes Risdiplam a more accessible option for individuals who prefer not to undergo repeated injections or infusions.

However, it is important to note that Risdiplam should be used with caution in pregnant women, as animal studies have shown potential risks to fetal development. For this reason, women of childbearing age taking Risdiplam are advised to use effective contraception during treatment.

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Risdiplam vs. Other SMA Treatments

Before the approval of Risdiplam, two other landmark treatments for SMA had been developed—Spinraza (nusinersen) and Zolgensma (onasemnogene abeparvovec). While all three treatments target the underlying cause of SMA, they differ in their mechanisms of action, administration, and cost.

• Spinraza: Spinraza was the first FDA-approved treatment for SMA. It is an antisense oligonucleotide that also targets the splicing of SMN2 mRNA to increase the production of SMN protein. However, Spinraza is delivered via an intrathecal injection directly into the cerebrospinal fluid, requiring a more invasive administration process. Despite its effectiveness, the need for ongoing lumbar punctures has been a drawback for some patients.

• Zolgensma: Zolgensma is a gene therapy that replaces the defective SMN1 gene with a functional copy. It is delivered as a one-time intravenous infusion, making it a potentially curative treatment. However, Zolgensma is currently approved only for infants under two years of age, limiting its use in older patients with SMA. Additionally, Zolgensma is one of the most expensive drugs in the world, with a price tag of over $2 million per treatment.

In contrast, Risdiplam offers a more convenient and accessible option, as it is taken orally at home. It is also approved for a broader age range of patients, from infants as young as two months to adults. While Risdiplam does not offer the one-time potential cure of Zolgensma, its daily dosing and non-invasive administration make it a practical choice for long-term management of SMA.

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Real-World Impact of Risdiplam

Since its approval, Risdiplam has had a profound impact on the lives of individuals with SMA and their families. The ability to take a daily oral medication at home has alleviated many of the logistical challenges associated with other SMA treatments, such as hospital visits for injections or infusions. Risdiplam has also expanded treatment options for patients who may not be eligible for gene therapy or who prefer not to undergo invasive procedures.

Moreover, Risdiplam has provided hope to individuals with later-onset SMA, who may have been overlooked by previous treatments primarily targeting infants and young children. The drug’s ability to improve motor function and slow disease progression in both children and adults has made it a valuable tool in the fight against SMA.

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Conclusion

Risdiplam (Evrysdi) represents a significant breakthrough in the treatment of spinal muscular atrophy, offering a convenient and effective oral therapy for a wide range of patients. By increasing the production of functional SMN protein through SMN2 splicing modification, Risdiplam helps to preserve motor neurons and improve motor function in individuals with SMA.

With its favorable safety profile, ease of administration, and broad applicability, Risdiplam has quickly become a high-profile drug in the SMA community. While it may not offer the one-time curative potential of gene therapy, Risdiplam’s daily oral dosing and ability to treat both children and adults make it a versatile and impactful treatment option for SMA patients.

As research continues and more data on long-term outcomes become available, Risdiplam is poised to play a central role in the management of SMA, offering hope and improved quality of life to individuals affected by this debilitating condition.

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