SMA: Three Major Drugs Developed in Five Years

SMA: Three Major Drugs Developed in Five Years

On the human chromosome 5, there is a gene named SMN1, which plays a crucial role in synthesizing SMN protein. SMN protein is vital for the survival of motor neurons, and if insufficient, motor neurons will gradually degenerate and die, leading to muscle weakness and atrophy in the body.

This muscle-wasting disease caused by the deletion of the SMN1 gene is clinically known as Spinal Muscular Atrophy (SMA), a rare autosomal recessive genetic disease that only manifests when both parents carry the defective gene.

Despite being labeled "rare," SMA has a significant impact. According to large-scale population screening data in China, the carrier rate of SMA is about 1 in 56, meaning 1 in every 9,788 babies is affected. It is extremely likely to cause infant mortality and is referred to as the "leading genetic killer of infants and toddlers."

Since its discovery in the 1990s, SMA has caused severe impacts. However, due to the lack of a clear molecular target, there were no disease-modifying drugs for SMA. In December 2016, Nusinersen sodium injection (brand name: Spinraza) was approved for marketing in the U.S., becoming the world's first disease-modifying drug for SMA, offering hope for overcoming SMA.

Centuries of Exploration

The earliest record of SMA dates back to 1891, when Austrian neurologist Guido Werdnig discovered noticeable limb weakness in a pair of 10-month-old brothers and named this "weak and powerless strange disease" SMA.

In the following years, German neurologist John Hoffman discovered seven similar patients who exhibited muscle weakness symptoms several months after birth, with a familial pattern. Hoffman also found degeneration of motor neurons in the anterior horn of the spinal cord in these patients, the fundamental cause of skeletal muscle dysfunction. Thus, the pathological features of SMA were identified.

As research on SMA deepened, more types of SMA were discovered. In 1956, Kugelberg and Welander reported adult-onset SMA with slow progression; in 1964, Professor Dubowitz found a type with a slow progression starting in infancy; in 1992, SMA was officially classified into Types I, II, and III, later expanding to include Type 0 (fetal onset) and Type IV (adult-onset).

While scientists could analyze SMA symptoms in detail, the true cause of SMA remained elusive, and treatments remained focused on symptomatic relief. The discovery of the SMN1 gene in 1995 was a breakthrough, marking the second milestone in the fight against SMA. It was then understood that SMA results from mutations or deletions in the SMN1 gene, leading to a cascade of symptoms like muscle weakness.

Based on this discovery, scientists began exploring therapies targeting the SMA-causing gene and the motor neuron survival protein. In the following five years, animal models of SMA, such as mice, zebrafish, and fruit flies, were developed, closely mimicking SMA symptoms and laying the foundation for drug development.

Eventually, the small nucleic acid drug Spinraza, developed by Biogen, was approved by the FDA in 2016. Not only did it break the long-standing lack of SMA-targeted drugs, but it also ushered in a new era for small nucleic acid drugs, becoming the best-selling small nucleic acid drug worldwide.

SMA Market Landscape

After Spinraza's launch, Roche's Evrysdi (risdiplam) and Novartis' Zolgensma (onasemnogene abeparvovec) were approved, forming a competitive three-way battle in the market.

As more new drugs are approved, the SMA drug market has undergone dramatic changes. According to a report by Business Research Insights, the global SMA market was valued at approximately $1.53 billion in 2023, and it is expected to reach $3.86 billion by 2032, with a compound annual growth rate of 10.7% during the forecast period.

1. Spinraza

Spinraza is an SMN2 gene splice modifier, an antisense oligonucleotide (ASO) with 18 bases, used to treat SMA caused by mutations or deletions in the SMN1 gene (located on chromosome 5q), resulting in insufficient SMN protein production.

The mechanism of Spinraza is based on the fact that the SMN1 gene is not the only gene capable of producing SMN protein. The SMN2 gene, located near the centromere, can also produce SMN protein, although a C→T substitution at exon 7 results in a splice variant that produces incomplete SMN proteins, leading to degradation and loss of function.

As a splice modifier for the SMN2 gene, Spinraza binds to a reverse regulatory sequence on exon 7, suppresses splice factors, and allows the retention of exon 7 during splicing, resulting in the production of full-length SMN mRNA and proteins. The drug is administered intrathecally, delivering the medication directly into the cerebrospinal fluid surrounding the spinal cord.

In multiple clinical trials, Spinraza has demonstrated good safety and efficacy, with some patients achieving developmental milestones beyond their natural growth and significant improvement in motor function scores.

Spinraza was licensed for global development, production, and commercialization by Biogen from Ionis in July 2016. It was approved by the FDA in December 2016, followed by EMA and NMPA approvals in 2017 and 2020, respectively.

As the first precision-targeted SMA therapy, Spinraza was priced at $125,000 per vial upon release. In its first year, Spinraza's sales reached $884 million and peaked at $2.406 billion in 2021. Despite a decline in revenue in the first three quarters of 2024, Spinraza still contributed $1.152 billion in revenue.

2. Evrysdi

Evrysdi is an oral small-molecule drug that selectively binds to two splicing regulatory sites in the pre-mRNA of the SMN2 gene, enhancing the recognition of U1 snRNP and modifying splicing, increasing full-length SMN mRNA and protein levels.

The drug is in liquid form and administered orally once daily, making it the first at-home SMA therapy. Approved by the FDA in August 2020, Evrysdi was also approved by the EMA and NMPA in March and June of 2021, respectively, and is marketed under the brand name "艾满欣" in China.

Unlike Spinraza, which requires intrathecal injection, Evrysdi’s oral administration improves patient compliance. Additionally, Evrysdi can cross the blood-brain barrier, widely distributing throughout the body, including the central nervous system and peripheral tissues.

In the U.S., the price of Evrysdi is $11,700 per 60 mg vial, with an annual treatment cost between $140,000 and $340,000, making it the least expensive SMA medication. In its first full year post-launch, Evrysdi’s global sales exceeded $650 million. In 2023, global sales reached $1.646 billion, a 34.6% year-over-year increase, with $950 million in sales during the first half of 2024, a 25% increase from the previous year.

3. Zolgensma

Zolgensma is a gene replacement therapy for the SMN1 gene. Using an adeno-associated virus serotype 9 vector, it delivers one or more copies of the SMN1 gene to the motor neurons' cell nuclei, allowing the foreign gene to express the target protein continuously inside the host cells, thereby treating the disease. Its main advantage is that a single intravenous infusion provides lifelong clinical benefits without integrating into the host genome, ensuring high safety.

The results of the Phase III STR1VE trial showed that 91% of infants with Type 1 SMA survived without the need for respiratory assistance, and 64% were able to sit independently for at least 30 seconds, demonstrating the strong therapeutic effect.

Zolgensma was approved by the FDA in May 2019 and has since been approved in more than 51 countries worldwide. Clinical trials began in China in 2022, but it has not yet been approved. The drug is priced at an astonishing $2.125 million per infusion, making it the most expensive drug globally.

After its launch in 2019, Zolgensma’s sales reached $361 million in just seven months, and in 2022, it generated $1.37 billion in sales. In 2023, sales dropped to $1.214 billion, with sales of $644 million in the first half of 2024, a 6% year-over-year increase.

In summary, the three currently approved SMA drugs each have their own advantages and have become blockbuster drugs with annual revenues exceeding $1 billion. Biogen's Spinraza, as the first precision-targeted drug, opened a new era in SMA treatment, with the largest number of treated cases. Novartis’ Zolgensma offers lifelong clinical benefits through a single infusion, providing long-term treatment possibilities for patients. Roche's Evrysdi, with its oral administration convenience, higher drug accessibility, and relatively lower price, is expected to gain momentum and become one of the mainstream SMA treatments in the near future.

However, these drugs also have certain limitations. For example, Spinraza cannot cross the blood-brain barrier and must be administered via intrathecal injection, causing additional discomfort to patients. The efficacy of Evrysdi is influenced by the patient’s age and SMA type. Zolgensma’s high cost and potential immune responses limit its widespread use. Therefore, developing more affordable and effective new drugs or exploring scientifically sound combination therapies remains the main focus of major pharmaceutical companies.