THE PRIMER

To help bring awareness to Spinal Muscular Atrophy (SMA), the leading hereditary cause of infant death, August has been named National Spinal Muscular Atrophy (SMA) month. In this Primer, we’ll explain SMA and the different therapeutic approaches to tackle this disease.

Our nervous system consists of the brain, spinal cord, and a vast network of nerves that feed into every body tissue. Motor neurons are nerve cells that send messages from the spinal cord to muscles, enabling movement.

A protein called the Survival Motor Neuron (SMN) Protein is necessary for the motor neurons to do their job. The Survival Motor Neuron 1 (SMN1) Gene produces most of the SMN Protein needed by the body. A second, closely related gene is the Survival Motor Neuron 2 (SMN2) Gene, which produces a much smaller amount of SMN Protein and is used as a sort of “backup” version of SMN1. So, if SMN1 doesn’t produce enough protein, SMN2 is there to help. However, SMN2 only produces ten percent of the needed SMA Protein, not enough to keep a person alive. Without functional SMN Protein, the neurons do not work correctly and eventually die. How soon they die depends on the extent of the SMN deficiency, which correlates with the severity of the disease: the less SMN produced, the more severe the disease. 

SMA is an orphan disease affecting about 1 in 10,000 babies born in the United States. The four generally accepted classifications of SMA are:

• Type 1: The most severe and the most common type of SMA. Symptoms are usually present within the first few months of life, and these babies often do not display movement of any kind. As the disease progresses, toddlers have trouble with swallowing and respiratory function. SMA Type 1 is usually fatal by age two.
• Type 2: Symptoms manifest between six and eighteen months. These children can typically sit but not stand or walk. Respiratory function is often compromised and is a significant concern; however, with the help of machines, many of these patients live into adulthood.
• Type 3: Symptoms occur after age one. These patients can usually walk but may lose that ability as the disease progresses. Respiratory function is less impaired, and life expectancy is near average.
• Type 4: This is the adult-onset form, typically manifesting at age 30 or later. Muscles gradually weaken, and the patient often needs a wheelchair later in life. Life expectancy is not affected.

Because SMA Type 1 is the most common and severe—about 60% of cases—most biopharma’s developing drugs aim to address this portion of the disease population. 

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ZOLGENSMA (Novartis; Zurich, Switzerland), SPINRAZA (Biogen; Cambridge, MA), and EVRYSDI (Roche; Basel, Switzerland) are the only drugs currently treating SMA in the United States. 

• ZOLGENSMA (onasemnogene abeparvovec-xioi) is a gene therapy used to treat children under two years old with SMA. 
• SPINRAZA is an antisense oligonucleotide (ASO) designed to treat SMA in pediatric and adult patients. 
• EVRYSDI is a splicing modifier of SMN2 Gene also designed to treat SMA in pediatric and adult patients. 

As a single-gene disorder, SMA is an ideal candidate for gene therapy approaches. Delivering a “good” copy of the mutated SMA1 Gene could potentially cure Spinal Muscular Atrophy.  

Scientists can safely deliver corrected genes into targeted cells using a “viral vector.” A viral vector is a virus stripped of its disease-causing ability. In the case of SMA type 1, the viral vector is an adeno-associated virus vector named AAV9. AAV9 is unique because it crosses the blood-brain barrier and delivers corrected copies of the SMN1 Gene into motor neuron cells in the brain.

In March 2023, Novartis released data from its long-term study, LT-001, highlighting the remarkable durability of ZOLGENSMA. In its ongoing 15-year study of patients who completed the Phase I START study showed that up to 7.5 years post-dosing, children maintained all previously achieved motor milestones. During LT-001, three additional patients also achieved the critical milestone of “standing with assistance.” As a one-shot treatment, ZOLGENSMA offers the potential of a one-and-done cure for SMA, differentiating it from SPINRAZA’s three-times-a-year dosing schedule, and EVRYSDI daily dosing schedule.

Before we explain how antisense works, let’s recall the central dogma of biology, which states that a gene produces mRNA, and mRNA produces the protein encoded by that gene. With this refresher, let’s take a look at the antisense drug SPINRAZA.

SPINRAZA is a short, synthetic piece of RNA. Its RNA sequence directs it to bind to the SMN2 mRNA. The binding of SPINRAZA changes how cells process the SMN2 mRNA, causing more of the information in the mRNA to be converted into protein. The result is a more significant amount of full-length, functional SMN Protein produced by the SMN2 Gene.

In 2023, Biogen announced new data and updates for SPINRAZA. The latest results from the study NURTURE demonstrate that early and sustained treatment with SPINRAZA for up to 5.7 years helped participants maintain and progress in motor function. After 11 months of additional follow-up since the 2020 interim analysis, all children who could walk alone held this ability, and one child gained the ability to walk alone, increasing the total number of ambulatory patients to 92 percent. Most children achieved motor milestones within age-appropriate timelines, and no major motor milestones were lost. 

The splicing modifier drug, EVRYSDI (Risdiplam), is a small molecule drug for treating SMA. SMN2 Gene has a single nucleotide difference, which causes exon 7 to be skipped to produce a truncated SMN protein. Risdiplam binds to pre-mRNA, changing the way the pre-mRNA produces the SMA mRNA. The binding of Risdiplam promotes the inclusion of exon 7, resulting in the production of full-length SMN2 mRNA, which ultimately makes a complete SMN Protein that compensates for the loss of the SMN1 Gene.

In June 2023, Genentech, a member of the Roche Group, announced new long-term data for EVRYSDI (risdiplam) from the pivotal FIREFISH study. After four years of treatment with EVRYSDI, many of the babies, now young children, continued to improve their ability to sit, stand, and walk without support. All the EVRYSDI-treated children alive at the time of the primary analysis were still alive at month 48. 

Spinal Muscular Atrophy, while a devastating disease, has witnessed remarkable advancements in treatment and understanding over the past decade. As science delves deeper into the genetic makeup of SMA and as technology evolves, it is optimistic to envision a future where SMA can be effectively treated or even cured. The journey of SMA from a little-understood disease to the forefront of genetic research is a testament to modern medicine’s wonders and the scientific community’s perseverance.

1. WHAT IS SPINAL MUSCULAR ATROPHY (SMA)?

SMA is a genetic disorder characterized by the loss of spinal cord nerve cells, leading to muscle wasting, weakness and in severe cases death.

2. HOW IS SMA CAUSED?

SMA is caused by mutations in the SMN1 Gene, which produces the Survival Motor Neuron (SMN) Protein essential for motor neuron function.

3. WHAT ARE THE DIFFERENT TYPES OF SMA?

There are four main types of SMA, ranging from Type 1 (most severe) to Type 4 (adult onset).

4. WHAT IS THE SIGNIFICANCE OF THE SMN2 GENE IN SMA?

While the SMN2 Gene also produces SMN Protein, its production is only ten percent of what is needed by the body.  However, even tiny amounts of functional SMN Protein can provide some motor nerve function.

5. WHAT ARE THE CURRENT TREATMENTS AVAILABLE FOR SMA?

ZOLGENSMA, SPINRAZA, and EVRYSDI are the three approved drugs to treat SMA. Each works in its own way to increase the production or functionality of the SMN Protein.

6. WHAT DIFFERENTIATES ZOLGENSMA FROM OTHER SMA TREATMENTS?

ZOLGENSMA is a one-shot gene therapy treatment, potentially offering a permanent cure for SMA instead of SPINRAZA, which requires regular dosing three times a year, and EVRYSDI, which requires daily dosing after a meal.