By: Nirali Ragha and Yostena Khalil, PharmD Candidates 2022; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Nausheen Hasan, PharmD, BCPPS; St. Louis Children’s Hospital
Spinal muscular atrophy, more commonly known as SMA, is a genetic disease. This disease primarily effects muscles; muscles start to get smaller, or atrophy, because nerve cells located in the spinal cord are not stimulating them. This atrophy hinders the patient's ability to eat, walk, or breathe. SMA is characterized by four different categories ranging from type 1 to type 4. The earlier in the age that a baby is diagnosed with SMA, the greater the impact on their motor function. Genetic testing (tests for any
variations in the SMN1 gene) and a muscle biopsy are both methods of diagnosing a pediatric patient with SMA; as of January 2019, SMA is now on the newborn screening for Missouri.1 The most severe type of SMA is type 1, which includes babies diagnosed at birth or in infancy.2 Pediatric patients with type 1 SMA have a life expectancy of fewer than 2 years.2 With the addition of new treatments, the survival rates in pediatric patients have improved tremendously, but at an extraordinary cost. Nusinersen (Spinraza) costs about $708,000 in the first year of treatment and about $354,000 in subsequent years due to it being a long-life therapy.3 Another treatment on the market is onasemnogene abeparvovec (Zolgensma), which retails at about $2.125 million dollars, but insurers have the ability to pay $425,000 a year for five years; however, coverage varies based on patient’s insurance.3
Zolgensma has a targeted approach by selecting the genetic root cause of SMA. It replaces the Survival of Motor Neuron 1 (SMN1) gene that is nonfunctioning. The SMN1 gene constitutes the critical point in making SMN protein, which is essential to the survival of the motor neuron cell.4 If the motor neuron cell is dead, then it will cause the muscles to weaken so that breathing, eating, and moving would become extremely difficult. Zolgensma is made up of a working copy of a human SMN gene. This gene is placed inside a vector.5 The vector then takes the new working human SMN gene to the motor neurons cell body. The vector is made from a particular virus that is known as adeno-associated virus 9 (AAV9).5 This particular vector is not seen as a foreign pathogen, thus our immune system does not attack it. Once the human SMN gene reaches its destination in the motor neurons cell body, it prompts the motor neuron to start producing SMN protein. Since the motor neuron will not be able to produce a sufficient amount of SMN protein, the motor neurons that have not died off will be able to survive.
Spinraza works by penetrating the central nervous system. In order to penetrate the central nervous system, children receive intrathecal injection through a lumbar puncture. Spinraza then uses the spinal fluid to move through the central nervous system. Children with SMA have a difficult time relaying messages from the brain to the motor cells. While taking Spinraza, the spine will act as a tunnel to relay motor messages from the brain to the body in a quicker motion. It contains an antisense oligonucleotide (ASO) which controls the mutations that are present in the affected chromosomes.6 The binding then targets RNA and regulates gene expression. This regulation then has the potential to enhance the functional SMN proteins.5
During phase 3 of a trial for Spinraza, called ENDEAR, there were 121 patients (age ≤ 7 months) with early-onset of SMA who received their first-time dose of Spinraza. The primary endpoint of this trial was to see if Spinraza could decrease the need for permanent ventilation and meeting the criteria for motor milestone responders using HINE-2 compared to patients not receiving treatment at all. The study found that 61% of patients on Spinraza survived without the need for permanent ventilation, compared to patients who were not receiving treatment.7 In addition, 51% of treated patients compared to 0% of untreated patients achieved the motor milestone responder criteria, which are defined by an HINE-2 score at 9 months. Patients on Spinraza achieve full head control, supine to prone rolling, independent sitting, and standing.6 The study also found that over time patients who were treated with Spinraza continued to improve quality of life, compared to patients who were untreated and saw a decline in motor milestones.
In the STR1VE clinical study for Zolgensma, 22 patients with SMA type 1 received a therapeutic dose of Zolgensma at an average mean age of 3.7 months.8 The results of this study showed that 91% of patients who received Zolgensma were alive and did not require any permanent breathing support at the age of 14 and 18 months. The result of patients who were able to sit without any assistance for at least 30 seconds at the age of 18 months was 59%.8 In addition, about 95% of patients achieved a CHOP INTEND score (a scoring system that measures motor function) of at least 40, which has a scale of 0-64 where higher scores indicate better motor function.8
Spinal muscular atrophy is an extremely dangerous genetic disease, and patients who have it have a very low rate of survival. Patients may be placed permanently on ventilators, and their ability to eat and walk may be hindered, as well. Fortunately, Spinraza and Zolgensma can improve both the quality and life span for these patients, but at a great cost. The STRIVE and ENDEAR trials have shown that Zolgensma and Sprinraza are effective for the treatment of SMA. Unfortunately, both these drugs are high-priced, and insurance may not be readily available for everyone.