Muscular dystrophy created a lot of news in 2016 with the controversial release of eteplirsen (Exondys 51), an antisense oligonucleotide indicated for a form of Duchenne muscular dystrophy. Exondys 51 was approved with considerable drama played out in the press.
What most people do not know is that there are numerous diseases that cause similar presentations of muscular weakness from both muscular as well as nerve pathology. Moreover, another antisense oligonucleotide was just approved for one of those diseases, called spinal muscular atrophy (SMA), a confusing condition that was first described more than 125 years ago.
Thomas Morrow, MD
In 1881, Guido Werdnig, a neurologist in Austria, described a familial degenerative disease that caused muscular hypotonia (weakness) starting at birth and that led to death by the age of 4 due to progressive weakening of the muscles and, eventually, respiratory failure. A few years later, Hermann Oppenheim describes a more benign form of muscular hypotonia, which he termed amyotonia congenital. Then, in 1956, Erik Kugelberg and Lisa Welander reported in the Archives of Neurological Psychiatry a juvenile form of muscular atrophy that simulated muscular dystrophy.
Since all of these illnesses appeared to be similar, they were lumped together into one illness, called spinal muscular atrophy (SMA), but then divided into several types based on the age of onset. The worst form, typically named after Werdnig and Hoffman is now termed SMA I, or infantile type, and it presents at birth or shortly after. SMA II presents later, between six and 18 months and SMA III, also called Kugelberg-Welander disease, shows up at about 12 months. The fourth form, called SMA IV, affects adults.
It was not until 1990 that Linda Brzustowicz described the actual genetic basis that tied all of these together and explained the cause. The common thread became the discovery of the survival motor neuron (SMN) gene, or more precisely genes (SMN1 and SMN2), because there are two different forms of this gene.
The genes are inactive during early development in utero and become active in the healthy mature fetus by creating the SMN protein that is critical to the survival and function of the nerves that control our muscles. When deficient, the nerve cells gradually die and the muscles that are served by the dead nerves cease to be functional.
All of us create SMN1 protein and SMN2 protein from the SMN1 and 2 genes, respectively. Oddly, humans have from one to many SMN2 genes but only one SMN1 gene. Based on the number of SMN2 genes you have, you will form either little or a lot of SMN2 protein. SMN2 gene creates a backup supply of the SMN protein, but one critical amino acid is different. Because of that one small variation, the protein is less stable and less active.
If the SMN1 gene is defective and you create no SMN1 protein, then you are totally dependent on the amount of SMN2 protein you create. And SMN2 protein is, in effect, a lesser version of the SMN1 protein.
The genetics of all this were very confusing until the SMN2 gene and its natural variability in number in the human population was sorted out.
The SMN gene is an autosomal recessive genetic illness, meaning that an individual inherits one gene from each parent. One in 50 people carry a defective copy of the SMN gene. SMA affects all races and both sexes, although it is twice as common in males. Its incidence is about 1 in 10,000 live births in the United States.
Recently, nusinersen, sold as Spinraza, became the first approved drug to treat SMA. It is a survival SMN-2–directed antisense oligonucleotide indicated for the treatment of SMA in pediatric and adult patients developed by Ionis Pharmaceuticals and Biogen. It is administered by injections into the spinal fluid (intrathecally).
To understand how the drug works, a quick review of protein synthesis might be helpful. Genes are strands of DNA that code for proteins, strings of amino acids. Ribosomes are the small factories that accept the DNA code and create the chain of amino acids that corresponds to the DNA code. The SMN2 gene has a defect that interferes with the “ordering” mechanism of the protein. Spinraza basically tricks the ribosomes into serving up an increased manufacture of SMN2.
The dosing schedule starts with three doses at 14-day intervals, followed by a dose 30 days later, then one every four months thereafter.
Spinraza was studied in a multicenter, randomized, double-blind, sham-procedure controlled study in 121 symptomatic infants who had SMA symptoms in the first six months of life. Patients were randomized to 2:1 to receive either Spinraza or sham injection. Length of treatment ranged from six to 442 days (the median was 261 days). The primary endpoint was the portion of responders reaching an improvement in motor milestones in the Hammersmith Infant Neurologic Exam, which measures seven different areas of motor milestone development using a scoring system with a maximum score of 26 points. These milestones included kicking, rolling, sitting, crawling, standing, walking, and head control. To be considered a responder, patients needed to exhibit at least a two-milestone improvement in the ability to kick or a one-milestone improvement in the other six areas and at the same time, exhibit improvement in more categories than worsening categories.
The approval was based on this study and some associated non-controlled studies. In this study, the endpoints were measured at a planned interim analysis based on patients who died, withdrew, or completed at least 183 days of treatment. Thus, only 52 actively treated patients and 30 sham-control patients were included in this analysis. At this analysis point, 40% of the active treated patients achieved a motor milestone response.
The study also looked at a second assessment called the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders. In this test set, 63% of the treated group demonstrated at least a 4-point improvement from baseline as compared to only 3% demonstrating the same improvement in the sham-control group. At the same time, only 4% of the actively treated group deteriorated at least 4 points as compared to 40% of the sham-control group.
The most common adverse reactions (occurring in at least 20% of patients and at least 5% more frequently than in the control patients) were upper- and lower-respiratory infections and constipation. There were a few reported cases of spontaneously resolving rashes in Spinraza-treated patients and a handful of other observations such as hyponatremia and reduction in growth rates in infants.
Biogen has announced a price of $125,000 per injection, which equates to $750,000 for the first year and $375,000 per year thereafter, which is not out of the range of other ultra-orphan drugs. But, remember, this approval was based on a controlled trial of just a half-year’s treatment and only 40% of patients demonstrated a response. Long-term studies have not been completed. And, importantly, there is no evidence that these infants will actually live any longer than their untreated peers.
Spinraza was also approved for older children and adults based on supporting “open-label uncontrolled trials” conducted in pre-symptomatic and symptomatic SMA patients. These trials included symptomatic patients ranging in age from 30 days to 15 years and presymptomatic patients from eight days to 42 days at the time of first dose.
Clearly, we have just scratched the surface when it comes to SMA. What is unclear is how managed care will respond to a drug that is priced this high and, so far, has been shown to have a rather modest effect.