A historic moment happens for all those who have been researching the Spinal Muscular Atrophy (SMA) disorder for decades - and, of course, for those carrying the disease as well. On 23 December 2016, the FDA, the US government's drug control body, approved the first and only treatment for SMA, named Spinraza (Nusinersen).
Spinal Muscular Atrophies (SMAs) have a genetic origin and are characterized by muscular atrophy secondary to the degeneration of motor neurons located in the anterior horn of the spinal cord. It is the second largest autosomal recessive disorder and affects approximately one in 10,000 births worldwide. The disease harms people's physical strength by acting on the motor nerve cells in the spinal cord. Couples who have given birth to an affected child carry a 25% risk of recurrence in each subsequent pregnancy.
SMA is caused by a mutation in the survival motor neuron 1 gene (SMN1). In a healthy person, such gene produces a protein that is critical to the function of the nerves that control our muscles. Without it, these nerve cells cannot function properly, leading, in some cases, to fatal muscle weakness. There are four main types of the disorder: I, II, III and IV, based on the age at which it manifests and the rate at which it progresses.
According to Dr. Alexandra Prufer, associate professor of Neuropediatrics at UFRJ and a specialist in the disease, the newly approved medicine represents an "exceptional advance". The doctor says that the medication acts directly on a fundamental factor in the genesis of this disease: the protein level, known as the survival motor neuron protein (SMN). "Spinraza acts on the SMN2 gene 'forcing' this gene to produce stable and functional SMN protein as if it were the SMN1 gene, which is altered in 95% of the people carrying SMA", Prufer explains. Therefore, in order for a patient to be indicated for a future prescription of the drug, it is essential to genetically confirm that, in fact, the manifestations are due to the alteration in this SMN1 gene - and not in others.
The neurologist says studies for the development of new drugs are time-consuming. They start from theoretical knowledge; then hypotheses are formulated of potential targets for substances, progressing to the preclinical phase (tests in test tube cells and in animals). If biochemical and cellular effects are satisfactory and no significant toxic effects are found in animals, the clinical research stage begins, in which new potential treatments are evaluated in humans. This step is divided into three phases. In the last, phase three, volunteers carrying the disease are sorted into the substance use group and the control group (those who will use placebo). Neither the volunteers nor the professionals involved know who is in each group and the observation period is long. In this funnel, 10,000 new substances are studied for a satisfactory output of only one.
According to the doctor, Spinal Muscular Atrophy was first described in 1890. One hundred years went by before the disorder's genetic mechanism became known and, in 2011, the first clinical phase of the first drug began.
Spinraza is the drug that completed phase 3 and was submitted for marketing evaluation. Two phase 3 trials presented relevant results and others are still underway with this medication. One of the surveys that showed impact involved children less than 7 months of age bearing a number of characteristics required to enter the survey. The results showed that those infants who used placebo maintained the same progressive course of the disease without having achieved motor development stages, while those who used the medication did not present worsening of muscle weakness, had fewer respiratory complications, needed less ventilator support and some started to gain motor development, such as: firming the head, then sitting and then standing, quite different from what is expected from the natural course of the disease.
Another research that also showed difference between the groups in relation to motor development included children from 2 to 12 years of age incapable of walking, with the forms known as type II and III of SMA.
The drug is given intrathecally, an injection into the space where the cerebrospinal fluid (which surrounds the spinal cord and brain) circulates. It is indicated for patients with types I, II and III of the disease, regardless of age. At the beginning of treatment with Spinraza, doses are more frequent (induction phase), progressing for doses with longer intervals (maintenance phase). This procedure must be done in a hospital.
Dr. Alexandra Prufer says that "there is a great expectation that this progressive disease can be stopped". The steps to follow for the release of the drug in Brazil, now, depend on the pharmaceutical company, which must submit the process for analysis of ANVISA.