The most expensive drug in the world is about to land in Spain. Two years after its approval in the United States and one after its authorization in Europe, Zolgensma, developed by Novartis, is pending an agreement between the Ministry of Health and the pharmaceutical company to be administered to newborns with spinal muscular atrophy. The treatment, which is inoculated intravenously for about an hour only once, it has a price of almost two million euros.
So far, four children have received the drug in Spain, all of them in the last half year. It has been acquired through so-called compassionate use, which allows the hospitals of the national health system to buy it even if it is not included in the portfolio of financed drugs. Around 1,200 infants in the world have already been treated. In our country it is expected that between 18 and 20 will benefit from it.
Because Zolgensma is indicated for the treatment of type 1 spinal muscular atrophy, the most serious of all: the life expectancy of children with this disease does not exceed two years in 80% of cases. His symptoms begin before six months of life, “many times abruptly,” he explains. Andrés Birth, neuropediatrician at Hospital Sant Joan de Deu.
“It affects the muscles closest to the body: raising the arms costs them more than moving the hands; have breathing and swallowing difficulties, and they are not able to keep their legs against gravity, not only to move them, they cannot stand up ”.
This is because your body does not make an essential protein for motor neurons, known as SMN. It is produced by two genes: SMN1 produces practically all of the protein, SMN2 around 10%.
This is why there are several types of spinal muscular atrophy. The disease only manifests itself when both parents carry the faulty SMN1 gene (about 1 in 50 people have it). The number of copies of the SMN2 gene will determine a greater or lesser severity of the disease: In types 2 and 3 (whose symptoms appear between 6 and 18 months) they continue to have breathing difficulties, but they can stand and even walk independently. 60% of children with SMA have type 1 and the degeneration is progressive: neurons that are lost no longer recover.
Spinal muscular atrophy treatment
The first medicine for spinal muscular atrophy arrived in Europe in 2017. It’s called Spinraza and it consists of an injection every four months in the lower back, into the cerebrospinal fluid. Its cost is about 70,000 euros per vial (about 210,000 euros per year). This year came an oral treatment that must be taken daily and whose price is set (in the US, price negotiation in Spain is secret) at $ 340,000 per year.
The advantage of Zolgensma over these two alternatives is that, while the others are administered throughout life, it is administered only once, since is a gene therapy that corrects the problem by introducing copies of the correct gene into the child’s body.
Gene therapies promised to revolutionize medicine in the late 1990s, as the Human Genome Project reached its final stage. However, his research came to a halt after a fatal accident: one of the first patients to try a gene therapy, Jesse Gelsinger, died at the age of 18 as a consequence of the strong immune response caused by the viral vector with which the DNA sequence was introduced that he was going to correct a congenital deficit he suffered.
From that moment, research in gene therapies focused on the discovery of safe viral vectors, which serve as transport to the DNA sequence. It is not easy, since they have to reach specific cells and introduce the genetic material so that the cell itself can manufacture the correct protein.
In the case of spinal muscular atrophy there is an additional difficulty: the blood-brain barrier is a network of blood vessels and blood tissues that are tightly linked in such a way that they prevent the passage of bacteria and harmful compounds into the brain. It is a wall that provides additional security to the brain, but also the great challenge of treating neurological diseases, because it also prevents the entry of drugs.
Neonatal screening for spinal muscular atrophy
Zolgensma use an adeno-associated vector 9, “very safe, low immunogenic, low inflammatory and relatively easy to produce” that is capable of crossing this barrier, he explains. Francina Munell, Coordinator of the Pediatric Neuromuscular Diseases Unit of the Vall d’Hebron University Hospital.
It is a virus that exists in nature but whose infection in humans hardly produces symptoms. People are usually immunized against it in the first years of life, so it is crucial to administer Zolgensma before immunity against it has been acquired, as the antibodies would block it and it would not be able to introduce the genetic material which, on the other hand, remains in the nucleus but is not incorporated into the genome: these are episomes that degrade after the production of the protein.
There is another crucial aspect to administer this therapy as soon as possible: the affected neurons do not recover. In practice, this implies that once symptoms begin, degradation is avoided but lost mobility is not recovered. That is why both Nascimiento and Munell are committed to incorporating the detection of SMN1 deficiency into neonatal screening programs –the heel test–.
“There are pilot neonatal screening initiatives in some communities, but a national screening program has not been established,” Nascimiento explains. So far, Zolgensma (as well as the other spinal muscular atrophy therapies) has been given once symptoms are detected in the baby.
In fact, so far, only Germany, the Netherlands, Poland and Serbia have approved this screening programAlthough only Germany has it underway with a pilot test of almost 300,000 births in which 40 cases were detected. “When treating them at the presymptomatic level, they reach the maximum of their motor function”, indicates the pediatrician.
For his part, Munell notes that protocols for the drug are still being established. Although its most common side effects are those of a mild infection (nausea, vomiting, fever, etc.), there may be cases of reduced platelets, hepatitis or muscle inflammation, which need to be evaluated and treated in the best way and by the suitable professional, so this therapy can only be administered in an experienced and multidisciplinary setting.
“Treatment must be initiated and administered in recognized clinical centers with experience in this type of therapy,” indicates Munell, who has participated, like Nascimiento, in a training for specialized journalists organized by the Atrevia communication agency.
“It is a disease of the entire hospital because the side effects that affect the liver, for example, we as neurologists are not going to know how to treat them in the best way.” The pediatrician indicates, however, that the protocols already exist and that “with daily practice we are improving them.”