Researchers Evaluate New Drug for Spinal Muscle Atrophy in Wider Range of Patients

The rarity of spinal muscular atrophy (SMA) means that promising new treatments can only be tested on a limited spectrum of patients before they are approved. Researchers evaluated a newly approved drug, onasemnogene abeparvovec, in a wider range of patients to obtain expanded data on its side effect profile. They report in the Journal of Neuromuscular Diseases that the drug is associated with an immune response against the adeno-associated viral vector and requires careful monitoring, but has shown no long-term adverse effects.

In recent years, the availability of an increasing number of drug treatments has dramatically altered the course of SMA. One of these is onasemnogene abeparvovec (Zolgensma®), a gene therapy based on an adeno-associated viral vector (AAV9) that introduces a functional copy of the SMN1 gene in motor neurons with a single intravenous injection.

SMA is considered an orphan disease because it affects only one in 6,000 to 10,000 newborns worldwide. Type 1 ADS accounts for about 60% of all cases. In the main clinical study on which the approval of onasemnogen abeparvovec was based, only 22 babies received this treatment. Twenty of them were alive and breathing without a permanent ventilator after 14 months, while normally only a quarter of untreated patients would survive without needing a ventilator. Based on these results, the United States Food and Drug Administration (FDA) approved treatment for all types of SMA up to the age of two, and the European Medical Agency (EMA) has extended the label to all patients with either an SMA phenotype. type 1 or have up to three SMN2 copies.

“SMA is a rare disease and the pivotal studies only included type 1 SMA patients up to the age of eight months,” explained Prof. Janbernd Kirschner, MD, Department of Pediatric Neurology, Bonn University Hospital , Bonn, Germany, principal investigator. “However, the FDA and EMA have approved the treatment for a wider range of patients, leading to discussions about the safety and effectiveness of the treatment in older and heavier patients and in those with of SMA type 2. “

The researchers report their experience with eight consecutive patients with ADS who were treated with the standard dose of onasemnogen abeparvovec (1.1 × 1014 vg / kg) at the University Hospital in Bonn, Germany. All patients received prophylactic immunosuppression with prednisolone for four weeks from the day before gene therapy. The patients (four men, four women, aged 10 to 37 months) weighed between seven and 12 kilograms. All of the patients had two or three copies of the SMN2 gene and had previously been treated with nusinersen, also approved for the treatment of SMA.

After treatment, all patients experienced a temporary increase in body temperature and increased levels of transaminases (transaminases are important enzymes in the synthesis of amino acids, which form proteins). In all but one patient, it was necessary to increase or prolong the standard dose of steroids to control the immune response. In one severe case, liver damage was associated with impaired liver function. This patient received steroid pulse therapy for five days, after which liver function fully recovered. After treatment, six patients presented with asymptomatic thrombocytopenia (abnormally low blood platelet count). Liver values ​​and blood count returned to normal or near normal levels during the post-treatment observation period. Four patients experienced increased troponin I levels, which may be a sign of heart damage, but cardiac evaluation did not show any abnormalities.

“Our experience with eight patients over eight months of age adds important findings to the growing body of evidence that treatment of AMS with onasemnogen abeparvovec is often associated with an immune response against the AAV vector,” noted Professor Dr Kirschner. “This immune response primarily affects the liver and the hematopoietic system and can be severe in some cases. However, it has been possible to control the immune response in all patients by proactive monitoring and adjusting the dose of steroids, and we do not We have not detected any long term side effects due to the immune response.

“It is premature to judge whether serious organ damage with long-term consequences can still be avoided. More research is needed to better understand the immune response after gene therapy and ideally to identify patients at risk for a more serious reaction.” , he concluded.

Spinal muscular atrophy (SMA) is a rare genetic neurodegenerative disease. It mainly affects the spinal motor neurons and causes progressive muscle weakness. The spectrum of severity ranges from severe cases onset in the first six months of life (SMA type 1) to later onset in childhood or adolescence (SMA types 2-4). SMA is caused by mutations in the survival motor neuron gene. Left untreated, type 1 AMS is associated with death or the need for permanent ventilation during the first two years of life.