Zolgensma contains viruses from the scAAV9 family, each of which transmits a synthetic DNA sequence corresponding to the SMN1 gene. After administration of the drug, these viruses "infect" cells (e.g. motoneuron cells), and the transmitted DNA sequence goes to the cell nucleus, where it begins encoding of the missing SMN protein.
Gene therapy does not change the genetic code of the patient or fix the genetic defect underlying SMA. The manufacturer's promoted term "gene replacement therapy" has been criticized by scientists as misleading. Changes in cell nuclei caused by AVXS-101 are not inherited.
Zolgensma starts acting quickly, the level of the SMN protein raises within a few days of administration. This makes the drug especially useful for treating newly diagnosed infants – at the stage when neuronal loss progresses more rapidly.
Taking a virus-based drug causes persistent resistance to this type of virus in the body. For this reason, Zolgensma can only be given once. Some people naturally have antibodies to this type of virus – a few percent of infants have resistance to AAV9, but as many as 50 percent of the adult population. Such persons may not take medicines based on this type of the virus.
The manufacturer is working on a form administered to the epithelial (i.e. lumbar punctuation), which could potentially be used in older patients, provided that efficacy and safety are proven.
The SMA Foundation, acting within SMA Europe, supports AveXis's efforts to develop and make this therapy available in Europe. We have participated, among other things, in the development of the objectives of European clinical trials of this therapy. We are also working with the European Medicines Agency to allow gene therapy to the European market.
Research on gene therapy for the SMA began in France in 2006, when Dr Martine Barkats's team funded by the AFM-Téléthon organization. He developed a method for supplying transgenes to motoneurons using the scAAV9 virus. Work continued and in 2011 Dr Barkats announced the "cure" of mice with severe spinal muscular atrophy using gene therapy.
Shortly afterwards, Dr. Brian Kaspar from the USA began working on the clinical application of this method. Thanks to multimillion-dollar funding by organizations such as SMA Europe, Cure SMA and Sophia's Cure Foundation, the method of genetic modification of Symptoms of SMA has been tested in mice and pigs, and safety in monkeys as well. Since 2013, the development of gene therapy has been conducted by Dr. Kaspar as part of his company AveXis (later, in 2018, acquired by Novartis).
In spring 2015, avxs-101 was first administered to a child with SMA as part of a registered clinical trial. By mid-2016, there were already 15 children in the study. In the following years, three more clinical trials were opened with infants, including two outside of the United States.
Based on the results of these studies, In October 2018, AveXis applied for this form of AVXS-101 to be allowed to enter the European Union, the United States and Japan. On May 24, 2019, the avxs-101 intravenous form was authorised for use in Children with SMA under the age of 24 months, including presymptomatic children. On 19th of March 2020 the procedure was also approved in Japan. The approval procedures in the European Union are still ongoing, although the EMA recommended Zolgensma for authorisation in European Union.
In the controversial decision, the manufacturer decided to price Zolgensma at $2.125 million per pack, making Zolgensma the world's most expensive drug.