Introduction to treatments
Spinal Muscular Atrophy is a degenerative muscle condition affecting the body's voluntary motor neurons. As these neurons become impaired, signals from the brain to various muscles fail. The muscles consequently become underused and atrophy. The most important treatment for SMA is therefore to keep working every muscle for as long as possible - use it or lose it!
The degree of impairment can vary widely, but regular physiotherapy, together with activities like swimming, chewing and even writing are all strongly encouraged to maintain maximum ability for as long as possible.
Historically there has been no medical treatment for SMA, but this changed in April 2017 when the European Medicines Agency granted marketing authorisation to Biogen for their drug, Spinraza (nusinersen). Since then, further drugs have been developed specifically targeting SMA. In general, these treatments aim to arrest further declines in muscle weakness. A significant portion of patients have even experienced improvements in motor milestone responders.
With SMA, when you waste time you waste muscles - patients must not be delayed starting treatment!
Spinraza was developed by Biogen and was approved in Ireland for treating patients with SMA Types I, II or III in June 2019.
For the lower motor neurons to function and remain healthy, the cells need to produce the survival motor neuron (SMN) protein. The ability to do this is mainly controlled by the survival motor neuron 1 (SMN1) gene. The survival motor neuron 2 (SMN2) gene also contributes to the production of SMN protein, though it only makes approximately 10% of that produced by SMN1. This is also why SMN2 is often called the SMN ‘back-up’ gene.
Individuals can have multiple copies of SMN2 and, in general, it seems that those with more copies have a less severe form of SMA. Most of the SMN protein made by SMN2 is missing an important piece called exon 7. The remaining protein produced by SMN2 includes exon 7 and is the same as that made by SMN1.
Antisense oligonucleotide drugs (ASOs) are small snippets of synthetic genetic material that bind to ribonucleic acid (RNA). They are often described as molecular patches because they can be specifically designed to target and affect how a particular gene is read. ASOs have great potential for SMA, because they can accurately target the SMN2 gene to essentially convert it into the SMN1 gene, i.e. they are small molecules “patching-up” SMN2 to act more like SMN1. So they can be used to fix splicing errors in genes such as SMN2. They do this by binding to the RNA template made by SMN2 and enhancing the inclusion of exon 7 into the SMN protein.
Spinraza is an antisense oligonucleotide that targets SMN2, causing it to make more complete SMN protein.
Treatment involves a loading dose of four 12 mg injections into the spinal canal on days 0, 14, 28 and 63. This is followed by a maintenance dose of one injection every four months thereafter.
Treatment in Ireland is currently restricted to patients under 18 years old, however in November 2020 Biogen submitted an application to the NCPE (National Centre for Pharmacoeconomics) to reimburse the treatment of adults. This was an important development as adults in Ireland with SMA currently have no access to treatment. The outcome of this application process is not expected before the end of 2021.
Patients with spinal muscular atrophy have a defect in a gene known as SMN1, which the body needs to make a protein essential for the normal functioning of nerves that control muscle movements. The active substance in Zolgensma, onasemnogene abeparvovec, contains a functional copy of this gene. When injected, it passes into the nerves from where it provides the correct gene to make enough of the protein and thereby restore nerve function.
Zolgensma was developed by Avexis, a pharmaceutical company now owned by Novartis. The drug is administered via a single intravenous injection, however there are strict criteria as to the patients that qualify:
- 5q spinal muscular atrophy
- bi-allelic mutation in the SMN1 gene
- SMA Type I; or patients with up to three copies of the SMN2 gene
- Young children up to 21kg (about three stone)
Zolgensma received EMA approval in May 2020, and is currently being assessed for reimbursed in Ireland. SMA Ireland lodged a Patient Submission Document with the NCPE as part of this process, the results of which are expected in 2021.
Similar to Spinraza, Everisdy is an 'anti-sense oligonucleotide' medicine. It modulates how effectively the survival motor neuron 2 (SMN2) gene is used to make SMN protein. Signals (called messenger RNAs) are generated from SMN2, and the drug selectively interacts with these, resulting in more SMN protein being made by cells throughout body.
Everisdy is administered orally, and can be taken at home. The US Food and Drug Administration approved Evrysdi in August 2020, and the European Medicines Agency simultaneously granted the drug priority designation. This places Everisdy on a pathway for accelerated evaluation in Europe, with an outcome likely in the first half of 2021.
Evrysdi has been trialled on a wide cohort of SMA patients, including adults into their 60s, exhibiting significant efficacy. While this drug is not yet generally available in Ireland, Roche has offered to provide early access to SMA sufferers through a Compassionate Use Programme, where the patient has no viable alternative.
Access to Roche’s Compassionate Use Programme must be hospital approved and it has been instigated by the National Children’s Hospital for under 18s unable to tolerate the spinal injection involved with Spinraza. Adults have thus far been denied this treatment option.