Onasemnogene abeparvovec for treating spinal muscular atrophy

Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular condition caused by a genetic mutation in the SMN1 gene on chromosome 5q. This causes a lack of survival motor neuron (SMN) protein, which causes motor neurones to malfunction, deteriorate and eventually die. People with the condition have a range of symptoms, including muscle weakness, and have worsening physical disability, mobility loss and respiratory dysfunction. SMA can be grouped into 5 main types (types 0 to 4), based on the age of onset and the maximum motor function reached. Type 0 SMA, the most severe, affects babies before birth. The babies do not develop any motor skills and often survive for only a few weeks after birth. Babies with type 1 SMA generally develop symptoms before they are 6 months old. They are unable to sit or roll because of severe muscle weakness, which gets worse over time. The muscle weakness also affects swallowing and breathing, and typically results in death within 2 years. In type 2 SMA, the onset of symptoms is between 6 months and 18 months. People with this condition may be able to sit at diagnosis but are likely to lose this ability over time. However, progressive loss of motor function means they have a reduced life expectancy compared with the general population. In type 3 SMA, there are varying degrees of muscle weakness, which appear between 18 months and 10 years. People with this condition can have a normal lifespan, and walk or sit unaided at some point, but many lose mobility over time. Most people with type 2 SMA and a proportion of those with type 3 SMA will develop scoliosis for which surgery will eventually be needed. Type 4 SMA, the least severe, affects adults, who may have only mild motor impairment and a normal lifespan.

Disease severity is associated with the time of symptom onset, and earlier onset is associated with more severe disease. The SMN2 gene also produces SMN protein, and the presence of SMN2 can compensate for the SMN1 deletion to some degree. The number of SMN2 gene copies is inversely related to the severity of SMA and can be used to predict the course of the disease.

Babies with type 1 SMA typically have 2 copies of the SMN2 gene (86%) but some will have 3 copies (6%) or 1 copy (7%). Babies with type 2 SMA typically have 3 copies of the SMN2 gene (87%) but some will have 2 copies (13%) and people with type 3 SMA typically have 3 copies (64%) or 4 copies (31%) of the SMN2 gene, with the rest having 2 copies (less than 1%). It is estimated that about 1 in 10,000 people are born with SMA, suggesting that about 65 people are born with SMA per year in England. About 60% of all new diagnoses of SMA are type 1 SMA.

SMA can be diagnosed before there are symptoms (that is, presymptomatically), if newborn screening is done. There is currently no newborn screening programme for SMA in England, but genetic testing is offered when a sibling has been diagnosed with SMA. A very small number of people are diagnosed with presymptomatic SMA in England each year.

Best supportive care for treating SMA consists of a multidisciplinary approach including respiratory, gastroenterology and orthopaedic care, nutritional support, physiotherapy, assistive technologies, occupational therapy and social care. However, the clinical and patient experts emphasised that best supportive care treatments do not affect disease progression, and babies with type 1 SMA have a very short life expectancy. Nusinersen is an active treatment available for treating SMA but not through routine commissioning. It is recommended by NICE through a managed access agreement for presymptomatic SMA and types 1, 2 and 3 SMA.