Title: Onasemnogene abeparvovec for treating pre-symptomatic spinal muscular atrophy (MAA partial review of HST 15) [ID4051]
Funder: Department of Health and Social Care

Abstract: Spinal muscular atrophy, or SMA, is a rare genetic disorder that causes muscle weakness and progressive loss of movement. It is most commonly caused by defects in the gene SMN1, which leads to degeneration of motor neurones in the spinal cord (this is termed ‘5q SMA’). The motor neurones most affected by this condition are those that allow walking, crawling, arm movement, head and neck movement, swallowing and breathing. SMA causes substantial disability and may lead to increased mortality and reduced life expectancy. The most severe types of SMA typically cause death before age 2 years, although people with later-onset types of SMA can live into adolescence or adulthood. The SMN2 gene also encodes the SMN protein and can partially compensate for the loss of the SMN1 gene. However, most SMN protein produced by this gene is not functional. An individual with SMA who has more copies of the SMN2 gene will produce more functional SMN protein and may be better able to compensate for the loss of the SMN1 gene, potentially leading to less severe disease[1] . SMA has substantial effects on families and carers, including the impact of caring for the patient, the need for specialist equipment and ongoing emotional, financial and social impacts._x000D_ _x000D_ SMA is a heterogeneous condition, with a range of severity, which is often grouped into 5 main types, based on the age of onset of symptoms and how much motor function the person has. The types of SMA decrease in severity from type 0, in which symptoms arise before birth and babies survive for only a few weeks, to type 4 (adult-onset) which is associated with mild motor impairment and a normal life span. Types 0 and 4 are rarely diagnosed. In SMA type 1, symptoms arise before age 6 months and babies are unable to sit independently; babies with SMA have low muscle tone (hypotonia) and severe muscle weakness which affects movement, swallowing and breathing. In type 2 SMA, the onset of symptoms is between age 7 and 18 months, and people with this condition are often severely disabled and unable to walk unaided. Type 3 SMA is a heterogeneous condition, with a varying degree of muscle weakness appearing between age 18 months and 18 years; most people with type 3 SMA can walk or sit unaided at some point, but many lose mobility over time. The number of SMN2 gene copies can differ by SMA type[2] . _x000D_ _x000D_ Currently in England, only a small number of children are diagnosed with SMA before symptoms appear (known as pre-symptomatic SMA) if a sibling has been diagnosed with SMA. Pre-symptomatic diagnosis is done through genetic testing. Without treatment, pre-symptomatic SMA later develops into other SMA types 0 to 4, depending on when symptoms occur._x000D_ _x000D_ It is estimated that approximately 1 in 10,000 people are born with SMA[1] , suggesting that about 65 people are born with SMA per year in England. Approximately 60% of all new diagnoses of SMA are SMA type 1[3] . _x000D_ _x000D_ NICE highly specialised technology appraisal guidance 15 recommends onasemnogene abeparvovec as an option for treating 5q spinal muscular atrophy with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of type 1 SMA in babies, only if they are 6 months or younger, or they are aged 7 to 12 months, and their treatment is agreed by the national multidisciplinary team. _x000D_ _x000D_ No active treatments are currently routinely available for pre-symptomatic SMA. NICE highly specialised technology guidance 15 recommends onasemnogene abeparvovec as part of a managed access agreement for treating babies with 5q presymptomatic SMA with a bi-allelic mutation in the SMN1 gene and up to 3 copies of the SMN2. NICE technology appraisal 755 recommends risdiplam for babies with pre-symptomatic SMA with 1 to 4 SMN2 copies and NICE technology appraisal 588 recommends nusinersen for treating pre-symptomatic SMA, both as part of managed access agreements. The use of risdiplam or nusinersen is not considered to be embedded in NHS clinical practice because the availability of these treatments is contingent on further evidence generation and review by NICE. Additionally, the significant uncertainties identified prevented NICE’s committee from making a positive recommendation during these appraisals, so these treatments are not considered to be routinely commissioned. Therefore, for the purposes of this review, risdiplam and nusinersen will not be considered as comparators. _x000D_ _x000D_ In the absence of active treatment, the condition is managed through multidisciplinary supportive care. Treatment usually follows guidelines from the International Conference on the Standard of Care for Spinal Muscular Atrophy [4],[5] . Supportive care strategies do not affect disease progression but aim to minimise the impact of disability, address complications and improve quality of life. These may involve respiratory, gastroenterology, and orthopaedic care, as well as nutritional support, physiotherapy, assistive technologies, occupational therapy and social care. _x000D_ _x000D_ This evaluation will consider onasemnogene abeparvovec use in people with presymptomatic SMA (which includes people who do not have clinical manifestations that are strongly suggestive of SMA). The evaluation will use data collected in the managed access agreement established through NICE’s highly specialised technology guidance 15 and in a recent clinical trial._x000D_ _x000D_ References_x000D_ 1. NORD “Spinal Muscular Atrophy” (2022) https://rarediseases.org/rarediseases/spinal-muscular-atrophy/#subdivisions (assessed April 2022)_x000D_ 2. Calucho M, et al. An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord. 2018 Mar;28(3):208-215._x000D_ 3. Spinal Muscular Atrophy UK (2018) What Is 5q Spinal Muscular Atrophy? - Spinal Muscular Atrophy UK (smauk.org.uk) (accessed June 2022)._x000D_ 4. Mercuri E et al. (2018) Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscular Disorders, 28(2): 103– 115._x000D_ 5. Finkel RS et al. (2018) Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscular Disorders, 28(3): 197–207.

Lay abstract: To appraise the clinical and cost effectiveness of onasemnogene abeparvovec within its marketing authorisation for treating pre-symptomatic spinal muscular atrophy.

Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL