Title: Ataluren for treating Duchenne muscular dystrophy with a nonsense mutation in the dystrophin gene (review of HST3) [ID1642]
Funder: Department of Health and Social Care

Abstract: Muscular dystrophies are a group of genetic disorders which cause muscle weakness and progressive disability. Duchenne muscular dystrophy is the most common and progresses most rapidly. It is caused by the presence of different types of mutations on the X-chromosome in the gene for dystrophin, a protein that is important for maintaining normal muscle structure and function. The main types of mutation are deletions (where part of the gene is deleted), insertions (where an additional piece of DNA is inserted into the gene), duplications (when part of the gene is repeated) and point mutations (when a single letter in the DNA code is changed and alters the information needed to produce a protein). A point mutation that leads to a stop signal being inserted into the middle of a gene, that stops the protein being produced, is known as nonsense mutation. These changes cause muscle fragility that progressively leads to weakness and loss of walking ability during childhood and adolescence. Boys only have one X chromosome, and thus one single copy of the dystrophin gene, hence they have a much higher probability of developing Duchenne muscular dystrophy than girls. A very small number of girls develop Duchenne muscular dystrophy._x000D_ _x000D_ Initial symptoms of Duchenne muscular dystrophy usually present between the ages of 1 and 3 years and children with the disease may appear weaker than other children, and have difficulty walking, standing, or climbing stairs, and may have behavioural or learning difficulties. After the age of 12 most children will need to use a wheelchair. During adolescence, breathing muscles can weaken, causing shallow breathing and a less effective cough mechanism, which can lead to chest infections. Weakness of the heart muscle, called cardiomyopathy, occurs in almost all patients by the age of 18 years. The life expectancy of people with Duchenne muscular dystrophy depends on how quickly and intensely muscle weakness progresses and how it affects the patient’s ability to breathe. The average lifespan is less than 30 years._x000D_ _x000D_ The prevalence of Duchenne muscular dystrophy is approximately 8.29 in 100,000. [1] Approximately 10% of patients with Duchenne muscular dystrophy carry a nonsense mutation in the dystrophin gene, equating to around 225 males aged over 2 years in England using current population size estimates. [2],[3] The proportion of these people who are able to walk is unknown. _x000D_ _x000D_ Increasing the time a patient is able to walk is one of the major aims of treatment. Treatment options for the management of Duchenne muscular dystrophy without ataluren do not treat the underlying cause of the disease and focus on alleviating symptoms and maintaining muscle strength. Interventions may include the use of steroids (associated with several side effects) and physical aids (such as wheelchairs, leg braces or crutches), exercise, physiotherapy, and occasionally orthopaedic surgery. In addition, other supportive treatments such as dietetic advice, prevention and treatment of bone fragility and the management of complications of long-term steroid therapy are required. In the later stages of Duchenne muscular dystrophy, treatments to help improve breathing and increase oxygen levels may be needed if lung function becomes impaired._x000D_ _x000D_ NICE highly specialised technologies guidance on ataluren for treating Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene considered use in people aged 5 years and older who can walk (HST3) in line with the managed access agreement. Since Highly Specialised Technologies guidance 3, the conditional marketing authorisation for ataluren has been extended to include people between the ages of 2 and 5 years and the managed access agreement was subsequently updated to include this extension. This evaluation will consider people aged 2 years and older, in line with the conditional marketing authorisation._x000D_ _x000D_ References_x000D_ 1. Norwood FL et al. (2009) Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain: 132(11); 3175-3186_x000D_ 2. Bladen CL et al. (2015) The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations. Human Mutation: 36(4); 395–402_x000D_ 3 Office for National Statistics. Population estimates for the UK, England and Wales, Scotland and Northern Ireland: mid-2020. Accessed January 2022.

Lay abstract: To evaluate the benefits and costs of ataluren within its marketing authorisation for treating Duchenne muscular dystrophy, resulting from a nonsense mutation in the dystrophin gene for national commissioning by NHS England.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL