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NICE has yesterday published draft guidance as part of its highly specialised technologies programme that recommends further clinical trials are carried out to demonstrate the benefits of sebelipase alfa (Kanuma, Alexion Pharma UK) for treating lysosomal acid lipase (LAL) deficiency, a rare inherited genetic disorder.

The draft guidance recommends that the research should be designed to generate robust evidence about the costs and benefits of long-term treatment with sebelipase alfa compared with shorter term treatment (‘bridging therapy’) followed by blood and marrow transplantation (also known as haematopoietic stem cell transplantation) in people diagnosed with rapidly progressive LAL deficiency before they were 6 months old.

Sebelipase alfa is not recommended for treating LAL deficiency in people who did not present with rapidly progressive LAL deficiency before they were 6 months old.

LAL is an enzyme that is responsible for breaking down fats in a part of the cell called the lysosome. Since the LAL enzyme is missing, or deficient, the fats build up in cells primarily in the liver, gastrointestinal and cardiovascular systems.

Rapidly progressing LAL deficiency in babies is usually diagnosed within the first weeks of life. It causes gastrointestinal and liver problems including malabsorption, growth failure, profound weight loss, steatorrhoea (excretion of fat in stools) and hepatomegaly (enlarged liver). Survival is less than 12 months and the median life expectancy of a baby with rapidly progressing LAL is 3.7 months.

In people presenting with symptoms later in life the rate of progression and severity and extent of symptoms is more variable. Children and adults with LAL deficiency frequently have abdominal pain, fatigue, diarrhoea, nausea, loss of appetite, itchy skin and a swollen abdomen. It is estimated that approximately 50% of children and adults with LAL deficiency progress to have liver complications such as fibrosis, cirrhosis or need a liver transplant within 3 years of the start of their symptoms. The life expectancy of people with LAL deficiency that presents after infancy is not clear because of the variability of symptom severity and rate of progression.

A variety of supportive therapies are used to try and slow the progress of the disease, including special diets and drugs for disease complications (for example, statins to reduce cholesterol).

Sebelipase alfa is a recombinant human lysosomal acid lipase enzyme replacement therapy and is the only active treatment available that specifically targets the underlying cause of LAL deficiency.

Based on the average yearly cost over 10 years for a patient starting treatment at 11 years of age, the total cost per person per year of treatment with sebelipase alfa is £491,992.

Commenting on the draft guidance Professor Carole Longson MBE, NICE Health Technology Evaluation Centre Director, said: “LAL deficiency can be a devastating condition, particularly where it progresses rapidly in babies less than 6-months old. There is a clear need for a treatment that can stop it progressing and let people with the condition live as normal a life as possible.

“The committee concluded that sebelipase alfa had a treatment effect compared with best supportive care. There was a lack of data on whether it completely reversed LAL deficiency over the long term and prevented complications of the condition.

“The committee considered that, even based on more optimistic assumptions of long-term treatment effect, the cost of sebelipase alfa would be very high, and that it would be higher relative to treatment benefits than it had previously regarded as acceptable. As a consequence the committee did not think that sebelipase alfa represented good value for money to the NHS to be used to treat everyone with LAL deficiency.

“The evidence of the benefits of sebelipase alfa for babies with rapidly progressive LAL deficiency was more compelling. The committee concluded that more research was needed to explore the potential benefits of using sebelipase alfa in babies to stabilise their condition before undertaking a bone marrow stem cell transplant aimed at curing the disease. In these circumstances, the use of sebelipase alpha would be likely to represent good value to the NHS.”

NICE has not yet issued final guidance to the NHS; these decisions may change after consultation. Consultees, including the company, healthcare professionals, patient/carer organisations and members of the public are now able to comment on the preliminary recommendations which are available for public consultation until 5pm on 10 March 2016. Comments received during this consultation will be considered by the Committee at its next meeting on 22 March 2016. Following this meeting, the next draft guidance will be issued.

The draft guidance recommends that people whose treatment with sebelipase alfa started within the NHS before the final guidance is published should be able to continue treatment until they and their NHS clinician consider it appropriate to stop. If applicable, this decision should be made jointly by the clinician and the child or young person, and their parents or carers.

For more information call the NICE press office on 0845 003 7782 or out of hours on 07775 583 813.

Notes to Editors

About the draft guidance

1. The draft guidance on sebelipase alfa will be available on the NICE websitefrom 
   18 February 2016.
2. NICE has prepared an illustration of the possible budget impact of sebelipase alfa for treating LAL deficiency in England, using information available in the public domain. This was based on the list price of sebelipase alfa and the company’s estimate of average yearly drug cost (£491,992 per person based on the average yearly cost over 10 years for a patient starting treatment at 11 years).
3. In this illustration, NICE have assumed that the number of people treated in year 1 is approximately the number of people currently diagnosed with LAL deficiency in England, which it heard from clinical experts to be approximately 10% of the estimated population from gene mutation studies.
4. NICE assumed that the number of people treated with sebelipase alfa would increase over time and not all people with milder symptoms would need to start treatment immediately. NICE assumed that all people whose LAL deficiency symptoms were severe enough to need treatment would continue to take sebelipase alfa.

Table 1 Calculation of budget impact by NICE

About sebelipase alfa

• Sebelipase alfa (Kanuma, Alexion Pharma UK) is a recombinant human lysosomal acid lipase. It has a marketing authorisation in the UK for long-term enzyme replacement therapy in patients of all ages with lysosomal acid lipase (LAL) deficiency.
  1. For babies under 6 months with rapidly progressing LAL deficiency, 1 mg/kg sebelipase alfa is administered by intravenous infusion once weekly. The dose may be escalated to 3 mg/kg once weekly based on clinical response.
  2. For children and adults who do not present with rapidly progressive LAL deficiency before they are 6 months old, 1 mg/kg sebelipase alfa is administered by intravenous infusion once every other week.

About LAL deficiency

1. Lysosomal acid lipase (LAL) deficiency is an inherited autosomal recessive lysosomal storage disorder. Mutations in the lysosomal acid lipase gene result in deficiency of the LAL enzyme. This causes abnormal accumulation of lipids, mainly in the gastrointestinal, hepatic and cardiovascular systems.
2. The prevalence of LAL deficiency in England is unknown. The estimated incidence of LAL deficiency is 1 in 500,000 to 1 in 1,000,000 in children presenting in infancy and 1 in 40,000 to 1 in 300,000 in those presenting in childhood or adulthood.
   • The rate of progression of LAL deficiency and its mortality differs markedly depending on when people present with symptoms. Babies under 6 months who present with LAL deficiency generally have a rapidly progressive condition, although some have a milder course. The rate of progression in children and adults is slower and more variable than in babies. Most people present with symptoms during childhood: 83% of patients present by 12 years, with a median age of onset of 5 years. 

About NICE

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