Appendix B NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE Proposed Highly Specialised Technology Evaluation Alipogene tiparvovec for treating familial lipoprotein lipase deficiency Draft scope (pre-referral) Draft remit/evaluation objective To evaluate the benefits and costs of alipogene tiparvovec within its licensed indication for treating adults with familial lipoprotein lipase deficiency for national commissioning by NHS England. Background Familial lipoprotein lipase deficiency (LPLD), also known as hyperlipoproteinaemia type I, is an inherited metabolic disorder of lipid metabolism. It is caused by the absence or low activity of lipoprotein lipase, due to mutations in the LPL gene which encodes the enzyme.1 Lipoprotein lipase is the enzyme responsible for uptake of triglycerides from the circulating chylomicrons into the tissues.2 LPLD is characterised by extremely high levels of chylomicrons in the blood. Chylomicrons are triglyceride-rich lipoprotein particles that transport dietary fat absorbed from the intestine to the organs like skeletal muscle, adipose tissue, and cardiac muscle for energy production and storage.3 Familial lipoprotein lipase deficiency may present in infancy or childhood with repetitive episodes of severe, colicky pain in the abdomen, repeated episodes of pancreatitis (inflammation of the pancreas), enlargement of the liver and spleen, and often failure to thrive. The severity of the symptoms depends upon the levels of chylomicrons in the blood. Acute pancreatitis is a life- threatening condition which requires intensive care; repeated attacks of pancreatitis may lead to chronic pancreatitis and diabetes in later life. Diagnosis is sometimes not confirmed until adolescence or adulthood and can involve genetic testing and/or measurement of enzyme activity.4 The prevalence of familial lipoprotein lipase deficiency is estimated to be 1 to 2 per million people which equates to approximately 50 to 100 people in England. Men and women are equally affected.5 Currently the management for LPLD in England consists of restriction of dietary fat intake to no more than 20 g/day in order to keep plasma triglyceride levels low.1 Essential fatty acids (linoleic and alpha linoleic acids) and fat soluble vitamins (vitamins A, D, E and K) supplementations are required for patients on fat restricted diet. In addition to that treatments for hypercholesterolaemia (such as fibrates, nicotinic acids and statins) may be prescribed but have limited value.6 Compliance with the strict dietary regimen is usually difficult to achieve and even with good compliance people often have high triglyceride levels. National Institute for Health and Care Excellence Draft scope for the proposed evaluation of alipogene tiparvovec for treating familial lipoprotein lipase deficiency Issue Date: March 2016 Page 1 of 5 Appendix B The technology Alipogene tiparvovec (Glybera, UniQure and Chiesi) is a gene therapy. It consists of a viral vector designed to deliver and express a variant of human LPL gene into the muscle cells of the patient enabling the muscle cells to produce the lipoprotein lipase enzyme. Alipogene tiparvovec is administered intramuscularly at multiple sites as a one-time treatment. Alipogene tiparvovec has a marketing authorisation for treating adult patients diagnosed with familial lipoprotein lipase deficiency with severe or multiple pancreatitis attacks despite dietary fat restrictions. It is indicated only for patients whose disease has been confirmed by appropriate genetic testing and who have detectable levels of the lipoprotein lipase enzyme in their blood. Intervention(s) Alipogene tiparvovec Population(s) Adults diagnosed with familial lipoprotein lipase deficiency and experiencing severe or multiple pancreatitis attacks despite dietary fat restrictions. Comparators Established clinical management (including dietary fat restrictions) Outcomes The outcome measures to be considered include: reduction in fasting triglyceride levels reduction in chylomicron levels after meals incidence of acute pancreatitis hospitalisation (including admissions to intensive care units) mortality adverse effects of treatment health-related quality of life (for patients and carers). Nature of the disease morbidity and patient clinical disability condition with current standard of care impact of the disease on carer’s quality of life extent and nature of current treatment options Impact of the new clinical effectiveness of the technology technology overall magnitude of health benefits to patients and, when relevant, carers heterogeneity of health benefits within the population National Institute for Health and Care Excellence Draft scope for the proposed evaluation of alipogene tiparvovec for treating familial lipoprotein lipase deficiency Issue Date: March 2016 Page 2 of 5 Appendix B robustness of the current evidence and the contribution the guidance might make to strengthen it treatment continuation rules (if relevant) Cost to the NHS and budget impact in the NHS and PSS, including Personal Social patient access agreements (if applicable) Services (PSS), and robustness of costing and budget impact Value for Money information technical efficiency (the incremental benefit of the new technology compared to current treatment) productive efficiency (the nature and extent of the other resources needed to enable the new technology to be used ) allocative efficiency (the impact of the new technology on the budget available for specialised commissioning) Impact of the whether there are significant benefits other technology beyond than health direct health whether a substantial proportion of the costs benefits, and on the (savings) or benefits are incurred outside of the delivery of the NHS and personal and social services specialised services the potential for long-term benefits to the NHS of research and innovation staffing and infrastructure requirements, including training and planning for expertise. Other considerations Guidance will only be issued in accordance with the marketing authorisation. The appraisal will include consideration of the costs and implications of genetic testing and measurement of enzyme activity, but will not make recommendations on specific diagnostic tests. Related NICE None recommendations and NICE Pathways Related National None Policy National Institute for Health and Care Excellence Draft scope for the proposed evaluation of alipogene tiparvovec for treating familial lipoprotein lipase deficiency Issue Date: March 2016 Page 3 of 5 Appendix B Questions for consultation Have all relevant comparators for alipogene tiparvovec been included in the scope? Which treatments, if any, are considered to be established practice for treating familial lipoprotein lipase deficiency? Are both molecular genetic testing and measurement of lipoprotein lipase enzyme activity required to confirm a diagnosis of LPLD in the NHS? Are there any subgroups of people in whom alipogene tiparvovec is expected to provide greater clinical benefits or more value for money, or other groups that should be examined separately? NICE is committed to promoting equality of opportunity, eliminating unlawful discrimination and fostering good relations between people with particular protected characteristics and others. Please let us know if you think that the proposed remit and scope may need changing in order to meet these aims. In particular, please tell us if the proposed remit and scope: could exclude from full consideration any people protected by the equality legislation who fall within the patient population for which alipogene tiparvovec is licensed; could lead to recommendations that have a different impact on people protected by the equality legislation than on the wider population, e.g. by making it more difficult in practice for a specific group to access the technology; could have any adverse impact on people with a particular disability or disabilities. Please tell us what evidence should be obtained to enable the Highly Specialised Technologies Evaluation Committee to identify and consider such impacts. Do you consider the technology to be innovative in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (is this a ‘step-change’ in the management of the condition)? NICE intends to evaluate this technology through its Highly Specialised Technologies Programme. We welcome comments on the appropriateness of evaluating this topic through this process. (Information on the Institute’s Highly Specialised Technologies interim methods and evaluation processes is available at: http://www.nice.org.uk/media/DE4/9A/HSTCombinedInterimProcessMethods. pdf. National Institute for Health and Care Excellence Draft scope for the proposed evaluation of alipogene tiparvovec for treating familial lipoprotein lipase deficiency Issue Date: March 2016 Page 4 of 5 Appendix B 1 Brunzell J (October 1999 [updated April 2014]) Familial Lipoprotein Lipase Deficiency, GeneReviews. 2 EMA (April 2004) Glybera - Summary of product characteristics. 3 Dixon JB (July 2010) Mechanisms of chylomicron uptake into lacteals, Annals of the New York Academy of Sciences. 1207(Supplement 1): E52–E57. 4 EMA (October 2013) Public summary of opinion on orphan designation: Adeno-associated viral vector expressing lipoprotein lipase for the treatment of lipoprotein lipase deficiency. 5 EMA (November 2012) Recommendation for maintenance of orphan designation at the time of marketing authorisation Glybera (alipogene tiparvovec) for the treatment of lipoprotein lipase deficiency. 6 Heart UK (2012) LPLD04 Fact Sheet - Treatment options. National Institute for Health and Care Excellence Draft scope for the proposed evaluation of alipogene tiparvovec for treating familial lipoprotein lipase deficiency Issue Date: March 2016 Page 5 of 5 .