Alipogene tiparvovec (AMT-011, Glybera) for lipoprotein lipase deficiency February 2009 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research February 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Alipogene tiparvovec (Glybera) for lipoprotein lipase deficiency Target group • Lipoprotein lipase deficiency - also known as familial chylomicronaemia or hyperlipoproteinaemia type I. Background Lipoprotein lipase deficiency (LPLD) is an inherited metabolic disorder, characterised by abnormally elevated plasma concentrations of chylomicrons and triglycerides. LPLD includes patients classified as having hyperlipoproteinaemia type 1 (also known as familial chylomicronaemia) due to a deficiency of lipoprotein lipase (LPL) and those with a deficiency of apolipoprotein C-II, a lipase activating protein. LPL hydrolyses the triglyceride component of circulating chylomicrons and very low density lipoproteins (VLDL). When LPL activity is reduced, chylomicrons accumulate within the bloodstream and cause symptoms such as: abdominal pain, an enlarged spleen and liver, eruptive xanthomas and potentially lethal pancreatitis. The gene encoding for LPL is located on chromosome 8 and is expressed mainly in skeletal muscle, adipose tissue, and heart muscle. Technology description Alipogene tiparvovec (AMT-011, Glybera) is an adeno-associated viral vector (AAV1) based gene therapy, administered intramuscularly (IM) at multiple-sites in a single session. AAV1 carrying the human variant LPLS447X gene is delivered to skeletal muscle, where it becomes active. The LPL protein is expressed and transported to the capillary endothelium where it binds to chylomicrons and VLDL. Alipogene tiparvovec is intended as a curative measure for patients with LPLD and, as well as enhancing chylomicron metabolism, may prevent episodes of pancreatitis. Innovation and/or advantages If licensed, alipogene tiparvovec will be the first therapy to potentially cure LPLD. Developer Amsterdam Molecular Therapeutics (AMT) B.V. Availability, launch or marketing dates, and licensing plans: Alipogene tiparvovec is a designated orphan drug in the EU. The company anticipate a Marketing Authorisation Application with the EMEA in Q3/4 2009. NHS or Government priority area This topic is relevant to The National Service Framework for Diabetes (2007), as many patients develop diabetes. Relevant guidance No relevant guidance on LPLD was identified. Clinical need and burden of disease LPLD is a very rare disorder with no data identified on the incidence and prevalence in the UK. It is estimated that approximately 1 in 1,000,000 people are affected in populations, which equates to approximately 52 people in England and Wales1. Prognosis 2 February 2009 National Horizon Scanning Centre News on emerging technologies in healthcare is thought to be relatively good when a very low fat diet is maintained with early mortality and morbidity mainly due to recurrent pancreatitis; these patients are also at risk of developing diabetes mellitus. A number of acquired conditions such as kidney and liver disease, alcoholism and diabetes mellitus may also raise triglyceride levels. There is debate about how closely LPLD is associated with accelerated atherosclerosis and increased cardiovascular risk independent of diabetes2,3. Existing comparators and treatments Currently there is no effective treatment or cure for LPLD. The primary objective is to reduce pancreatitis by preventing chylomicronaemia. Patients must follow a lifetime diet with extremely low fat intake at less than 20g per day (<10% of total daily intake in calories). A 20g to 40g per day medium-chain triglyceride diet may be used to supplement calorie intake. Pharmacological treatment options include statins, nicotinic acid, fibrates and fish oils (no evidence of specific benefit in patients with LPLD). Fat soluble vitamins A, D, E and K and mineral supplements are recommended. Efficacy and safety Trial CT-AMT-010; LPLD; CT-AMT-011-01; LPLD; NCT008913064: phase II with 5 year phase II/III, with long term Alipogene Tiparvovec; extension. follow up. phase II/III. Sponsor AMT. AMT. AMT. Status Conference abstract5,6. Conference abstracts7,8 Ongoing interim results. Location Netherlands. Canada. Canada Design Open label, dose Open label. Open label, non-controlled. escalating. Participants n=8; adults; LPLD (LPL n=14; adults; LPLD. n=8 (planned); adults; and activity ≤ 20%, LPL mass Randomised to AMT-011 LPLD (LPL activity ≤ schedule >5% of normal, TG levels 1x1012 gc/kg and 20%, TG levels > > 10mmol/L). immunosuppression or 10mmol/L); previous Randomised to AMT-010 AMT-011 3x1011 gc/kg or pancreatitis. 1x1011 gc/kg (n=4) or AMT-011 3x1011 gc/kg and Received AMT-011 1x1012 AMT-010 3x1011 gc/kg immunosuppression. gc/kg with mycophenolate (n=4) intramuscular (IM) mofetil and cyclosporine administration. (for 12 weeks) and IV methylprednisolone (single dose). Follow-up 12 week initial observation 12 week initial observation 12-14 week treatment period with 5 years long period with 15 years long period with 1 year term follow up. term follow up. extension. Primary Median fasting Triglycerides (TG) levels; TG levels. outcomes triglycerides (TG) ≤10 metabolic indicators; mmol/L or a ≥40% serious adverse events; reduction on top of a fat viral shedding. free diet. Secondary LPL protein mass & Reduction of chylomicrons outcomes activity; immune response. and/or chylomicron-TG Safety including ratio; safety. 3 February 2009 National Horizon Scanning Centre News on emerging technologies in healthcare pancreatitis events. Key results At 12 weeks all patients At end of year 1 no had reduced median TG episodes of pancreatitis level (p<0.007), with a reported. Fat mean reduction of 27% accumulations in skin or and 41% for AMT-010 retina disappeared or 1x1011 gc/kg and 3x1011 reduced. In 2 diabetic gc/kg. Pancreatitis events patients, reduction of reduced from 0.49 to 0.04 insulin resistance observed. episodes per year per All patients reported patient. increase in energy. At 18 to 31 months TG levels were not significant reduced from baseline. Expected 12 weeks study started Interim follow up results Study started in April reporting finished April 2007. Long by end of 2009. 2009, main study end date term follow up results estimated November 2009. expected by end 2009. Adverse No serious AE’s observed. One episode of pancreatitis - effects immediately after injection not judged to be related to interventional therapy. Estimated cost and cost impact The cost of alipogene tiparvovec is not yet known. Potential or intended impact – speculative Although alipogene tiparvovec has potential to make a significant impact in patients with LPLD the requirement for patients to receive ongoing immunosuppression is uncertain. Patients will still need to adhere to a lipid-restricted diet. Patients ;Reduced morbidity Reduced mortality or increased ; Improved quality of life for length of survival patients and/or carers Quicker, earlier or more accurate Other: None identified diagnosis or identification of disease Services Increased use Service reorganisation required ; Staff or training required Decreased use ; Other: dependent on whether None identified patients see a specialist and the frequency of visits. Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed ; New costs: addition to current ; Savings: Fewer hospitalisations Other: therapy and requires 3 months of for pancreatitis immunosuppressive therapy References 1 Orphanet. Hyperlipoproteinemia type 1. http://www.orpha.net/consor/cgi- bin/Disease_Search.php?lng=EN&data_id=3263&Disease_Disease_Search_diseaseGroup=hyperlipoproteinem 4 February 2009 National Horizon Scanning Centre News on emerging technologies in healthcare i&Disease_Disease_Search_diseaseType=Pat&Disease(s)%20concerned=Hyperlipoproteinemia-type- 1&title=Hyperlipoproteinemia-type-1&search=Disease_Search_Simple Accessed 27 November 2008. 2 Nierman M C, Rip J, Twisk J et al. Gene therapy for genetic lipoprotein lipase deficiency: from promise to practice. The Journal of Medicine (Netherlands) 2005; 63: 14-19. 3 Benlian P, Genne JL, Foubert L et al. Premature atherosclerosis in patients with familial chylomicronaemia caused by mutations in the lipoprotein lipase gene. New England Journal of Medicine 1996;335:848-54. 4 ClinicalTrials.gov. Efficacy and safety of human lipoprotein lipase (LPL) [S447X] expressed by an adeno- associated viral vector in LPL-deficient subjects. http://www.clinicaltrials.gov/ct2/show/NCT00891306?term=NCT00891306&rank=1 Accessed 04 August 2009. 5 Nierman MC, Twisk J, Hermens WT et al. Biodistribution of AAV1-LPLS447X vector sequences after intramuscular administration to lipoprotein lipase deficient patients. American Society of Gene Therapy annual meeting 2007. Molecular Therapy; 15; Supplement 1; S132. 6 Franssen R, Stroes ESG, Kuivenhoven JA et al. Safety and efficacy of AMT-010 gene therapy in lipoprotein lipase deficiency (LPLD).International Symposium on Atherosclerosis 2009. Poster. 7 Gaudet D, Methot J, Essiembre C et al. Biodistribution of AAV1-LPLS447X