EMEALAL-DMARKETING

Congress SummaryREPORT 2016

In 2016, Alexion attended three European congresses (EAS, EASL and ESPGHAN) that focused on hepatology and lipidology, the overall object of which was to raise awareness of lysosomal acid lipase deficiency (LAL-D) and provide insight into novel treatment options, such as the enzyme replacement therapy (ERT), sebelipase alfa.

This report is intended to summarise the key messages from the congress activity and is a useful report to build in 2017 upon the foundations laid in 2016. We hope you find the report helpful in summarising the prog-ress made and we look forward to working with you througout this year to continue the enhancment of knowl-edge in the field of LAL-D.

51st Annual Meeting of theEUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER (EASL)

Chairperson: Vlad Ratziu Pitié-Salpêtrière Hospital, Paris, France

Speakers: Jesús Quintero Hospital Vall d’Hebron, Barcelona, Spain Uta Drebber University of Cologne, Cologne, Germany Patrick Gerner University of Freiburg, Freiburg, Germany Suresh Vijay Birmingham Children’s Hospital, Birmingham, UK

Alexion activities: Commercial + medical booth / Symposium / Market Research / Meet the Expert(s) at booth

49th Annual Meeting of theEUROPEAN SOCIETY FOR PAEDIATRIC GASTROENTEROLOGY,HEPATOLOGY AND NUTRITION (ESPGHAN)

Chairperson: Valerio Nobili Bambino Gesù Children’s Hospital, Rome, Italy

Speakers: John J Gargus Center for Autism Research and Translation, University of California, USA Fiona White Manchester Centre for Genomic Medicine, Manchester, UK

Alexion activities: Commercial + medical booth / Symposium / Market Research / Meet the Expert(s) at booth

84th EUROPEAN ATHEROSCLEROSIS SOCIETY CONGRESS (EAS)

Chairperson: Thomas Stulnig Medical University of Vienna, Vienna, Austria

Speakers: Elmar Aigner University of Salzburg, Salzburg, Austria Patrick Gerner Freiburg University, Freiburg, Germany

Alexion activities: Commercial + medical booth / Symposium / Limited Market Research / Meet the expert (o�cial session following sympo)

31 MAY 2016

26 MAY 2016

16 APRIL 2016

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I N T E R N A L U S E O N L Y

INTRODUCTIONLysosomal Acid LipaseDeficiency (LAL-D)

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LYSOSOMAL ACID LIPASE DEFICIENCY (LAL-D) IS A RARE AUTOSOMAL ANDPROGRESSIVE GENETIC DISORDER THAT AFFECTS PATIENTS OF ALL AGES.1,2

LAL-D IS SEVERELY UNDERDIAGNOSED AND IS ASSOCIATED WITH SIGNIFICANTMORBIDITY INVOLVING PROGRESSIVE DAMAGE IN MULTIPLE ORGAN SYSTEMSAND PREMATURE MORTALITY.

Lysosomal acid lipase (LAL) is a ubiquitous enzyme that catalyses the lysosomal hydrolysis of cholesteryl esters (CEs) and triglycerides (TGs) to free cholesterol, glycerol and free fatty acids (FFAs). Mutations in the LIPA gene result in complete or near-complete loss of enzyme functionality, resulting in acute comorbidities, multi-organ damage and premature mortality. LAL-D affects lipid metabolism and results in multi-organ damage in the majority of patients, including the cardiovas-cular (87%), liver (86%), spleen (36%) and GI (22%) systems1,2

LAL-D is a disease that presents as a clinical continuum affecting infants, children, and adults. Historically, the infant presentation of LAL-D was referred to as Wolman disease. Presentation in children or adults was histori-cally called cholesteryl storage disease (CESD). It was not appreciated until later that these conditions are actu-ally different manifestations of the same disease and that they are both caused by mutations within the LIPA geneLAL-D in infants progresses rapidly, resulting in liver failure and premature death, often within the first 6 months of life. Clinical manifestations include growth failure, hepatosplenomegaly, adrenal calcification, persistent vom-iting, diarrhoea and abdominal distension.1

Progression of the disease is due to lysosomal accumulation of TGs and CEs and, in the long-term, results in fibrosis and cirrhosis of the liver, liver failure requiring transplantation and dyslipidaemia leading to accelerated atherosclerosis.2

Certain key phenotypes have been identified to support differentiation of LAL-D and include elevated transami-nase, low-density lipoprotein (LDL) and total cholesterol levels, in combination with reduced levels of high-density lipoprotein (HDL), as well as hepatomegaly, splenomegaly and steatosis and/or fibrosis. The diagnosis of LAL-D can be confirmed by an enzyme-based dry blood spot test for LAL activity.Nutritional management is essential to controlling gastrointestinal (GI) symptoms of patients with LAL-D, and modified diets should be implemented in any patient with LAL-D diagnosis.Sebelipase alfa, recently approved in Europe and the USA, is the first ERT for LAL-D and has been shown to slow disease progression markers. Therefore, it is vital to identify patients early who may benefit from such treatment.

CORRECT DIAGNOSIS OF LAL-D IS CHALLENGING OWING TO SYMPTOM SIMILARITY WITH OTHER METABOLIC DISORDERS AND A LACK OF AWARENESS OF THIS RARE DISEASE.

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The pathophysiology of LAL-D was discussed at the all three congresses, underpinning the essential need for physicians and other healthcare workers to be educated on the underlying cause of disease in order to understand the mechanism of action of LAL-D.

LAL-D is a genetic autosomal recessive lysosomal storage disorder that is caused by mutations in the LIPA gene on chro-mosome 10, which encodes the enzyme LAL.2 The most common mutation leading to LAL-D (present in 60% of patients) is the E8SJM mutation.3 However, LAL-D is often under - or misdiagnosed, arising from lack of clinical awareness.

On a cellular level, the LDL receptor facilitates the uptake of TGs and cholesterol, which is delivered to the lysosome. Under physiologically normal circumstances, hydrolysis of LDL by LAL releases FFAs and free cholesterol (FC), which are essential for cellular functions. In patients with LAL-D, diminished or absent enzyme activity leads to accumulation of TGs and CEs in the lysosome (causing it to swell). FC and FFAs are not released from the cell, leading to upregulation of LDL receptor, increased cholesterol uptake and increased LDL levels (by enhancing lipogenesis and cholesterol synthesis), thus creating a positive feedback loop 2,4,5 and potentiating the detrimen-tal effects of LAL-D. Furthermore, signalling via nuclear receptors, such as the liver X receptor, reduces HDL levels (Figure 1). Dyslipidaemia, which is characterised by increased levels of LDL and decreased HDL, as well as irregular lipid deposition, are often the hallmarks of LAL-D.6

The lysosomal accumulation of CEs and TGs leads to progressive multi-organ damage, affecting the liver, spleen, GI tract and the cardiovascular system.1,2,7

Figure 1. Biology of LAL-D.2

PATHOPHYSIOLOGY

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CLINICAL MANIFESTATIONS

Hepatic manifestations included hepatomegaly (99% of patients) and elevated liver enzymes (89%), with evidence of dysfunction/cirrhosis (e.g. portal hypertension, occurring in 65 - 70% of patients).1 Liver histopathol-ogy shows microvesicular steatosis and fibrosis/cirrhosis (85% of patients).8 Splenomegaly (due to macrophagic accumulation of CEs) occurs in up to 80% of patients with LAL-D.9 Intestinal manifestations of LAL-D are primarily due to infiltration of histiocytes/macrophages to the proximal colon, resulting in: intestinal malabsorption / steat-orrhoea, diarrhoea, vomiting, failure to thrive (in infants) and abdominal pain.10 Moreover, several metabolic disturbances are evident in LAL-D, such as elevation of LDL and TG levels, and HDL reduction.1,6

In all patients, raised total cholesterol occurs, and >95% have LDL values above normal, with ~80% of patients having LDL values >200 mg/dL. Low HDL values are common.1

LDL infiltrates into healthy blood vessels, leading to inflammation and formation of atherosclerotic plaques. Thus, LAL-D patients are at risk of developing advanced arteriosclerosis, coronary heart disease (myocardial infarction) and other cerebrovascular events.1

When investigating clinical features of LAL-D, Burton et al.11 found elevated levels of ALT and AST in the majority of patients. In addition, most patients present with elevated levels of LDL (>200 mg/dL) and total cholesterol, despite receiving lipid-lowering therapies, and almost 50% of patients display low levels of HDL (below 40 mg/dL).

CLINICAL MANIFESTATIONS AND DIAGNOSIS

CLINICAL MANIFESTATIONS IN 135 PATIENTS WITH LAL-D WHO SURVIVED THE FIRST YEAR OF LIFE

1000 10 20 30 40 50 60 70 80 90

100%

90%

87%

74%

22%

HEPATIC MANIFESTATION

METABOLIC DISTURBANCES

CARDIOVASCULAR DISORDERS

SPLENOMEGALY

GI MANIFESTATION

Clinical manifestations of LAL-D are numerous and multi-systemic. In 135 patients with LAL-D who survived the first year of life, 100% had hepatic manifestations, >90% had metabolic disturbances, 87% had cardiovascular disorders, 74% had splenomegaly and 22% had GI manifestations.1

DISEASE SIMILARITY TO LAL-D CONSIDER LAL-D

DIAGNOSIS DIAGNOSIS OF LAL-D CAN BE CHALLENGING.1,2,12 IN ADDITION TO LACK OF CLINICAL AWARENESS, THE LONG DURATION BETWEEN INITIAL SYMPTOMS AND DIAGNOSIS IN SOME PATIENTS IS CONSISTENT WITH OTHER METABOLIC DISEASES.11

In particular, the noted abnormalities of hepatomegaly, elevated liver enzymes and/or fatty liver and dyslipidaemia, may be confused with more common disorders such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic syndrome and/or familial hypercholesterolaemia (Table 1).11

Thus, in the advent of ERT, it is important to identify patients that may benefit from such treatment and the pattern of dyslipidaemia may play a vital role in the diagnosis of LAL-D. However, it should be noted that, with progressing liver disease, hyperlipidaemia may resolve, making a LAL-D diagnosis more difficult.

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TABLE 1. Differential diagnosis of LAL-D.

LAL-D is further characterised by hepatomegaly, splenomegaly and steatosis, and/or fibrosis as assessed by biopsy. However, it has to be noted that, although a liver biopsy can provide a definitive diagnosis of NAFLD, LAL-D should be ruled out with laboratory testing. The simple test of total lipase activity to diagnose LAL-D17, with and without selective inhibition of LAL activity, assesses dried blood spot extracts with the substrate 4-methylumbelliferyl palmitate ± lalistat2 (a potent and specific LAL inhibitor).In affected cases, LAL activity has typically been 5% of normal mean. For a reliable test result, an adequate sample quality is indispensable. The blood spot needs to fill at least one entire circle on the dry blood spot card. The sample must be fully dry (ideally, overnight without exposure to direct sunlight or heat) and accompanied by a desiccant packaged in an airtight sealed bag for shipment.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

Wilson disease

Metabolic syndrome

Familial combinedhyperlipidaemia

Heterozygous familial hypercholesterolaemia

Non-alcoholic fattyliver disease

Asymptomatic hepatomegaly, isolatedsplenomegaly, persistently elevated AST and ALT,fatty liver, cirrhosis13

Decreased HDL and elevated TGs2

Decreased HDL and elevated LDL2

Elevated LDL2,15

Some patients may have elevated ALT,with or without hepatic steatosis16

No signs of central nervoussystem involvement14

Signs of metabolic syndromeand dyslipidaemia2

Laboratory values similar to FCHwith ALT > ULN2

Laboratory values similar to HeFHwith ALT > ULN, or no confirmed mutationfor HeFH-related gene2,15

NAFLD/NASH with ALT > ULN,and dyslipidaemia2

ALT, alanine aminotransferase; AST, aspartate aminotransferase; FCH, familial combined hyperlipidaemia; HeFH, heterozygous familial hypercho-lesterolaemia; HDL, high-density lipoprotein; LAL-D, lysosomal acid lipase deficiency; LDL, low-density lipoprotein; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; TG, triglyceride; ULN, upper limit of normal.

Testing for LAL-D should be performed in patients with liver and/or lipid abnormalities in line with the criteria detailed in Figure 2.1,18

IN A MULTI-ORGAN DISEASE SUCH AS LAL-D, IT IS OF GREAT IMPORTANCE TO OBTAIN A DIAGNOSIS AND TREAT EARLY TO PREVENT MULTI-ORGAN INVOLVEMENT AND TO BETTER ADDRESS LONG-TERM HEALTH.

Another aspect to consider is the difference in presentation between adults and infants; adrenal calcifications are seen more frequently in infants than in adults with LAL-D, in around 50% of cases.4,19

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Figure 2. Diagnostic pathway for LAL-D testing

CLINICAL MANIFESTATIONS AND DIAGNOSIS

The information on this slide is intended as educational information for healthcare professionals. It does not replace a healthcare professional's judgement or clinical diagnosis.aAt baseline, patients in a clinical trial evaluating a potential treatment for LAL-D had a mean LDL-c of 5.4 mmol/L and a mean HDL-c of 0.8 mmol/L; 73% (48/66) of patients had ALT ≥1.5x ULN and <3x ULN, and 27% (18/66) of patients had ALT ≥3x ULN. An ALT ≥1.5x ULN according to specified gender-specific normal ranges was one of the eligibility criteria for enrollment2,5; bAbove age- and gender-specific ULN1; cIn adult patients (mmol/L): LDL-c ≥4.1 (≥3.4 in patients on LLMs)1-3; dIn adult patients (mmol/L): HDL-c ≤1.0 (males)/≤1.3 (females)1-3; eBMI ≤95th percentile for age and gender.1,4

ALT, alanine aminotransferase; BMI, body mass index; LLM, lipid-lowering medication;NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ULN, upper limit of normal

1. Reiner Ž, et al. Atherosclerosis. 2014;235(1):21-30 5. Bernstein DL, et al. J Hepatol. 2013;58(6):1230-12432. Burton BK, et al. N Engl J Med. 2015;373(11):1010-1020 6. Burton BK, et al. J Pediatr Gastroenterol Nutr. 2015;61:619-253. Daniels SR, et al. Pediatrics. 2008;122(1):198-208 7. Hamilton J, et al. Clin Chim Acta. 2012;413(15-16):1207-12104. Data on file, Alexion Pharmaceuticals 8. Grundy SM, et al. Circulation. 2004;109(3):433-438

TEST FOR LAL-D WITH AN ENZYMATIC BLOOD TEST

or

or!)

DYSLIPIDEMIALDL-c (mmol/L): ≥3.4a,c orHDL-c (mmol/L): ≤1.2a,d

SUSPECTEDFCH

SUSPECTEDHeFH

SUSPECTEDMETABOLICSYNDROME

PERSISTENTLYELEVATED ALTa,b

MICROVESICULAROR

MIXED STEATOSIS

UNEXPLAINEDHEPATOMEGALY

FURTHER CONSIDERATIONS

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DIAGNOSTIC CASE STUDIES Presented by Professor John J Gargus at ESPGHAN 2016The female infant was born full-term at a normal weight, and although breastfed well, did not gain weight in her first 2 weeks. This was considered to be within normal limits, and the mother was advised to supplement breastfeeding with bottle feeds. At 10 weeks, the baby presented with diarrhoea and, by 11 weeks, was sent for evaluation to the paediatric oncology department due to severe failure to thrive, abdominal distension, suspected abdominal mass and a primary concern for neuroblastoma. Diagnostic tests showed suprarenal calcification, although LAL-D should also be considered in the absence of adrenal calcifica-tion. Although hepatomegaly and splenomegaly were observed, liver function tests were only mildly above the upper limit of normal (ULN), and urine organic acids and plasma amino acids were normal. Stool fat was elevated, but only subtle abnormali-ties in total cholesterol were observed. Crucially, consultation with a paediatric gastroenterologist led to evaluation of lysosomal enzymes and subsequent metabolic genetics testing, which demonstrated that LAL activity was nearly zero and confirmed a diagnosis of LAL-D.

Presented by Professor John J Gargus at ESPGHAN 2016A baby boy with no birth complications was first identified with haemoglobin E disease, elevated C4 acylcarnitines, failure to thrive, anaemia and a normal abdomen at 3 months old, and was treated with increased feeds and iron supplements. At 4 months old, he was briefly hospitalised with low haemoglobin and high AST levels; examinations showed a distended tender abdomen, splenomegaly and ascites, but a normal liver. The infant was given a transfusion and discharged, but was re-hospitalised at 5 months due to constant severe vomiting. Examination showed splenomegaly, ascites and hepatomegaly, and a computed tomography scan identified steatosis of the liver, ascites and calcified adrenal glands. At 5.5 months, the baby required transferral to intensive care with tachycardia, pericardial effusion, hypertonia and dystonic movements. A presump-tive diagnosis of Wolman disease was made by the radiologist on the basis of the calcified adrenals, which was subsequently confirmed by enzyme assay. The marked failure of this infant to thrive under the age of 6 months and sustained weight loss over several percentiles made him eligible for the clinical trial evaluating ERT in infants (LAL-CL03).

Presented by Professor Patrick Gerner at EASL 2016A 53-year old woman had problems starting in early childhood and described herself as ‘always very thin’. She had suffered from lifelong chronic diarrhoea and cachexia. However, her condition was not actively investigated until adulthood. In 1991, aged 29 years, she presented with massive hepatomegaly which extended to the iliac crest, although her liver enzymes were normal. Wilson’s disease, autoimmune hepatitis and viral hepatitis were ruled out. An abdominal ultrasound identified slightly hyperechogenic liver parenchyma. Mild gastritis was diagnosed with oesophagogastroduodenoscopy (EGD), and her ileoco-lonoscopy was normal. She had an intolerance to fatty foods, without signs of pancreatic insufficiency. At this stage, following multiple investigations by various physicians, her diagnosis was ‘probably anorexia nervosa’. Five years later, she presented with severe diarrhoea and significant weight loss, and her body mass index had decreased from 17.0 to 15.2 kg/m2. Steatosis hepatitis was identified by ultrasound. The EGD showed mild duodenitis, and again her ileocolonoscopy was normal. A liver biopsy showed microvesicular steatosis, mild portal inflammation, but no fibrosis. Clinical biochemistry identi-fied high cholesterol and LDL levels (227 and 169 mg/dL, respectively) with low HDL levels (40 mg/dL). Her blood levels of AST and ALT were elevated (46 and 53 U/L), although gamma-glutamyl transferase levels were normal (22 U/L). At this stage, the patient suffered severe liver pain (which required high doses of analgesics, including opiates), diarrhoea (5 stools/day), significant cogni-tive restriction (short-term memory) and constant hunger and exhaustion. Her quality of life score was only 2/10. A further liver biopsy in 2003 showed microvesicular steatosis (20%), grade 2 fibrosis and CD68 positive (immunohistochemical staining) macrophages laden with a foamy material. Based on this histopathology, LAL-D was suspected. This diagnosis was confirmed by the dried blood spot test (low LAL activity) and subsequent genetic analysis (homozygous mutation in the LIPA gene). Over 10 years later, in 2014, this patient commenced ERT in clinical trial LAL-CL06.

CASE 1

CASE 2

CASE 3

NUTRITIONAL ISSUE NUTRITIONAL INTERVENTION PRODUCT CHOICE

Fat malabsorption/utilisation

Protein malabsorption

Low albumin

Poor weight gain

Poor tolerance of feed volume

Failure to tolerate modified enteral feeds

Fat-soluble vitamin deficiency

EFA deficiency

Low total fat, MCT-based formula

Elemental low-fat feed

Increase protein ≥4 g/kg/day

Increase calories: concentrate formula, additional carbohydrate, additional MCTs?

Decrease volume, increase frequency; continuous feeds

Modified TPN:low fat, high protein, high glucose

Supplement

Supplement

Monogen® (lowest LCTand total fat content)

Modular feed ·Amino acids ·Glucose polymer ·MCT emulsion ·Micronutrients ·EFAs/LCPs

Glucose polymerMCT emulsion

Use modified lipid source, e.g. SMOFlipid™

Key Omega (Vitaflo®)

EFA, essential fatty acid; LCP, long-chain polyene; LCT, long-chain triglyceride; MCT, medium-chain triglyceride; TPN, total parenteral nutrition

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NUTRITIONAL MANAGEMENT

Presented by Ms Fiona White at ESPGHAN 2016

THE MANAGEMENT OF NUTRITION IN PATIENTS WITH LAL-D IS ESSENTIAL TO PREVENT FAILURE TO THRIVE IN CHILDREN AND WEIGHT LOSS AND MALNUTRITION IN PATIENTS OF ALL AGES.

In infants with LAL-D, there are a variety of nutritional issues to address, including malabsorption of proteins and fats, poor weight gain, poor tolerance of feed volume, failure to tolerate modified enteral feeds, and deficiencies of fat-soluble vitamins and essential fatty acids. Individual nutritional interventions with a range of feed products are available for each of these issues, and the task of the nutritionist is to identify the optimal combination to reduce symptoms and to establish growth of the infant (Table 2).

Table 2. Management of nutritional issues in infants with LAL-D

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SEBELIPASE ALFA IS A RECOMBINANT HUMAN LAL THAT COMPENSATES FOR LOST ENZYME ACTIVITY IN PATIENTS WITH LAL-D IN ITS CAPACITY AS NOVEL ERT.

The enzyme binds to cell-surface receptors and is internalised into lysosomes, where it catalyses the lysosomal hydrolysis of CEs and TGs to FC, glycerol and FFAs.6,20

In 2015, sebelipase alfa was approved in Europe and the USA21,22 for long-term ERT in patients of all ages with LAL-D. The recommended starting dose in infants (< 6 months of age) presenting with rapidly progressive LAL deficiency is 1 mg/kg administered as an intravenous infusion once weekly. Dose escalation to 3 mg/kg once weekly should be considered based on clinical response.The recommended dose in children and adults who do not present with rapidly progressive LAL deficiency prior to 6 months of age is 1 mg/kg administered as an intravenous infusion once every other week. The total volume of the infusion should be administered over approximately 2 hours. A 1 hour infusion may be considered after patient tolerability is established. The infusion period may be extended in the event of dose escalation.20,21,22

Sebelipase alfa is contraindicated in patients who experience life-threatening hypersensitivity to the active substance or are allergic to egg or any of the excipients.20 Following the first sebelipase alfa infusion, including the first infusion after a dose escalation, patients should be observed for 1 hour in order to monitor for any signs or symptoms of anaphylaxis or a severe hypersensitivity reaction.

TO DATE, EIGHT STUDIES, INCLUDING NATURAL HISTORY OF LAL-D OR CLINICAL TRIALS ASSESSING SEBELIPASE ALFA, HAVE BEEN INITIATED.11,23,24,25,26

One pivotal trial was ARISE, which was a multi-centre, randomised, placebo-controlled, double-blind Phase 3 trial designed to assess sebelipase alfa efficacy and safety in children and adults with LAL-D over 20 weeks (Figure 3). Patients were randomised to receive sebelipase alfa (n=36) or placebo (n=30). Following the double-blind phase, patients not already receiving sebelipase alfa were switched in a 32-week extension phase.

Figure 3. Study design of the phase III ARISE trial.26

SEBELIPASE ALFA for the treatment of LAL-D

* Excluded (n=20); inclusion criteria not met (n=17) or declined to participate (n=3)† One patient temporarily discontinued dosing in the double-blind period, although this patient successfully restarted therapy in the open-label extension. Two patients were excluded from per protocol analysis, one due to deviation of time window between week 18 and week 20 and one as they received less than 9 complete double-blind study drug infusions‡ One patient was excluded from per protocol analysis due to deviation of time window between week 18 and week 20

ENROLLMENT(N=86)

randomisationand allocation*

Intervention withsebelipase alfa (N=36)

Placebo (N=30)

Open-labeltreatment period (N=35)

Open-labeltreatment period (N=35)

Follow upand analysis †

Follow upand analysis ‡

▶20 WEEKS ▶32 WEEKS

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IMPACT ON TRANSAMINASEPatients with baseline ALT ≥1.5 x ULN were included in the study. In patients receiving sebelipase alfa, a rapid reduction in ALT levels was reported within the first 4 weeks of treatment, which was sustained throughout the core and extension phases. No change in ALT levels was seen in the placebo group compared with the sebelipase alfa group (p<0.001) after 20 weeks of treatment; however, ALT levels rapidly followed the same trend when patients were switched to the active treatment, with an overall reduction in ALT of 53.3% and 51.2%, respectively.20,26 ALT level response to sebelipase alfa was significant compared with placebo across baseline ALT groups stratified into ALT <3 x ULN and ≥3 x ULN.27

IMPACT ON CHOLESTEROL LEVELS A similar trend as observed for ALT was reported for LDL levels. Following an initial increase in LDL, sebelipase alfa steadily reduced LDL levels over the entire study period.26 Despite continuous small reductions in the placebo group, significant differences were observed between both treatment arms (p<0.001) at Week 20. Once patients were switched to sebelipase alfa, LDL levels decreased to the same extent as previously observed with active treatment in the first 20 weeks. Levels of HDL increased significantly with sebelipase alfa compared with placebo (p<0.001) in the first 20 weeks, after which they stabilised. No changes were reported in patients receiving placebo. However, when switched to active treatment, patients achieved HDL levels that were comparable to those of patients receiving active treatment in the core phase. Again, serum lipids responded to sebelipase alfa therapy independent of baseline ALT levels.27 Although LDL and HDL levels were improved, the effect of sebelipase alfa on cardiovascular morbidity and mortality has not been established.26

LIVER HEALTH Magnetic resonance imaging assessments demonstrated a significant difference in the reduction of liver fat content achieved with sebeliapse alfa and placebo (32% and 4% reduction, respectively; p<0.001).20 Liver steatosis was assessed by liver biopsy. Significant differences (p=0.0184) were reported between the placebo and the sebelipase alfa groups for both outcome categories (worsened or improved). In the placebo group, 50% of patients showed worsening of steatosis, whereas 50% reported improvements defined as an absolute decrease of 5% fat in haematoxylin- and eosin-stained sections. In comparison, 94% of patients treated with sebelipase alfa reported improvements for liver steatosis, providing evidence that treatment with sebelipase alfa is effective in reversing the LAL-D disease phenotype.27

ADVERSE EVENTSSebelipase alfa was well tolerated with an adverse-event (AE) profile expected for ERT. The rate of infusion reac-tions was comparable between both treatment arms. Common AEs with sebelipase alfa included metabolism and nutrition disorders, immune system disorders, cardiac disorders, vascular disorders, GI disorders, and skin and subcutaneous tissue disorders.20

SEBELIPASE ALFA for the treatment of LAL-D

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CASE STUDIES

Presented by Professor Patrick Gerner at EAS 2016A three-year-old boy presented with initial symptoms of LAL-D. Elevated levels of transaminases of unknown aetiology were reported after blood examination was performed to establish the cause of his gastroenteritis. His physical and cognitive development was normal and owing to transaminases being only slightly elevated, common causes of childhood hepatopathy, such as alpha-1-antitrypsin deficiency, hepatitis B and C, cytomegalovirus, Epstein-Barr virus, autoimmune hepatitis and Wilson‘s disease, were dismissed.

At 10 years old, extended investigations were performed to assess the cause of persistently increased transami-nase levels and significant hepatosplenomegaly. Laboratory results demonstrated mildly elevated AST and ALT, normal GGT values, significantly elevated LDL, and normal HDL and triglyceride levels. Sequencing of the LDL recep-tor indicated polymorphism, not associated with familial disease. Ultrasound and MRI testing suggested signifi-cant hepatomegaly, slight parenchymal steatosis and a slightly enlarged spleen. Liver puncture analyses showed activated macrophages, grade 3 fibrosis, microvesicular steatosis and cirrhosis. Familial combined hyperlipidae-mia and other familial forms of hypercholesterolaemia were not suspected, as these disorders do not usually pres-ent with abnormal liver profiles; thus, based on the observed symptoms, LAL-D was diagnosed. Diagnosis was confirmed by genetic analysis and evidence of common mutations in the LIPA gene, as well as marked reductions in enzymatic activity of LAL determined using the dry blood spot test.17

The patient received initial therapy with the lipid-lowering agent pravastatin 20 mg; however, due to treatment-emerging side effects, this therapy was replaced by simvastatin 40 mg for 1 year, ezetimibe 10 mg and ultimately a combination of atorvastatin 40 mg and ezetimibe, which he continues to receive at age 20 years.

Over the 10 years since diagnosis, an expected dramatic reduction in TC levels was accompanied by a steady increase in liver transaminases. Sebelipase alfa, 1mg/kg (or 3mg/kg if we know the dosing regime) every other week, was considered a suitable option for this patient and treatment commenced in May 2016. First infusions were well tolerated and termination of lipid-lowering agents is being considered.

CONCLUSION

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In summary, LAL-D is a progressive disease with significant morbidity and early mortality across all age groups, and is rapidly fatal in infants. The exact prevalence is unknown and is variable depending on ethnic background and geographic location, but is likely to be underestimated. Specific clinical scenarios should prompt testing for LAL-D, including hepatomegaly, elevated liver transaminases with high LDL and low HDL, suspected NAFLD, NAFLD/NASH with elevated ALT despite dietary modifications, microvesicular or mixed steatosis, cryptogenic cirrhosis, familial combined hyperlipidaemia or heterozygous familial hypercholesterolaemia with ALT above ULN and no confirmed mutation, and suspected Wilson’s disease. Diagnosis can be confirmed using a simple, minimally invasive screening test – the dry blood spot measurement of LAL enzyme activity. Other evaluations that may aid diagnosis include liver biopsy, which can prompt a LAL-D diagnosis, and genetic sequencing of the LIPA gene to provide additional information for patients. In patients diagnosed with LAL-D, ERT has been shown to change the course of the disease, with a positive impact on outcomes. In infants with LAL-D, nutritional intervention is an essential part of treatment.

IN 2016 WE HAVE SEEN A SUCCESSFUL CONGRESS YEAR IN WHICH ALEXION HAVE HAD THE PLEASURE OF COLLABORATING WITH EXPERTS. TOGETHER WE HAVE ENHANCED THE KNOWLEDGE ON LAL-D, TO ACCURATELY DIAGNOSE PATIENTS AND PROVIDE A SOLUTION FOR THIS DISEASE. WE ARE VERY MUCH LOOKING FORWARD CONTINUING OUR WORK IN COLLABORATION WITH ALL EMEA COUNTRIES IN 2017.

EMEA LAL-D Team

REFERENCES

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Acknowledgements: Writing assistance was provided by Juliane Moloney, Lucy Smithers and Mia Cahill, ApotheCom