Lal d report 2016

1. EMEA
LAL-D
MARKETING
Congress Summary
REPORT 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 the
EUROPEAN 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 the
EUROPEAN 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 (officialsessionfollowingsympo)
31 MAY 2016
26 MAY 2016
16 APRIL 2016
1
I N T E R N A L U S E O N L Y

2. INTRODUCTION
Lysosomal Acid Lipase
Deficiency (LAL-D)
2
LYSOSOMAL ACID LIPASE DEFICIENCY (LAL-D) IS A RARE AUTOSOMAL AND
PROGRESSIVE GENETIC DISORDER THAT AFFECTS PATIENTS OF ALL AGES.1,2
LAL-D IS SEVERELY UNDERDIAGNOSED AND IS ASSOCIATED WITH SIGNIFICANT
MORBIDITY INVOLVING PROGRESSIVE DAMAGE IN MULTIPLE ORGAN SYSTEMS
AND 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 gene
LAL-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-densitylipoprotein(LDL)andtotalcholesterollevels,incombinationwithreducedlevelsofhigh-density
lipoprotein(HDL),aswellashepatomegaly,splenomegalyandsteatosisand/orfibrosis.ThediagnosisofLAL-Dcan
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.
Sebelipasealfa,recentlyapprovedinEuropeandtheUSA,isthefirstERTforLAL-Dandhasbeenshowntoslowdisease
progressionmarkers.Therefore,itisvitaltoidentifypatientsearlywhomaybenefitfromsuchtreatment.
CORRECT DIAGNOSIS OF LAL-D IS CHALLENGING OWING TO SYMPTOM SIMILARITY WITH OTHER METABOLIC
DISORDERS AND A LACK OF AWARENESS OF THIS RARE DISEASE.

3. 3
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-DisageneticautosomalrecessivelysosomalstoragedisorderthatiscausedbymutationsintheLIPAgeneonchro-
mosome10,whichencodestheenzymeLAL.2 ThemostcommonmutationleadingtoLAL-D(presentin60%ofpatients)
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
(Figure1).Dyslipidaemia,whichischaracterisedbyincreasedlevelsofLDLanddecreasedHDL,aswellasirregular
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

4. 4
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
duetoinfiltrationofhistiocytes/macrophagestotheproximalcolon,resultingin:intestinalmalabsorption/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.Inaddition,mostpatientspresentwithelevatedlevelsofLDL(>200mg/dL)andtotalcholesterol,despite
receiving lipid-lowering therapies, and almost 50% of patients display low levels of HDL (below 40 mg/dL).
CLINICALMANIFESTATIONSANDDIAGNOSIS
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

5. 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.
5
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).
Inaffectedcases,LALactivityhastypicallybeen5%ofnormalmean.Forareliabletestresult,anadequatesample
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.
CLINICALMANIFESTATIONSANDDIAGNOSIS
Wilson disease
Metabolic syndrome
Familial combined
hyperlipidaemia
Heterozygous familial
hypercholesterolaemia
Non-alcoholic fatty
liver disease
Asymptomatic hepatomegaly, isolated
splenomegaly, 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 nervous
system involvement14
Signs of metabolic syndrome
and dyslipidaemia2
Laboratory values similar to FCH
with ALT > ULN2
Laboratory values similar to HeFH
with ALT > ULN, or no confirmed mutation
for 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.

6. 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 toconsideristhedifferenceinpresentationbetweenadults andinfants;adrenal calcificationsare
seen more frequently in infants than in adults with LAL-D, in around 50% of cases.4,19
6
Figure 2. Diagnostic pathway for LAL-D testing
CLINICALMANIFESTATIONSANDDIAGNOSIS
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):1230-1243
2. Burton BK, et al. N Engl J Med. 2015;373(11):1010-1020 6. Burton BK, et al. J Pediatr Gastroenterol Nutr. 2015;61:619-25
3. Daniels SR, et al. Pediatrics. 2008;122(1):198-208 7. Hamilton J, et al. Clin Chim Acta. 2012;413(15-16):1207-1210
4. 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
!)
DYSLIPIDEMIA
LDL-c (mmol/L): ≥3.4a,c or
HDL-c (mmol/L): ≤1.2a,d
SUSPECTED
FCH
SUSPECTED
HeFH
SUSPECTED
METABOLIC
SYNDROME
PERSISTENTLY
ELEVATED ALTa,b
MICROVESICULAR
OR
MIXED STEATOSIS
UNEXPLAINED
HEPATOMEGALY
FURTHER CONSIDERATIONS

7. 7
DIAGNOSTICCASESTUDIES
Presented by Professor John J Gargus at ESPGHAN 2016
The 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 2016
A 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 2016
A 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
slightlyhyperechogenicliverparenchyma.Mildgastritiswasdiagnosedwithoesophagogastroduodenoscopy(EGD),andherileoco-
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’.
Fiveyearslater,shepresentedwithseverediarrhoeaandsignificantweightloss,andherbodymassindexhaddecreasedfrom17.0
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
sufferedsevereliverpain(whichrequiredhighdosesofanalgesics,includingopiates),diarrhoea(5stools/day),significantcogni-
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
confirmedbythedriedbloodspottest(lowLALactivity)andsubsequentgeneticanalysis(homozygousmutationintheLIPAgene).
Over 10 years later, in 2014, this patient commenced ERT in clinical trial LAL-CL06.
CASE 1
CASE 2
CASE 3

8. 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 LCT
and total fat content)
Modular feed
·Amino acids ·Glucose polymer ·MCT emulsion
·Micronutrients ·EFAs/LCPs
Glucose polymer
MCT 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
8
NUTRITIONALMANAGEMENT
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

9. 9
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.
TherecommendeddoseinchildrenandadultswhodonotpresentwithrapidlyprogressiveLALdeficiencypriorto
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
substanceorareallergictoeggoranyoftheexcipients.20 Followingthefirstsebelipasealfainfusion,includingthe
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
SEBELIPASEALFAfor 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)
randomisation
and allocation*
Intervention with
sebelipase alfa (N=36)
Placebo (N=30)
Open-label
treatment period (N=35)
Open-label
treatment period (N=35)
Follow up
and analysis †
Follow up
and analysis ‡
▶20 WEEKS ▶32 WEEKS

10. 10
IMPACT ON TRANSAMINASE
Patients 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
patientsshowedworseningofsteatosis,whereas50%reportedimprovementsdefinedasanabsolutedecreaseof
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 EVENTS
Sebelipase 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
SEBELIPASEALFAfor the treatment of LAL-D

11. 11
CASESTUDIES
Presented by Professor Patrick Gerner at EAS 2016
A 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
physicalandcognitivedevelopmentwasnormalandowingtotransaminasesbeingonlyslightlyelevated,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,
normalGGTvalues,significantlyelevatedLDL,andnormalHDLandtriglyceridelevels.SequencingoftheLDLrecep-
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-
miaandotherfamilialformsofhypercholesterolaemiawerenotsuspected,asthesedisordersdonotusuallypres-
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.

12. CONCLUSION
12
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

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