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Lysosomal Acid Lipase Deficiency: Biology, Clinical Manifestations, Diagnosis, and Novel

Approach to Treatment

Mark A. Goldberg, M.D.Medical and Regulatory Strategy

Synageva Biopharma Corp.

Associate Clinical Professor of MedicineHarvard Medical School

September 26, 2014

DisclosureMark Goldberg, M.D. discloses the following relationships with commercial companies:

• Employee and shareholder of Synageva Biopharma

Learning ObjectivesAt the end of this presentation the 

participant will be able to:

1. Understand the biology and the clinical manifestations of lysosomal acid lipase deficiency

2. Know how to test for lysosomal acid lipase deficiency

3. Understand treatment options for patients with lysosomal acid lipase deficiency

Lysosomal Acid Lipase (LAL) Deficiency: A single disease, with marked clinical heterogeneity

Lysosomal Acid Lipase (LAL) Deficiency: A single disease, with marked clinical heterogeneity

Historical terms to describe the disease

– “Wolman disease” - 1956 by Dr. Wolman

• Infant who died at the age of ~two months: GI symptoms, hepatosplenomegaly, poor weight gain, and bilateral adrenal calcifications

– “Cholesteryl Ester Storage Disease (CESD)” - 1963 by Dr. Fredrickson

• 12y/o with hypercholesterolemia + hepatomegaly (300-500x increase in CE on biopsy)

Underlying cause is the same1,2

– Autosomal recessive disease affecting lipid metabolism due to mutations in the LIPA gene encoding lysosomal acid lipase

– Results in lysosomal accumulation of lipids (cholesteryl esters and triglycerides)

1. Patrick and Lake : “Deficiency of an acid lipase in Wolman’s disease”, Nature, 19692. Burke and Schubert : “Deficient activity of hepatic acid lipase in cholesterol ester storage disease”, Science, 1972Cortner et al: “Genetic variation of lysosomal acid lipase”, Pediatric Research, 1976Goldstein, et al: “Role of lysosomal acid lipase in the metabolism of plasma Low density lipoprotein,” JBC, 1975

Biology of Lysosomal Acid Lipase (LAL)Biology of Lysosomal Acid Lipase (LAL)

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Healthy Individuals LAL Deficient Patients

Nucleus

LDL particle

Hepatocyte

• Normal lipid homeostasis

• Hydrolysis yielding free cholesterol and free fatty acids

LAL

Normal Lysosome

Nucleus

LDL particle

Hepatocyte

• Disruption of lipid homeostasis

• Accumulation of lipid in lysosome

Enlarged Lysosome

LAL

LAL Deficiency GeneticsLAL Deficiency Genetics

Mutations have variable expression of protein– Distinction on clinical progression is not based on enzyme activity –

variable assay methods/substrate.

Common mutation (splice mutation) E8SJM-1

• Autosomal recessive

• LIPA gene maps to chromosome 10q23.2iq23.3

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Lysosomal Acid Lipase Deficiency (LAL D) presents across a clinical continuum

Lysosomal Acid Lipase Deficiency (LAL D) presents across a clinical continuum

Affected liver removed during transplant surgery age 9

Often fatal within first 6 months of life

Marked growth failure in first few months of life AND

Rapidly progressive liver disease

Atherosclerosis

Infants Children & Adults

Complications of chronic liver disease (bleeding varices and ascites)

Dyslipidemia: Increased LDL, and decreased HDL

Common Aspects

Autosomal recessive disorder of lipid metabolism

Increased morbidity and early mortality

Fatty liver, elevated transaminases fibrosis/cirrhosis

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Disease Spectrum

Rapid Disease Progression in LAL D Infants

Rapid Disease Progression in LAL D Infants

Rapidly progressive and fatal

Prominent hepatic and GI manifestations– Persistent vomiting, diarrhea

– Abdominal distension

– Profound growth failure

– Hepatomegaly and liver failure

– Splenomegaly

Adrenal calcification frequently present

Incidence: ~1/500,000

Treatment options:

– No safe and effective therapies

– HSCT (and liver transplant) have limited success and high mortality

1Data on File, Synageva BioPharma Corp.

Kaplan-Meier Estimate: Survival in LAL D Infants with Growth Failure* Kaplan-Meier Estimate: Survival in LAL D Infants with Growth Failure*

*Population shown are subjects who did not undergo HSCT or liver transplantSource: Jones et al, WORLD 2014 poster #113

Upper 95% Confidence Limit

Survival Function Estimate

Lower 95% Confidence Limit

n is number of patients at risk

No untreated subject with growth failure (presenting

before 6 months) survived to 12 months of age

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Time Point1 Median Age

Age at Symptom Onset 1.0 Month

Age at Diagnosis 2.6 Months

Age at Death 3.7 Months

LALD Presenting in InfantsTypical Sign/Symptoms & Differential LALD Presenting in InfantsTypical Sign/Symptoms & Differential

Clinical Age <1 year Vomiting and/or Diarrhea Abdominal distention Hepatomegaly and/or splenomegaly Growth failure

Laboratory Elevated transaminases Elevated ferritin Elevated triglycerides Coagulopathy Cytopenias

Imaging Hepatomegaly and/or splenomegaly Adrenal calcifications (may not be present)

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Prolonged "gastroenteritis" with growth

failure

Hemophagocytic lymphohistiocytosis

(HLH)

Glycogen storage disease

Cryptogenic liver cirrhosis

Niemann-Pick disease Type C

Chanarin Dorfman syndrome

Galactosemia

Fructose intolerance and other amino acid

metabolism disorders

Typical Findings Differential Diagnosis

Shortened lifespan and morbidity

Prominent hepatic manifestations

– Fatty liver (microvesicular steatosis)

– Elevated transaminases

– Fibrosis  and cirrhosis

– Liver failure (often early in life)

Cardiovascular involvement– Elevated LDL cholesterol– Low HDL frequently observed– Variably elevated triglycerides– Accelerated atherosclerosis

Other manifestations:– splenomegaly– GI manifestations– Lymphadenopathy

Prevalence:  1:40,000 – 1/300,000

Affected liver removed during transplant surgery age 9

LAL Deficiency presenting in childhood or adulthood: A rare disease with a common phenotypeLAL Deficiency presenting in childhood or adulthood: A rare disease with a common phenotype

Presentation in Children & AdultsPresentation in Children & Adults

More frequent presentation of LAL Deficiency

Historically known as Cholesteryl Ester Storage Disease

2013 literature review1

– >80% of patients presented before 12 years of age – Death due to progressive liver disease occurred as early as 7 years of age

– 64% had fibrosis and/or cirrhosis

Disease presentation is variable– Hepatic manifestations and dyslipidemia dominate the clinical picture.

– Some are diagnosed in childhood, while others remain undiagnosed until adulthood

High potential for delayed or misdiagnosis– Metabolic syndrome: combination of fatty liver, elevated serum

transaminases, and dyslipidemia

– Focusing on non-obesity may increase the suspicion for LAL D

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ALT Elevation Is Common, Persistent And Present From A Young Age

• ALT values were persistently elevated• The majority (458 of 499 values; 92%) ALT values were above 43 U/L with only a

small proportion (41 of 499 values; 8%) of values being ≤ 43 U/L at any time.• ALT values were generally comparable in subjects with and without biopsy-proven

fibrosis and/or cirrhosis

Age  (years)By Subject

value < 43

value > 43

Quinn et al. WORLD 2014

N=48

LDL Elevation is Common

• Most LDL values (88%; 270 of 306) were > 100 mg/dL, with many values in a range indicative of substantial dyslipidemia in the study population.

• LDL values > 100 mg/dL were common even if LLM had been initiated, with 27 subjects having at least 1 LDL value > 100 mg/dL while receiving LLM.

By Subject

Quinn et al. WORLD 2014

(N=48)

Hig

hest

Rec

orde

d To

tal C

hole

ster

ol

(mg

/dL)

LAL Deficiency Not Widely Recognized As a Cause of Low HDLLAL Deficiency Not Widely Recognized As a Cause of Low HDL

Lowest Recorded HDL (mg/dL)

High (> 240 mg/dL)Desirable (<200 mg/dL)

Target - Men(>40 mg/dL)

FM

Unknown

Target - Women(>50 mg/dL)

Tripuraneni et al. NLA 2013

Hig

he

st r

eco

rded

To

tal

Ch

ole

ster

ol

(mg

/dL

)

Lipid Abnormalities In LALD are Broader than Classically Described Type II HyperlipidemiaLipid Abnormalities In LALD are Broader than Classically Described Type II Hyperlipidemia

Highest recorded Triglyceride (mg/dL)

High (> 240 mg/dL)

Desirable ( < 200 mg/dL)

High ( 200‐500 mg/dL)Normal  < 150 mg/dL) Very High ( > 500 mg/dL)

FM

NLA 2013

Clinical Summary from Bernstein et al. Clinical Summary from Bernstein et al.

Median Age of Onset

5 years of ageMale (birth – 44) Female (1 month-68)

Distribution of Age of Onset (131 pts)

116 (89%) presented between age 3 and 12 years, 15 (11%) had onset or diagnosis during adolescence or as adults. 5 patients whose diagnoses were made at autopsy

Hepatomegaly Presented in 134 (99%) of patients

Splenomegaly Presented in 100 (74% ) of patients

TransaminaseLevels

Elevated AST and/or ALT activities in all cases

Review of the 135 cases/publications describing LALD

Bernstein et al. Cholesteryl Ester Storage Disease: Review of the Findings in 135 Reported Patients with an Under-Diagnosed Disease. J Hepatology. 2013 Jun;58(6):1230-43

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Clinical Summary from Bernstein et al. (cont)Clinical Summary from Bernstein et al. (cont)

Liver Injury and/or Liver Failure (135 pts)

• Occurred in all patients• Death due to liver disease progression: 7- 56 years old• 50% of deaths were in patients under 21 years of age.

Liver Biopsy(112 (83%) pts)

• A striking orange-yellow in color • Diffuse, uniform microvesicular steatosis • 72 (64%) had fibrosis and/or cirrhosis

• Findings were consistent among patients, and appeared independent of age, genotype, or other factors

Bernstein et al. Cholesteryl Ester Storage Disease: Review of the Findings in 135 Reported Patients with an Under-Diagnosed Disease. J Hepatology. 2013 Jun;58(6):1230-43

Management Options & Clinical TrialsManagement Options & Clinical Trials

Infants– Electrolyte replacement, parenteral nutrition, formula modifications, etc.

Children & Adults– Statins/lipid lowering agents – but liver disease progression can still occur1

Hematopoietic stem cell or liver transplantation– Has been associated with serious complications (e.g., death, graft-versus-host disease)

Enzyme replacement therapy (ERT) – Sebelipase alfa is an investigational ERT

– Reported encouraging phase ½ results in LAL deficient adults2

– Ongoing trials for LAL deficient infants (LAL-CL03) and children/adults (ARISE)

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1. Bernstein et al. Cholesteryl Ester Storage Disease: Review of the Findings in 135 Reported Patients with an Under-Diagnosed Disease. J Hepatology. 2013 Jun;58(6):1230-432. Balwani, et al. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology. 2013 Sept: 58 (3) : 950–57

Sebelipase Alfa: Pre-Clinical and Clinical Development

Sebelipase Alfa: Pre-Clinical and Clinical Development

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Sebelipase alfa

Targeting and ActivitySebelipase alfa

Targeting and Activity

Terminal mannose/GlcNac and mannose-6-phosphate (M6P) for targeted delivery

Uptake into key cells

Lysosomal localization demonstrated

Corrects enzyme deficiency

Lysotracker red Overlap imagesOregon green-labeled sebelipase alfa

0

1

2

3

4

5

6

0 0.16 0.5 1.6 5

Cel

lula

r L

AL

Act

ivit

y (n

Un

its/

cell)

sebelipase alfa (ug/ml)

Normal Human Fibroblasts

LD Fibroblasts

0 0.16 0.5 1.6 5.0

LAL Deficiency Rat ModelReproduces Key Aspects of Human DiseaseLAL Deficiency Rat ModelReproduces Key Aspects of Human Disease

Accumulation Lipid Substrate in Liver, Spleen and Gut

Growth failure Increased Mortality

Maximal life span in LAL-/- rats is approximately 14 weeks

Rat model 1st described Japan 1990 (Yoshida H, Kuriyama M. Lab Animal Sci. 1990;40(5):486-9.

Sebelipase alfaPreclinical Targeting and ActivitySebelipase alfaPreclinical Targeting and Activity

In Vivo Activity

* sebelipase alfa 5mg*kg-1 once weekly for 4 weeks

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Sebelipase alfaPreclinical Targeting and ActivitySebelipase alfaPreclinical Targeting and Activity

In Vivo Activity

* sebelipase alfa 5mg*kg-1 once weekly for 4 weeks

sebelipase alfa (SBC-102) Restores Normal Growth And Increases Survival in Preclinical Disease Modelsebelipase alfa (SBC-102) Restores Normal Growth And Increases Survival in Preclinical Disease Model

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Improvements In Growth And Organ Size Is Associated With Correction Of Underlying PathologyImprovements In Growth And Organ Size Is Associated With Correction Of Underlying Pathology

SBC-102

Placebo

Liver Sebelipase alfa

Sebelipase alfa

LAL-CL03 (Phase 2/3 Trial)LAL-CL03 (Phase 2/3 Trial)

LAL D infants with growth failure first 6 months of life Open label Intra-patient dose

escalation of sebelipase alfa – 0.35 mg/kg to 3 mg/kg

Once weekly dosing Multicenter N= 8 - 10

Primary Endpoint: Survival at 12 months of age

Key Secondary Endpoints: Safety and tolerability Survival beyond 12 months of

age Growth Liver parameters (AST, ALT,

GGT, Alk Phos, Bilirubin) Lipids Development (Denver II) Pharmacokinetics

EndpointsTrial Design

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Valayannopoulos et al. WORLD 2014

Key Inclusion & Exclusion CriteriaKey Inclusion & Exclusion Criteria

Inclusion:– Confirmed diagnosis of LAL D

– Growth failure with onset before 6 months of age

• Weight decreasing across at least 2 of the 11 centile lines on WHO weight for age chart OR

• Body weight in kg below the 10th centile AND no weight gain for the 2 weeks prior to screening OR

• Loss of ≥ 5% of birth weight in a child older than 2 weeks

– Infants with rapidly progressive course if no growth failure*

Exclusion:– Myeloablative preparation, or other systemic pre-transplant

conditioning

– Previous hematopoietic stem cell or liver transplant*Exceptional circumstance and requires review with the safety committee prior to enrollment

29Valayannopoulos et al. WORLD 2014

Patient Disposition & Baseline CharacteristicsPatient Disposition & Baseline Characteristics

Data as of June 2014

9 patients enrolled

Median age at time of first infusion: 3.0 months – Range 1.1 – 5.8 months

Range of time in the trial: 0.6 to 31.8 months

Laboratory Values:Parameter Median Range

ALT 96 U/L 16-297 U/L

AST 125 U/L 71-716 U/L

Bilirubin 7 umol/L 2.4-464 umol/L

Hemoglobin 9.3 g/dL 7.2-10.2 g/dL

Platelets 173 x109/L 39-563 x109/L

Signs and Symptoms:• Diarrhea or Vomiting (6 of 9)

• Hepatomegaly (7 of 9)

• Splenomegaly (6 of 9)

• Adrenal calcification (4 of 9)

30Valayannopoulos et al. WORLD 2014

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Kaplan-Meier Estimate of Survival in LAL D Infants with Growth Failure*: Results of Natural History StudyKaplan-Meier Estimate of Survival in LAL D Infants with Growth Failure*: Results of Natural History Study

*Population shown are subjects who did not undergo HSCT or liver transplantSource: Jones et al, LDN 2014 poster #113

Upper 95% Confidence Limit

Survival Function Estimate

Lower 95% Confidence Limit

n is number of patients at risk

No untreated subject with growth failure (presenting

before 6 months) survived to 12 months of age

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0 6 12 18 24 30

Patient Age (Months)

Alive and continuing on sebelipase alfa

Deceased (not related to sebelipase alfa)

Survival (12 months of age)

Initial Survival Data with Sebelipase Alfa

Sebelipase Alfa Phase 2/3 Data in Infants: EfficacySebelipase Alfa Phase 2/3 Data in Infants: Efficacy

Patient 1

Patient 2

Patient 6

Patient 7

Patient 8

Patient 9

Patient 3

Patient 4

Patient 5

36 40

Source: Synageva as of June 2014

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Infusion HistoryAge at Death

Relationship to sebelipase alfa

Cause of Death

1 infusion (0.35 mg/kg/wk)3

monthsNot related

Complications of disease

1 infusion (0.35 mg/kg/wk)2

monthsNot related

Complications of non-protocol specified

abdominal paracentesis

4 infusions • 2 infusions (0.35 mg/kg/wk)• 2 infusions (1.0 mg/kg/wk)

4months

Not relatedComplications of

disease

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6 Subjects continue on sebelipase alfa3 Deceased Subjects

• Not related to sebelipase alfa

Dosing StatusDosing Status

Valayannopoulos et al. WORLD 2014

Growth Curve of Subject 1Growth Curve of Subject 1

Subject 1 (M)

Age (months)

We

igh

t (k

g)

34

Survival at 12 months of age

Growth Curves of the Other Surviving Subjects

Growth Curves of the Other Surviving Subjects

Subject 9 not shown (received only a single infusion at time of data cut)Valayannopoulos et al. WORLD 2014

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SafetySafety

Majority of SAEs:– Were not related to sebelipase alfa– Related to documented central line infections or hospitalizations for

empirical treatment with antibiotics

3 related SAEs – Occurred in a single subject in association with the same infusion

• Fever (malaise)• Malaise with tachycardia • Tachycardia

– Resulted in overnight hospitalization• Treated with IV antibiotics empirically for possible line bacteremia (all cultures

negative)

• Majority of IRRs have been mild • Fever• Vomiting

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Valayannopoulos et al. WORLD 2014

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Anti-Drug AntibodyAnti-Drug Antibody

4 subjects developed anti-drug antibody (ADA)– Subject 3 - ADA positive after 7 weeks on treatment

– Subject 5 - ADA positive after 8 weeks on treatment

– Subject 6 - ADA positive after 16 weeks on treatment

– Subject 1 - ADA positive after 58 weeks on treatment

No apparent change in clinical response after ADA development

37Valayannopoulos et al. WORLD 2014

Sebelipase Alfa: Experience in Adults

Sebelipase Alfa: Experience in Adults

102 wk data

R. Tripuraneni et al. Effect of Sebelipase in Adults with Lysosomal Acid Lipase Deficiency Oral presentation EAS 2014

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Phase 1/2 Trial Design with Sebelipase alfa in Adults with LAL DeficiencyPhase 1/2 Trial Design with Sebelipase alfa in Adults with LAL Deficiency

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Characteristics and Baseline Test ResultsCharacteristics and Baseline Test Results

Parameter Population

Age (median, yrs) 29

Male:Female (n) 6:3

White (n) 9

Weight (median, kg) 72

BMI (median, kg/m2)BMI ≥ 30 kg/m2 (n)

25.21

Hepatomegaly (n) 8

Lipid lowering meds (n)Statins (n)

76

Elevated* ALT or AST (n) 2

*Elevated: ≥1.5xULN and <3xULN.

RED = abnormal value

Lab Analyte Reference Range

Median (Range)

ALT (U/L) ≤67 76 (22 to 119)

AST (U/L) ≤50 56 (37 to 69)

Total Chol (mg/dL) 69-232 182 (116 to 391)

LDL (mg/dL) ≤162 135 (70 to 300)

HDL (mg/dL) ≥35 39 (22 to 49)

Triglycerides (mg/dL)

≤199 108 (80 to 277)

Improvement in TransaminasesImprovement in TransaminasesMean percent decrease: 58% ALT and 28% AST (wk 104)

n=8n=9

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Improvement in Dyslipidemia ProfileImprovement in Dyslipidemia Profile

n=8n=9

Mean percent decrease: 54% LDL, 31% TG (wk 104)Mean percent increase: 18.4% HDL (wk 104)

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Rapid, Sustained Reduction inLiver Volume and Fat Fraction (MRI)Rapid, Sustained Reduction inLiver Volume and Fat Fraction (MRI)

Per

cen

t C

han

ge

Fro

m C

L04

Bas

elin

e

-9% -14%

-35%

-55%

Liver Volume Liver Fat Fraction

-42%

‐60

‐50

‐40

‐30

‐20

‐10

0

10

Week 10Week 24Week 52

‐10%‐12%

‐9%

‐42%

‐35%

‐55%

n=8n=8 n=7 n=7n=7 n=6

Safety ProfileSafety Profile

No drug-related serious adverse events (SAE) in this trial

One unrelated SAE: cholecystitis and cholelithiasis– The subject underwent elective cholecystectomy.

– The subject has continued in the study.

No evidence of anti-drug antibodies in subjects tested to date in this study

Most infusion-related reactions (IRR) were mild, mainly GI related (diarrhea, abdominal cramping).

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ARISE Trial ARISE Trial

* Age- and gender-specific ULN provided by the central laboratory performing the assayhttp://www.clinicaltrials.gov/ct2/show/NCT01757184

Study Design• Randomized, double-blind, placebo

controlled• Multi-center global trial• N = 50

Endpoints• Normalization in ALT*• Change in LDL, non-HDL, TG, HDL • Normalization in AST• Change in liver volume and liver fat

content• Improvement in liver histopathology

June 30, 2014

Specialty Patient Populations

Hepatologists • All non-obese* patients with

• Persistent hepatomegaly OR

• Unexplained elevation in transaminase

• Cryptogenic cirrhosis

• Microvesicular steatosis or macro/microvesicular steatosis • can also do additional IHC staining

Lipidologists • Non–obese: LDL >=160mg/dL & HDL <40mg/dL (males) or <50mg/dL(females)

• Presumed familial hypercholesterolemia (FH) patients with unclear family history

• Presumed FH patients who have negative genetic testing for the genes encoding LDLR, APO B, and PCSK9 genes

Which Patient to Test for LAL D?

*Non obese definition: adults <30 kg/m2 or <95th percentiles in those less than 18 years of age

Blood Test for LAL DBlood Test for LAL D

LAL activity is determined by via a LAL specific inhibitor

Allows for the possibility of testing high risk populations

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Hamilton J, et al. Clin Chim Acta. 2012;413:1207-10.

Recent Development of Dry Blood Spot Assay Allows for Easy Testing

LAL Activity

Labs That Perform LAL D Testing (US)Labs That Perform LAL D Testing (US)

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Laboratory Contact InformationDBS

MethodGenetic

SequencingLeukocyte

AssayMassachusetts General Hospital (MGH)*Boston, MA

Phone: 1-617-967-2045E-mail: KABURKE@mgh.harvard.eduWeb site: www.massgeneral.org/research/resourcelab.aspx?id=43

x x –

Seattle Children’s Hospital and University of Washington*Seattle, WA

Rhona Jack, PhD Phone: 1-206-987-2216Web site: www.seattlechildrens.org/labman x x –

Baylor College of MedicineHouston, TX

Phone: 1-800-411-GENE (4363)Website: www.bcm.edu/research/medical-genetics-labs/ – x x

GeneDxGaithersburg, MD

Phone: 1-301-519-2100E-mail: genedx@genedx.comWeb site: www.genedx.com/

– x x

PreventionGenetics, Marshfield, WI

Phone: 1-715-387-0484E-mail: clinicaldnatesting@preventiongenetics.comWebsite: http://preventiongenetics.com/

– x x

Thomas Jefferson University,Philadelphia, PA

David A. Wenger, PhD Phone: 1-215-955-4923E-mail: David.Wenger@jefferson.eduWeb site: www.jefferson.edu/jmc/departments/neurology/programs/neurogenetics/lysosomal_diseases.html

– – x

Laboratory Corporation of AmericaResearch Triangle Park, NC

Phone: 1-800-345-4363Web site: www.labcorp.com/wps/portal/provider/testmenuLAL Assay test code: 402300

x – –

HIBM*Encino, CA

Phone: 1-818-789-1033Web site: http://hibm.org/hrg/www/pages/ x x –

48*accepts samples from around the world

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SummarySummary

LAL deficiency is an under-recognized cause of cirrhosis, accelerated atherosclerosis, and early death

It usually presents in childhood

Key signs in children and adults include: (not all are required)

– Elevated transaminases, hepatomegaly and/or microvesicular steatosis

– Dyslipidemia (elevated LDL and low HDL)

Diagnosis can be made via a simple blood test

Analysis of sebelipase alfa in the ongoing clinical trials

– Improved growth & survival in infants

– Produces sustained improvements in the biochemical markers of liver damage, and the dyslipidemia in the adults

– Safety and tolerability profile is encouraging after administration of more than >300 infusions.

4950

US and European Guidelines: Endorse Testing to Rule Out LAL D

ESPGHAN = European Society for Pediatric Gastroentereology, Hepatology and NutritionChalasani et al. Gastroenterol. 2012;142:1592-1609Vajro P, et al. JPGN. 2012;54:700-13

• Symptoms overlap with hereditary disorders• Rule out LAL D in microvesicular steatosis cases

• Nonspecific symptoms of NAFLD overlap with genetic-metabolic causes

• Rule out LAL D before diagnosing NAFLD

Liver Disease: Two Rare DiseasesLiver Disease: Two Rare Diseases

Wilson disease

Symptoms >3y of age

Acute presentation at any age >3y

Chronic progressive disease

Autosomal recesive

LAL Deficiency

Symptoms from infancy

Acute presentation in infancy

Chronic progressive disease >2y of age

Autosomal recesive

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Is tested in each child with liver disease >3y

Should we routinely test for LAL D in children with liver disease?

Thank you!