SynagevaFinalMod4LALD4-24-14CLEAN

LAL Deficiency (LAL D) Learning System
Module 4: Sebelipase
Alfa Clinical Trials

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LAL DEFICIENCY (LAL D) LEARNING SYSTEM: MODULE 4: SEBELIPASE ALFA CLINICAL TRIALS
INTERNAL USE FOR TRAINING PURPOSES ONLY. DO NOT DISTRIBUTE
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Contents
Module 4: Sebelipase Alfa Clinical Trials .....................................................1
Lesson 1: Sebelipase Alfa.............................................................................2
Lesson 2: LAL-CL01 and LAL-CL04 Extension Trial .......................................6
Lesson 3: Sebelipase Alfa Trials That Have Not Reported Results.............15
Lesson 4: Registry for LAL Deficiency.........................................................21
Take Home Points ......................................................................................25
Glossary......................................................................................................27
References..................................................................................................29

MODULE 4: SEBELIPASE ALFA CLINICAL TRIALS
1
Module 4: Sebelipase Alfa Clinical Trials
This module describes sebelipase alfa and reviews key completed and
ongoing clinical trials of sebelipase alfa and the available results. It also
discusses the patient registry for LAL deficiency supported by Synageva.

2
Lesson1: Sebelipase Alfa
Learning Objectives
Aftercompleting this lesson,you will be ableto:
 Describe the role of sebelipase alfa
 Describe howsebelipasealfaisproduced
 Describe the targetingandactivityof sebelipase alfa
Overview
Sebelipase alfa(formerlyknownas SBC-102) is a recombinantform of the
humanlysosomal acidlipase (LAL) enzyme underdevelopmentbySynageva
as an enzyme replacementtherapy for LAL Deficiency. [Synageva 2014
Sebelipase alfa p1 para1] Enzyme replacementtherapyinvolvesthe
administrationof enzymestopatientswhohave anenzyme deficiency
disease,suchasLAL D. [Taber's 2014 enzyme replacement therapy]
How sebelipase alfa is produced [7_Testing-Diagnostics-LAL D
Overview_June 2013.ppt Slide 52, Synageva 2014 Overview]
Synagevacreatesandproducesrecombinantproteinsusingproprietary
technology. Toproduce sebelipasealfa, the transgene isinsertedintothe
genome of Gallusgallus.The oviductcellsthentranscribe the sebelipase
alfagene and translate the sebelipase alfamRNA intothe protein:
sebelipase alfa.(Foradescriptionof howgenesare usedtomake proteins,
see Module 1: GeneticsBackgrounder.)
Sebelipase alfaisproducedinthe eggwhite,whichisaprotein-friendly
environment.(Thisisalsoone reasonwhypatientswitheggallergieswere
excludedfromclinical studies.) The proteinispurifiedaccordingto
establishedindustrystandards. Thistechnologyyieldsconsistentexpression
levelsandqualityof sebelipasealfaacrossproductionlinesandmultiple
generations.
Figure 4-1 summarizesthe productionof sebelipase alfa.

3
Figure 4-1: Synageva Expression Platform [7_Testing-Diagnostics-LAL D
Overview_June 2013.ppt Slide 52]
GMP = Good ManufacturingPractices
Sebelipase alfa targeting and activity
Sebelipase alfa,like naturallyoccurringlysosomal enzymes,isa
glycoprotein,whichmeansitisa proteinwithsugarpolymersattached.For
glycoproteinenzyme replacementtherapytobe effective,the glycoprotein
mustbe able tobindto its receptor,be takenupby the cell,andbe
transportedtothe lysosome where itcanexertitsaction.
Receptor binding:Sebelipasealfaisdesignedtobindspecificallytoeither
mannose or mannose-6-phosphate receptorsoncells.The mannose
receptorisfoundparticularlyon reticuloendothelial cells,includingKupffer
cellsinthe liver, monocytes,andmacrophages.The mannose-6-phosphate
receptorispresentona wide varietyof cell types, includinghepatocytes
and otherepithelial cell types.
Transport to lysosomes:Studiesusinglabelingwithfluorescentdyeshave
shownthat,afterbindingtothese receptors, sebelipasealfaistakenupby
cellsandtransportedtolysosomes.Figure 4-2showsthe resultsof adye
labelingstudy.Inthe study, sebelipasealfawaslabeledwithagreen
fluorescentdye (Oregongreen),adye thatglowsgreenwhenexposedto
blue/greenlight,andcellswerelabeledwithLysotrackerred,afluorescent
dye that bindsspecificallytolysosomesandglowsredwhenexposedtored

4
light.Afterthe labeledcellswere incubatedwithlabeled sebelipase alfa,the
cellswere illuminatedwithgreenlight,andthe resultingglow fromthe
sebelipase alfawasphotographed(Figure 4-2A).Thiswas repeatedwithred
light,showingthe lysosomes(Figure4-2B). The imagesoverlayexactly
(Figure 4-2 C),showingthatthe sebelipase alfawastransportedtothe
lysosomes.
Figure 4-2: Fluorescent dye labeling study showing transport of
sebelipase alfa to lysosomes
A B C
Sebelipasealfa labeled
with Oregon green
Lysosomes labeled with
Lysotracker red
Overlaid images
Biological action: The biological activityof sebelipase alfawas
demonstratedinacell culture experiment.Inthe experiment,fibroblasts
froma patientwithLALD were incubatedwith sebelipasealfa,andcellular
LAL enzyme activitywasmeasured.Incubationwith sebelipasealfawas
foundto increase cellularLALactivity(see Figure 4-3).

5
Figure 4-3: Impact of varying concentrations of sebelipase alfa on
cellular LAL activity in LD fibroblasts
Thus,the data demonstrate thatrecombinanthuman sebelipase alfahas
appropriate glycanstructuresthatallowitto bindto mannose ormannose-
6-phosphate receptors,be takenupbycells,and be transportedto
lysosomeswhereitisbiologicallyactive.

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Lesson2: LAL-CL01 and LAL-CL04
Extension Trial
Learning Objectives
 Reviewthe objectives,design,andefficacyandsafetyresultsfor
LAL-CL01
 Reviewthe objectives,design,andefficacyandsafetyresultsfor
LAL-CL04
Overview
LAL-CL01 wasthe firsthumanstudyof sebelipase alfa. [Balwani 2013 p1 abstract]
 Initial resultswere publishedin2013 byBalwani etal.:
 Balwani M, BreenC,Enns GM, etal. Clinical effectandsafetyprofile of
recombinanthumanlysosomalacidlipase inpatientswithcholesteryl
esterstorage disease. Hepatology. 2013;58(3):950–957.
 Additional resultsoutto90 weeksare alsoavailable.
Objective
The objective of LAL-CL01 wasto evaluate the safety,tolerability,and
pharmacokineticsof sebelipasealfainadultsubjectswithLALD.[Balwani 2013
p1 abstract, p2 col 1 para3]
Design
LAL-CL01 wasa Phase 1/2 open-label studyconducted across6sitesin4
countries.[Balwani 2013 p2 col 2 para2]
Primary outcome measures
The primaryoutcome measuresof LAL-CL01 were safetyandtolerabilityof
weeklyinfusionsof sebelipasealfaover4weeks.Safetyandtolerability
were assessedbyroutine monitoringof patientsforadverse events(AEs)
and bymonitoringchangesfrombaselineinphysical examinationfindings,
vital signs,clinical laboratoryevaluations,immunogenicitytests,and

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concomitanttherapies. [Balwani 2013 p3 col 2 para2, ClinicalTrials.gov2014 Balwani p1
primaryoutcome measures]
Secondary outcome measures
The secondaryoutcome measureswere pharmacokineticsof sebelipasealfa
deliveredbyIV infusionaftersingleandmultiple dosesover4weeks.
[ClinicalTrials.gov2014 Balwani p2 secondaryoutcome measures]
Pharmacodynamics assessmentsincluded: [Balwani 2013 p3 col 2 para2]
 Analysisof hepatictransaminases(ALT,AST)
 Lipidparameters[total cholesterol,triglycerides,highdensitylipoproteins
(HDL),and lowdensitylipoproteins (LDL)]
 Serumferritin
 Gamma glutamyl transferase (GGT)
 Alkaline phosphatase(ALP)
Key inclusion and exclusion criteria
Patientseligible tobe includedinLAL-CL01were requiredtohave
documentedLALD and to be between18and 65 yearsof age.Inclusion and
exclusioncriteriaare presentedinTable 4-1.
Table 4-1: LAL-CL01 Key Inclusion and Exclusion Criteria [Balwani 2013 p3
col 1 para3, col 2 para1]
Inclusion criteria Exclusion criteria
 Documented LAL D with
hepatomegaly and/or
transaminases ≥1.5 times the upper
limitof normal (ULN)
 Use of lipid-loweringagents allowed
if patient was on a stabledose for
≥4 weeks
 Severe hepatic dysfunction (Child-
Pugh Class C)
 Aspartate aminotransferase(AST)
and/or alaninetransaminase(ALT)
persistently elevated to greater
than 3 times the ULN
 Chronic liver diseaseattributed to a
causeother than LAL D
 Serological evidenceof hepatitis B
virus or hepatitis C virus
 Score of ≥8 on a screening Alcohol
Use Disorders Identification Test
 Previous hematopoietic bone
marrow or liver transplant
 Known hypersensitivity to eggs

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Patient population
Nine patientsmetstudyeligibilitycriteriaandwere enrolledinLAL-CL01.All
nine patientsreceived 4weeklyinfusions. [Balwani 2013 p4 col 1 para3] Of these
9 patients,8patientscontinuedtothe extensionstudyLAL-CL04.[Balwani
2013 p3 Fig 1] The demographicsandbaseline disease characteristicsof the
studypopulationare presentedinTables4-2and 4-3.
Sevenpatientshadahistoryof hepatomegalyand/orsplenomegaly.Eight
patientshadclinical evidence of hepatomegalywhenphysicallyexamined.
Two patientspresentedwithevidenceof more advancedliverdisease(one
patienthadcirrhosisand portal hypertension,the otherhad periportal
fibrosis).Sevenpatientswere receiving≥1lipid-loweringmedicationat
enrollment;all of these patientswere beingtreatedwithlipid-modifying
therapies,includingstatinsandothermedications.Nochangeswere made
inlipid-modifyingtherapiesduringthe study. [Balwani 2013 p4 col 1 para4–c2
para1]
Table 4-2: Demographics [Whitley 2014 Slide 8]
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)
25.2
1
Hepatomegaly (n) 8
Elevated ALT or AST* (n) 2
Usinglipid-lowering medications (n)
 Statins** (n)
7
6
*Elevated =>1.5xULN and <3xULN
** Subject 3 stopped statin therapy between LAL-CL01 andLAL-CL04

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Table 4-3: Baseline Laboratory Values [Whitley 2014 Slide 8]
Laboratory Value Reference Range Median Range Units
ALT ≤67 76 22 to 119 U/L
AST ≤50 56 37 to 69 U/L
Total Cholesterol 69 to 232 182 116 to 391 mg/dL
1.8 to 6.0 4.7 3.0 to 10.1 mmol/L
LDL ≤162 135 70 to 300 mg/dL
≤4.2 3.58 1.81 to 23.3 mmol/L
HDL ≥35 39 22 to 49 mg/dL
≥0.9 1.0 0.6 to 1.3 mmol/L
Triglycerides ≤199 108 80 to 277 mg/dL
≤2.25 1.2 0.9 to 3.1 mmol/L
RED = abnormalvalue
Note: laboratory measurements oflipids aretypically reported in mg/dLin the US andin mmol/L internationally
Screening and treatment
Eligible patientsweretreatedin 3dose cohorts:
 0.35 mg/kg (Cohort1: patients1–3)
 1 mg/kg(Cohort2: patients4–6)
 3 mg/kg(Cohort3: patients7–9)
In eachcohort, patientswere administeredonce-weeklyinfusionsof
sebelipase alfaandwere monitoredforsafety.
Followingcompletion of the lastinfusiononDay21, patientsreturnedon
Day 28 and Day 52 for assessmentof safetyandthe magnitude and
reversibilityof effectsonserumtransaminases,lipids,andothermarkersof
disease activity.Patientsonlipid-loweringmedicationscontinuedontheir
medicationsata stable dose throughoutthe study.

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LAL-CL04
 PatientscompletingLAL-CL01were eligibleforthe LAL-CL04 extension
study,whichfollowedpatientstoWeek12.
 Patientsresumedtreatmentwith4once-weeklyinfusionsof sebelipase
alfaat the same dose as inthe LAL-CL01 study(0.35, 1, or 3 mg/kg)
before transitioningtoevery-other-weekinfusions(1or 3 mg/kg).
 Patientsinthe once-weekly0.35mg/kg dosingregimenmovedto1
mg/kgeveryotherweek.
 Patientsinthe 1 and 3 mg/kgonce-weeklydosingcohortsremainedon
the same dose but receivediteveryotherweek.
Figure 4-4 presentsthe studydesignof LAL-CL01and LAL-CL04.
Figure 4-4: Study design of LAL-CL01 and LAL-CL04 [Balwani 2013 p3 Figure
1, Whitley 2014 Slide 6]
Subjects (18–65 yrs) were requiredto havedocumented LALD, hepatomegaly,and/or transaminases
>1.5x ULN, andwereallowedto beon a lipid-lowering agent (stable dose for ≥ 4 weeks)
Results
LAL-CL01 results
Liver transaminases
Followinginitiationof treatmentinLAL-CL01withsebelipase alfa,levelsof
livertransaminases(ALTandAST) decreasedrapidly intothe normal range.
ThisreductioninASTand ALT was observedwithin2weeksof the first
infusionandlevelscontinuedtodecrease inmostpatientsthroughDay28.
By Day 28, approximately1weekafterthe fourthinfusion,transaminases

11
had normalizedinall 6patientswithabnormal baseline ALTandin4 of 6
patientswithabnormal baselineAST.Forthe setof all nine patients,
treatmentwasassociatedwithstatisticallysignificantdecreases(P≤0.05) in
AST andALT frombaseline toDay28. [Balwani 2013 p5 col 1 para2] When
patientsstopped treatmentatthe endof LAL-CL01, transaminases
increased.
Serumlipids
There wasa transientincrease intotal cholesterol,triglycerides,andLDL
betweenbaseline andDay28 inLAL-CL01. This transientincrease was
believedtobe due tomobilizationof accumulatedlipids. [Balwani 2013 p6 col 1
para3, p8 col 1 para1]
Followingthisinitialasymptomaticincreaseinlipidlevels,there wasan
overall improvementineachparameteruntil levelswere below their
baseline values. [Balwani 2013 p6 col 1 para3]
Safetyresults
Sebelipase alfawaswell toleratedacrossawide range of doses. [Balwani 2013
p8 col 1 para1] The 9patientswhoenrolledinLAL-CL01completedthe study
withno seriousadverse effects(SAEs),treatment-relateddiscontinuations,
withdrawals,ordose reductions. [Balwani 2013 p4 col 2 para2]
LAL-CL04 12-week results
Liver transaminases
All 8 patientswhoreinitiated sebelipase alfainLAL-CL04had rapid
reductionsintransaminasessimilartothose seeninLAL-CL01.[Balwani 2013
p5 col 2 para2–p6 col 1 para1]Decreaseswere sustainedatDay 28 (LAL-CL01;
P<0.05) andat 12 weeks(LAL-CL04;P<0.05) [Balwani 2013 p5 col 1 para2, p6 col 1
para1]
Serumlipids
Ongoingtreatmentwith sebelipasealfainLAL-CL04demonstratedthe
followingbyWeek12:
 Mean decrease fortotal cholesterol (44± 41 mg/dL; 22% decrease,
P=0.047)
 Mean decrease forLDL (29 ± 31 mg/dL;27% decrease, P=0.078)
 Mean HDL increasedfrom35 ± 9 mg/dL to 40 ± 9 mg/dL (15% increase,
P=0.016)
 Mean decrease fortriglycerides(50± 38 mg/dL; 28% decrease, P=0.016)

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Safetyprofile
The safetyprofile forLAL-CL04was consistentwithLAL-CL01through12
weeks,withnofindingsof clinical concern. [Balwani 2013 p4 col 2 para4]
No treatment-relatedseriousadverseevents(SAEs)were reported.One
patientexperienced anSAE,acute cholecystitisandcholelithiasis,which
was unrelatedtosebelipase alfatreatment. The patientunderwentan
elective cholecystectomyandcontinuedinthe study. [Balwani 2013 p4 col 2
para3][Whitley2014 Slide 11]
Infusion-relatedreactions(IRRs) weremildandincludednausea,headache,
and diarrhea. [Whitley2014 Slide 11]
LAL-CL04 90-week results
Liver transaminases
Data up to 90 weeksof follow-upare available for6patients.At90 weeksof
follow-upthe meanpercentchange inALTand ASTwas 46% and36%,
respectively. [Whitley2014 Slide 9] Figure 4-5showsthe improvementof
transaminasesthrough90 weeks.
Figure 4-5: Improvement in transaminases [Whitley 2014 Slide 9]
ALT, alanine transaminase; AST, aspartateaminotransferase(AST); ULN, upper limit ofnormal; QW,
every week;QOW, every other week
Serumlipids
At Week90, the percentchange from the LAL-CL01 baseline inlipid
parameterswasassessed.The meanpercentreductioninLDLwas 50%. The
meanpercentreductionintriglyceride levelswas46%.There wasa 40%
increase inmeanHDL at Week90. [Whitley2014 Slide 10] Figure 4-6showsthe

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improvementinthe dyslipidemiaprofile with sebelipase alfathrough90
weeks.
Figure 4-6: Improvement in dyslipidemia profile [Whitley 2014 Slide 10]
LDL, low-density lipoprotein;HDL,high-density lipoprotein;TRG, triglycerides; QW,every week; QOW,
every otherweek
Safetyresults
Through90 weeks,there were nodrug-relatedSAEs. There were 6Grade 2
“moderate”IRRsand 2 Grade 3 “severe”IRRs.One patientpausedtherapy
afterexperiencingahypersensitivity-like reaction.He underwentskin
testingandadditional immunoglobulintesting.He wasable toresume
therapyafterreviewof the resultswiththe safetycommittee. [Whitley2014
Slide 12] MostIRRs were mildandprimarilyGIrelated(e.g.,diarrhea,
abdominal cramping). [Whitley2014 Slide 11] There wasnoevidence of anti-
drug antibodiesinpatientswhoreceived sebelipasealfa.[Whitley2014 Slide 12]
Conclusions
Balwani etal. concludedthatchildrenandadultswithLALD whoare treated
withsebelipase alfaexperience anormalizationof serumtransaminasesand
an improvementinthe lipidprofile. [Balwani 2013 p7 col 1 para2–c2 para1, p8 col 1
para1] Thisisthe first-in-humanevidence thatenzymereplacementtherapy
corrects abnormalitiesassociatedwithLALD.The baselinedisease
characteristicsforthe 9 patients were variable,butthe clinical effectof
sebelipase alfaproducedaconsistenteffectacrossthe cohortsregardlessof
dose. [Balwani 2013 p8 col 1 para1]

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The 90-weekresults suggestevidence thatlong-termtreatmentof LALD
withsebelipase alfaproducessustainedimprovementsinthe biochemical
markersof liverdamage andinthe dyslipidemiaassociatedwithLALD.
Basedon resultsfromadministrationof more than 300 infusions, sebelipase
alfaappearsto be well tolerated. [Whitley2014 Slide 13]
Additional datafromrandomizedcontrol studiesare neededtobetter
understandthe efficacyandsafetyprofile of sebelipasealfa.

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Lesson 3: SebelipaseAlfa Trials
That Have Not Reported Results
Learning Objectives
 Identify keyclinical trialsof sebelipasealfathathave notyetreported
results
 Reviewthe objectivesforsebelipase alfaclinical trialsinLALD that
have not yetreportedresults
 Reviewthe designforsebelipasealfaclinical trialsinLALD that have
not yetreportedresults
Thissectionpresentsinformationforsome trialsof sebelipasealfaforwhich
resultshave notyetbeenreported.
ARISE(LAL-CL02)
ARISEstands forAcidLipase ReplacementInvestigatingSafetyandEfficacy.
ARISEis a Phase 3 multicenterstudyof sebelipase alfainpatientswith
LAL D. The studyhas completedrecruitmentandisongoing.
Objective
The objective of ARISEisto evaluate the efficacyandsafetyof 1 mg/kgIV
infusionsof sebelipasealfaadministeredeveryotherweekinchildrenand
adultswithLAL D. [ClinicalTrials.gov2014 p1 purpose]
Design
ARISEis a Phase 3, multicenter,randomized,placebo-controlled,double-
blindstudythatwill evaluate the safetyandefficacyof every-other-weekIV
infusionsof sebelipasealfa(1mg/kg) versusplaceboinpatientswithLALD.
The primaryoutcome measure isthe proportionof subjectswhoachieve
ALT normalization,whichisdefinedashavinganALT below the age- and
gender-specificULN providedbythe central laboratoryperformingthe
assayrelative toplacebo. The studywill consistof a20-weekdouble-blind
treatmentperiod followedby anopen-label extensionperiodof upto 130
weeks.

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The study hasnumeroussecondaryoutcomes,whichare presentedin
Table 4-4.
Table 4-4: Key Secondary Outcome Measures [ClinicalTrials.gov 2014 ARISE
p2 bullets]
Assessment Intervals Measure
At Weeks 20, 52,and
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 Relative change in LDL
 Relative change in non-HDL cholesterol
 Proportion of subjects with an abnormal baseline
AST (i.e., >ULN) who achieve normalization of AST
 Relative change in triglycerides
 Relative change in HDL
 In the subsetof subjects where performed
 Relative change in liver fatcontent and in liver
volume
 Proportion of subjects who show improvement in
liver histopathology
 Incidenceof Adverse Events, Serious Adverse
Events, IRRs, and Anti-Drug Antibodies (ADAs)
At Weeks 52 and 78  Proportion of subjects who achieveALT
normalization
Study population
To participate inARISE,patientswere requiredtobe 4 yearsof age or older
withLAL D. Enrollmentinthisstudyendedat66 patients.Inclusionand
exclusioncriteriaare presentedinTable 4-5.

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Table 4-5: ARISE Inclusion and Exclusion Criteria [ClinicalTrial.gov 2014 p3
criteria]
 ≥4 years of age
 Deficiency of LAL enzyme activity
confirmed by dried blood spot (DBS)
testing at screening
 ALT ≥1.5x ULN
 Female subjects of childbearing
potential must not be pregnant or
breastfeeding
 Subjects receivinglipid-lowering
therapies must be on a stabledose
of the medication
 Subjects receivingmedications for
the treatment of non-alcoholic fatty
liver diseasemustbe on a stable
dose
 Severe hepatic dysfunction (Child-
Pugh Class C)
 Previous hematopoietic or liver
transplantprocedure
 Received treatment with high-dose
corticosteroids (acuteor chronic)
within 26 weeks
LAL-CL03
LAL-CL03 isa Phase 2/3 multicenterstudyof sebelipasealfain infantswith
growthfailure due to LAL D. The study iscurrentlyrecruitingpatients.
[Synageva 2014 LAL-CL03 p5 para4][ClinicalTrials.gov 2014 LAL-CL03 p1 A, B, C]
Objectives [ClinicalTrials.gov2014 LAL-CL03;Synageva 2014 LAL-CL03 p272.1-2.3]
The primaryobjective of LAL-CL03 isto evaluate the effectof sebelipasealfa
therapyon survival at12 monthsof age in infantswithgrowthfailure due to
LAL D. [ClinicalTrials.gov 2014 LAL-CL03 p1 D]
The secondaryobjectivesof LAL-CL03are:[ClinicalTrials.gov 2014 LAL-CL03 p2 E]
 Long-termsafetyof sebelipasealfain infantswithgrowthfailure due to
LAL D; patientswill be followedforup to 3 years
 Survival beyond12monthsof age;patientswill be followedforup to3
years
Design
LAL-CL03 isa Phase 2/3 open-label,repeat-dose,dose escalationstudyof
sebelipase alfain infantswithgrowthfailuredue toLAL D. Eligible patients

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will receiveonce-weekly IV infusionsof sebelipase alfafor upto 3 years.
[ClinicalTrials.gov2014 LAL-CL03 p1 C]
Study population
Approximately10patientsare expectedto be enrolledin LAL-CL03.
[ClinicalTrials.gov 2014 LAL-CL03 p2 F] Keyinclusionandexclusioncriteriaare
presentedinTable 4-6.
Table 4-6: LAL-CL03 Inclusion and Exclusion Criteria [ClinicalTrials.gov2014
LAL-CL03 p2 G]
 Subject's parent or legal guardian
provides written informed
consent/permission prior to any
study procedures
 Male or female infantwith
documented decreased LAL
activity relativeto the normal
range of the lab performing the
assay or documented result of
molecular genetic testing
(2 mutations) confirminga
diagnosis
 Growth failurewith onset before
6 months of age
 Clinically importantconcurrent
disease
 Has received an investigational
product other than sebelipasealfa
within 14 days prior to the firstdose
 Subject is older than 24 months of age
 Myeloablativepreparation,or other
systemic pre-transplantconditioning,
for hematopoietic stem cell or liver
transplant
 Previous hematopoietic stem cell or
liver transplant
LAL-CL06 [Synageva 2014 emailcorrespondence]
Overview
The primaryobjective of studyLAL-CL06 isto evaluate the safetyof
intravenousinfusionsof sebelipase alfaina more broadpopulationof LAL D
patientsthanpreviouslystudied.Suchpatientsmayhave beenexcluded
fromenrollmentinotherstudiesof LAL D because of age,disease
progression, previous treatmentbyhematopoieticstemcell orliver
transplantation,lesscommondisease manifestations,ordisease
characteristicsthatwouldpreclude participationinaplacebo-controlled
study.
LAL-CL06 isanticipatedtostart inApril 2014 and run throughApril 2016.
Design
LAL-CL06 isan open-label study thatwill include infants>8months,
children,andadults.Eligible patientswill receive sebelipase alfaata dose of

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1 mg/kgeveryotherweek. Inclusionandexclusioncriteriaare presentedin
Tables4-7 and 4-8.
Table 4-7: LAL-CL06 Inclusion Criteria [Synageva 2014 email correspondence]
Inclusion criteria
1. Patient will be> 8 months of age at the time of dosing.
2. Confirmation of LAL D diagnosisas determined by the central lab.
3. Patients > 8 months but < 4 years of age at Screening will haveat least1 of
the followingdocumented clinical manifestationsof LAL D:
Dyslipidemia
 Elevated transaminases (ALT ≥1.5x ULN)
 Impaired growth
 Suspected malabsorption
 Other clinical manifestation of LAL D
4. Patients ≥ 4 years of age at Screening will haveat least1 of the following
documented clinical manifestations of LAL D:
 Evidence of advanced liver disease
 Histologically confirmed diseaserecurrencein patients with pastliver or
hematopoietic transplant
 Persistentdyslipidemia
 Suspected malabsorption
 Other clinical manifestation of LAL D
Table 4-8: LAL-CL06 Exclusion Criteria [Synageva 2014 email correspondence]
Exclusion criteria
1. Patient has known causes of active liver diseaseother than LAL D which have
not been adequately treated.
2. Patient received a hematopoietic stem cell or liver transplant<2 years from
the time of dosing.
3. Patient with co-morbidities other than complications dueto LAL D which are
irreversibleor associated with a high mortality risk within 6 months, or would
interfere with study complianceor data interpretation.

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LAL-CL08 [Synageva 2014 emailcorrespondence]
Objective
LAL-CL08 isan open-label,repeat-dose,studyof sebelipasealfaininfants
< 8 monthsof age withrapidlyprogressiveLALDeficiency. The primary
objective of the studyistoevaluate the safetyandtolerabilityof sebelipase
alfain infantswithrapidlyprogressive LALD. Thisstudyis anticipatedto
start inApril 2014 and runthrough April 2017.
Design
LAL-CL08 will include infants<8 monthsof age withrapidlyprogressive
LAL D. Eligible subjectswill receive once-weeklyinfusionsof sebelipasealfa
for upto 3 years. All subjectswill be evaluatedforsafety,tolerability,and
efficacy. Inclusionandexclusioncriteriaare presentedinTable 4-9.
Table 4-9: LAL-CL08 Inclusion and Exclusion Criteria [Synageva2014 email
correspondence]
1. Subject's parent or legal guardian (if
applicable) consents to participation
in the study
2. Confirmation of LAL D diagnosisas
determined by a Sponsor's
approved central laboratory
3. Substantial clinical concerns,in the
opinion of Investigator and Sponsor,
of rapid diseaseprogression
requiringurgent medical
intervention including,butnot
restricted to, the following:
 Marked abdominal distension
and hepatomegaly
 Failureto thrive
 Disturbanceof coagulation
 Severe anemia
 Siblingwith rapidly progressive
courseof LAL D
1. Clinically importantconcurrent
disease
2. Subject will be> 8 months of age at
the time of firstdosing
3. Subject has received an
investigational medicinal product
other than sebelipasealfa within 14
days prior to the firstdoseof
sebelipasealfa in this study
4. Myeloablativepreparation,or other
systemic pre-transplant
conditioning, for hematopoietic
stem cell or liver transplantation
5. Previous hematopoietic stem cell or
liver transplant
6. Known hypersensitivity to eggs

21
Lesson 4: Registry for
LAL Deficiency
Learning Objectives
 Describe the objectivesof the RegistryforLysosomal AcidLipase
Deficiency(LALD)
 Describe the functionsof the RegistryforLysosomal AcidLipase
Deficiency(LALD)
Overview
The LAL DeficiencyRegistryisamulti-center,internationalregistrythatuses
observational methodstocollectlongitudinaldatafrompatientswith
lysosomal acidlipase deficiency(LALD) inorder to create a knowledge base
to helpimprove the care of these patients. [LAL D Registry2014 Work p1 para1]
The Registryissponsored,funded,andadministeredbySynageva
BioPharma. [LAL D Registry2014 Sponsor p1 para1, LAL D Registry2014 Governance p1
para1] The LALDRegistrycan be accessedat
https://www.laldeficiencyregistry.com.
Objectiveof the Registry
The LAL D Registrycollectslongitudinal data.Ideally,the information
gatheredwill be usedforthe followingpurposes: [LAL D Registry2014 Work p1
para2]
 To furtherunderstand LALD, itsprogression,andanyassociated
complications
 To evaluate the long-termeffectivenessof therapeuticandsupportive
interventions
 To improve care throughevidence-basedpatientmanagement
 To understandthe relationshipbetween LALDand access to care

22
Registry participants
PatientsdiagnosedwithLALD or individualswhoare carriersof the disorder
may be includedinthe LALD Registry. Those whochoose toparticipate in
the LAL D Registrymustprovide informedconsent. Inclusionisindependent
of treatmentstatusortreatmentchoice.The Registryincludesbothliving
and deceasedpatients.Carriersmustprovideevidence of atleastone
mutationinthe LIPA gene or evidence of aparentor childwhowas
diagnosedwithLALD. [LAL D Registry2014 Work p1 para3]
Other information in the Registry
The Registryalsoprovidesadditional informationforphysiciansaswell as
for patientsandtheirfamilies:
 Bibliography:listsjournal articlesthatprovide informationonLALD [LAL D
Registry2014 Bibliography]
 News:providesnewsoneventsandsourcesof informationthatmaybe
of interesttothe LAL D community [LAL D Registry2014 News]
 Clinical trial overview:providesasummaryof completedandactive
clinical trialsinLALD [LAL D Registry2014 Clinical Trials]
 Patientandprofessionalorganizations:provideslinkstopatientand
professionalorganizationsthatserve the LALD community
Patientorganizationsprovide information,advocacy,networking,and
supportresourcesforaffectedpeople andtheirfamilies.Informationon
professionalorganizationsthathealthcare providerscancontact for
informationandsupportare alsoprovided.
Tables4-10 and 4-11 listpatientandprofessional organizationsthatserve
the LAL D community.

23
Table 4-10: Patient Organizations [LAL D Registry 2014 Patient Organizations]
Patient Organization Description
LAL SOLACE Organization
(Support Organization for
LAL Deficiency - Advocacy,
Care, and Expertise)
Created by parents to providesupport for patients and families of infant, child,and adult
patients with LAL D
LAL Deficiency Source Website for patients and healthcareprofessionalshas recently launched to providemore
information on LAL D, includingthesigns and symptoms of the disease,diagnostic testing
and resources for patients and caregivers
Rare DiseaseAdvocacy
Research and Education
(RARE) Project
Raises awareness of rarediseases;unifies,equips,and empowers the global raredisease
community; and funds innovations to supportrare diseaseresearch
Childhood Liver Disease
Research and Education
Network (ChiLDREN)
Collaborativeteam of doctors, nurses,research coordinators,medical facilities,and
patient supportorganizations in the US, Canada,and London working together to
improve the lives of children and families dealingwith rareliver diseases
NORD (National
Organization for Rare
Disorders)
Provides information and resources for patients with rare diseases;healthcareteams
provideadvocacy and serve as liaisonsbetween the rarediseasepatient community and
national institutions
EURORDIS European-focused, non-governmental, patient-driven allianceof patient organizations
representing rare diseases patientorganizationsin over 48 countries
Rare Connect Partnership between EURORDIS and NORD
CLIMB (Children Livingwith
Inherited Metabolic
Diseases)
Provider of free metabolic diseaseinformation to young people, adults,families,
professionals,and other interested groups in the United Kingdom (UK)
VaincreLes Maladies
Lysosomales (VML)
Parent-led organization in Francethatsupports research on lysosomal storagedisorders
(LSDs); supports health services in improvingpatientquality of lifeand supports families
Ben’s Friends Network of patient communities dedicated to providingsupportfor patients of rare
diseases
Genetic Alliance Non-profit health advocacy organization focused on genetics
Network of >1,000 disease-specific advocacy organizationsaswell as universities,private
companies,government agencies, and public policy organizations
PatientsLikeMe Forum for patients to shareand learn from real-world,outcome-based health data
Uses data sharingto align patientand industry interests
The Liver Care Foundation Advocates and generates public awareness aboutliver health
RareShare Social hub buildingcommunities for patients,families,and healthcareprofessionals

24
Table 4-11: Professional Organizations [LAL D Registry 2014 Professional
Organizations]
Professional Organization Description
LAL Deficiency Source Website for patients and healthcareprofessionals
has recently launched to provide more
information on LAL D, includingthesigns and
symptoms of the disease,diagnostictesting,and
resources for patients and caregivers
Lysosomal Disease
Network
Collects information and provides linksto
resources for the individual LSDs,includingLAL D
Societies for
PediatricGastroenterology,
Hepatology and Nutrition
NASPGHAN (North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition)
LASPGHAN (Latin American Society for Pediatric
ESPGHAN (European Society for Paediatric
APPSPGHAN (Asian Pan Pacific Society for
Pediatric Gastroenterology,Hepatology and
Nutrition)
WCPGHAN (World Congress of Pediatric
Seek to improve the treatment and management
of gastrointestinal,hepatobiliary, pancreatic,and
nutritional disorders in children through
information and resources for parents, patients,
and medical professionals
National Lipid Association
(NLA)
Seeks to enhance the practiceof lipid
management in clinical medicineby enhancing
medical knowledge, clinical skills,and related
activities to improve patient outcomes
Society for Inherited
Metabolic Disorders
(SIMD)
Seeks to increaseknowledge of and promote
research in inborn errors of metabolismin
humans
SSIEM (Society for the
Study of Inborn Errors of
Metabolism)
Focused on inherited metabolic disorders and
related topics
Promotes the exchange of ideas through scientific
meetings, publications,and other means

25
Take HomePoints
 Sebelipase alfa(formerly knownasSBC-102) is a recombinantformof the
humanlysosomal acidlipase (LAL) enzyme under investigational
developmentbySynagevaasan enzyme replacementtherapyforLAL
Deficiency (note:sebelipasealfahasnotreceivedregulatoryapproval for
commercial use andisunderclinical development).
 To produce sebelipase alfa,the transgene isinsertedintothe genomeof
Gallus gallus;oviductcells thentranscribe the sebelipase alfagene and
translate the sebelipase alfamRNA intothe protein: sebelipase alfa.
 Afterbindingtospecificreceptorsoncells, sebelipasealfaistakenupby
cellsand transported tolysosomes.
 Cellsincubatedwithsebelipase alfahave been foundtoincrease cellular
LAL activity.
 Recombinanthuman sebelipase alfahasanappropriate glycanstructure
that allowsitto bindtomannose or mannose-6-phosphate receptors,be
takenup bycells,and be transportedto lysosomeswhere itisbiologically
active.
 InterimstudyresultsfromLAL-CL01/04 show that adultswithLALD who
are treatedwith sebelipase alfaexperience anormalizationof serum
transaminasesandanimprovementinthe lipidprofile.
 Interim90-weekresults fromLAL-CL01/04demonstrate thatlong-term
treatmentof LAL D with sebelipase alfaproducessustained
improvementsinthe biochemical markersof liverdamage andinthe
dyslipidemiaassociatedwithLALD.
 InterimstudyresultsfromLAL-CL01/04 show that sebelipase alfaappears
to be well tolerated.
 The ARISE studywill evaluatethe efficacyandsafetyof 1 mg/kgIV
infusionsof sebelipasealfaadministeredeveryotherweekinchildren
and adultswithLALD.
 The primaryobjective of LAL-CL03 isto evaluate the effectof sebelipase
alfatherapyon survival at12 monthsof age inchildrenwithgrowth
failure due toLAL D.
 The primaryobjective of the LAL-CL06 studyisto evaluate the safetyand
efficacyof intravenousinfusionsof sebelipasealfainamore broad
populationof LALD patientsthanpreviouslystudied.

26
 The primaryobjective of the LAL-CL08 studyisto evaluate the safetyand
tolerabilityof sebelipase alfaininfantswithrapidlyprogressiveLALD.
 The LAL DeficiencyRegistryisamulti-center,internationalregistrythat
usesobservational methodstocollectlongitudinaldata frompatients
withlysosomal acidlipase deficiency(LALD) inorderto create a
knowledge base to helpimprove the care of these patients.

GLOSSARY
27
Glossary
cholecystectomy removal of the gallbladder by laparoscopic or abdominal surgery [Taber's 2014
cholecystectomy]
cholecystitis inflammation of the gallbladder wall [Taber’s 2014 cholecystitis]
cholelithiasis presence of ≥1 gallstonein the gallbladder [Merck Manual2014 cholelithiasis]
endothelial cells type of cell that lines blood and lymph vessels;they are usually flattened and form a sheet
one cell thick [Taber’s 2014 endothelial cell]
enzyme replacement
therapy
therapy involvingthe administration of enzymes to patients who have congenital or
acquired enzyme deficiency disease [Taber’s 2014 enzyme replacement therapy]
Gallus gallus domestic chicken
glycoprotein compound consistingof a carbohydrate(sugar) and a protein [Taber’s 2014 glycoprotein]
hepatocyte liver cell [Taber’s 2014 hepatocyte]
Kupffer cell macrophage found in the liver;see macrophage [Taber’s 2014 Kupffer cell]
macrophage mature monocyte that has settled in tissue;they ingest and destroy foreign antigens and
microorganisms and area key element of the immune system [Taber’s 2014 macrophage]
mannose type of simplesugar produced by certain plants such as legumes [Taber’s 2014 mannose]
monocyte mononuclear white blood cells thatcirculatein the bloodstreamfor about 1 day before
maturing into macrophages; they area key element of the immune system [Taber’s 2014
monocyte]
oviduct fallopian tube; tube that extends from the ovary to the uterus and conducts ova from the
ovary to the uterus and sperm from the uterus to the ovary [Taber’s 2014 oviduct]
periportal fibrosis fibrosis(the repair and replacement of inflamed tissueby connective tissue) that occurs
around the portal vein and its branches [Taber's 2014 periportal, fibrosis]
portal hypertension high blood pressurein the portal vein, the vein that brings mostof the blood drainingfrom
the intestines to the liver;obstruction of the normal blood flow through the liver results in
blood backingup into the venous system, from which complicationscan develop [Taber's
2014 portal hypertension, portal vein, andhypertension]
recombinant DNA DNA produced by a technical process in which segments of DNA from one organismare
artificially manipulated or inserted into the DNA of another organismthrough gene
splicing(insertion of a portion of a gene from one chromosome or one species into a gene
from another); the inserted genetic material is copied when the when the hostgenetic
material is reproduced;gene splicingpermits isolation and examination of the properties
and action of specific genes [Taber’s 2014 recombinant DNA, gene splicing]

GLOSSARY
28
reticuloendothelial cells cell that is partof the mononuclear phagocytic system, which includes monocytes and
macrophages [Taber’s 2014 reticuloendothelial cell, mononuclear phagocytic system]
transgene a genetic sequence that is taken from one organismand inserted into the DNA or RNA of
another organism[Taber’s 2014 transgene]

REFERENCES
29
References
Balwani M, BreenC,Enns GM, etal. Clinical effectandsafetyprofile of recombinanthumanlysosomal acid
lipase inpatientswithcholesteryl esterstorage disease. Hepatology. 2013;58(3):950–957.
ClinicalTrials.gov.A MulticenterStudyof SBC-102 (SebelipaseAlfa) inPatientsWithLysosomal AcidLipase
Deficiency/ARISE(AcidLipase ReplacementInvestigatingSafetyandEfficacy).
http://www.clinicaltrials.gov/ct2/show/NCT01757184?term=lysosomal+acid+lipase+deficiency&rank=6.
AccessedJanuary22, 2014.
ClinicalTrials.gov.AnObservational Studyof PatientswithLysosomal AcidLipaseDeficiency/Cholesteryl Ester
Storage Disease Phenotype.
ClinicalTrials.gov. LAL-CL04:ExtensionStudytoEvaluate the Long-TermSafety,Tolerability,andEfficacyof SBC-
102 (Sebelipase Alfa) inAdultSubjectswithLysosomal AcidLipase Deficiency.
http://www.clinicaltrials.gov/ct2/show/study/NCT01488097?term=synageva&rank=7.AccessedJanuary22,
2014.
ClinicalTrials.gov.Safety,TolerabilityandPharmacokineticsof SBC-102(Sebelipase Alfa) inAdultPatientswith
Lysosomal AcidLipase Deficiency.
ClinicalTrials.gov. LAL-CL03:Trial inChildrenwithGrowthFailure Due toEarlyOnsetLysosomal AcidLipase (LAL)
Deficiency/WolmanDisease.
GoldbergM. Lysosomal AcidLipase Deficiency:AnOverview [PowerPointslides].November26,2013.
LAL DeficiencyRegistry. AboutLALDeficiency.
https://www.laldeficiencyregistry.com/PhysicianLandingPage.aspx?criteria=divContent2.AccessedFebruary12,
2014.
LAL DeficiencyRegistry.Bibliography.
2014.
LAL DeficiencyRegistry.Clinical Trials.
https://www.laldeficiencyregistry.com/PhysicianLandingPage.aspx?criteria=divContent11.AccessedFebruary
17, 2014.
LAL DeficiencyRegistry.HowDoesthe RegistryWork?
2014.

REFERENCES
30
LAL DeficiencyRegistry.News.
17, 2014.
LAL DeficiencyRegistry.PatientOrganizations.
17, 2014.
LAL DeficiencyRegistry.ProfessionalOrganizations.
17, 2014.
LAL DeficiencyRegistry.RegistryGovernance.
2014.
LAL DeficiencyRegistry.RegistrySponsor.
2014.
Merck Manual. Cholelithiasis.
http://www.merckmanuals.com/professional/hepatic_and_biliary_disorders/gallbladder_and_bile_duct_disord
ers/cholelithiasis.html.AccessedFebruary18,2014.
Synageva.LAL-CL03 Protocol.Anopenlabel,multicenter,dose escalationstudytoevaluate the safety,
tolerability,efficacy,pharmacokinetics,andpharmacodynamicsof sbc-102 inchildrenwithgrowthfailure due to
lysosomal acidlipase deficiency.2014.
Synageva.LAL-CL06 Protocol.A multicenter,open-labelstudyof sebelipase alfainpatientswithlysosomal acid
lipase deficiency. 2013.
Synageva.LAL-CL08 Protocol. A Phase 2, openlabel, multicenterstudytoevaluate the safety, tolerability,
efficacy,and pharmacokineticsof sebelipase alfaininfantswith rapidly progressive lysosomal acidlipase
deficiency. 2014.
Synageva. Sebelipase alfa. http://www.synageva.com/programs-clinical-development-sebelipase-alfa.htm.
AccessedFebruary17, 2014.
Synageva.SynagevaExpressionPlatform.http://www.synageva.com/science-and-technology-synageva-
expression-platform.htm.AccessedFebruary17,2014.
Taber’sMedical DictionaryOnline.www.tabers.com/tabersonline.AccessedFebruary17,2014.

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