JerryVockley,M.D.,Ph.D.Cleveland FamilyProfessorofPediatrics

ProfessorofHumanGeneticsUniversity ofPittsburghChiefofMedicalGenetics

DirectoroftheCenterforRareDiseaseTherapyChildren’sHospitalofPittsburgh

EmergingtherapiesforFAODs

• TheInternationalNetworkforFattyAcidOxidationResearchandManagement(INFORM)hasbeenformedinordertopromulgateinformationontheresearchandmanagementofdisordersoffattyacidoxidation.

• TheNetworkwillprovideacollaborativeframeworkforongoingcommunicationandresearchbetweenthemembers.

Missionstatement

• Researchfunding– NIH– Ultragenyx– Stealth– Reata– Mitobridge– Wellstat

• Consulting– AmericanGeneTherapies– Mitobridge

Conflictsofinterest

ThankstoInnsbruck

INFORM Inaugural Symposium: September 6, 2014 Innsbruck, Austria

WelcometoLyon

INFORM Second Annual Symposium: September 4-5, 2015 Lyon, France

Markyourcalendars!

INFORM Third Annual Symposium: May 9-11, 2016Boston, MA USA

Organizingcommittee

Nicola Longo, M.D., Ph.DCo-ChairProfessor of PediatricsUniversity of Utah School of Medicine

Sponsorsandpartners

Startingline

Anaplerotictherpy

PC

X

X

• Triheptanoin– FDAphase2complete– Publicationoncompassionateuse– Phase3soon?

• Anti-inflammatories• Bendavia (StealthBiotherapeutics)• RTA408(Reata Pharm.,Inc.)• Mitobridge• Uridine• Ravicti inMCAD(Horizon)

FAODsclinicaltrials

TriheptanoinTreatmentHistory

AgeatStartof

Treatment*

DurationofTreatment

<1year 1-2years 2-5years >5years TotalN(%)

0-1month(Neonates) - - - 2 2

1month-2years(Infants) 1 - 1 3 52-12years(Children) - - - 10 10

12-16years(Adolescents) - - - - -

>16years(Other) - - 1 2 3TotalN (%) 1 - 1 17 20

*Doselevelsvariedovertimeandpersubject.Targetdoselevelswereinitially2-4g/kgandlater1-2g/kgTriheptanoin.

Hospitaldays/year

Hypoglycemicevents/year

Rhabdo hospitalizations

• LC-FAODleadtofrequentcomplications/hospitalizations• Treatmentwithtriheptanoinappearstoreducethehospitalizationsandhospitaldays

• Hypoglycemichospitalizationswerenearlyeliminated• Rhabdomyolysishospitalization#notchanged• Additionalstudiesplanned

Triheptanoin

Decrease inEventRate

Decrease in#ofHospitalizationDays

TotalEvents 30% 67%

Hypoglycemia 96% 98%

Rhabdomyolysis No Change 60%

FDAtriheptanointrial

Doubly-labeled water (DLW) measure of TEE completed at home.

SubjectsDiagnosis Triheptanoin C7 MCT C8

CPT-2 (n) 5Age 21-64; BMI 18-33

6Age 8-43; BMI 17-35

VLCAD (n) 4Age 7-38; BMI 17-31

5Age 23-42; 22-31

LCHAD/TFP (n) 7Age 7-29; BMI 14-24

5Age 8-17; BMI 15-23

TOTAL: 16 16

Participant Characteristics Triheptanoin C7 MCT C8

Age (years) 7 - 64 8 - 43

BMI (kg/m2) 14-33 15-35

Males (n) 6 6

Females (n) 10 10

Adverseevents

ExpectedAdverseEventC-7 C-8

#ofevents #ofsubjects #ofevents #ofsubjects

Diarrhea/LooseStools/Steatorrhea 9 5 12 6GastrointestinalUpset 24 11 38 12Emesis/Vomiting 7 6 0 0MusculoskeletalPain/Cramping/ElevatedCPK 16 11 18 10Rhabdomyolysis(hospital admission) 7 5 7 4Fatigue/Lethargy 3 3 2 2

UnexpectedAdverseEventC-7 C-8

#ofevents #ofsubjects #ofevents #ofsubjects

Headache 17 5 7 3ViralIllness 22 15 17 11LocalizedPainNotAssociatedwithRhabdomyolysis 5 4 2 2Dermatitis 1 1 4 4

• No difference in GI upset or diarrhea between groups• Emesis occurred in 6 subjects, only in triheptanoin group• No difference in rhabdomyolysis, fatigue, or unexpected AE’s

Triheptanoin is similarly tolerated as MCT

• Nodifference inGIupsetordiarrheabetween groups• Emesis occurredin6subjects, onlyintriheptanoin group• Nodifference inrhabdomyolysis, fatigue,orunexpected AE’s

ExpectedAdverseEventC-7 C-8

#ofevents #ofsubjects #ofevents #ofsubjects

Diarrhea/LooseStools/Steatorrhea 9 5 12 6GastrointestinalUpset 24 11 38 12Emesis/Vomiting 7 6 0 0MusculoskeletalPain/Cramping/ElevatedCPK 16 11 18 10Rhabdomyolysis(hospital admission) 7 5 7 4Fatigue/Lethargy 3 3 2 2

UnexpectedAdverseEventC-7 C-8

#ofevents #ofsubjects #ofevents #ofsubjects

Headache 17 5 7 3ViralIllness 22 15 17 11LocalizedPainNotAssociatedwithRhabdomyolysis 5 4 2 2Dermatitis 1 1 4 4

Triheptanoin is similarly tolerated as MCT

Improvedcardiacfunction

7% increase LV ejection fraction in Triheptanoin group

Triheptanoin MCT-10

-5

0

5

10LV

Eje

ctio

n Fr

action

%p=0.03

Triheptanoin MCT-20

-10

0

10

20

End

Syst

olic

Vol

ume

(ml)

p=0.03

Triheptanoin MCT-40

-20

0

20

40

End

Dia

stol

ic v

olum

e (m

l)

Triheptanoin MCT-60

-40

-20

0

20

40

LV w

all m

ass

(mm

)

p=0.09

Ejection Fraction End Diastolic Volume

End Systolic Volume LV wall mass

Treadmillresponse

• Significantly lowerHeartRateforsameworkperformedwithTriheptanoin supplementation

• p=0.05adjustedforbaseline• Mean-7beatsperminute >MCT

warm-up 1-10 11-20 21-30 31-40 80

100

120

140

160

Time (min)

Hea

rt R

ate

(bea

ts p

er m

inut

e)

Baseline End of Study

MCT before treadmill MCT or Triheptanoin before treadmill

warm-up 1-10 11-20 21-30 31-40 80

100

120

140

160

Time (min)

Hea

rt R

ate

(bea

ts p

er m

inut

e)

Triheptanoin

MCT *p=0.05

Comparedtopreviousstudy

• MCTê HR15bpm comparedtocarbohydrate• Triheptanoinê HR7bpm comparedwithMCT

warm-up 1-10 11-20 21-30 31-40 80

100

120

140

160

180

Time (min)

Hea

rt R

ate

(bea

ts p

er m

inut

e) CHOMCT

warm-up 1-10 11-20 21-30 31-40 80

100

120

140

160

180

Time (min)

Hea

rt R

ate

(bea

ts p

er m

inut

e)

TriheptanoinMCT

Behrend et al. MGM 2012 105: 110-115

• MCTê HR15bpmcomparedtocarbohydrate• Triheptanoinê HR7bpmcomparedwithMCT

ImprovementwithC7>C8

warm-up 1-10 11-20 21-30 31-40 80

100

120

140

160

180

Time (min)

Hea

rt R

ate

(bea

ts p

er m

inut

e) CHOMCT

warm-up 1-10 11-20 21-30 31-40 80

100

120

140

160

180

Time (min)H

eart

Rat

e(b

eats

per

min

ute)

TriheptanoinMCT

• TriheptanoinsimilarlytoleratedasMCT• Noobservedskeletalmuscleeffect• CardiaceffectofTriheptanoin– ImprovedLVejectionfraction–LowerHRforsameworkperformed

• SimilarCPK,acylcarnitines &ketones

Conclusions

Alongsummer

With Permission

• Datacollectionstillinprogress• ~12patientswithsevere,life-threateningcardiomyopathywhileonMCT

• AllbutonerecoveredwithC7treatment

Cardiomyopathy

• Openlabel• 25patientstreated• Resultsreportedat24weeks• 8patientsqualifiedforexercisetesting

Ultragenyx phase2trial

• Safety– Safeandwelltolerated– Nonewpotentialrisksidentified– MostcommonadverseeventsGI(similartoMCT)

• Exerciseresults(8patients)– 60%increaseinexerciseenergygeneratedcomparedtobaseline

– 28%increasein12minutewalkdistancecomparedtobaseline

• Generaloutcome– Decreaseinoverallmajormedicalevents– Eventratetobereportedat78weeks

Ultragenyx phase2 results

InflammationinVLCADpatients

0 10 20 30 40 50 60 70 80 90

100

IL-8 IL-12 IL-17 INFγ MCP-1 MIP-1β 0"

50"

100"

150"

200"

250"

300"

350"

Control" Pa/ent" Control" Pa/ent" Control" Pa/ent"

NFkb" TNFa" CEBPb"

0"

200"

400"

600"

800"

1000"

1200"

1400"

Control" Pa/ent"

IFNg"

Blood cytokine levels Macropahge surface markers

The Mitochondrion

• 100s-1000spercell• Bacterialorigins• Cytoplasmic• Subcellularorganelles• Dynamic,pleomorphic,motile

Mitochondria

Cardiolipin

CH2

O

P

OCH2

CH

O

CO

CH2

OCO

C

O. O.P

OCH2

O.

CH2

CH

CH2OCO

CO

H HOO

- -

TAZ

Monolysocardiolipin

• Cardiolipinbindingtetrapeptide(D-Arg-dimethyl-Tyr-Lys-Phe-NH2

• Up-regulatesexpressionofnuclearencodedmito genes

• Reducescardiomyocyte apoptosispost-ischemia

• Decreasesamyloidβ inducedmitoabnormalities

• Improvesskeletalmusclefunciton

Bendavia

corepressorcorepressor

PPRE

coactivatorcoactivator

↑ Fatty acidoxidation

Fatty acid oxidationgenes

Generegulation

• Semi-synthetictriterpenoid• Nrf2promoteractivator(inducesPGC1a)

• ImprovesantioxidantgeneresponsetooxidativestressinFriedrich’sataxiacells

• RelatedcompoundimprovessurvivalinALSmousemodel

• ETCdeficiencystudyinprogress• Mitobridgewithsimilarcompounds

RTA408

N-(2-cyano-3,12-dioxo-28-noroleana-1,9(11)-dien-17-yl)-2,2-difluoro-propanamide

• Regulatesmito ATP-sensitivepotassiumchannel– PreventsATPdepletion,Ca++ overload,andROSproduction

– Regulatesmito volumeandpH• Activationofmito-KATPincreasesATPsynthesisrateinhypoxictissues

• Decreasesinflammatorysignalling?

Uridinetriacetate

• CommonK304EMCADmutationisafoldingdefect

• MCADmetabolizesphenylbutyryl-CoAassubstrate

• Bindingpocketanaloguesarestrongchaperonins

• Phenylbutyryl-CoAasachaperonintherapyforMCADdeficiency

MCADdeficiency

MCADandphenylbutyrate

Theskyisthelimit

Justdoit!

ThankYou!

Questions?