Novel therapies for inborn errors of fatty acid oxidation: A - - PowerPoint PPT Presentation

Center for Rare Disease Therapy

Novel therapies for inborn errors of fatty acid oxidation: A personalized medicine approach

Jerry Vockley, M.D., Ph.D.

University of Pittsburgh Cleveland Family Endowed Chair in Pediatric Research Children’s Hospital of Pittsburgh Chief of Medical Genetics Director of the Center for Rare Disease Therapy

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• Research funding

– NIH – Ultragenyx Pharmaceuticals – Reneo Phamaceuticals – Reata Pharmaceuticals – Moderna Pharmaceuticals – Biomarin Pharmaceuticals

• Consulting

– American Gene Technologies – Moderna Pharmaceuticals – Cobalt, Inc – DNARx – Rand Corporation

Conflicts of Interest

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The central dogma

DNA replication DNA transcription RNA Splicing mRNA translation

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• Multiple pathways
• Functionally and physically

interact

• Overlap in clinical symptoms
• Secondary symptoms may

dominate clinical picture

Energy metabolism interactions

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The mitochondrion

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• 100s-1000s per cell
• Bacterial origins
• Cytoplasmic
• Subcellular organelles
• Dynamic, pleomorphic,

motile

Mitochondria

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CPTII Com III

ETFDH

ETF ETF ETF ETF ETF ETF ETF

1 4 5 9 8 10 11 7 2 3

ETF

6

Matrix ACADs Membrane ACADs

QH2 NADH H+ H+

Inner Membrane Inter Membrane Space Mitochondrial Matrix

TFP Com IV

QH2 Com I

Energy protein complex model

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Clinical implications

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A house of cards

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Complete oxidation to CO2 and H20

Harvesting energy

Source ATP/molecule Total ATP 7 FADH2 2 14 7 NADH 3 21 8 Acetyl-CoA 10 80 Activation

• 2
• 2

NET 123

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Interupted oxidation to CO2 and H20

Energy in long chain FAODs

Sourcec ATP/molecule Total ATP 7 FADH2 7 NADH 8 Acetyl-CoA Activation

• 2
• 2

NET

• 2

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Anaplerotic therpy

PC

X X

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• Double blind comparison of C7

vs C8

• 4 month treatment
• Functional and metabolite

before and after treatment

FDA triheptanoin trial

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

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• Triheptanoin similarly tolerated as

MCT

• No observed skeletal muscle effect
• Cardiac effect of triheptanoin

– Improved LV ejection fraction – Lower HR for same work performed

• Similar CPK, acylcarnitines & ketones

Conclusions

warm-up 1-10 11-20 21-30 31-40 80 100 120 140 160 180

Time (min) Heart Rate (beats per minute)

CHO MCT

Heart Rate

31-40 warm-up 1-10 11-20 21-30 31-40 80 100 120 140 160 180

Time (min) Heart Rate (beats per minute)

Triheptanoin MCT

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Ultragenyx clinical trial

Characteristic n (%) Prior treatment with MCT 27 (93) Clinical Manifestations

Skeletal Myopathy Hepatic Disease Cardiac Disease

25 (86)

3 (10) 2 (7)

Disease Historya

Rhabdomyolysis Muscle Pain Exercise Intolerance Hypoglycemia Muscle Weakness Cardiomyopathy 26 (90) 22 (76) 21 (72) 18 (62) 16 (55) 13 (45)

aOccurring in >32% of subjects.

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78 Week outcomes

Major Clinical Event Mean (SD) Annualized Event/Year Pre-treatment Post- treatment % Change P Valueb Overall MCEs Rhabdomyolysis Events Hypoglycemia Events Cardiac Events 1.69 (1.61) 1.30 (1.50) 0.32 (0.91) 0.07 (0.27) 0.88 (1.14) 0.83 (1.15) 0.02 (0.12) 0.02 (0.12)

• 48.1
• 36.1
• 92.8
• 69.6

0.021 0.119 0.068 0.309 Hospitalizationsa Rhabdomyolysis Hypoglycemia Cardiomyopathy 1.39 (1.35) 1.03 (1.90) 0.30 (0.83) 0.07 (0.27) 0.65 (1.01) 0.63 (1.00) 0.02 (0.12)

• 53.1
• 38.7
• 100.0
• 69.6

0.016 0.104 0.067 0.309

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Safety

• 29 subjects (100%) with ≥1 treatment emergent adverse

event (TEAE)

• 19/29 subjects (66%) had treatment-related AEs
• 19 subjects (66%) serious AEs

– 1 SAE (gastroenteritis) was considered possibly related to study drug

• No subjects died
• 1 subject discontinued from study (moderate diarrhea)
• 3 subjects discontinued UX007 (unrelated to study drug)

– Moderate myalgia – Mild GE reflux and vomiting – Mild pain

Most Frequent TEAEs % Diarrhea 55 Rhabdomyolysis 48 Vomiting 48 Upper respiratory tract infection 41 Viral gastroenteritis 34 Headache 31 Pyrexia 31 Abdominal pain 28 Gastroenteritis 21

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CPTII Com III

ETFDH

ETF ETF ETF ETF ETF ETF ETF

1 4 5 9 8 10 11 7 2 3

ETF

6

Matrix ACADs Membrane ACADs

QH2 NADH H+ H+

Inner Membrane Inter Membrane Space Mitochondrial Matrix

TFP Com IV

QH2 Com I

Energy protein complex model

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VLCADD oxygen consumption is impaired

20 40 60 80 100

• 100

100 200 300 400

FB773 FB777 FB671 FB833 WT

Oligomycin FCCP Rotenone / Antimycin A

+ Glucose

Time (minutes)

OCR (pmol/min)

780 773 774 777 671 833 WT

cin FCCP e /

• se

tes)

in)

WT FB671 FB773 FB833

50 100 150

****

+ Glucose

**** ****

pmol/min/cells

WT FB671 FB773 FB833

100 200 300

****

+ Glucose

**** ****

pmol/min/cells

***

• se

*** ***

ells

WT FB671 FB773 FB833

50 100 150 200

****

• Glucose

**** ****

pmol/min/cells

WT FB671 FB773 FB833

100 200 300 400

****

• Glucose

**** ****

pmol/min/cells

***

• se

*** ***

ells

A B C D

• se

ells

*

• se

ells

E

Basal respiration Reserve capacity

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Superoxide production is increased in LC-FAODs

+ Glucose + Glucose – Glucose + Glucose

VLCADD LCHADD

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Cytokines in VLCAD patients

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Antioxidant treatment of VLCADD

JP4-039 D 40 D 40

2000 4000 6000

***

##

AFU

WT FB671

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JP4 Rx of LCHADD deficiency

HADHA common mutation 1528G>C mutation LCHAD LCHAD

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Inhibitor induced chaperonin effect

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TMZ stabilization of FAO proteins

Trimetazidine (TMZ)

VLCADD fibroblasts

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• Dimeric phospholipid
• Conical shape maintains membrane

curvature, optimizes electron transfer

• Anionic CL serves as a proton trap on the
• uter leaflet of the IMM channeling

protons to ATP synthase

• Monolysocardiolipin acetyltransferase

contained on C-terminus of αTFP (HADHA)

Cardiolipin (CL)

doi: 10.3389/fgene.2015.00359

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Cardiolipin binding peptide Rx

LCHADD

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• PPARd agnonists more potent than

bezafibrate

• Increase in expression and function of

VLCAD

• Clinical trial starting this year

Transcriptional activators

D M S O 0 .3 n M 3 n M 3 0 n M 1 0 0 0 2 0 0 0 3 0 0 0 4 0 0 0

A C A D V L m R N A

E x p re s s io n (N o rm a lize d C o u n ts ) M A-0211 + 6 5 %

* * *

+ 9 3 %

* * * *

+ 1 1 2 %

* * * * D M S O . 3 n M 3 n M 3 n M 0 .0 0 .5 1 .0 1 .5 2 .0 2 .5

P a lm ita te fa tty a c id

• x id a tio n

nm ol

3H -FA h

• 1 mg
• 1 p ro te in

M A-0211

* * * *

D M S O 3 n M 3 n M 0 .0 0 .2 0 .4 0 .6 0 .8 1 .0

A C A D V L P ro te in

E x p re s s io n (V L C A D /G A P D H ) M A-0211 + 1 8 0 %

* D M S O 3 n M 3 n M 1 2 3 4

C 1 6 S p e c ific A c tiv ity

V L C A D , S p . A c tiv ity

*

M A-0211

VLCAD patient derived fibroblasts

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VLCAD mRNA Treatment

20 40 60 80 100 WT Null +0.25 +0.5 +1 +2 +4

Average specific activity nmol/min/mg VLCAD mRNA added

VLCAD (42 kDa)

KO KO 0.5 µg/g 0.5 µg/g WT WT

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• K304E MCAD mutation is a folding

defect

• MCAD metabolizes phenylbutyryl-

CoA as substrate

• Binding pocket analogues are strong

chaperonins

• Phenylbutyryl-CoA as a chaperonin

therapy for MCAD deficiency

MCAD deficiency

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MCAD and phenylbutyrate

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Clinical trial urine acylglycines

16.69 12.69 14.55 5.18 12.15 1.71 3.19 2.11 7.31 6.6 6.87 4.21 0 G 2 G/M2/DAY 4 G/M2/DAY 6 G/M2/DAY mg/g Creatinine Pheylbutyrate Dose

Urine Acylglycines

Subject 1: 3-Phenypropionylglycine Subject 3: 3-Phenypropionylglycine Subject 4: n-Hexanoylglycine

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• Ben Van Houten
• Peter Wipf
• Abbe de Vallejo
• Melanie Gillingham
• James Conway
• Simon Watkins

Collaborators

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Thank you!