Jain Cystic Fibrosis - NAMCP Cystic Fibrosis.pdfCystic Fibrosis-Update Manu Jain MD MS ......

Cystic Fibrosis-Update

Manu Jain MD MS

Professor of Medicine and Pediatrics

Director of Adult CF

Feinberg School of Medicine

Lecture Outline

• Epidemiology of CF

• Pathophysiology and genetics

• Diagnostics

• Targeting the genetic defect

CF TimelineYear Journal Article / Event

1938 CF of the pancreas and its relation to celiac disease.

1951 Heat prostration in fibrocystic disease of the pancreas and other conditions.

1953 Abnormal electrolyte composition of sweat in CF

1955 Creation of CFF – spearheaded by families of children with CF

1959 A test for concentration of electrolytes in sweat in CF utilizing pilocarpine by iontophoresis.

1964 A therapeutic regimen for patients with CF.

1966 CFF patient registry formed

1979 Dried-blood spot screening for CF in the newborn.

1983 Chloride impermeability in CF.

1988 Effect of nutrition on survival is confirmed

1989 Identification of the CF gene: genetic analysis.

2003 Evidence for benefit leads to recommendation for universal CF NBS

2011 A CFTR potentiator in patients with CF and the G551D mutation.

Epidemiology of CF

• Prevalence1

• United States ~ 30,000 (1 of every 3,500 babies born)

• Worldwide ~ 70,000

• Change in patient demographics

• Increased life expectancy1

• Improved overall lung function1,2

1) Cystic Fibrosis Foundation, 2015. 2) VanDevanter et al. Pediatr Pulmunol. 2008;43:739-44.

Newborn Screening for CF

• Mandated nationwide• 66% of new diagnoses made in the first year of life• Step-wise process:

– Measurement of IRT– If elevated, then repeat IRT or CFTR genotyping– If still elevated or mutation detected, then sweat chloride test

• Sweat chloride test = best initial diagnostic test

Age ≤ 6 mo Age > 6 mo

CF is unlikely < 30 mmol/L < 40 mmol/L

Intermediate 30-59 mmol/L 40-59 mmol/L

Consistent with CF ≥ 60 mmol/L ≥ 60 mmol/L

Cystic Fibrosis Foundation, 2015.

Diagnostic Complexity

• Patients not identified via NBS– Normal or equivocal sweat chloride test results

• 6.8% patients diagnosed ≥ 16 years old• Clinical presentation

– Often diagnosed in adolescence or adulthood– Genetic mutation – less common defect– Mild disease – respiratory, GI, pancreatic– Atypical symptoms – infertility, sinusitis– Infection with typical CF respiratory pathogens

Cystic Fibrosis Foundation, 2015. Knowles, et al. N Engl J Med. 2002;347(6):439-42.

Patients with CFCFF Patient Registry, 2013

Num

ber

of P

atie

nts

Year

49.7%

29.2%

Median Predicted Age of SurvivalCFF Patient Registry, 2013

Pat

ient

Age

Year

33.4

40.7

40

50

60

70

80

90

100

6 8 10 12 14 16 18 20 22 24 26 28 30

CF Pulmonary Function Decline

Age

Med

ian

% P

redi

cted

F

EV

1

Parallel lines

Cystic Fibrosis Foundation Patient Registry 2007.

20071990

}

Gender Gap

Improved Patient Survival:Evidence-Based Strategies

NBS program and step-wise

diagnostics

Complete nutritional

management

Pancreatic enzyme

replacement

Enhanced chest

physiotherapy

Specialized CF care centers

Aggressive antibiotic regimens

Parkins, et al. Ther Adv Respir Dis. 2011;5(2):105-19.

Pathophysiology of CF

• Heterogeneous, autosomal recessive disorder

• Over 2,000 mutations in the CFTR gene have been described

• CFTR protein is a chloride channel

• Mutated CFTR protein leads to lower or absent chloride transport


CFTR Channel

• CF is due to genetic mutations that affect the CFTR protein Impacts synthesis and transfer of the CFTR

protein to the apical membrane of epithelial cells Influences gating or conductance of chloride and

bicarbonate ions through the channel

• CFTR dysfunction results in: Imbalance of ion transport and epithelial

secretions in the lungs, GI tract, pancreas, and liver

Derichs, et al. Eur Respir Rev. 2013;22:58-65.

CFTR Channel

Mucus

Inside cell

Outside cell

Normal CFTR Defective CFTR

Normal CFTR and ENaC activity: Healthy ASL

Normal mucociliary clearance

Defective CFTR, compromised chloride transport, and ENaC

overactivity:Dehydrated ASL

Poor mucociliary clearance

ENaC

Na+

Chloride ions

CF-Related Lung Disease

AbnormalCFTR

Reduced ASL Impaired mucociliary clearance

Obstruction

Obstruction

Obstruction

Inflammation

Inflammation

Inflammation

Infection

Infection

Infection

Structural damage

Pulmonary insufficiency

Bronchiectasis

Respiratory failure

Respiratory Pathogens Over TimeCFF Patient Registry, 2013

Pat

ient

s (%

)

Age (Years)

Aerosolized Antibiotics

• Rationale for use– To deliver a high dose of mediation to the site of

infection– To minimize systemic exposure and toxicity– To overcome sputum binding– To optimize PK / PD parameters

• Agents– TSI = tobramycin solution for inhalation– AZLI = aztreonam lysine inhalation solution– TIP = tobramycin inhaled powder

Geller. Respir Care. 2009;54(5):658-70.

TSI for Chronic Airway Infection

Clinical Study

Study Design N Dosage Study Results

Ramsey1 RCT 520300 mg twice daily for 28 days, 3 on / off cycles

Improvement in microbial response, pulmonary function (P < 0.05)Less hospitalizations, fewer IV antibiotics used

Moss2 OL 93300 mg twice daily for 28 days, 12 on / off cycles

Improvement in pulmonary function sustained for study duration (P < 0.05)

Murphy3 OL 184300 mg twice daily for 28 days

Decrease in hospitalizations, concurrent antibiotic use (P < 0.05)

1) Ramsey, et al. NEJM. 1999;340:23-30. 2) Moss, et al. Chest. 2002;121:55-63. 3) Murphy, et al. Pediatr Pulmonol. 2004;38(4):314-20.

TSI for Chronic Airway Infection

Study design• Longitudinal,

regression analysis

• N = 12,740 patients from CFF patient registry

• Study duration = 10 years

Study results• TSI use was

associated with a 21% reduction in the odds of subsequent year patient mortality (P < 0.05)

Sawicki, et al. Pediatr Pulmonol. 2012;47:44-52.

AZLI vs TSI forChronic Airway Infection

Cha

nge

in F

EV

1(%

Pre

dict

ed)

from

Bas

elin

e

0 2 4 8 12 16 20 24 28 32 36 40 44 48

Assael, et al. J Cyst Fibros. 2013;12:130-40.

Weeks

*

Protein Repair: Mutation-Specific Treatment

Missense:AA deletion

(F508del)

VX-770VX-809

Nonsense:AA substitution

PTC124

Fajac, et al., ECFS 2011; Symposium 12 Oral

Mu

tati

on

Typ

e Missense:AA change

(G551D)

Class IV Class VClass IIClass I Class III

Reducedquantity

Altered Cl-

conductance

Processing& trafficking

defects

Proteinsynthesisdefects

Defectiveregulation

Po

ten

tial

the

rap

y

Missense:AA change

Missense:mRNA processing

VX-770

De

fec

t R

es

ult

AA = amino acid

‡

Most Common MutationsCFF Patient Registry, 2013

* Patients with one or two alleles

Homozygotes = 46.5%Heterozygotes = 39.9%{

97% of patients have had their mutations identified through

genetic testing

Patients* (%)

F508del 86.4

G542X 4.6

G551D 4.4

R117H 2.8

N1303K 2.5

W1282X 2.3

R553X 1.8

Normal

CFTR Mutations

Defect in CFTR Protein

Reduced Quantity of CFTR at Cell Surface

Reduced Function of CFTR at Cell Surface

CFTR Mutations Reduce the Amount or Function of CFTR at the Cell Surface

Approach to Restoring CFTR Function

Potentiators:Increase the flow of ions through CFTR present at the cell surfaceCorrectors:Increase the cellular processing and delivery of CFTR proteins to the cell surface ER ER

Hours

Seconds

CFTR Modulation

• Address the underlying genetic anomaly of CF

• Restore the function of the CFTR protein

• CFTR modulators:


Ivacaftor CFTR potentiator

AtalurenPremature stop codon suppressor – enables the formation of a functioning protein in patients with nonsense genetic mutations

- Lumacaftor- VX 661

CFTR correctors – move defective CFTR protein to proper place in cell membrane and improve its function as a chloride channel

Mutation Classification

Class Mutation CFTR Examples

I Nonsense;frame-shift

No functional CFTR G542X 12%

IIMissense; amino acid deletion

CFTR trafficking defect, some CFTR

F508del 86%

III MissenseAbnormal channel function, block in regulation

G551D 5%

IV MissenseAbnormal channel function, altered conductance

R117HD1152H

5%

V Missense; splicing defect

Reduced synthesis of CFTR3849+10kbC→T5TA455E

5%

VI Missense Decreased stability of CFTR 4326delTC Rare

Derichs, et al. Eur Respir Rev. 2013;22:58-65. Boyle, et al. Lancet Resp Med. 2013;1:158-63.

Ivac

afto

r

Ivacaftor:STRIVE Clinical Trial

Ramsey, et al. N Engl J Med. 2011;365:1663-72.

Day 15 8 16 24 32 40 48 Weeks

Cha

nge

in F

EV

1(%

Pre

dict

ed)

from

Bas

elin

e

Day 15 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48-60

-55

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

PlaceboVX-770

Ch

ang

e in

sw

eat

chlo

rid

e co

nce

ntr

atio

nm

mo

l/L

(m

ean

, 95%

CI)

Change from Baseline in Sweat Chloride

Treatment effect through Week 24– 47.9 mmol/L

P < 0.0001

Treatment effect through Week 48– 48.1 mmol/L

P < 0.0001

Ivacaftor

• Mechanism of action– Increases the time that activated CFTR channels at the

cell surface remain open; thereby, restoring CFTR function

• FDA approved for patients with the following genetic mutations:

Cystic Fibrosis Foundation, 2015. Flume, et al. Chest. 2012;142(3):718-24.

G551D R117H G178R S549N S549R

G551S G1244E S1251N S1255P G1349D







F508del 86%


G551D 5%


R117HD1152H

5%



5%



CF

TR

cor

rect

ors

Combination Approach: CFTR Potentiator Ivacaftor Doubled the In Vitro Activity of VX-809

-9 -8 -7 -6 -5 -40

10

20

30

40

Log M [VX-809]

F5

08

de

l-C

FT

R A

cti

vit

y(%

wt-

CF

TR

)

VX-809+

Ivacaftor

VX-809alone

CFTR corrector

CFTR potentiator

F508del-CFTR

Van Goor et al. Pediatr Pulmonol 2009;44(S32):154absS9.4

Wainwright CE et al. N Engl J Med 2015;373:220-231.

Ivacaftor with Lumacaftor

Wainwright CE et al. N Engl J Med 2015;373:220-231.

Ivacaftor with Lumacaftor







F508del 86%


G551D 5%


R117HD1152H

5%



5%



Ata

lure

n

Premature Termination Codons

Ataluren with TSI

Kerem, et al. Lancet Respir Med. 2014;2(7):539-47.

*

*P = 0.43

Rel

ativ

e C

hang

e in

FE

V1

(% P

redi

cted

)

8 16 24 320 40 48 Weeks

(N = 44)(N = 42)

Ataluren without TSI

Kerem, et al. Lancet Respir Med. 2014;2(7):539-47.

*

*P < 0.05

Rel

ativ

e C

hang

e in

FE

V1

(% P

redi

cted

)

8 16 24 320 40 48 Weeks

(N = 72)

BMI Trend

10

12

14

16

18

20

22

24

2004 2006 2008 2010 2012 2014 2016

2004 2006 2008 2010 2012 2014 2016

24

22

20

16

14

12

10

BMI

YEAR

Before Kalydeco

After Kalydeco

24 year woman with G551D/d508F

CF Severe Pulmonary Exacerbations

2010 2011 2012 2013 2014 2015

Kalydeco StartedCFPE CFPE CFPE CFPE CFPE

42 year old man with R117H-5T/del508F

HRCT ChestPre-Ivacaftor Post-Ivacaftor

Hepatic SteatosisPre-Ivacaftor Post-Ivacaftor

Sinus DiseasePre-Ivacaftor Post-Ivacaftor

Restoring CFTR Function Decreases Rate of Decline in FEV1

*p < 0.001.

Sawicki, McKone…Konstan et al, Poster 207

Effect of Decreased Rate of Decline in FEV1

20

30

40

50

60

70

80

90

100

6 16 26 36 46 56 66 76 86

G551D With Ivacaftor

F508del/F508del

FEV

1 %

P

red

icte

d

Age in Years

Lung Transplant

FEV1 change doesn’t predict CFPE reduction-Orkambi

F508del/G542XF508del/F508del

A second corrector further enhances in vitro F508del CFTR function

Courtesy of Fred Van Goor

CFTR Modulation

Agent(s) Phase I Phase II Phase III Available

Ivacaftor

Ataluren

Ivacaftor + Lumacaftor

Ivacaftor + VX 661

Riociguat

QBW251

N91115


CF-Summary

• Genetic Disease- CFTR– Autosomal Recessive

– Defect in Ion Transport: Cl-, Na, H20

• Cycle- Infection, Inflammation, Mucus– Innate Immunity-likely primary defect

– Antibiotics, Mucolytics, Anti-inflammatory, Rehyrdrators

• CFTR Modulation– Protein Repair– Gene Therapy

– RNA editing

– ENaC Inhibition

Jain Cystic Fibrosis - NAMCP Cystic Fibrosis.pdfCystic Fibrosis-Update Manu Jain MD MS ......

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