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Advances in the Management of Cystic Fibrosis: A Closer Look at the Roles of CFTR Modulation Therapy

Susanna A McColley, MDAssociate Chief Research OfficerStanley Manne Children’s Research InstituteAnn & Robert H. Lurie Children’s Hospital of ChicagoProfessor of PediatricsNorthwestern University Feinberg School of Medicine

Disclosures

• Consultant: Vertex Pharmaceuticals Inc., Novartis Pharmaceuticals Company, AbbVie Pharmaceuticals

• Funding sources: Cystic Fibrosis Foundation, Cystic Fibrosis Foundation Therapeutics, Inc, NIH, AHRQ

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Objectives• Assess newly approved and emerging CFTR-targeted treatment strategies

according to their mechanism of action, efficacy, and safety• Examine the role of CFTR modulation therapy in the treatment and management of

cystic fibrosis• Discuss the importance of genetic testing in suspected adult-onset CF• Analyze optimal strategies to manage and monitor CFTR modulator-related adverse

events in cystic fibrosis patients• Explore strategies to employ a multidisciplinary approach to management of the CF

patient, and communicate effectively with patients and their families about the role of genetic analysis

CF and CFTR

• Autosomal recessive disorder– ~1:4400 births

• >2000 sequence variants; disease liability of most is unclear– 70% of patients worldwide have at least

one copy of F508del– Other pathogenic mutations: 5% or fewer– Updated diagnostic consensus in press

• Multi-organ expression and manifestations– lungs, pancreas, liver, sweat gland, GI

tract, vas deferens, others

• Median survival ~40 yrs in US• Median age of death mid-20s

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Pathogenic mechanisms of CF lung disease

Defective CF Gene Product

Defective Ion Transport

Airway Surface Liquid Depletion

Defective Mucociliary Clearance

Obstruction

InflammationInfection

Molecular mechanisms of CFTR dysfunction

CFTR gene

CFTR transcript

ribosome +polypeptide chain

mature CFTR

immature CFTR

Y

nucleus

ER

TGN

endosomalcompartment

plasmamembrane

proteosome

I

II

III IV

V

VI

NMD

Y

Y Y

Y

‘Severe’ ‘Mild’

Most CF patients diagnosed during

adulthood have mild CF mutations

associated with pancreatic sufficiency

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CF End Stage Bronchiectasis

Between the gene defect and end stage lung disease: “severe” phenotype• Most infants with CF are healthy at birth

– 15-20% rate of meconium ileus• Malnutrition and pulmonary inflammation occur in the first weeks to months after

birth

“Cystic fibrosis is not a disease. It is an inherited predisposition that becomes a disease if it is not treated properly.”

Warren Warwick, MD, around 1990

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Without pancreatic enzyme replacementtherapy, CF is fatalearly in life• Malnutrition/ vitamin deficiency

related direct mortality• “the nutritional state

deteriorates with advance of the infection”

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Early growth predicts childhood survival

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Yen, Quinton and BorowitzJ Pediatrics 2012

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The CF lung is nearly normal at birth

Early pulmonary inflammation in CF

• 16 CF infants (mean age 6 months) diagnosed by NBS in Colorado; 11 disease controls (mean age 12 months)

• CF infants with increased markers of inflammation even when cultures negative

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Khan TZ, Wagener JA et al. Early pulmonary inflammation in infants with cystic fibrosis. AJRCCM 1995; 151:1075-82.

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Small airways disease is present during the first months of life in CF infants diagnosed by NBS

Sly, PD et al: American Journal of Respiratory and Critical Care Medicine 2009; 180:146-152

Stoltz DA et al. N Engl J Med 2015;372:351-362

Structural Airway Abnormalities in Cystic Fibrosis

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Stoltz DA et al. N Engl J Med 2015;372:351-362

Model of Host-Defense Defects in the Airway of a Person with Cystic Fibrosis

Early pathophysiology of CF: summary and opportunity• Infants with CF are healthy but have severe physiologic abnormalities that must be

treated early to avoid a progressive decline in health• The earliest possible diagnosis followed by disease modifying therapy is essential

to prevent CF lung disease• CFTR modulator therapies may be disease modifying, when given early in life, but

clinical trials are just beginning:– https://clinicaltrials.gov/ct2/show/NCT02797132?term=VX15-809-115&rank=1

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Between the CFTR gene mutation and lung disease: “mild” phenotype• CF may present in the second, third, fourth or later decade of life with

sinopulmonary disease• Illustrative case: “Ellen”

– Became ill with dyspnea and cough at age 28 during her second pregnancy– Continued to have cough and sputum production after giving birth– Denied significant respiratory symptoms as a child– Spirometry with obstructive defect, FEV1 ~50% predicted– CT scan with bronchiectasis– Sweat chloride values 40 mEq/L– CFTR gene mutation panel: F508del, R117H/7T– In spite of having all recommended pulmonary treatments, FEV1 ~ 40% predicted at age 40

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Importance of CFTR mutation testing• Aids in diagnosis

– Important for therapy and for monitoring of potential complications – Adults with CF at risk of

• Infertility (men)• Reduced fertility (women)• Recurrent acute pancreatitis • CF related diabetes• Pulmonary complications prevalent in CF (ABPA, mycobacterial infections)

– Increasingly, aids in therapy

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Gene mutation testing in CF• CFTR mutation panels

– May test from 23 (ACOG panel) to 100s of mutations– Will miss rare mutations, deletions/ duplications– Currently less costly than sequencing

• CFTR gene sequencing– Finds any sequence variant in the CFTR gene

• Still misses deletions/ duplications: need to order separately– Will find disease causing mutations, but also mutations of variable or unknown disease liability– Disease liability of rare mutations is being analyzed in CFTR2: www.cftr2.org

• Essential to have appropriate genetic counseling when testing is performed for any genetic testing– Discuss false negative, identification of mutations of unknown significance– Discuss consequences on family members, notification of possible carrier status– Best done by a certified genetic counselor

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CF care is multidisciplinary

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A nutrient dense, liberal fat diet is associated with increased survival• Survival compared between large CF Centers in Boston and Toronto

(1972-1981)• 10-20 year old patients in Boston were shorter than patients in

Toronto. Toronto males weighed more than Boston males. • Mean forced expiratory volume in one second (FEV1) was not different• Median age of survival: Boston 21 years, Toronto 30 years

– the two curves showed a marked separation from age 10 • The only difference in care was diet: fat restriction in Boston, liberal fat

in Toronto• “The differences in growth and survival in these two patient groups,

with similar age-specific pulmonary function, suggest further examination of nutritional guidance and intervention in CF, especially regarding the traditional restriction of dietary fat.”

– Corey, M. McLaughlin, F J. Williams, M. Levison, H: A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. Journal of ClinicalEpidemiology. 41(6):583-91, 1988.

Nutrition and pulmonary outcomes are correlated

22“the nutritional state deteriorates with advance of the infection”

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US children with CF have a normal BMI

Consistent practice improves BMI in CF children

Multidisciplinary care teams support good nutrition in children and adults with CF• RD: dietary assessment and counseling,

recommendations for supplemental tube feeding

• Nurse: family counseling and support• Social worker: family counseling and

support; referral to resources for food insecure families

• Physician: support of diet, prescription of adequate pancreatic enzymes, diagnosis of comorbidities attributing to poor nutrition

24Savant AP, et al. BMJ Qual Saf2014;23:i81-i89

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Population FEV1 is improving

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…but FEV1 is insensitive to early structural lung disease

Lung Clearance Index

• Multi-breath washout technique assesses:– Gas mixing – Airway patency/ obstruction

• Tidal breating; no effort• Inert tracer gas:

– SF6: wash in and out– N2: wash out with 100% O2

• More diseased airways take longer to wash out

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not detected by FEV1n=254 (52.5%)

424038363432302826242220181614121086420-2-4-6-8

FEV1 (SD-S)-16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8

Lung Clearance Index

Kraemer R, et al. Am J Respir Crit Care Med. 2005; 171: 371-378.

co-abnormaln=208 (42.9%)

not detected by LCIn=5 (0.5%)

co-normaln=20

(4.1%)

LCI

(SD

-S)

CFF Consensus Guidelinesrh-DNase

inhaled antibiotics

hypertonic saline ibuprofen

azithromycin

Early structurallung damage

Obstruction

Signs/Symptoms

Spirometric loss

Risk factors for disease

Evidence of disease

“Silent” process*

Targeting of Interventions

CFF Guidelines

rh-DNase

inhaled antibiotics

hypertonic saline

ibuprofen

azithromycin

Fix or replace CFTR

Gene therapy

Ion channel agents

CFTR modulators

1. Kirchner KK et al. Am J Respir Crit Care Med. 1996;154:1426-1429. 2. De Jong PA et al. Eur Respir J. 2004;23:93-97; 3. VanDevanter DR et al. Pediatr Pulmonol.2008;43:739-744.

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Multidisciplinary care for good pulmonary outcomes• Respiratory and physical therapists

– evaluate posture, teach airway clearance techniques and use of inhalational medications– collaborate with patients and physicians in making treatment decisions on maintenance therapies

• Social workers and psychologists– Screen for depression and anxiety and offer referrals, in accordance with recent practice

guidelines– Refer to programs to offset high medication co-pays

• Nurses– Spend about half their time getting prior authorization for specialty medications!

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Molecular mechanisms of CFTRdysfunction

CFTR gene

CFTR transcript

ribosome +polypeptide chain

mature CFTR

immature CFTR

Y

nucleus

ER

TGN

endosomalcompartment

plasmamembrane

proteosome

I

II

III IV

V

VI

NMD

Y

Y Y

Y

‘Severe’ ‘Mild’

F508del

G551D and others

R117H

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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

Courtesy of Vertex Pharmaceuticals

Class I/II Class III/IV/V

OptimizedPotency and Efficacy

Potentiator HTS

Corrector HTS

VX-770 VX-809

Screened >300,000 Compounds

Synthesized >5,000 Compounds

Approach to Identify and Improve CFTR Potentiators and Correctors

Cell based optical assays using cells expressing F508del-CFTR

Cultured human airway epithelia isolated from CF patients

0

25

50

Non-CF HBE

F508del-HBE

cAMP Agonist

5 min

Chl

orid

e T

rans

port

(A

/cm

2)

Courtesy of Vertex Pharmaceuticals

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VX-770 effects in human bronchial epithelial cells

33Van Goor F, Hadida S, Grootenhuis PD et al. PNAS 2009;106:18825-18830.

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Ivacaftor phase 3 clinical trial (> 12 years)

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• FDA approved for G551D mediated CF in 2012• Similar trial results seen in subjects with 8 “non-G551D gating

mutations”; FDA approval for expanded use in 2014• Approved for R117H mediated CF with lung disease in 2015• Label extended to 2-5 year olds • 0-24 month study in progress

Ivacaftor is disease modifying

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Sawicki GS et al Sustained benefit from ivacaftor demonstrated by combining clinical trial and CF patient registry data. AJRCCM 2015; 192:836-42.

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Ellen• Participated in the extension and open label follow-on trials of ivacaftor in CF

patients with the R117H mutation• Improvement in FEV1 and exercise tolerance• Reduced exacerbations• Example of severe “mild” disease and positive effect of a modulator effective for

her specific gene mutation

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Ivacaftor therapy in CF• Marked efficacy• Well tolerated• Expensive• Indicated for ~6% of the population with CF

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Nearly half of US CF patients are homozygous for the F508del mutation

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Using chamber studies of cAMP-stimulated Cl- flux in F508del-HBE (normalized to non-CF HBE)

Vehicle VX-770 VX-809+ VX-770

VX-809

**

*

F50

8del

-CF

TR

Act

ivit

y(%

no

rmal

CF

TR

)

40

0

30

20

10

Cilia

N

Untreated

VX-809

Cell Surface F508del-CFTR

Cytoplasmic CFTR

Functional Additivity of VX-809 and VX-770 in Human Airway Cultures Isolated from F508del CF Patients

Courtesy of Vertex Pharmaceuticals

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Combined therapy results age 12+

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Exacerbation reduction is not predicted by FEV1 improvement

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McColley SA et al, North American Cystic Fibrosis Conference 2015

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Lumacaftor-ivacaftor combination therapy has a disease modifying effect• Similar to ivacaftor, ongoing treatment with lumacaftor-ivacaftor reduces the rate

of lung function decline in F508del homozygotes, compared to untreated F508del homozygotes in the Cystic Fibrosis Foundation patient registry

• These data are being presented at the North American Cystic Fibrosis Conference 10/27/16-10/29/16

• A graph of these data will be displayed at the time of this presentation

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Lumacaftor-ivacaftor approved for 6-11 year olds• Lumacaftor-ivacaftor recently approved for 6-11 year olds

– Based on open label safety study– Open label study results being presented at the North American CF Conference 10/27-10/29/16– Placebo-controlled study with efficacy measures underway– Additional slides will be displayed at the time of this presentation

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Monitoring for toxicities and assessing efficacy in individual patients• All patients taking ivacaftor or lumacaftor-ivacaftor should have transaminases

monitored every 3 months for 12 months after initiating therapy• Dose reductions recommended for moderate to severe liver disease (Child-Pugh

Classification)• Children < 12 years old should have an eye exam prior to starting therapy due to

the occurrence of cataracts in exposed rat pups– Ocular safety study has been recently completed, not yet reported

• Chest tightness (“respiration abnormal”) occurs in some patients when initially starting lumacaftor-ivacaftor therapy– Mechanism unknown– Rarely leads to discontinuation of drug

• Monitoring efficacy can be difficult in patients with milder disease– Disease modification and exacerbation reduction benefit

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Lung disease

Genetic

CFTRmodifiergenes

gender Behavior

exercise smoking

diet

adherence

Therapy

healthcaresystem

CF center

Environment

Luck

infections

socioeconomicspollution

second-hand smoke

nutrition (PI)

siblings

timelydiagnosisexacerbation

rate

CFRD

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Summary• Onset of CF lung disease is a post-natal event • Nutritional and pulmonary abnormalities occur very early in life• Lung disease is present even when FEV1 is normal• Genetic testing is important in diagnosis and, increasingly, for therapeutic

considerations• Analyze optimal strategies to manage and monitor CFTR modulator-related adverse

events in cystic fibrosis patients• Multidisciplinary care is essential• CFTR modulation therapy has an increasing role treatment and management of

cystic fibrosis• Modulator therapy may reduce morbidity/ mortality over time

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