A Rising Generation - Mayo Clinic School of Continuous ... - Cystic Fibrosis.pdf©2015 MFMER |...

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A Rising GenerationExploring the Pharmacotherapy Advancements for Cystic Fibrosis

P. Zach White, PharmDPGY1 Pediatric Pharmacy ResidentPharmacy Grand Rounds March 1, 2016


Pre-Assessment QuestionWhat is the newest FDA-approved treatment category for cystic fibrosis? A) Mucolytics B) Cystic fibrosis transmembrane conductance

regulator protein (CFTR) modulators C) Pancreatic enzyme replacementD) Inhaled antibiotics


Objectives• Discuss the pathophysiology of cystic fibrosis

(CF)• Review current pharmacotherapy treatments for

CF• Explore the literature assessing the efficacy of

newer pharmacotherapy agents for CF


Cystic Fibrosis• Autosomal recessive disease causing a mutation

of the CFTR gene located on chromosome 7• Affecting the lungs, pancreas, intestines, sweat

glands, and vas deferens• 70,000 people have CF worldwide

- 40% in the United States

• 1,000 new cases diagnosed annually

Cystic Fibrosis FoundationEur Respir J. 2015 Jul;46(1):133-41

CFTR: cystic fibrosis transmembrane conductance regulator protein


Early Detection

• 75% of patients are diagnosed by 2 years of age- All 50 states implement newborn screening

- Elevated immunoreactive trypsinogen

• 50% of CF population is now > 18 years of age- 75% of the CF population will be > 18 years old by 2025

US Pharm. 2015;40(7): 45-49


Life Expectancy

European Lung White BookEur Respir J. 2015 Jul;46(1):133-41

Pancreatic Enzymes

Airway Clearance

Antistaphylococcal Antibiotics

Antipsuedomonal Antibiotics

Lung Transplant

Inhaled Tobramycin

Age

(Yea

rs)

05

101520253035404550

1930 1940 1950 1960 1970 1980 1990 2000 2010 2015

CFTR Modulators



Normal CFTR Function

Na+ Na+Cl- Cl-

CFTR Na+ Channel

Pancreas

Lungs

H2OH2O

Na+


Cl-


CF Pathophysiology

CFTR gene defect

Defective ion transport

Airway surface liquid depletion

Defective mucociliary clearance

Mucus obstruction

Infection Inflammation

Respir Care 2009; 54(5);595-602


Genetic Variants in CF• Over 1800 CFTR genetic mutations identified

Most Common CFTR MutationsPhe508del (formerly ∆F508) 394delTTG551D 3905insTG542X Q359K/T360N1303K 621+1G->TW1282 R117HR553X R1162X

Cystic Fibrosis Foundation


CF Mutation Classes

Class Description Mutation ExampleI No CFTR synthesis G542XII CFTR incorrectly processed and does not

reach cell membrane Phe508del

III CFTR reaches cell membrane but there is abnormal channel regulation G551D

IV CFTR reaches cell membrane but openchannel time is reduced R334W

V Reduced CFTR synthesis R117HVI CFTR reaches cell membrane but rapid

protein turnover leads to shortened t½ 1811+1.6kbA>G

t½: half-life European Lung White Book


CFTR in Cystic Fibrosis

Cl- Cl- Cl-

H2O H2O

Na+Na+

Na+

Group II Mutation“Correctors”

mRNA

Group III Mutation“Potentiators”


Assessment Question #1

Which of the following about CF is false?

A) Phe508del is the most common genetic mutation B) CFTR mutations affect Cl-, Na+, and H2OC) Average life expectancy is now over 40 years of ageD) CFTR is a Na+ channelE) All the above are true


Current Pharmacotherapy Pulmonary Management Nutrition Support

Airway clearance- Hypertonic saline- Dornase alpha- Acetylcysteine

Pancreatic Enzymes- Acid blockers

Bronchodilators Nutritional Support- High caloric diet- Appetite stimulants

Antibiotics Fat-soluble vitamin supplementationAnti-inflammatory medicationsCFTR modulators

US Pharm. 2015;40(7): 45-49


MucolyticsDrug Route Indication Comment

Sodium Chloride7% Inhaled Mucolysis and sputum

induction

• >6 years old• Used chronically• Administer after a

bronchodilator

Dornase alfa Inhaled Mucolysis

• Cleaves extracellular DNA

• > 3 months of age• Used chronically

Acetylcysteine Inhaled

Adjunctive treatment of bronchopulmonary disorders caused by mucous obstruction

• Not for chronic use• Administer after

bronchodilator

US Pharm. 2015;40(7): 45-49


Antibiotics • Pseudomonas aeruginosa

Drug Route Comment

Tobramycin Inhaled/IV

• BID for 28 days, alternating 28-day periods

• Home inhaler• IV: once daily dosing

Aztreonam Inhaled/IV • Inhaled for >7 years oldCefepime

Ceftazidime IV • Higher doses in pediatrics with resistant pseudomonas

Azithromycin Oral • 3 days weekly

US Pharm. 2015;40(7): 45-49AM J Respir Crit Care Med Vol 180. pp 802-808, 2009


Anti-inflammatory Agents• Routine use of oral or inhaled corticosteroids is

not recommended• Short courses of systemic corticosteroids may

offer benefit without long-term adverse effects• CF Foundation concludes there is not sufficient

evidence to recommend the routine use in the setting of an acute exacerbation

AM J Respir Crit Care Med Vol 180. pp 802-808, 2009


Enzyme Replacement• Obstructed pancreatic and biliary ducts

- Decreased absorption of fat, protein, and fat-soluble vitamins

• Pancrelipase- Titrated to effect (i.e. steatorrhea)

- Not to exceed 2,500 lipase U/kg/meal

- Best absorbed by increasing pH of gastric acid

- Do not crush/chew - can sprinkle on applesauce

US Pharm. 2015;40(7): 45-49


‘Tune-Up’• 14 day hospitalization course

- scheduled or unscheduled

• Goal: Improve respiratory function and prevent rehospitalization due to pulmonary exacerbations or pneumonia

• IV antibiotics, vest therapy, chest x-rays, hearing tests, pulmonary function tests, nutrition optimization

AM J Respir Crit Care Med Vol 180. pp 802-808, 2009


Assessment Question #2Which of the following is true regarding current pharmacotherapy treatment of CF?A) Absorption of fat-soluble vitamins is not of concern in patients with CFB) Dornase alpha works by osmotically drawing water into the thickened mucus layer C) Pancreatic enzymes should not be taken with regards to meals or snacks D) Routine use of systemic corticosteroids are not recommended in patients with CF


A CFTR Potentiator in Patients with Cystic Fibrosis and the G511D Mutation

Ramsey et. alN Engl J Med 2011;365:1663-72


A CFTR Potentiator in Patients with Cystic Fibrosis and the G511D Mutation

Patient Number N = 161

Study Design Randomized, double-blind, placebo-controlled, international trial

Interventions Ivacaftor 150 mg every 12 hours vs. placebo

Duration 24 weeks, with treatment effect assessed through week 48

Inclusion• At least one G551D CFTR mutation• >12 years of age• FEV1 40% to 90% of predicted normal value

Primary Outcome Absolute change from baseline in the % of FEV1 at 24 weeks

Secondary Outcomes• Absolute change in weight gain through week 48• CFQ-R scores assessing quality of life through week 48• # pulmonary exacerbations through week 48

N Engl J Med 2011;365:1663-72.FEV1: forced expiratory volume in 1 secondCFQ-R: Cystic Fibrosis Questionnaire-Revised


Results

Result Ivacaftor P value

Primary OutcomeAbsolute change from baseline in the % of FEV1

10.6 < 0.001

Secondary OutcomesAbsolute change in weight (kg) 2.7 < 0.001Absolute change in CFQ-R from baseline 8.6 < 0.001Pulmonary exacerbation risk reduction 55% 0.001

FEV1: forced expiratory volume in 1 secondCFQ-R: Cystic Fibrosis Questionnaire-Revised


IvacaftorKalydeco®

FDA Approval January 2012

IndicationTreatment of CF in patients > 2 years old that have one of the following mutations: G551D, G1244E, G1249D, G1278R, G551S, S125IN, S1225P, S549N or S549R

Contraindications None

Limitations Not effective in patients homozygous for F508del CFTR mutation

Supplied 150 mg tablets50 mg or 75 mg unit-dosed oral granule packets

Metabolism CYP3A

Dosing• Patients > 6 years of age: 150 mg q12h • Patients 2-6 years of age and > 14 kg: 75 mg q12h• Patients 2-6 years of age and < 14kg: 50 mg q12h

Pearls Take with fat-containing meal

Cost $300,000 annually

Kalydeco (ivacaftor) package insert; Vertex Pharmaceuticals Inc; Feb 2016

CYP: cytochrome P450


Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for

Phe508del CFTRWainwright et. al

N Engl J Med 2015;373:220-31


TRAFFIC and TRANSPORT trialsPatient Number N = 1108

Study Design Phase III, multinational, randomized, double-blind, placebo-controlled, parallel-group

Interventions LUM-IVA 600-125 mg once daily vs. LUM-IVA 400-125 mg twice daily vs. placebo

Duration 24 weeks

Inclusion• Homozygous for Phe508del CFTR mutation• >12 years of age• FEV1 40% to 90% of predicted normal value

Primary Outcome Absolute change from baseline in the % of FEV1 at 24 weeks

Secondary Outcomes• Absolute change in BMI through week 24• CFQ-R scores assessing quality of life• # pulmonary exacerbations through week 24

N Engl J Med 2015;373:220-31.LUM-IVA: lumacaftor/ivacaftorFEV1: forced expiratory volume in 1 secondBMI: body-mass index CFQ-R: Cystic Fibrosis Questionnaire-Revised


Baseline Demographics

Characteristic Placebo N = 371

LUM–IVA600 mg daily

N = 368

LUM-IVA 400 mg q12h

N = 369Female sex (%) 48.8 49.5 49.3

Mean age (years) 25.4 24.5 25.3

Baseline FEV1 (%) 60.4 60.8 60.5

Mean BMI 21.0 21.0 21.5

% use of maintenance medicationsBronchodilatorsDornase alphaInhaled antibioticsAzithromycinInhaled hypertonic salineInhaled glucocorticoids

92.275.769.562.859.359.3

92.978.563.063.353.557.9

93.274.061.058.361.557.5

N Engl J Med 2015;373:220-31.LUM-IVA: lumacaftor/ivacaftorFEV1: forced expiratory volume in 1 secondBMI: body mass index


Results

ResultLUM–IVA600 mg

dailyP value

LUM-IVA 400 mg q12h

P value

Primary Outcome% FEV1 absolute change from baseline

3.3 < 0.001 2.8 < 0.001

Secondary OutcomesAbsolute BMI change from baseline

0.28 <0.001 0.24 < 0.001

Absolute change in CFQ-R from baseline

3.1 0.007 2.2 0.05

FEV1: forced expiratory volume in 1 secondBMI: body-mass index CFQ-R: Cystic Fibrosis Quiestionaire-Revised


Pulmonary Exacerbations

0

50

100

150

200

250

300

Pulmonary Exacerbations

PlaceboLUM-IVA 600-125 mgLUM-IVA 400-125 q12h

P < 0.001

P < 0.001

Num

ber o

f Eve

nts


Events Leading to Hospitalization

0

5

10

15

20

25

30

35

40

45

50

Events Leading to Hospitalization


39%P = 0.003

61%P < 0.001

Eve

nt R

ate/

48

wee

ks


Events Leading to IV Antibiotic Treatment

0

10

20

30

40

50

60

70

Events Leading to IV Antibiotic Treatment


45%P < 0.001

56%P < 0.001

Eve

nt R

ate/

48

wee

ks


Safety

Placebo LUM–IVA600 mg daily

LUM-IVA 400 mg q12h

Serious AE 28.6% 22.8% 17.3%

Discontinuation due to AE 1.6% 3.8% 4.6%

Most common adverse eventsInfective pulmonary exacerbationCoughIncrease in sputum production

49.9%40%

18.9%

39.3%32.8%14.9%

35.8%28.2%14.6%

AE: adverse event


Subgroup Analysis

• FEV1 > 70% not statistically significant in 1 of 2 studies for the LUM-IVA 400-125 mg q12h group

• Otherwise, subgroup analysis showed no other differences in FEV1 outcomes

SubgroupsPatients < 18 years of age or > 18 years of age

GenderFEV1 <70% or >70%

Pseudomonas aeruginosa positive/negative


Lumacaftor-IvacaftorOrkambi®

FDA Approval July 2015

Indication Treatment of CF in patients > 12 years old that are homozygous for the F508del mutation in the CFTR gene

Contraindications None

Supplied LUM-IVA 200 mg-125 mg tablets

Metabolism LUM excreted unchanged in the fecesIVA metabolized by CYP3A

Dosing

• No dose adjustments needed for mild hepatic impairment• Mild adjustments needed for moderate hepatic impairment• If patient is taking strong CYP3A inhibitors, initiate LUM-IVA at

half of the dose for first 7 days of treatment

Pearls Take with fat-containing meals

Cost $259,000 annually

LUM-IVA: lumacaftor/ivacaftor Orkambi (lumacaftor/ivacaftor) package insertVertex Pharmacetuicals, Inc; Feb 2016


Assessment Question #3Which of the following is true about the results of lumacaftor-ivacaftor when compared to placebo? A) LUM-IVA reduced the rate of pulmonary exacerbations, improved

FEV1, and had significantly more serious adverse events

B) LUM-IVA reduced the rate of pulmonary exacerbations, did not show FEV1 improvement, and did not have more serious adverse events

C) LUM-IVA reduced the rate of pulmonary exacerbations, improved FEV1, and did not have more serious adverse events

D) None of the above

LUM-IVA: lumacaftor-ivacaftorFEV1: forced expiratory volume in 1 second


Assessment

Strengths LimitationsWide range of FEV1 included Did not include patients < 12 yearsApplicable to a significant percentage of CF patients

Difficult to extrapolate to patients heterozygous for F508del

Patients randomized appropriately Didn’t assess potential benefit to patients with G511D mutation

Appropriate subgroup analysis

FEV1: forced expiratory volume in 1 second


Conclusions

Authors’ Conclusions• LUM-IVA is a milestone treatment for 45% of CF patients homozygous

for Phe508del• LUM-IVA has an acceptable side-effect profile

Seminarian’s Conclusions • LUM-IVA provides moderate FEV1 benefit and significant benefit in

preventing pulmonary exacerbations to patients with the most common type of CFTR mutation

• The side effect profile makes it an attractive pharmacotherapy adjunct • Cost can be a deal-breaker for many patients• Studies need to be conducted to determine effectiveness for patients

heterozygous for Phe508del


New Treatment Ideas in the Pipeline• Inhaled drug to repair CFTR-encoded mRNA in

hetero- or homozygous Phe508del• Combination corrector and anti-inflammatory• Drugs that prolong effects of hypertonic saline• Anti-infective agent nearly identical to iron

shown to kill resistant pseudomonas• Different formulations of pancreatic enzyme

replacement

Cystic Fibrosis Foundation


Treatment Agents Closest to ApprovalCFTR Modulation• Ataluren (Phase 3)

• VX-661 + ivacaftor (Phase 3)

Restore Airway Surface Liquid• Inhaled Mannitol (Phase 3)

Anti-Infective• Inhaled Levofloxacin (Phase 3)

• Inhaled Liposomal Amikacin (Phase 3)

• Vancomycin Inhalation Powder (Phase 2)Cystic Fibrosis Foundation


Overall Conclusions • The life expectancy for the CF patient is rising

- 75% of CF patients > 18 years of age by 2025

• Pharmacotherapy focusing on CFTR modulation• LUM-IVA showed improvement in exacerbation

prevention for patients with the most common CFTR mutation

• New agents continue to improve the quality of life for CF patients


P. Zach White, PharmDPGY1 Pediatric Pharmacy [email protected]

A Rising GenerationExploring the Pharmacotherapy Advancements for Cystic Fibrosis

A Rising Generation - Mayo Clinic School of Continuous ... - Cystic Fibrosis.pdf©2015 MFMER |...

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