Pathophysiology & Treatment of CF-upper and lower airways South Eastern European Cystic Fibrosis Conference

Bucharest – 19-20 September 2015.

Elke De Wachter – UZ Brussel, Brussels, Belgium.

Pathophysiology of airway disease in CF

Reproduced from Kreda et al 2005 Miol Biol Cell 16, 2154

CF-infant- studies :

Mucus-plugging:

Due to abnormal ASL

- Mucus layer: entraps inhaled particles and bacteria

- Periciliary liquid layer (PCL): low viscosity layer for normal ciliary beating (mucus transport)

CF: Thick mucus layer

Small PCL → impaired mucociliary clearance

Entraped particles →

Macrophages + neutrophils: release of cytokines → inflammation and goblet cell metaplasia

Normal airway

CF- airway

M Mall, R Boucher, in Cystic fibrosis in the 21st century, Prog Resp Res

Pathophysiology of airway disease in CF

Adapted from: A G Ziady, P B Davis in Cystic Fibrosis in the 21st century, Progr in Respir Research 2006

Treatment of the lower airways

Airway clearance: physio / sports/ medication

Treating Infections: Systemic, inhaled AB

Treating Inflammation: Cortico, Ibuprofen, AZM

Lung transplantation

CFTR-modulation therapy Ivacaftor, lumacaftor, other…

Gene-therapy

Airway clearance therapy

• Pulmozyme

• Hypertonic saline

• Bronchitol

• Physiotherapy

• Sports

Airway clearance therapy Pulmozyme® (Dornase alfa, rhDNase)

• Purified solution recombinant human deoxyribonuclease: cleaves DNA → reducing viscoelasticity

Pulmozyme®

Pulmozyme®

Fuchs HJ et al. N Engl J Med 1994; 331: 637-642.

Once daily 2,5 ml = 2500 IU nebulised

Hypertonic saline • Sterile water + NaCl concentration between 3-7%

• Hypertonic solution: attracts water into lumen of the respiratory tract

• Hydrates viscous mucus

• Improves mucociliary clearance

• Improves Pulmonary function

• Reduces exacerbations

• Generally less potent than Pulmozyme, BUT:

• Individual difference in response

• Cheaper

• Add-on during exacerbations, or long-term

Elkins NEJM 2006 ; Heijerman et al JCF 2009

Bronchitol®: Mannitol

• Naturally occuring sugar (Polyol)

• Inhalation of dry powder:

• Improves airway-hydratation

• Improves mucociliary clearance

• Stimulates cough

Bilton et al. JCF 2012

Bronchitol®: Mannitol

• Phase 3 (26 w)

• Improvement of pulmonary function

• Decreases pulmonary exacerbations (p<0.001)

• Approved by EMA

in april 2012: CF-Adults

• No reimbursement in many countries

Bilton et al. JCF 2012

Treatment of the lower airways

Airway clearance: physio / sports/ medication

Treating Infections: Systemic, inhaled AB

Treating Inflammation: Cortico, Ibuprofen, AZM

Lung transplantation

CFTR-modulation therapy Ivacaftor, lumacaftor, other…

Gene-therapy

Treating infections:

• Treating acute exacerbations

• Oral antibiotics

• Systemic antibiotics

• Treating chronic infections – colonisation

• Inhaled antibiotics

Inhaled antibiotics • Tobramycine (TOBI®)

• Aminoglycoside: bactericidal antibiotic against Gram neg (Pseudomonas aeruginosa)

• TIS: Tobramycin Solution for Inhalation (300 mg/5ml)

• 28d ON/OFF:

• Reduced sputum density in Ps aeruginosa

• Improvement of pulmonary function

• 10% at week 20, maintenance during extension phase

• Less excerbation, needing IV-courses

• 28d can eradicate Pseudomonas aeruginosa in early phase

Ramsey NEJM 1993; Heijerman JCF 2009

Tobramycin inhalation

• Generally well tolerated:

• no renal toxicity

• No hearing loss

• Tinitus reported (! In combination with exposure to loud noise) (NACFC2013)

• Bronchial hyperresponsiveness

• Tobramycine Dry powder: TOBI-Podhaler®

• 4 capsules 2x/d

Heijerman JCF 2009;

Colistimethate sodium

• Polymyxin antibiotic

• Bactericidal against Ps aeuginosa and other Gram-negatives, and damages cell-membranes

• Colomycin® for inhalation: 2x 1-2 milj U/d

• Widely used in UK, Belgium

• Generally well tolerated, but also bronchoconstriction

• Dry powder formula: Colobreathe®: 2x1 caps/d

Aztreonam Lysine

• Synthetic monobactam

• Active against gram negatives, and beta-lactamase producing strains

• AZLI: Cayston®

• Approved in USA in 2010

• Expensive (2885 euro/28d)

• 28d ON/OFF – 3x75 mg/d

• E-flow

• Well tolerated

• Results better with 3x/d compared to 2x/d

• Improvement in pulmonary function

• Improvement in clinical signs

• Lesser need for IV AB-treatment

• Decrease in Ps Aeruginosa CFU-density

• Might be helpful in Burkholderia cepacia complex

• Compared to TOBI, slightly better results

Heijerman JCF 2009; Plosker GL 2010; Oermann. Ped. Pulmonol. 2010 ; Parkins, Expert Rev. Respir Med 2010

Aztreonam Lysine

Treatment of the lower airways

Airway clearance: physio / sports/ medication

Treating Infections: Systemic, inhaled AB

Treating Inflammation: Cortico, Ibuprofen, AZM

Lung transplantation

CFTR-modulation therapy Ivacaftor, lumacaftor, other…

Gene-therapy

Treating inflammation • Oral Corticosteroids:

• Older studies: high dose of oral prednisolone (1-2 mg/kg alternate day) • Slows down progression of lung disease

• BUT: adverse events!! • Impaired glucose metabolism

• Cataract

• Impaired growth

→ Unjustifible to use oral corticosteroids for long-term in CF

• Has a role in treatment of ABPA, not in classical exacerbations

Inhaled corticosteroids

• Justified in case of associated bronchial hyperresponsiveness and recurrent wheezing: context of asthma

• Risk of adrenal suppression and cushing in association with other drugs (Cyp450)

• Risk of slowing linear growth in children in case of high doses fluticasone proprionate

• In children 6-12 slower decline in FEV1, not in adults (Belgian study)

T N Hilliard, IM Balfour-Lynn in Cystic fibrosis in the 21st century, E De Wachter JCF 2003, De Boeck ERJ 2011

Ibuprofen

• High dose Ibuprofen slows decrease in lung function

• BUT!

• Renal failure

• Gastro-intestinal problems: peptic ulcer disease and bleeding

• Currently no clear consensus about benefit of chronic high dose Ibuprofen in CF

• New anti-inflammatory drugs under investigation

Konstan NEJM 1995;

Azithromycin • Macrolide antibiotic

• Intrinsic anti-inflammatory effect:

• Effect on neutrophil phagocytosis, degranulation, migration and apoptosis

• Suppresses pro-inflammatory cytokines

• Inhibits production of alginate and Flagellins by Ps Aruginosa: infuences bio-film formation

• Reduces sputum-viscosity

• Positive effect on FEV1

• Generally 3d/w, duration of therapy unknown

Treatment of the upper airways

Communicating vessels

Upper airways and CF

• First passage of respiratory microbes

• First nose, than lungs?

• Chronic rhinosinusitis

• Postnasal drip

• Cough

• Influences sleep

• Development of nasal polyps, chronic sinusitis in children and adults

• Post-transplant patients: source of gram negatives, anaerobes

Treatment of upper airways

Upper airway clearance

Treatment of infections (UA)

• Local treatment

• Adding Antibiotics in the nose-rincage-system

• Systemic antiobiotics

• In case of exacerbation

• In preparation for surgical intervention

• Chronic basis: Flucloxacilline

Treatment of inflammation (UA)

• Topic corticosteroids

• Momethasonfuorate

• Fluticasonfuorate

• Treating nasal polyps:

• Surgery

What will the future bring?

CFTR-modulators

• Correct defect based on class-mutation

Figure: Copyright © 2015 VERTEX

Kalydeco® (Ivacaftor):

Ramsey et al. NEJM 2011, Press Release Vx jul 2014

• ‘Potentiator’: Opens CFTR = gating

FEV1

Event-free

subjects

Change in weight CFQ-R

KALYDECO® FDA approved

• In Europe (EMA): approval in july 2012

• CF ≥ 6 jaar, min 1x G551D

• Extended with other gating mutations: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R

• Price for 1 year therapy/patiënt: >300 000 $

Other CFTR-modulators • Correcting Class-1mutations

• Ataluren (TranslarnaTM)

• Helps readthrough

• New study in patients without aminoglycoside in inhalation

• Correcting Class-2mutations: Correctors

• Helps trafficking

• In F508del : in combination with Kalydeco®: lumacaftor, Vx661 good results (FEV1, exacerbations, use of IV antibiotics) (Traffic – Transport)

• Correcting Class-4 mutations: under investigation…

PTC-therapeutics; Wainwright NEJM2015;

Genetherapy

• ‘UK CF Trust Gene therapy consortium’

• Insert normal CFTR into the gene of the patient (organ-specific)

• Need for an appropriate vector (Cationic Liposome (GL67A) + plasmid DNA (pGM169) – Lentivirusses)

• No destruction by immune system

• Less flu-like symptoms

• Reaches nucleus

• Nebulisation by jet nebuliser

• For all CF: not depending on class-mutation

E Alton ECFC2015;

Conclusion: Effect of therapy on survival in CF

S Martiniano 2014. Figure adapted from JP Clancy AJCCM 2012

For better en healthy lungs