"Management and Treatment of Patients with Cystic fibrosis (CF)

"Management and Treatment of Patients with Cystic fibrosis (CF) Dr. Malena Cohen-Cymberknoh Pediatric Pulmonology and CF Center Hadassah Hebrew-University Medical Center Jerusalem, Israel Afula, March 1 st 2017

CF- Introduction CF is the most common serious genetic disease Previously patients died in early infancy and childhood For those born in 2000, the UK CF data estimate survival greater than 50 years Advances in CF care are largely responsible for the improved lifespan New therapies directed towards underlying defect promise to open a new era of CF therapeutics

CF Median Life Expectancy Median Survival Age (Years) Year

Genetics of CF- the CFTR gene Autosomal-recessive Inheritance In 1989 the CFTR gene was discovered The CFTR gene resides on the long arm of chromosome 7 More than 1800 mutations in the CFTR gene associated with disease have been reported The most common mutation- DelF508 (75%)

H 2 O Cl - Na + H 2 O CFTR Na + Cl - ENaC Cl - Cl - camp Ca 2+ K + 2Cl - K + Na + K + Na +

CFTR gene mutation CFTR defect Electrolyte transport abnormalities Excesive/abnormal mucus production Bacterial Infection Neutrophil dominated Inflammation Progressive lung damage Death

Respiratory Presentations of CF Chronic cough Recurrent/ chronic bronchitis or pneumonia Severe wheezing/ hyperinflation Tachypnea/ retractions Atelectasis Hemoptysis Pneumothorax Bronchiectasis Staph/ Pseudomonas colonization in the respiratory tract Chronic pansinusitis Nasal polyps Clubbing

Incidence of Major Airway Pathogens by Patient Age Cystic Fibrosis Patient Registry 2010

Pseudomonas aeruginosa in the CF lungs Chronic P. aeruginosa (PA) lung infection is the cause of much of the morbidity and most of the mortality in CF patients ~80% of CF adults have chronic PA infection; once a chronic infection is established, it is very difficult to eradicate Aggressive early eradication therapy have to be initiated as soon as the pathogen is detected, which can delay the onset of chronic infection

Risk of eradication failure increased by with delayed CF diagnosis Successful eradication increased with each additional sputum culture taken Delayed detection of PA infection leading to delayed treatment and growth of multiresistant organisms is associated with eradication failure M. Cohen-Cymberknoh et al, Journal of Cystic fibrosis 2016

Gastrointestinal Presentations of CF Meconium ileus (~15%) Prolonged neonatal jaundice Steatorrhea Rectal prolapse Mucoid impacted appendix Recurrent intussusception Recurrent pancreatitis Liver disease ~30%- fatty liver, focal/multilobar biliary cirrhosis Distal Intestinal Obstruction Syndrome (DIOS)

Metabolic Presentations of CF Salty taste Failure to thrive Hypoproteinemia, edema Vitamin A, E, D deficiency Hemolytic anemia (Vitamin E deficiency) Salt depletion - Metabolic alkalosis Azoospermia/CBAVD- male infertility (98%)

CF diagnosis NPD One or more characteristic clinical features of CF or Sweat test Gold standard diagnose CF a Results: family history of positive Cl > 60 mmol/l- neonatal positive screening Cl < 40 mmol/l- negative Cl = 40-60 mmol/l- borderline Together with: Abnormal sweat chloride values on 2 occasions or abnormal Nasal Potential Difference (NPD) identification of two (CFTR) mutations CF diagnostic consensus, Rosenstein et al. J Pediatr 1998

Zielenski, Respiration 2000 Spectrum of phenotypes

Classic and non-classic CF Early pulmonary involvement (>95%) (CBAVD) (CBAVD)

* * * * 21 y.o. male CF-PI patient 21 y.o. male CF-PS patient Simanovsky and Cohen-Cymberknoh et al, Chest 2013

A more negative correlation between FEV 1 % and Age in the CF-PI group No correlation between FEV 1 % and %BMI in the CF-PS group a comparison of disease characteristics for (PCD and) CF should distinguish between CF-PI and CF-PS as different entities Good correlation between TBS and Age in the CF-PI and CF-PS groups Good correlation between FEV 1 % vs. TBS in the CF-PI and CF-PS groups M. Cohen-Cymberknoh, Chest 2014

Improving Quality of Life

The 10 Golden Rules of CF Care 1.Maintain good nutrition and correct nutritional deficiencies 2.Daily chest physiotherapy 3.Enhance mucociliary clearance (inhaled hypertonic saline & Pulmozyme) 4.Avoid and early treat new acquisition of pseudomonas infection 5.Suppression of chronic pseudomonas infection (inhaled antibiotics) 6.Early and aggressive treatment of pulmonary exacerbation 7.Anti-inflammatory therapy 8.Early identification and treatment of complications 9.Centered care with frequent regular visits 10.Strict adherence to all the above therapies Cohen-Cymberknoh et al, ERJ 2014

Class III Regulation (G551D) R Five Class CFTR Mutations Class II Protein processing (DelF508) R Cl - A new type of individualized treatment R X in R CF: Class IV Impaired Conductance (R1152H) Class I No protein synthesis (W1282X) Cl - R Class V Mutation class specific therapy Reduced number

Classes of CFTR Mutations Normal I II III IV V No Block in Block in Altered synthesis processing regulation conductance G542X W1282X F508del G551D R117H D1152H Reduced synthesis 3849+10kbC >T 5T A455E 12% 87% 5% 5% 5% Premature Stop Mutations 60% in Ashkenazi Jewish patients

Normal Flow of Genetic Information Results in Full-Length Protein Production Normal Translation Normal Stop Codon Ribosomes Amino acid Protein mrna Full-length Protein

Nonsense Mutation Halts the Flow of Genetic Information and Results in Truncated Protein Production Premature Termination Nonsense (Premature Stop) Codon Normal Stop Codon Protein mrna Truncated Protein

Wilschanski et al. NEJM 2003

Ataluren Has Been Designed to Overcome Nonsense Mutations Ataluren Nonsense (Premature Stop) Codon Normal Stop Codon YIELD Protein mrna Fulllength Protein

Mean relative change in percent-predicted FEV 1 from baseline to week 48 Ataluren is already registered for patients with Duchenne Muscular Dystrophy carrying nonsense mutations Kerem E et al. Lancet Respir Med. 2014

Classes of CFTR Mutations Normal I II III IV V No Block in Block in Altered synthesis processing regulation conductance G542X W1282X F508del G551D R117H D1152H Reduced synthesis 3849+10kbC >T 5T A455E 12% 87% 5% 5% 5% CFTR gating mutations CFTR that not open and close properly

Ramsey, B et al. New Engl J Med 2011

Ivacaftor (Kalydeco), a CFTR potentiator for Class 3 mutations Improves sweat chloride levels Improves lung function Improves weight Improves time-to-first pulmonary exacerbation Improves OGTT and insulin secretion 2012

Jerusalem Marathon 10 km March 2016

Classes of CFTR Mutations Normal I II III IV V No Block in Block in Altered synthesis processing regulation conductance G542X W1282X F508del G551D R117H D1152H Reduced synthesis 3849+10kbC >T 5T A455E 12% 87% 5% 5% 5%

F508del Results in Defective Processing, Defective Gating, and Reduced Surface Stability The F508del mutation affects the processing and trafficking of the resultant CFTR proteins Golgi The result is little to no CFTR protein delivered to the apical cell surface The small amount of F508del-CFTR that may reach the apical cell surface has reduced function and accelerated turnover Proteasome ER Nucleus Wang XR, Li C. Biomolecules 2014

Increased Activity of DF508 CFTR with Lumacaftor in Combination with Ivacaftor + CFTR potentiator (Ivacaftor) F508del-CFTR + CFTR corrector (Lumacaftor) + CFTR potentiator (Ivacaftor) F508del-CFTR Chloride Transport (% of normal CFTR) 40 30 20 10 0 No drug P=0.0189 P=0.0033 ivacaftor Alone (3 μμm) P=0.0119 lumacaftor Alone (3 μμm) P=0.0288 lumacaftor + ivacaftor (3μμM + 3μμM) Modified from Van Goor et al. PNAS 2011

2015

Elborn et al. ECFS 2015 ppfev 1 : Up to 48 Weeks of Treatment

Analysis of Pulmonary Exacerbations: Pooled

Our Orkambi experience One patient homozygous for Phe508del 40 y/o, married + 3 Severe lung disease, CF-related diabetes 60 ppfev1 before and after Orkambi 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Orkambi months

Number of patients with CF in Israel n=687 175 171 Males / Females 56% / 44% 135 77 96 33 Soroka Hadassah Rambam Schneider Carmel Sheba

Pulmonary function (FEV 1 median) in Israel 76 74 72 70 68 66 64 62 60 58 70.7%

Percentage of adult CF patients in Israel 60 55 50 52 Patients 18y= 53.4 58% 58 58% 45 43 40 35 30 2007 2009 2011 1 2 3 4 2013 EU 51.8%

CF Survival is Improving Orkambi Dorothy Andersen, 1938 Restore CFTR function CFF Drug Pipeline

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