1. Update on Cystic Fibrosis – treatments and new products Dr Caroline Pao, Consultant Respiratory Paediatrician, Royal London Hospital

2. Caroline Pao Consultant Respiratory Paediatrician Royal London Children’s Hospital

3.  1595 Prof Pauw described 1 st case of CF  1606 salty infants bewitched and die  1938 D Andersen ‘fibrocystic disease of the pancreas’  1946 genetic basis of disease (AR)  1948 di Sant'Agnese heat wave  1959 Gibson + Cooke sweat test  1989 CFTR gene identified  1938 median survival 6mo, 1962 10yr

4.  1939 pancreatic enz suppl, 1980s microspheres (creon, pancrease)  1980s nutrition  1993 gene therapy, 2012 1 st multi dose trial  1990s Dnase, Tobi, Azithromycin, Urso  2012 Vertex VX770 Ivacaftor G551D  ….VX809 delF508  ….Ataluren PTC124

5.  AR C7 life limiting condition  >1,500 genes identified  1:25 carriers (>2.000.000 in UK)  1:2,500 have CF (10,000 in UK)  Median life expectancy now 43.5yr  Cost £100 million pa England  UK newborn screening since Oct 2007  Affects multiple organs, esp lungs and GIT

9. 1950s Today

13.  Cayston (neb aztreonam)  75mg tds  Active against ps a and Burkholderia cepacia  Improvement in lung function and respiratory symptoms

14. Tobi Podhaler  ≥6y  Dose 112mg (4 capsules) bd  Reduced time cf nebs  Portable  No need to clean equipment Colobreathe  Dose 125mg (1,662,500 IU in 1 capsule) bd

15. Facilitates increased Cl - transport by potentiating channel open probability (gating) of G551D-CFTR protein

16. ≥6yr G551D/- 150mg bd po with high fat snack N=320 England STRIVE and ENVISION studies >10.6% improvement FEV1 Reduction in sweat Cl - Increased weight £182,625 pp pa

18. Therapies designed to correct the function of the defective protein -- the cystic fibrosis transmembrane conductance regulator (CFTR) -- made by the CF gene Allows chloride and sodium (salt) to move properly in and out of cells lining the lungs and other organs

19. Reduced Cl - secretion increases active Na + absorption in epithelial cells, promoting water reabsorption from lumen and dehydration of mucus layer and viscid secretions Ataluren forces translational read-through of class I mutations in the endoplasmic reticulum Lumacaftor and VX 661 are correctors of class II mutations, enabling traffic of defective protein to the cell surface Ivacaftor is a potentiator of class III mutated proteins to prop open chloride channels on the cell membrane, promoting ion flux Mechanisms of CF gene- modifying therapy

20. 2-5yr ≥1 CFTR gating mutation Phase 3 recruiting KONDUCT R117H/- Phase 3 recruitment completed KONNECTION Non-G551D gating mutation (G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D) Phase 3 recruitment completed

21. Novel corrector designed to move defective CFTR protein to proper place in the airway cell membrane and improve Cl - channel function

22.  2 nearly identical Phase 3 trials  Safety and effectiveness  Aged ≥12 years  delF508/delF508  Phase: 3 recruiting  6-11yr  Phase: 1 recruiting

23.  Safety and effectiveness of VX-661 alone and in combination with Ivacaftor  F508del/F508del  Phase: 2 recruiting  Promising results in combination with Ivacaftor

24.  Nonsense mutation adults/children  Clinical benefit  Open label extension- long-term safety  Phase: 3 recruiting completed  Lower decline in lung function and lower rate of pulmonary exacerbations compared to placebo

25.  36 cities in 11 countries  N=238  ≥6y CF  ≥1 nonsense mutation (X/?)  Ataluren 10/10/20mg/kg or placebo  48/52  +ve trend overall but not sig  Improvement in those not on inh antibiotics at baseline

27.  New injectable compound modulates function of defective CFTR protein and decreases inflammation in the lung  Increases levels of S-nitrosoglutathione (GSNO) which is decreased in CF  Increases amount of CFTR that reaches the cell membrane  Stabilizes CFTR so that function can be improved

28.  Safety, tolerability and PK  Injected once daily for 7 days  ≥18 years  F508del/F508del  Phase: 2 recruiting

29. In cystic fibrosis, changes in salt transport within cells dehydrate mucus, causing it to become thick and sticky. Targets proteins other than CFTR Improve movement of salt in and out of cells Allows mucus to be more hydrated and cleared more easily

30.  Inhaled dry powder form of mannitol (osmotic agent)  Help rehydrate CF secretions and improve airway clearance  Safety and efficacy  Phase: 3 trial completed  Approved for treatment of CF in Australia and UK

31. Drugs being studied for their ability to reduce inflammation in the lungs of people with cystic fibrosis, which should help decrease chronic damage to lung tissue.

32.  Humanized monoclonal Fab fragment that targets a Pseudomonas aeruginosa virulence factor (Type III secretion system)  Reduces local inflammation in lung  Shown to reduce bacterial load in some animal model systems, but not predicted to kill or suppress the growth of Pseudomonas aeruginosa in vivo

33.  Multi-center randomized, double-blind, placebo-controlled trial  Safety and effectiveness of KB001A to increase time-to-need for antibiotic treatment for worsening respiratory tract signs and symptoms  Aged 12 - 50  Chronic Pseudomonas aeruginosa  Phase 2 recruiting

34.  Phosphodiesterase inhibitor  Single center trial  Symptoms related to lung inflammation and infection  ≥12 years Phase: 2 trial Completed

35. The compounds in this category are being evaluated for their effectiveness in fighting acute and chronic lung infections by destroying infection-causing bacteria that enter into the airways and colonize

36.  Phase 2b trial met the primary endpoint of Pseudomonas aeruginosa reduction in sputum and improvements in lung function were also demonstrated

37.  Phase 3 130 sites 11 countries  N=288 >12yr  Chronic Ps a on TSI x3 in past 1yr  FEV1 25-85%  Clinically stable  Levofloxacin 240mg bd v TSI 300mg bd  28/7 on / 28/7 off  No difference between 2 treatments

38.  Inhaled liposomal amikacin  Combined data of European and U.S. Phase 2 clinical trials in people with CF colonized with Pseudomonas aeruginosa showed improved lung function and reduction in P. aeruginosa density compared to placebo  Phase 3 trial for NTM recruiting

39.  For treatment of MRSA  US multicentre phase 2 trial recruiting

40. Specially formulated supplements include vitamins, as well as enzymes that increase both fat and vitamin absorption, allowing better nutrition for people with CF, who can become malnourished as a result of thick mucus clogging the pancreas

41.  Not from animal source  Phase 3 trial completed  No safety concerns  Coefficient of fat absorption improved  Submitted to FDA

43.  12yr girl delF508/delF508  Takes neb Dnase od, HS bd  Salb inh bd  Physio bd  Likes Tobi Podhaler because she can use it on way to school, no need to clean and done in few seconds without needing to rely on mum to prepare and clean equipment

44.  RLH 5 children G551D ≥6yr  Sweat Cl pre 96post 38  Average weight gain 2.4kg in 3/12  FEV 1 variable but up to 12% increase  Reduced exacerbations  BUT…

45.  2 brothers with CF  SP 17yr delF508/delF508, fully compliant  RP 14yr delF508/G551D, non adherent  Compliance