Cystic Fibrosis the future Pathophysiologic cascade Abnormal Gene Abnormal CFTR Therapy Gene replacement Protein replacement Gene read through therapy Abnormal sodium chloride & water movement through cell Ion channel modulations Restore airway surface liquid Dr Marleen Moens Revalidatiecentrum voor kinderen en jongeren, respiratoire afdeling UZ Gasthuisberg, mucoteam Leuven Abnormally thick and dry mucous Bronchial airway Thickened mucous Mucolytic drugs obstruction VICIOUS CIRCLE Mucous clearance techniques Infection Release of protease & DNA Antimicrobials Inflammation Progressive lung tissue destruction Anti-inflammatory agents Respiratory failure Lung transplant Pulmozyme Pulmozyme = DNAse lysis of DNA bacteria and inflammtory cells Stabilisation of lung function Aerosol 1 x / day 5 years old LF < 1% decline/year Side effect: hoarseness Tobi Tobi Inhalation of tobramycine chronic colonisation of Pseudomonas aeruginosa stabilisation of lung function less respiratory exacerbations side effect: resistance hoarseness and tinnitus 1
Therapeutics Development Program Discovery Awards Therapeutics Development Awards Therapeutics Development Network Low-hanging Fruit CF Services Pharmacy 22 24 NaCl 7% osmotic effect Hypertonic saline Lung function less respiratory exacerbations slight improvement of lung function side effect: bronchospasm, dyspnea, pharyngitis NEJM 26 354,3 NEJM 26 354,3 Exacerbations Azithromycine Anti-inflammatory properties: inhibits biofilm formation, quorum-sensing of P aeruginosa stimulates phagocytosis reduces mucus production and cytokine production Stabilisation of longfunction Less respiratory exacerbations Less use of antibiotics NEJM 26 354,3 2
Inhaled Antibiotics in Development Disease modifying drugs Inhaled monobactam Aztreonam Lysine for inhalation (Gilead) Inhaled flouroquinolones Ciprofloxacin Dry Powder for Inhalation (Bayer) Levofloxacin Solution for Inhalation (MPEX) Inhaled Liposomal Ciprofloxacin (Aradigm) Inhaled aminoglycosides Tobramycin Dry Powder for Inhalation (Novartis) Arikace (liposomal amikacin) (Transave) Inhaled aminoglycoside/phosphonic acid Tobramycin/Fosfomycin for Inhalation (Gilead) Designed to cure the core problem of CF Gene therapy Protein repair Influence on ion fluxes more chloride outside less sodium inside More water on the epithelial layer Pathophysiologic cascade Abnormal Gene Therapy Gene replacement Abnormal CFTR Abnormal sodium chloride & water movement through cell Protein replacement Gene read through therapy Ion channel modulations Restore airway surface liquid CFTR gene (CF transmembrane regulator protein) >15 mutations different classes Abnormally thick and dry mucous Bronchial airway Thickened mucous Mucolytic drugs obstruction VICIOUS CIRCLE Mucous clearance techniques Infection Release of protease & DNA Antimicrobials Inflammation Progressive lung tissue destruction Anti-inflammatory agents Respiratory failure Lung transplant CFTR mutation Classes: I II III IV V Normaal II III IV V Activity of Cl channel Sweat test Pilocarpine iontoforesis abnormal: Cl > 6 meq/l normal: Cl < 3 meq/l Nasal potential difference test(npd) Cl secretion (nose) Adapted from Hospital Practice, 1997 No CFTR G542X Destruction ΔF58 No activation N133K Defective conduction R117H Decreased synthesis A455E 3
Transepithelial chloride transport: Sweat Test Transepithelial chloride transport: Nasal Potential Difference (NPD): Gene Therapy Pathophysiologic cascade Abnormal Gene Therapy Gene replacement Abnormal CFTR Protein replacement Gene read through therapy First choice as real curative therapy Abnormal sodium chloride & water movement through cell Ion channel modulations Restore airway surface liquid BUT vector problem duration insufficient clinical effect Abnormally thick and dry mucous Bronchial airway Thickened mucous Mucolytic drugs obstruction VICIOUS CIRCLE Mucous clearance techniques Infection Release of protease & DNA Antimicrobials Inflammation Progressive lung tissue destruction Anti-inflammatory agents Respiratory failure Lung transplant CFTR mutation effect on CFTR protein function Normal class I II III IV V Normaal II III IV V Normal translation of genetic information a full-length protein is synthesised Normal Translation Ribosomes Normal Stop Amino acid Protein mrna Full-length Protein Adapted from Hospital Practice, 1997 No CFTR G542X Destruction ΔF58 No activation N133K Defective conduction R117H Decreased synthesis A455E 4
Nonsense mutation = premature stop of translation PTC124 ignores the nonsense mutation truncated protein PTC124 Nonsense (Premature Stop) Normal Stop Premature Termination Nonsense (Premature Stop) Normal Stop YIELD Protein mrna Fulllength Protein Protein mrna Truncated Protein Phase 2a studies met PTC 124 PTC124 ameliorates NPD PTC124: slight positive effect on FEV 1 PTC124 phase 2b/3 is planned 5
CFTR mutation effect on CFTR protein function Normal class I II III IV V Normaal II III IV V Potentiator Potentiator: Increase activity of CFTR channel Adapted from Hospital Practice, 1997 No CFTR G542X Destruction ΔF58 No activation N133K Defective conduction R117H Decreased synthesis A455E Potentiator increase CFTR activity cell cultures Phase 2a Study of CFTR Activity (% wt-cftr) Ussing chamber studies using /F58del-HBE cultures 12 1 8 6 4 2 /F58del-HBE Wild-type-HBE Untreated Untreated Single donor lung All data expressed as % wt-cftr N = 7 EC5 for /delf58 = 238 +/- 2 Primary Endpoints: Safety and tolerability Secondary Endpoints: Biomarkers of CFTR activity and lung function PK parameters Subjects with were chosen for the initial study due to the normal trafficking of -CFTR to the cell surface Nasal Potential Difference Direct measure of CFTR function and other ion channels in the upper airway Forced Expiratory Volume (FEV 1 ) Measure of lung function Sweat Chloride Concentration Measure of CFTR function that is commonly used to diagnose CF Part 1 Random, Dubbel-Blind, Placebo Controle dosed Q12 hr Part 2 *Distinct subjects from Part 1 Studie Design Group A: 1 Subjects ( Mutation) Group B: 1 Subjects ( Mutation) 19 Subjects ( Mutation)* N=4 N=4 N=2 N=4 N=4 N=2 14-day 25 mg 75 mg PBO 7 to 28d Wash-out 14-day 75 mg 25 mg 14-day 7 to 28d Wash-out PBO 75 mg 15 mg 15 mg 75 mg PBO N=8 15 mg N=7 25 mg N=4 PBO 14-day PBO 28-day B E T T E R Mean Change [95% CI] 5-5 -1-15 -2-25 Change in NPD with (mv) -1.74 Part 1: 14-Day -1.55-4.72* Placebo 25mg 75mg 15mg * p <.5 p <.1 within subject comparison -5.4 Mean Change [SD] 5-5 -1-15 -2-25 Distinct subjects in Part 1 and 2.25 Part 2: 28-Day -4.31* Placebo 15mg 25mg * p <.5 within subject comparison -1.14* 6
Change in sweat chloride with 8-32.9* -4.4 * 6-42.3 * 4 2-2.3 1-27.6 6-32.4-52.8-52.6 4 2 4 2 3 2 11.6 1 7.4 7. 1 Placebo 25mg 75mg 15mg 15mg Placebo 15mg Placebo CFTR mutation Correctors effect on CFTR protein function class I II Normaal III II 25mg p <.1 within subject comparison p <.5 within subject comparison Distinct subjects in Part 1 and 2 Normal -1 25mg p <.1 within subject comparison p <.5 within subject comparison * p <.1 within subject comparison Individual Subject Change in FEV1 from Baseline at Day 28 Mean Change from Baseline 3 8 Percent Change from Baseline in FEV1 4.8 Mean Percent Change from Baseline in FEV1 [SD] Mean Change from Baseline [95% CI] (mmol/l) 1 Mean Change from Baseline 12 Mean Change from Baseline [SD] (mmol/l) Mean Change from Baseline 4.4 Percent Change from Baseline in FEV1 Part 2: 28-Day Part 1: 14-Day 12 Improvement of FEV1 with IV III V IV V Corrector: get more CFTR channels in cell surface VX-89 Cl Cl F58del Adapted from Hospital Practice, 1997 No CFTR Destruction G542X ΔF58 No activation Defective Decreased conduction synthesis N133K R117H A455E Corrector and potentiator Effect on delf58 CFTR Activity Vertex Program Oral medication Corrector: Increases cell surface density and function of delf58-cftr Cl Cl Cl VX-89 Cl : Increases channel opening of corrected delf58-cftr ClCl F58del Cl Cl Cl ClCl 3 2 1 Corrector + Cl Corrector: get more CFTR channels in cell surface Corrector 4 Untreated Potentiator: Increase activity of CFTR channel F58-CFTR Activity (% wild-type CFTR) F58-HBE Dubbel doel: 7
and VX-89 Development Status : Continue analysis of the Phase 2a study Phase 3 studies were initiated in may 29 randomized, double-blind, placebo-controlled Pathophysiologic cascade Abnormal Gene Abnormal CFTR Abnormal sodium chloride & water movement through cell Abnormally thick and dry mucous Therapy Gene replacement Protein replacement Gene read through therapy Ion channel modulations Restore airway surface liquid VX-89: Phase 1 healthy volunteer studies Phase 2 safety study in delf58 patients in 29 Bronchial airway Thickened mucous Mucolytic drugs obstruction VICIOUS CIRCLE Mucous clearance techniques Infection Release of protease & DNA Antimicrobials Inflammation Anti-inflammatory agents Progressive lung tissue destruction Respiratory failure Lung transplant P2Y2 activator Denufosol activation of alternative chloride channels improvement of Airway surface liquid improvement of mucociliary transport side effect: temporarily lower FEV 1 Bronchitol = mannitol a sugar attracting water better lung function A current challenge for investigators and patients One goal is a better way to measure improvement Nasal Potential Difference testing Lung clearance index a more accurate lung function test M P We want better drugs We want quality and efficient research A European network for CF research A lot of work for investigators and patients Chest 28 8
Our goal is to cure CF New Drugs Realistic expectations We never know in advance which drug will be a success for future treatment of CF Discovery/Screening Pre-IND Synthesis and Purification Animal Testing 2% Pre-IND Success Rate 5% Phase 1 Clinical Studies Success Rate Phase 2 Short-term Long-term Phase 3 Review NDA Post-marketing 8% Success Rate Avg: 5-7 yrs Avg: 6-7 yrs Avg: 1 yr Standard Avg: 6 mo Priority 9