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(Orkambi™) for the Management of Persons with Cystic Fibrosis and Two F508del CFTR Mutations

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(Orkambi™) for the Management of Persons with Cystic Fibrosis and Two F508del CFTR Mutations Cystic Fibrosis Foundation Confidential Materials 8/28/2015 Considerations for the use of lumacaftor and ivacaftor fixed dose combination oral tablets (Orkambi™) for the management of persons with cystic fibrosis and two F508del CFTR mutations Executive Summary The lumacaftor and ivacaftor fixed dose combination oral tablet (Orkambi™, Vertex Pharmaceuticals, Inc.) is the second Food and Drug Administration (FDA) approved member of a new pharmacologic class of drugs termed cystic fibrosis transmembrane conductance regulator (CFTR) modulators.[1] CFTR modulators target the underlying defect (reduced CFTR function) that causes disease sequelae (Figure 1) and are fundamentally different from other chronic cystic fibrosis (CF) treatments that address the ‘downstream’ complications and clinical manifestations of CF. Figure 1. Underlying etiology of CF lung disease and targets of chronic respiratory therapies. Mutant CFTR (top) results in reduced CFTR protein activity at the epithelial cell surface and creates a cascade of altered lung physiology and inflammatory status leading to disease progression and death in a majority of patients. Chronic CF respiratory therapies are targeted at downstream manifestations of reduced CFTR activity. CFTR modulators partially restore mutant CFTR protein activity and blunt this cascade at its origin. This same phenomenon occurs with other affected organ systems, particularly the GI tract, where substantial morbidity is associated with reduced CFTR expression. Adapted from [2]. In two identical, randomized, placebo-controlled Phase 3 clinical trials, lumacaftor/ivacaftor was shown to result in a significant, clinically meaningful, sustained improvement in pulmonary function among individuals with CF ≥12 years old and two copies of the F508del CFTR mutation. Persons with CF and only a single F508del CFTR mutation do not appear to benefit from lumacaftor/ivacaftor treatment. Page 1 Cystic Fibrosis Foundation Confidential Materials 8/28/2015 Overall, lumacaftor/ivacaftor treatment was relatively safe, albeit with a relatively small incidence of clinically meaningful and potentially serious associated liver damage. Other, less serious, adverse events associated with the lumacaftor/ivacaftor treatment include dyspnea, abnormal respiration, flatulence, menstrual abnormalities, and rash. Given the life-shortening nature of CF associated with carriage of two F508del CFTR mutations, and in particular noting that the primary cause of premature death in this patient population is directly or indirectly related to irreversible loss of pulmonary function, the demonstrated sustained improvement of pulmonary function with lumacaftor/ivacaftor treatment in this population is suggestive of clinically meaningful disease modification. Page 2 Cystic Fibrosis Foundation Confidential Materials 8/28/2015 Cystic Fibrosis (CF) CF is an autosomal recessive disease resulting from the inheritance of a mutant allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene from each parent.[3-5] The CFTR protein is an ion channel responsible for the movement of chloride[6] and bicarbonate[7] across the apical surface of epithelial cells of the sweat glands, pancreas, gastrointestinal, and reproductive tracts, as well as airway epithelia and submucosal glands.[6,8] Inheritance of mutant CFTR alleles leads to a reduction of CFTR activity at the cell surface; the extent to which CFTR activity is reduced influences the severity of pathophysiologic sequelae associated with CF.[8] Individuals carrying a single CFTR mutation (i.e., CF “carriers”) have somewhat reduced CFTR protein activity on cell surfaces (~85%) but are unaffected. Persons with CF (i.e., those carrying two mutant CFTR alleles) in which one mutation retains residual (but reduced) CFTR function have less aggressive disease phenotypes and better overall survival than their peers who carry two CFTR mutations resulting in little or no CFTR activity.[8] Certain pathophysiologic manifestations of CF arise in utero. Most CF newborns are now identified for definitive diagnostic evaluation based upon elevated blood levels of immunoreactive trypsinogen (IRT) caused by pancreatic ductile/duct blockage, pancreatic autodigestion, and enzyme leakage.[9] CF males are born without a functional vas deferens, and 10-15% of CF newborns are diagnosed with meconium ileus caused by reduced water and bicarbonate secretion in the gut.[8] From birth, reduced CFTR activity in CF sweat glands hampers an individual’s ability to recover salt from their sweat.[8] This provides the basis for the definitive test for CF: pilocarpine-induced iontophoresis (the CF “sweat test”), where a definitive diagnosis of CF is associated with a sweat chloride concentration exceeding 60 mmol/L.[9] CF organ system pathologies persist and evolve after birth. Nearly 90% of infants with CF lose all exocrine pancreatic function and experience a lifetime of pancreatic insufficiency.[8] Risk of CF- related diabetes mellitus increases with age, occurring in more than a quarter of individuals 25 years of age and older.[10] Gastrointestinal complications include decreased bicarbonate secretion from the pancreatic duct, resulting in extraordinarily low pH in the small intestine contributing to fat and fat- soluble vitamin malabsorption and associated steatorrhea, poor growth, and increased risk of gallstones, renal stones, and hepatobiliary disease.[8] Impaired nutritional status, CF-related diabetes mellitus, and biliary cirrhosis are all associated with morbidity and mortality. The organ system responsible for the greatest proportion of premature CF deaths, the respiratory system, appears essentially normal at birth with complications arising from reduced CFTR activity in the sinuses and respiratory tract apparent soon thereafter.[11-18] Reduced CFTR activity depletes apical surface liquid volume in the airway, producing mucus with increased adhesivity and cohesivity, causing small airway plugging. This obstruction, as well as associated neutrophilic Page 3 Cystic Fibrosis Foundation Confidential Materials 8/28/2015 inflammation, can be identified as air trapping and bronchial wall thickening by high-resolution computerized tomography (HRCT).[16,17] Opportunistic bacteria enter the upper and lower respiratory tract by inhalation or aspiration, where they are unable to be cleared; bacterial growth and expansion leads to increased local inflammation.[11-14] In infancy, this triad of chronic obstruction, infection, and inflammation sets in motion a lifelong degradation of lung structure and function,[8,18- 20] ultimately contributing to the premature deaths of persons with CF. Respiratory failure directly or indirectly accounts for over 80% of mortality in CF.[10] CFTR Mutations More than 2,000 unique, mostly rare, human mutations of CFTR have been catalogued, [21] but not all have been confirmed to cause disease. Those CFTR mutations known to cause complications of CF have been categorized into five basic classes, labeled I-V, based upon the major defect they confer on normal CFTR protein homeostasis and function (Table 1).[22-24] CFTR mutations that affect the biosynthesis of full length protein molecules comprise mutation class I.[22-24] Remaining CFTR mutations are categorized based on whether they affect protein processing and maturation (class II), ion channel gating or regulation (class III), channel conductance (class IV), or whether a reduced amount of “normal” CFTR protein is produced (class V).[22-24] Table 1. CFTR Mutation Class Designations and Phenotypes Mutation CFTR Mutant CFTR Activity Class Phenotype Alleles (examples) G542X, W1282X, R553X, Defective synthesis I 621+1G->T, 1717-1G->A, of full length protein R1162X, 3659delC Defective protein Minimal II F508del, I507del, N1303K processing (Markedly Reduced from Normal) Defective chloride III channel gating or G551D, R560T regulation Defective chloride IV R117H, R347P,R334W, G85E channel conductance Residual 3849+10kbC->T, 2789+5G>A, (Reduced from Normal) Reduced level of V 711+1G>T, A455E, normal protein 1898+1G>A, 218delA Classes I-III CFTR mutations comprise roughly 90% of identified human CFTR mutations and are considered “severe” mutations in that they result in markedly reduced or absent CFTR protein function.[25] Individuals with CF carrying two mutations of classes I-III are at significantly higher risk for pancreatic insufficiency,[26] early bacterial lung infection,[27] and mortality.[28,29] Classes of Page 4 Cystic Fibrosis Foundation Confidential Materials 8/28/2015 CFTR mutation are not exclusive; there can be “overlap” where individual CFTR mutations can confer defects in homeostasis characteristic of more than one mutation class.[23] CFTR mutations are recessive; individuals with CF carrying two different CFTR mutations in which one mutation retains some modest CFTR activity (e.g., class IV or V mutations) are less prone to progressive disease and early mortality than are individuals carrying two mutations associated with little or no CFTR activity.[25] For this reason, CF carriers (who carry one mutant CFTR allele and one normal allele) are not afflicted with CF, regardless of the class of CFTR mutation they carry. Further, although 90% of characterized CFTR mutations appear to be of classes I-III, distributions are somewhat different within CF populations due to survivor effects, where persons with CF and class IV and V mutations have a survival advantage. As CF populations age, the proportion of class I-III mutant CFTR alleles
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