(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.

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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.

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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

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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

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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 in the population is somewhat reduced. An individual’s CFTR genotype is not the sole determinant of their disease aggressiveness or rate of disease progression. Analyses of disease progression conducted among CF monozygous twins, dizygous twins, and sibling pairs suggest that approximately half of observed variability in CF disease progression within a given CFTR genotype can be attributed to genetic diversity beyond CFTR mutation, with environmental factors accounting for the remaining variability.[30,31]

Rationale for Chronic Treatment with CFTR Modulators

CFTR modulators target the underlying cause of cystic fibrosis. Modulators are thus fundamentally different than any other treatments available today, all of which address the symptoms of the disease rather than the root cause.

Recently, new small molecule pharmacologic classes termed CFTR “potentiators” and “correctors” (collectively termed CFTR “modulators”) have been described.[1] CFTR potentiators can alter the activity of class III mutations that compromise CFTR gating and increase CFTR-mediated ion movement across epithelial surfaces.[32] The most prevalent class III CFTR mutation is G551D, which is carried by about 4% of persons with CF in the US.[10] Ivacaftor (Kalydeco®; Vertex Pharmaceuticals) [32] is a small molecule CFTR potentiator that has been shown to increase CFTR- mediated ion movement across the surfaces of CF cells with the G551D mutation in vitro[32] and in vivo.[33,34] Ivacaftor has been approved by the Food and Drug Administration for the treatment of persons with CF age 2 years and older who have one of the following CFTR mutations: G551D, 1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H.[35]

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CFTR correctors are small molecules that facilitate the intracellular processing of misfolded mutant CFTR proteins, decrease the degradation of mutant CFTR protein within the cell, and increase the amount of mutant CFTR protein that successfully reaches the epithelial cell surface. Lumacaftor is a small molecule CFTR corrector that has been shown to increase the quantity of mutant CFTR protein derived from the class II CFTR mutation F508del that reaches the epithelial cell surface in vitro. Importantly, F508del, the most common mutant CFTR allele among persons diagnosed with CF in the US, also has the properties of a gating mutation. Thus, treatment of F508del protein at the cell surface with the potentiator ivacaftor increases CFTR activity.[36] Combined exposure to lumacaftor and ivacaftor has been shown to increase CFTR function in epithelial cells with the F508del CFTR mutation in vitro. A fixed dose combination oral tablet of lumacaftor and ivacaftor (Orkambi™; Vertex Pharmaceuticals, Inc.) has been approved by the FDA for persons with CF 12 years of age and older and with two copies of the F508del CFTR mutation.[37]

The fixed dose combination therapy of lumacaftor and ivacaftor has been shown to improve lung function as well as confer benefits in non-respiratory organ systems.

As previously noted, CF is a recessive genetic disease, with the “severity” of multi-organ CF pathologies inversely related to the amount of CFTR protein activity present at epithelial surfaces. For CF patients carrying CFTR mutations shown to be effectively treated by CFTR modulators, increasing CFTR protein activity by modulator treatment likely produces an immediate improvement in airway surface liquid properties which contribute to observed lung function benefits. Because approved modulators are systemic therapies, pathologies related to CFTR functional deficiencies in organ systems outside the respiratory tract are also favorably affected by these drugs.

Initiating treatment with modulators in patients with indicated CFTR mutations earlier in the CF disease progression process has greater potential for overall lifetime benefit.

Prevention of lung disease progression, regardless of an individual’s current disease stage, is a primary goal of CF management, as CF-associated structural lung damage is irreversible and associated with increased morbidity and mortality. Although increasing airway CFTR function with modulators may have the potential to slow or delay future lung disease progression, it would not be expected to reverse structural damage and associated pathologies patients have experienced prior to treatment initiation (e.g., irreversible lung damage, pancreatic insufficiency, or azoospermia). Thus, earlier intervention with modulating therapies has a greater potential for sparing the structure and function of

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Cystic Fibrosis Foundation Confidential Materials 8/28/2015 organ systems affected by deficient CFTR activity rather than delaying treatment until irreversible damage has occurred.

Selection of the Lumacaftor/Ivacaftor Dose The commercial dosage of the lumacaftor/ivacaftor combination treatment is 400 mg lumacaftor plus 250 mg ivacaftor BID. This dosage was identified in studies 809-101 and 809-102 (Table 2), which relied on changes from baseline in sweat chloride concentration and FEV1 in subjects with CF to estimate efficacy. Table 2. Lumacaftor/ivacaftor studies used to determine dosing of the combination treatment

Study 809-101 Location United States, Canada, European Union Purpose Pharmacokinetics, pharmacodynamics, and dose-ranging Subjects 93 CF patients, ≥ 18 years Design Randomized, double-blind, placebo controlled, parallel group Placebo 25 mg lumacaftor QD Doses 50 mg lumacaftor QD 100 mg lumacaftor QD 200 mg lumacaftor QD Duration 28 days Endpoints Change in sweat chloride, nasal potential difference, FEV1, CFQ-R respiratory domain

Study 809-102* Location United States Purpose Pharmacokinetics, pharmacodynamics, and dose-ranging Subjects 97 CF patients, ≥ 12 years, at least one F508del CFTR mutation Design Double-blind, placebo controlled Placebo 200 mg lumacaftor QD/200 mg lumacaftor QD + 150 mg ivacaftor BID 200 mg lumacaftor QD/200 mg lumacaftor QD + 250 mg ivacaftor BID Doses 400 mg lumacaftor QD/400 mg lumacaftor QD + 250 mg ivacaftor BID 600 mg lumacaftor QD/600 mg lumacaftor QD + 250 mg ivacaftor BID‡ 400 mg lumacaftor BID/400 mg lumacaftor BID + 250mg ivacaftor BID‡† Duration 14-28 days

Endpoints Change in sweat chloride, FEV1, CFQ-R respiratory domain *Cohorts 2 and 3 [38], ‡ doses studied in Phase 3, † ultimate approved regimen In Study 809-101, 93 subjects were randomized to receive 25, 50, 100, or 200 mg of lumacaftor or placebo once daily for 28 days; 89 received study drug. While sweat chloride and nasal potential difference measures suggested some possible small degree of lumacaftor activity at the highest (200 mg)

dose, there were no consistent positive changes in FEV1 [38]. As such, the study identified the need to study higher doses of lumacaftor which were subsequently assessed in study 809-102.

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Study 809-102, a randomized, double-blind placebo-controlled, multi-cohort study, was the principle justification for dose-selection.[39] 809-102 had 4 cohorts: • Cohort 1 assessed the effect of low dose lumacaftor alone and in combination with the marketed dose (150 mg twice daily) or a higher dose (250 mg twice daily) of ivacaftor • Cohort 2 assessed the effect of higher doses of lumacaftor (up to 600 mg once daily) alone and in combination with high dose ivacaftor (250 mg twice daily) • Cohort 3 assessed the effect of a 400 mg twice daily dose of lumacaftor alone and in combination with ivacaftor (250 mg twice daily) • Cohort 4 assessed a dose of lumacaftor (400 mg) in combination with ivacaftor (250 mg) twice daily for a longer (56 day) treatment period. The results obtained from Cohorts 2 and 3 were determined to be the most relevant for the purpose of determining the effect of lumacaftor monotherapy and the potential clinical activity for the lumacaftor/ivacaftor combination, and doses studied in these cohorts were advanced to Phase 3 studies.

Demonstration of Lumacaftor/Ivacaftor Efficacy

Two identical 24-week, randomized, blinded, placebo-controlled, parallel group Phase 3 studies (809-103 and 809-104) were conducted to characterize the safety and efficacy of 400 mg lumacaftor/250 mg ivacaftor BID as well as 600 mg lumacaftor QD/250 mg ivacaftor BID in subjects with CF and two F508del mutations. After a 28 day screening period, eligible patients were randomized 1:1:1 to receive either placebo or one of the two lumacaftor/ivacaftor combination regimens for 24 weeks. Subjects who completed the 24 week treatment periods of these two studies were allowed to enroll in extension study 809-105.

Study eligibility was based on a confirmed diagnosis of CF as well as the presence of two copies of the F508del CFTR mutation. In addition, subjects had to be at least 12 years old with normal renal liver function, could not be chronically infected with Burkholderia cenocepacia, B. dolosa, or Mycobacterium abscessus, could not have history or evidence of cataracts or lens opacity at screening. Patients were excluded due to abnormal liver function if 3 or more of the following categories were met: ≥3 × upper limit of normal (ULN) for aspartate aminotransferase (AST), ≥3 × ULN for alanine aminotransferase (ALT), ≥3 × ULN for gamma-glutamyl transpeptidase (GGT), ≥3 × ULN for alkaline phosphatase, or ≥2 × ULN for total bilirubin. Patients who had been treated for pulmonary exacerbation or respiratory tract infection, or who had experienced a change in their CF therapies within 4 weeks prior to the proposed study initiation date were also excluded.

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Enrollment for each study was planned for approximately 167 subjects per treatment group, providing ~99% power to detect a treatment-associated 5% predicted absolute FEV1 difference between active and placebo groups (the primary efficacy endpoint) assuming a standard deviation of 8% predicted and a 10% dropout rate while employing a 2-sided test for superiority at the α = 0.025 significance level. Ultimately, ~187 patients per treatment group were enrolled in each study, allowing substantially more power to detect a smaller treatment effect.

The primary endpoint (absolute FEV1 difference between active and placebo groups) was assessed as the average of treatment effects observed at Weeks 16 and 24 of treatment. Five pre-specified secondary endpoints were studied 1) average relative change from baseline in per cent FEV1% predicted at weeks 16 and 24; 2) absolute change from baseline in body mass index (BMI) at week 24; 3) absolute change from baseline in Cystic Fibrosis Questionnaire– Revised (CFQ-R) respiratory domain, a CF- specific patient reported outcome that assesses respiratory symptoms, score at week 24; 4) FEV1 response defined as ≥5% increase in average relative change from baseline in percent predicted FEV1 at weeks 16 and 24; 5) number of pulmonary exacerbations through week 24. The primary analysis was to be based on a mixed effects model for repeated measurements (MMRM) for the pooled study results. A multiplicity adjustment approach using a simple Bonferroni correction and a hierarchical testing procedure was used to control the overall Type I error rate at 0.05 for the primary endpoint and the 5 key secondary endpoints across the two lumacaftor/ivacaftor dosing regimens.

In all, 1122 subjects were enrolled in studies 809-103 and 809-104, with 1108 subjects (549 and 559, respectively) receiving at least 1 dose of study drug (Table 3). Patient retention across studies was 96-99%. In 809-103, 25 patients (4.6%) stopped medication early and 12 (2.2%) also withdrew from the study. In 809-104, 29 patients (5.2%) terminated study drug early and 14 (2.5%) withdrew from the study. The most common reason for discontinuation from study drug treatment was adverse events, occurring in 18 (3.3%) patients in study 809-103 and 19 (3.4%) patients in study 809-104.

Primary Efficacy Endpoint: FEV1

Sustained improvement in FEV1% predicted is recognized as an important surrogate for clinical benefit in cystic fibrosis because a) studies have demonstrated that a 10% predicted decrease in FEV1 is associated with a 2-fold increased risk of 2-year mortality[40] and b) about 80% of CF deaths today result directly or indirectly from loss of lung function.[10] In studies 809-103 and 809-104, patients randomized to either lumacaftor/ivacaftor regimen had statistically significant absolute improvements in

FEV1% predicted compared to patients randomized to placebo, as assessed by the average of the treatment effects at Week 16 and at Week 24 (Table 4).

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Table 3. Subject Demographics for Studies 809-103 and 809-104

Study 809-103 Study 809-104 LUM 600 LUM 400 LUM 600 LUM 400

Placebo /IVA 250 /IVA 250 Placebo /IVA 250 /IVA 250 Sex, n (%) Male 100 (54) 97 (53) 98 (54) 90 (48) 89 (48) 89 (48) Female 84 (46) 86 (47) 84 (46) 97 (52) 96 (52) 98 (52) Age, years n 184 183 182 187 185 187 Mean 25.0 24.7 25.5 25.7 24.3 25.0 SD 10.8 9.71 10.1 10.0 8.31 9.0 Range 12-64 12-54 12-57 12-55 12-48 12-54 Weight, kg n 184 183 182 187 185 187 Mean 59.1 58.6 60.6 58.5 58.2 59.2 SD 11.7 11.7 12.2 13.1 12.9 12.1 Range 35.0-93.0 29.0-90.0 31.0-101.0 27.0-98.0 30.0-99.8 35.0-105.0

FEV1, % predicted n 181 182 180 185 184 185 Mean 60.45 61.18 60.48 60.37 60.49 60.59 SD 13.22 13.31 14.29 14.32 13.83 14.01 Range 34.0-88.0 31.1-92.3 34.8-94.0 33.9-99.8 34.4-90.4 31.3-96.5

FEV1 disease stage, n (%) <40% predicted 11 (6.0) 12 (6.6) 12 (6.6) 17 (9.1) 12 (6.5) 17 (9.1) 40 to <70% predicted 122 (66.3) 122 (66.7) 116 (63.7) 116 (62.0) 119 (64.3) 117 (62.6) 70 to <90% predicted 48 (26.1) 47 (25.7) 51 (28.0) 49 (26.2) 51 (27.6) 49 (26.2) ≥90% predicted 0 (0.0) 1 (0.5) 1 (0.5) 3 (1.6) 2 (1.1) 2 (1.1)

Table 4. Absolute FEV1 Change from Baseline in Phase 3 Studies

Study 809-103 Study 809-104 LUM 600 LUM 400 LUM 600 LUM 400 Placebo /IVA 250 /IVA 250 Placebo /IVA 250 /IVA 250 N=184 N=183 N=182* N=187 N=185 N=187*

Baseline FEV1 (% predicted) 60.5 61.2 60.5 60.4 60.5 60.6 Average Change from Baseline at −0.4 3.6 2.2 −0.2 2.5 2.9 Weeks 16 and 24 (% predicted) Difference from placebo 4.0 2.6 2.6 3.0 -- -- (% predicted) (2.6, 5.4) (1.2, 4.0) (1.2, 4.1) (1.6, 4.4) * -marketed dose regimen, 400 mg lumacaftor and 250 mg ivacaftor, BID

Improvements in FEV1% predicted observed over 24 weeks in Studies 809-103 and 809-104 among patients randomized to receive either the 600 mg lumacaftor QD/250 mg ivacaftor BID regimen or the 400 mg lumacaftor BID/250 mg ivacaftor BID regimen were observed to be fully retained in a subsequent extension study (809-105) in which patients continued to receive their same lumacaftor/ivacaftor regimen (Figure 2).[38]

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Figure 2. Mean changes from Baseline in FEV1 % Predicted in Studies 809-103 and 809-104 for Patients Randomized to Receive Lumacaftor/Ivacaftor or Placebo. Results from a 24-week extension study (809-105) are also shown.

The ‘maintenance’ of FEV1 improvement observed over 48 weeks in studies 809-103, 809-104, and 809-105 among patients receiving either lumacaftor/ivacaftor regimen (Figure 2) is notable in that previous extended studies of chronic CF pulmonary therapies that treat symptoms (e.g., dornase alfa, tobramycin inhalation solution) have shown that initial gains in pulmonary function are not similarly maintained over extended periods. Figure 3 provides a qualitative comparison of previously published mean relative FEV1 changes from baseline for study subjects treated with dornase alfa[41] and

tobramycin inhalation solution[42] with relative FEV1 change from baseline values observed among patients treated with lumacaftor/ivacaftor over 48 weeks in studies 809-103, 809-104, and 809-105.

Comparisons with historical controls such as those made in Figure 3 have a number of potential pitfalls, not the least of which is that standards of CF management have evolved over time. For instance, approximately three quarters of 809-103 and 809-104 patients were also receiving dornase alfa and approximately two thirds were receiving inhaled antibiotics during the studies. Presumably, these benefits associated with lumacaftor/ivacaftor are in addition to those associated with these other chronic pulmonary therapies in those patients. With these limitations in mind, it is worth noting that although the

initial mean relative FEV1 benefits observed among historical CF cohorts treated with both dornase alfa and inhaled tobramycin are greater than those observed among patients treated with lumacaftor/ivacaftor, the lumacaftor/ivacaftor benefit appears to be more stable over extended periods. While the data relating to the long-term ability of lumacaftor/ivacaftor to reduce lung disease progression are not yet available, this is a property that has been identified for the other approved CFTR modulator therapy, ivacaftor.[43]

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Figure 3. Qualitative comparison of mean relative FEV1% predicted change from baseline from historical CF cohorts treated with inhaled tobramycin [42], dornase alfa [41] and 809-103, 809,104, and 809-105 patients treated with lumacaftor/ivacaftor. A). Lumacaftor/ivacaftor results showing consistency of benefit over the 48 week study period. B). Historical inhaled tobramycin and dornase alfa data showing general trend of reduced mean benefit over extended treatment. C). Superimposition of trend arrows from A and B.

Secondary Efficacy Endpoints

In addition to different methods for demonstrating the lumacaftor/ivacaftor-associated FEV1 benefit, investigators studied the effects of lumacaftor/ivacaftor treatment on body mass index (BMI), patient perception of respiratory benefit as captured by the Cystic Fibrosis Questionnaire-Revised respiratory domain, and pulmonary exacerbation rates (Table 5).

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Table 5. Secondary Efficacy Endpoints for Studies 809-103 and 809-104 in Hierarchical Order.

Study 809-103 Study 809-104 Pooled Studies

LUM600 LUM400 LUM600 LUM400 LUM600 LUM400 IVA250 IVA250 IVA250 IVA250 IVA250 IVA250 N = 183 N = 182 N = 185 N = 187 N = 368 N = 369

Relative change from baseline in FEV1 % predicted Treatment 6.7% 4.3% 4.4% 5.3% 5.6% 4.8% difference to (4.3%, 9.2%) (1.9%, 6.8%) (1 .9%, 7.0%) (2.7%, 7.8%) (3.8%, 7.3%) (3.0%, 6.6%) placebo P<0.0001 P = 0.0006 P = 0.0007 P<0.0001 P<0.0001 P<0.0001 (95% CI) 2 Change from baseline in Body Mass Index (kg/m ) Treatment 0.16 0.13 0.41 0.36 0.28 0.24 difference to (-0.04, 0.35) (-0.07, 0.32) (0.23, 0.59) (0.17, 0.54) (0.15, 0.41) (0.11, 0.37) placebo P = 0.1122 P = 0.1938 P<0.0001 P = 0.0001 P<0.0001 P = 0.0004 (95% CI)

Change from baseline in CFQ-R respiratory domain Treatment 3.9 1.5 2.2 2.9 3.1 2.2 difference to (0.7, 7.1) (-1.7, 4.7) (-0.9, 5.3) (-0.3, 6.0) (0.8, 5.3) (0.0, 4.5) placebo P = 0.0168a P = 0.3569 P = 0.1651 P = 0.0736 P = 0.0071 P = 0.0512 (95% CI) Patients with ≥5% relative improvement in FEV1 % predicted Odds ratio to 2.94 2.06 2.96 2.38 2.95 2.22 placebo (1.88, 4.59) (1.29, 3.28) (1.88, 4.64) (1.52, 3.73) (2.15, 4.05) (1.61, 3.07) a a a a (95% CI) P<0.0001 P = 0.0023 P<0.0001 P = 0.0001 P<0.0001 P<0.0001

Number of pulmonary exacerbations Rate ratio to 0.72 0.66 0.69 0.57 0.70 0.61 placebo (0.52, 1.00) (0.47, 0.93) (0.52, 0.92) (0.42, 0.76) (0.56, 0.87) (0.49, 0.76) a a a (95% CI) P = 0.0491 P = 0.0169 P = 0.0116 P = 0.0002 P = 0.0014 P<0.0001 Notes: Within each treatment group for Studies 809-103 and 809-104, the treatment difference was considered statistically significant if P≤0.0250 and if all previous tests within the testing hierarchy also met this level of significance. No hierarchy was applied to pooled tests: treatment differences with P≤0.025 were considered statistically significant. a-Endpoint nominally significant at P≤0.0250 level; however, it was not considered statistically significant within the framework of the testing hierarchy.

When data were pooled from the two identical studies, significant changes indicative of lumacaftor/ivacaftor regimen-associated benefit compared to placebo were observed. However, the prospective statistical analysis plan employed by the sponsor for the purpose of registration was hierarchical: designed to account for multiplicity of tests. Statistical tests were conducted that compared each of the two lumacaftor/ivacaftor treatment regimens separately against placebo in each study in a pre- specified order. If any test in the sequence did not achieve statistical significance (P≤0.025), then all subsequent tests for that dosage regimen in that study would be considered insignificant, regardless of apparent P value for the test. The order of hierarchal testing of secondary endpoints was as in Table 5; significant P values for tests derived after ‘failure’ of a test higher in the hierarchy are noted with a superscripted ‘a’.

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As seen in Table 5, both lumacaftor/ivacaftor treatment groups in Study 809-103 failed to achieve statistical significance for the secondary endpoint ‘change from baseline in BMI’, although the trend in change was in favor of treatment over placebo. Similarly, both lumacaftor/ivacaftor treatment groups in 809-104 failed to reach statistical significance for improvement in CFQ-R respiratory domain, the next hierarchical test. Thus, all subsequent secondary endpoints beyond these measures were considered ‘not statistically significant’, regardless of P values.

Although the use of a hierarchical strategy is important for ensuring that the probability of Type I error is not inflated during testing of secondary endpoints, the totality of efficacy evidence within the secondary endpoints (both the trends in every measure within every treatment group as well as the those of the pooled study results) are indicative of overall lumacaftor/ivacaftor-associated benefits. Perhaps the most clinically compelling measure among secondary endpoints is the lumacaftor/ivacaftor-associated reduction in rate of pulmonary exacerbations, a measure which was placed late in the hierarchy because of concerns that it would be less likely to be demonstrated based on study sample sizes. Although prospectively defined hierarchical testing rules require that we consider these results ‘not statistically significant’, point estimates for reduced exacerbation across treatment groups for pooled studies were consistently in favor of lumacaftor/ivacaftor treatment over placebo, with >50% reductions in rates of IV antibiotic treatments and hospital admissions for the LUM400/IVA250 group (Figure 4).

Figure 4. Rates of Pulmonary Exacerbations Requiring IV Antibiotic Treatment and Hospital Admission by Treatment Group across Studies 809-103 and 809-104. P values shown are for the difference between treatment and placebo, but were nominally, but not statistically significant by predefined hierarchical analysis plan.

A halving of the rate of IV treatments and hospital admissions for exacerbation, as highlighted in Figure 4, is clinically very meaningful; no other chronic CF pulmonary therapy has demonstrated this magnitude of exacerbation risk reduction. Reduction of exacerbation risk is important because IV treated pulmonary exacerbations have been associated with reduced quality of life,[44] reduced physical capacity,[45,46] acceleration of lung function decline,[47,48] permanent loss of lung function,[49,50] and

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Cystic Fibrosis Foundation Confidential Materials 8/28/2015 decreased survival.[51-54] Further, treatment of exacerbations is associated with hearing loss,[55] increased risk of renal impairment,[56] and renal failure.[57,58]

Lumacaftor/Ivacaftor Safety

Safety Database

A total of 1108 persons with CF were included in the safety evaluation of lumacaftor/ivacaftor (738 of whom received lumacaftor/ivacaftor; 369 received 400 mg lumacaftor/250 mg ivacaftor BID, 369 600 mg lumacaftor QD/250 mg ivacaftor BID, and 370 patients received placebo).

Deaths, Serious Adverse Events, and Discontinuations due to Adverse Events

There were no deaths reported during studies 809-103 and 809-104. One death, however, was reported to have occurred during the uncontrolled safety extension termed study 809-105. This patient

was a 24 year old female with baseline FEV1 of approximately 50% predicted who had been randomized to receive 400 mg lumacaftor/250 mg IVA 250 mg BID in study 809-103 who developed a pulmonary exacerbation 175 days into the open-label extension. She was hospitalized for one week and discharged home on IV antibiotic therapy, where she worsened and was readmitted several days after discharge. Her status continued to worsen and she was placed on mechanical ventilation and transferred to another hospital where she was placed on extracorporeal membrane oxygenation therapy. She died of respiratory failure on day 197 of her participation in the extension study.

As is common with CF, most serious adverse events (SAEs), classified as events that are life- threatening or requiring hospitalization, were related to pulmonary exacerbations, which occurred in approximately 13% of patients who received lumacaftor/ivacaftor therapy and 24% of patients who received placebo. Other SAEs occurred relatively infrequently (< 2% in any group) and included hemoptysis and distal intestinal obstruction syndrome (again typical of CF). An additional patient who received 400 mg lumacaftor/250 mg ivacaftor was reported to have hepatic encephalopathy.

Thirty-seven patients (3.3%) discontinued treatment due to an adverse event during the 24-week placebo-controlled studies. Adverse events leading to treatment discontinuation were more common in the LUM/IVA treatment groups compared to placebo groups (4.2% vs 1.6%). This difference was driven by small increases above placebo in the several AEs such as bronchospasm (0.3% vs 0%), dyspnea (0.3% vs 0%), and blood CPK increased (0.5% vs 0%).

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Specific Safety Concerns

Liver-related safety concerns have been noted previously for ivacaftor monotherapy in persons with CF and G551D CFTR mutations.[58] While there were no differences between lumacaftor/ivacaftor treatment groups compared to placebo in overall adverse events thought to be liver related (5.4-6.0% across treatment groups), more patients receiving lumacaftor/ivacaftor had liver-related adverse events that were classified as SAEs or resulted in discontinuation from treatment (0.9% and 0.5% for lumacaftor/ivacaftor vs 0.0% for placebo). There were no discernable differences in aspartate transaminase (AST) or alanine transaminase (ALT) elevations alone between treatment groups, however, three patients receiving lumacaftor/ivacaftor (0.4%) had both ALT or AST elevations >3 times the upper limit of normal as well as total bilirubin elevations >2 times the upper limit of normal; no patients who received placebo were observed to have these sort of elevations. Overall, the hepatic safety analyses indicate that lumacaftor/ivacaftor treatment may be associated with liver-related adverse events as there were more SAEs, AEs leading to discontinuation, and transaminase elevations associated with bilirubin elevations in CF. For these reasons, lumacaftor/ivacaftor prescribing information suggests caution be exercised when treating patients with advanced liver disease, including close monitoring after treatment initiation and dose reduction.[35] The prescribing information also notes the potential for drug-drug interactions with lumacaftor/ivacaftor, stating that “use with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index may decrease systemic exposure of the medicinal products and co-administration is not recommended. Hormonal contraceptives should not be relied upon as an effective method of contraception and their use is associated with increased menstruation-related adverse reactions. Use with strong CYP3A inducers may diminish exposure of ivacaftor, which may diminish its effectiveness; therefore, co-administration is not recommended.”[35]

As a result of dose-dependent decrease in pulmonary function observed in patients who received lumacaftor monotherapy, Vertex performed a safety analysis grouping together respiratory-related adverse events. CF patients who received lumacaftor/ivacaftor had an increased frequency of respiratory symptoms (particularly dyspnea and abnormal respiration) at frequencies of 23% and 10% compared to 8% and 3% in patients who received placebo, respectively (Table 6). Three of the events among lumacaftor/ivacaftor treated patients lead to treatment discontinuation compared to none in the placebo group; two of these events were reported as SAEs. These drug-related respiratory AEs/SAEs tended to occur early after initiating therapy (median time to onset was about 2 days). These data suggest that treatment with lumacaftor/ivacaftor can cause increased respiratory symptoms and AEs in some CF patients that can be severe enough to cause treatment discontinuation or thought to be life-threatening of require hospitalization (SAE). The lumacaftor/ivacaftor prescribing information states that “chest

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Cystic Fibrosis Foundation Confidential Materials 8/28/2015 discomfort, dyspnea, and respiration abnormal” were observed more commonly during treatment initiation, as well as that clinical experience in patients with FEV1 <40% predicted is limited and that additional monitoring of these patients is recommended during initiation of therapy.

Treating clinicians should also be aware of an elevated risk of cataracts with lumacaftor/ivacaftor. Non-congenital lens opacities/cataracts have been reported in pediatric patients receiving ivacaftor monotherapy (Kalydeco®). For this reason, baseline and follow-up examinations are recommended in pediatric patients initiating lumacaftor/ivacaftor treatment.[35]

Common Adverse Events

Common adverse events are listed in Table 6. Most AEs are reflective of what would be expected in individuals with CF and show little difference between placebo and lumacaftor/ivacaftor treatment, with the exception of dyspnea, abnormal respiration, flatulence, and rash favoring placebo and pulmonary exacerbation and pulmonary function test decreased favoring ivacaftor/lumacaftor treatment.

Table 6. Adverse Events occurring in >5% of patients and in greater proportions in lumacaftor/ivacaftor-treated patients than in placebo-treated patients

LUM600/ LUM400/ All Placebo IVA250 IVA250 LUM/IVA N=370 N=369 N=369 N=738 Headache 58 (15.7) 58 (15.7) 58 (15.7) 116 (15.7) Dyspnea* 29 (7.8) 55 (14.9) 48 (13.0) 103 (14.0) Hemoptysis 50 (13.5) 52 (14.1) 50 (13.6) 102 (13.8) Diarrhea 31 (8.4) 36 (9.8) 45 (12.2) 81 (11.0) Nausea 28 (7.6) 29 (7.9) 46 (12.5) 75 (10.2) Respiration abnormal* 22 (5.9) 40 (10.8) 32 (8.7) 72 (9.8) Oropharyngeal pain 30 (8.1) 44 (11.9) 24 (6.5) 68 (9.2) Pyrexia 34 (9.2) 35 (9.5) 33 (8.9) 68 (9.2) Upper respiratory tract infection 20 (5.4) 24 (6.5) 37 (10.0) 61 (8.3) Viral upper respiratory tract infection 25 (6.8) 28 (7.6) 23 (6.2) 51 (6.9) Flatulence* 11 (3.0) 20 (5.4) 24 (6.5) 44 (6.0) Blood CPK increased 20 (5.4) 14 (3.8) 27 (7.3) 41 (5.6) Rash* 7 (1.9) 16 (4.3) 25 (6.8) 41 (5.6) Sinusitis 19 (5.1) 24 (6.5) 16 (4.3) 40 (5.4) Rhinorrhea 15 (4.1) 17 (4.6) 21 (5.7) 38 (5.1) Vomiting 11 (3.0) 21 (5.7) 16 (4.3) 37 (5.0) Influenza 8 (2.2) 16 (4.3) 19 (5.1) 35 (4.7) Constipation 21 (5.7) 12 (3.3) 14 (3.8) 26 (3.5)

*-significantly more common among patients treated with lumacaftor/ivacaftor

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CF Populations Likely to Benefit from Lumacaftor/Ivacaftor

Lumacaftor/ivacaftor has been approved by the US Food and Drug Administration for the management of persons with CF 12 years of age and older who carry two copies of the F508del CFTR mutation. In vitro and in vivo studies of lumacaftor/ivacaftor conducted to date suggest that individuals with CF and only a single F508del mutation are unlikely to experience clinical benefit from the treatment. The safety and efficacy of lumacaftor/ivacaftor in persons with CF who carry two copies of the F508del CFTR mutation but are less than 12 years of age has yet to be demonstrated in randomized controlled clinical trials. However, there is no biochemical/physiologic basis to assume that younger individuals would not have the potential to benefit from lumacaftor/ivacaftor, as its pharmacologic target (reduced F508del CFTR function) is present from birth.

Although Studies 809-103 and 809-104 excluded individuals within the indicated population who presented with specific additional conditions, such as chronic Burkholderia cenocepacia, B. dolosa, or Mycobacterium abscessus airway infection, these were pragmatic exclusions introduced by the sponsor to reduce response variance across safety and efficacy measures. There is absolutely no basis to conclude that individuals with CF and these chronic infections would not benefit from lumacaftor/ivacaftor. Given individuals with these chronic infections are at increased risk for accelerated disease progression and increased mortality, their potential for real clinical benefit may actually exceed those of their uninfected peers. Similarly, although patients treated recently for pulmonary exacerbations were excluded from study enrollment to ensure clinically stability at treatment initiation, there is no basis to conclude that individuals with CF and two F508del CFTR alleles who are also prone to frequent pulmonary exacerbations would not benefit from lumacaftor/ivacaftor. Again, the increased morbidity and mortality risks associated with pulmonary exacerbations and the significant reduction in pulmonary exacerbations associated with lumacaftor/ivacaftor treatment suggest that these patients have great potential for treatment benefit.

The primary clinical benefit shown to be associated with lumacaftor/ivacaftor administration in

studies 809-130 and 809-104 was sustained improvement in pulmonary function as measured by FEV1.

This observation would suggest that patients who have evidence of FEV1 decline and/or who have been

identified as at substantial risk for immediate future FEV1 decline have the greatest potential for lumacaftor/ivacaftor benefit. However, it is important to note that younger CF patients with essentially

‘normal’ lung function are at higher risk of rapid near-term FEV1 loss than their peers who have already experienced substantial lung function decline.[47] That, coupled with strong evidence that CF lung disease begins shortly after birth,[16-18,20] suggests that individuals with CF and two copies of the

F508del CFTR mutation with apparently ‘normal’ lung function (i.e., FEV1 >90% of their predicted

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value) will experience a meaningful delay of lung disease progression (which is evident before FEV1 loss;[14-18]) with lumacaftor/ivacaftor therapy. Finally, because mortality risk has been shown to

increase two-fold with every 10% predicted loss of FEV1 in persons with CF,[40] individuals with very low lung function (i.e., with FEV1 <40% predicted) can be considered to have the greatest immediate medical need for agents that can slow or stop lung disease progression, and there is every reason to consider treatment of these individuals.

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