Start ORKAMBI today. INDICATIONS AND USAGE IMPORTANT SAFETY INFORMATION. Sydney Age 4

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1 F O R H E A L T H C A R E P R O F E S S I O N A L S For ptients ge 2 yers nd older who re homozygous for the F508del muttion 1,2 Modify the course. Strt tody. Sydney Age 4 F508del/F508del INDICATIONS AND USAGE is combintion of lumcftor nd ivcftor indicted for the tretment of cystic fibrosis (CF) in ptients ge 2 yers nd older who re homozygous for the F508del muttion in the CFTR gene. If the ptient s genotype is unknown, n FDA-clered CF muttion test should be used to detect the presence of the F508del muttion on both lleles of the CFTR gene. Limittions of Use The efficcy nd sfety of hve not been estblished in ptients with CF other thn those homozygous for the F508del muttion. Use in Ptients With Advnced Liver Disese Worsening of liver function, including heptic encephlopthy, in ptients with dvnced liver disese hs been reported. Liver function decompenstion, including liver filure leding to deth, hs been reported in CF ptients with pre-existing cirrhosis with portl hypertension while receiving. Use with cution in ptients with dvnced liver disese nd only if the benefits re expected to outweigh the risks. If is used in these ptients, they should be closely monitored fter the initition of tretment nd the dose should be reduced

2 Importnt Sfety Informtion Importnt Sfety Informtion USE IN PATIENTS WITH ADVANCED LIVER DISEASE Worsening of liver function, including heptic encephlopthy, in ptients with dvnced liver disese hs been reported. Liver function decompenstion, including liver filure leding to deth, hs been reported in CF ptients with pre-existing cirrhosis with portl hypertension while receiving (lumcftor/ivcftor). Use with cution in ptients with dvnced liver disese nd only if the benefits re expected to outweigh the risks. If is used in these ptients, they should be closely monitored fter the initition of tretment nd the dose should be reduced LIVER-RELATED EVENTS Serious dverse rections relted to elevted trnsminses hve been reported in ptients with CF receiving. In some instnces, these elevtions hve been ssocited with concomitnt elevtions in totl serum bilirubin It is recommended tht ALT, AST, nd bilirubin be ssessed prior to inititing, every 3 months during the first yer of tretment, nd nnully therefter. For ptients with history of ALT, AST, or bilirubin elevtions, more frequent monitoring should be considered. Ptients who develop incresed ALT, AST, or bilirubin should be closely monitored until the bnormlities resolve Dosing should be interrupted in ptients with ALT or AST greter thn 5 x upper limit of norml (ULN) when not ssocited with elevted bilirubin. Dosing should lso be interrupted in ptients with ALT or AST elevtions greter thn 3 x ULN when ssocited with bilirubin elevtions greter thn 2 x ULN. Following resolution of trnsminse elevtions, consider the benefits nd risks of resuming dosing RESPIRATORY EVENTS Respirtory events (e.g., chest discomfort, dyspne, nd respirtion bnorml) were observed more commonly in ptients during initition of compred to those who received plcebo. These events hve led to drug discontinution nd cn be serious, prticulrly in ptients with dvnced lung disese (percent predicted FEV 1 (ppfev 1 ) <40). Clinicl experience in ptients with ppfev 1 <40 is limited, nd dditionl monitoring of these ptients is recommended during initition of therpy EFFECT ON BLOOD PRESSURE Incresed blood pressure hs been observed in some ptients treted with. Blood pressure should be monitored periodiclly in ll ptients being treted with DRUG INTERACTIONS Substrtes of CYP3A Lumcftor is strong inducer of CYP3A. Administrtion of (lumcftor/ivcftor) my decrese systemic exposure of medicinl products tht re substrtes of CYP3A, which my decrese therpeutic effect. Co-dministrtion with sensitive CYP3A substrtes or CYP3A substrtes with nrrow therpeutic index is not recommended my substntilly decrese hormonl contrceptive exposure, reducing their effectiveness nd incresing the incidence of menstrution-ssocited dverse rections, e.g., menorrhe, dysmenorrhe, menorrhgi, menstrul irregulr. Hormonl contrceptives, including orl, injectble, trnsderml, nd implntble, should not be relied upon s n effective method of contrception when co-dministered with Strong CYP3A Inducers Ivcftor is substrte of CYP3A4 nd CYP3A5 isoenzymes. Use of with strong CYP3A inducers, such s rifmpin, significntly reduces ivcftor exposure, which my reduce the therpeutic effectiveness of. Therefore, co-dministrtion with strong CYP3A inducers is not recommended CATARACTS Cses of non-congenitl lens opcities hve been reported in peditric ptients treted with nd ivcftor, component of. Although other risk fctors were present in some cses (such s corticosteroid use nd exposure to rdition), possible risk ttributble to ivcftor cnnot be excluded. Bseline nd follow-up ophthlmologicl exmintions re recommended in peditric ptients inititing tretment with ADVERSE REACTIONS Serious dverse rections, whether considered drug-relted or not by the investigtors, tht occurred more frequently in ptients treted with included pneumoni, hemoptysis, cough, incresed blood cretine phosphokinse, nd trnsminse elevtions. These occurred in 1% or less of ptients The most common dverse rections in ptients ge 12 yers nd older in Phse 3 trils (Trils 1 nd 2) occurring in 5% of ptients treted with (N=369) vs plcebo (N=370) nd t rte higher thn plcebo were dyspne, nsophryngitis, nuse, dirrhe, upper respirtory trct infection, ftigue, respirtion bnorml, blood cretine phosphokinse incresed, rsh, fltulence, rhinorrhe, nd influenz The sfety profile in ptients ge 6 through 11 yers from n open-lbel Phse 3 tril (Tril 3; N=58) nd plcebo-controlled Phse 3 tril (Tril 4; ptients treted with, N=103 vs plcebo, N=101) ws similr to tht observed in Trils 1 nd 2. Additionl common dverse rections were reported in Tril 4, but were not reported in Trils 1 nd 2. The dverse rections in Tril 4 tht occurred in 5% of ptients treted with with n incidence of 3% higher thn plcebo included: productive cough, nsl congestion, hedche, bdominl pin upper, nd sputum incresed. The sfety profile in ptients ge 2 through 5 yers from n open-lbel Phse 3 tril (Tril 6; N=60) ws similr to tht in ptients ged 6 yers nd older Click here for full Prescribing Informtion. 2 3

3 Importnt Sfety Informtion 2-5 (lumcftor/ivcftor) ws studied in ptients ge 2 through 5 yers Ages 2-5 Study Design TRIAL 6 STUDY DESIGN 1,3 SELECTED BASELINE CHARACTERISTICS 3 SCREENING lumcftor 100 mg/ivcftor 125 mg q12h grnules (<14 kg; n=19) or lumcftor 150 mg/ivcftor 188 mg q12h grnules ( 14 kg; n=41) WASHOUT (lumcftor 100 mg/ ivcftor 125 mg q12h) n=19 (lumcftor 150 mg/ ivcftor 188 mg q12h) n=41 TOTAL N=60 Men ge, months (rnge) 31.6 (24-40) 49.9 (25-69) 44.1 (24-69) Dy -28 Bseline N=60 Week 24 Week 26 SwCl, mmol/l (rnge) ( ) ( ) ( ) BMI, kg/m 2 (rnge) ( ) ( ) ( ) Ptients remined on currently prescribed CF therpies (including during the wshout) 3 BMI z-score (rnge) ( ) 0.30 ( ) 0.17 ( ) KEY INCLUSION CRITERIA 3, Confirmed CF dignosis, F508del homozygous, cliniclly stble, 2 through 5 yers of ge Body weight 8 kg t screening PRIMARY ENDPOINT 3 Sfety nd tolerbility up to Week 24, including ssessments of dverse events, clinicl lbortory vlues, nd spirometry TRIAL 6 LIMITATIONS The study ws open lbel nd not plcebo controlled; therefore, cuslity cnnot be ttributed 3 All ptients in the study knew they were on ctive drug, which my hve introduced bis relted to wreness of tretment SELECTED SECONDARY ENDPOINTS 3 Absolute chnge from bseline t 24 weeks for: swet chloride level, b BMI, nd BMI z-score Key exclusion criteri included hemoglobin <10 g/dl; ALT, AST, or totl bilirubin >2 x ULN; bnorml renl function; n cute upper or lower respirtory infection, pulmonry excerbtion, or chnges in therpy (including ntibiotics) for pulmonry disese within 28 dys before Dy 1; nd history of ctrct/lens opcity or evidence of ctrct/lens opcity determined to be cliniclly significnt. 3 b Assessed t Week 24 nd t Week Use in Ptients With Advnced Liver Disese Worsening of liver function, including heptic encephlopthy, in ptients with dvnced liver disese hs been reported. Liver function decompenstion, including liver filure leding to deth, hs been reported in CF ptients with pre-existing cirrhosis with portl hypertension while receiving (lumcftor/ivcftor). Use with cution in ptients with dvnced liver disese nd only if the benefits re expected to outweigh the risks. If is used in these ptients, they should be closely monitored fter the initition of tretment nd the dose should be reduced ALT, lnine minotrnsferse; AST, sprtte minotrnsferse; BMI, body mss index; q12h, every 12 hours; SwCl, swet chloride; ULN, upper limit of norml. 4 5

4 2-5 Overview of sfety results from Tril 6 Ages 2-5 Study Design The sfety profile in Tril 6 ws similr to tht in ptients ged 6 yers nd older (see pges 16-19) 1 ADVERSE EVENT (Preferred Term) Respirtory symptom-relted dverse rections 4 TOTAL, N=60 N (%) Ptients with ny dverse event of specil interest of respirtory symptoms 3 (5.0) Dyspne 3 (5.0) DISCONTINUATIONS AND SERIOUS ADVERSE EVENTS Respirtion bnorml 1 (1.7) Sfety 3 ptients (5%) discontinued due to dverse events (3 with trnsminse elevtions) 1 4 ptients (6.7%) experienced serious dverse events (1 with gstroenteritis virl, 1 with constiption, nd 2 with infective pulmonry excerbtions of CF) 4 Medin time to onset of first event ws 2 dys nd medin durtion of the events ws 1.5 dys 4 No respirtory events led to tretment interruption or discontinution 4 Liver-relted dverse rections 1 ELEVATED ALT OR AST TOTAL, N=60 n (%) (ALT >3 x ULN) or (AST >3 x ULN) 9 (15.0) (ALT >5 x ULN) or (AST >5 x ULN) 7 (11.7) (ALT >8 x ULN) or (AST >8 x ULN) 5 (8.3) 1 ptient hd elevted totl bilirubin t bseline, but no elevtions were observed during the study. No ptients hd totl bilirubin levels >2 x ULN 1,4 3 ptients discontinued lumcftor/ivcftor tretment permnently due to trnsminse elevtions 1 Liver-relted Events Serious dverse rections relted to elevted trnsminses hve been reported in ptients with CF receiving (lumcftor/ivcftor). In some instnces, these elevtions hve been ssocited with concomitnt elevtions in totl serum bilirubin It is recommended tht ALT, AST, nd bilirubin be ssessed prior to inititing, every 3 months during the first yer of tretment, nd nnully therefter. For ptients with history of ALT, AST, or bilirubin elevtions, more frequent monitoring should be considered. Ptients who develop incresed ALT, AST, or bilirubin should be closely monitored until the bnormlities resolve Dosing should be interrupted in ptients with ALT or AST greter thn 5 x upper limit of norml (ULN) when not ssocited with elevted bilirubin. Dosing should lso be interrupted in ptients with ALT or AST elevtions greter thn 3 x ULN when ssocited with bilirubin elevtions greter thn 2 x ULN. Following resolution of trnsminse elevtions, consider the benefits nd risks of resuming dosing 6 7

5 2-5 Swet chloride results (phrmcodynmics) BMI z-score nd BMI results Secondry Endpoint: Absolute Chnge in Swet Chloride 5 Secondry Endpoint: Absolute Chnge in BMI z-score 5 Sfety Absolute Chnge in Swet Chloride From Bseline (mmol/l), Men (95% CI) n Bseline 56 Totl (N=60) Wk 4 45 Men bseline: mmol/l mmol/l Wshout Wk Wk mmol/l Absolute Chnge in BMI z-score From Bseline, Men (95% CI) n Bseline 60 Dy Totl (N=60) Wk 4 60 Wk 8 60 Men bseline: 0.17 Wk Wk Swet Chloride/ BMI z-score MEAN ABSOLUTE WITHIN-GROUP CHANGE IN SWEAT CHLORIDE From bseline t Week 24 (n=49): mmol/l (95% CI -35.7, -27.6) reduction 1,5 After wshout, from Week 24 to Week 26 (n=48): mmol/l (95% CI 28.9, 37.1) 1,5 There ws no direct correltion between decrese in swet chloride levels nd improvement in lung function (ppfev 1 ) 1 MEAN ABSOLUTE WITHIN-GROUP CHANGE IN BMI AND BMI z-score For BMI z-score from bseline t Week 24 (n=57): (95% CI 0.14, 0.45) 5 For BMI from bseline t Week 24 (n=57): (95% CI 0.07, 0.47) 5 Plese see pge 5 for Limittions of Tril 6 Plese see pge 5 for Limittions of Tril 6 Respirtory Events Respirtory events (e.g., chest discomfort, dyspne, nd respirtion bnorml) were observed more commonly in ptients during initition of (lumcftor/ivcftor) compred to those who received plcebo. These events hve led to drug discontinution nd cn be serious, prticulrly in ptients with dvnced lung disese (percent predicted FEV 1 (ppfev 1 ) <40). Clinicl experience in ptients with ppfev 1 <40 is limited, nd dditionl monitoring of these ptients is recommended during initition of therpy Effect on Blood Pressure Incresed blood pressure hs been observed in some ptients treted with (lumcftor/ivcftor). Blood pressure should be monitored periodiclly in ll ptients being treted with CI, confidence intervl; ppfev 1, percent predicted forced expirtory volume in 1 second. 8 9

6 2-5 (lumcftor/ivcftor) results Avilble s orl grnules SAFETY (PRIMARY ENDPOINT) THE ORAL GRANULES ARE SUPPLIED AS FOLLOWS 1 : 60 PATIENTS AGE 2 THROUGH 5 YEARS WERE STUDIED IN TRIAL 6 1 The sfety profile ws similr to tht in ptients ged 6 yers nd older 1 Serious dverse rections included gstroenteritis virl, constiption, nd infective pulmonry excerbtion of CF 4 DESCRIPTION OF SELECTED ADVERSE DRUG REACTIONS 3 ptients (5%) hd respirtory symptom-relted dverse events 4 No respirtory events led to tretment interruption/discontinution 56-count crton (contins 56 unit-dose pckets of lumcftor 100 mg/ivcftor 125 mg per pcket); NDC Swet Chloride/ BMI z-score 9 ptients (15%) hd elevted trnsminses (>3 x ULN) 4 3 ptients (5%) discontinued from the study, ll due to trnsminse elevtions 4 SUMMARY OF SELECTED SECONDARY ENDPOINT RESULTS Not ctul size. MEAN ABSOLUTE CHANGE FROM BASELINE AT 24 WEEKS (WITHIN-GROUP) Swet chloride BMI z-score mmol/l (95% CI -35.7, -27.6) 1, (95% CI 0.14, 0.45) 5 56-count crton (contins 56 unit-dose pckets of lumcftor 150 mg/ivcftor 188 mg per pcket); NDC Ages 2-5 Summry LIMITATIONS Not ctul size. The study ws open lbel nd not plcebo controlled; therefore, cuslity cnnot be ttributed 3 All ptients in the study knew they were on ctive drug, which my hve introduced bis relted to wreness of tretment (lumcftor/ivcftor) orl grnules re smll white to off-white grnules 10 11

7 (lumcftor/ivcftor) ws studied in over 250 ptients ge 6 through 11 yers TRIAL 3 PHASE 3, OPEN-LABEL SAFETY STUDY 1,6,7 24 WEEKS (FOLLOWED BY 2-WEEK WASHOUT) lumcftor 200 mg/ivcftor 250 mg q12h (n=58) WASHOUT All ptients in this study remined on currently prescribed CF therpies (including during the wshout) KEY INCLUSION CRITERIA Confirmed CF dignosis, F508del homozygous, cliniclly stble, 6 through 11 yers of ge Percent predicted FEV 1 40% PRIMARY ENDPOINT Sfety nd tolerbility, including ssessments of dverse events, clinicl lbortory vlues, nd spirometry (FEV 1 ) up to 24 weeks ADDITIONAL ASSESSMENTS 7 Absolute chnge in swet chloride: -From bseline t Dy 15 nd t Week 24 -From Week 24 t Week 26 (wshout period) TRIAL 4 PHASE 3, DOUBLE-BLIND, PLACEBO-CONTROLLED EFFICACY AND SAFETY STUDY 2,8 24 WEEKS lumcftor 200 mg/ivcftor 250 mg q12h (n=103) Plcebo q12h (n=101) All ptients in this study remined on currently prescribed CF therpies KEY INCLUSION CRITERIA b Confirmed CF dignosis, F508del homozygous, cliniclly stble, 6 through 11 yers of ge Screening LCI 2.5 score 7.5 Percent predicted FEV 1 70% PRIMARY ENDPOINT Absolute chnge in LCI 2.5 from bseline through Week 24 ADDITIONAL ASSESSMENTS* Key Secondry Endpoints Absolute chnge from bseline in: Swet chloride (verge t Dy 15 nd t Week 4) BMI t Week 24 CFQ-R Respirtory Domin score through Week 24 Other Secondry Endpoints (selected) Absolute chnge from bseline: In ppfev 1 through Week 24 In BMI z-score t Week 24 8 In swet chloride t Week 24 8 EXTENSION STUDY OPEN-LABEL EXTENSION OF TRIALS 3 AND 4 9 All ptients in this study remined on currently prescribed CF therpies Key exclusion criteri included history of coloniztion with orgnisms such s Burkholderi cenocepci, Burkholderi dolos, or Mycobcterium bscessus, or 3 or more bnorml liver function tests (ALT, AST, ALP, GGT 3 x ULN, or totl bilirubin 2 x ULN), ALT or AST >5 x ULN, or bilirubin >2 x ULN. 1,6 b Key exclusion criteri included 2 or more bnorml liver function tests (AST, ALT, GGT, ALP 3 x ULN), ALT or AST >5 x ULN, or bilirubin >2 x ULN WEEKS Continued ( ) lumcftor 200 mg/ivcftor 250 mg q12h c Strted (Plcebo ) lumcftor 200 mg/ivcftor 250 mg q12h c c Subjects who turned 12 yers of ge on or before Dy 1 of the Tril 3 ension Study begn receiving lumcftor 400 mg/ivcftor 250 mg q12h on Dy 1. Subjects who turned 12 yers of ge fter the Dy 1 visit of the Tril 3 ension Study begn receiving lumcftor 400 mg/ivcftor 250 mg q12h t their next scheduled visit. 9 d Key exclusion criteri included: LFT bnormlity in the previous study for which cler cuse ws not identified, defined s 2 or more tests of AST, ALT, GGT, or ALP 3 x ULN, ALT or AST >5 x ULN, totl bilirubin >2 x ULN, or other LFT bnormlities tht would hve posed n dditionl risk; or poor complince in the previous study (Trils 3 or 4). 9 e Bseline for the ension Study is defined s bseline from Trils 3 or 4. 9 GGT, gmm glutmyltrnsferse; LCI, lung clernce index; LFT, liver function test. KEY INCLUSION CRITERIA d Completed Tril 3 (including wshout) or Tril 4 PRIMARY ENDPOINT Sfety nd tolerbility of long-term tretment, including ssessments of dverse events, clinicl lbortory vlues, nd spirometry from bseline[superscript e] ADDITIONAL ASSESSMENTS Key Secondry Endpoints Absolute chnge from bseline in e : LCI 2.5 Swet chloride BMI CFQ-R Respirtory Domin score Selected Other Secondry Endpoints Absolute chnge in: - ppfev 1 - BMI z-score Ages Study Designs * Power for secondry endpoints, including key secondry endpoints, ws limited. Anlysis of secondry endpoints ws not djusted for multiplicity 2 CFQ-R, Cystic Fibrosis Questionnire-Revised

8 Limittions nd disclosures Bseline chrcteristics of Trils 3 nd 4 LIMITATIONS OF TRIAL 3 The study ws open lbel nd not plcebo controlled 7 ; therefore, cuslity cnnot be ttributed to drug effect LIMITATIONS OF THE EXTENSION STUDY The following trils for (lumcftor/ivcftor) were conducted in different ptient popultions nd re not ment to be comprtive BASELINE CHARACTERISTICS TRIAL 3 24 WEEKS 1,7,12 TRIAL 4 24 WEEKS 13 The study ws open lbel nd not plcebo controlled; therefore, cuslity cnnot be ttributed to drug effect 10 (n=58) (n=103) Plcebo (n=101) All ptients in the study knew they were on ctive drug, which my hve introduced bis relted to wreness of tretment 10 Sex, femle, % Enrollment in the ension Study ws limited only to those ptients who met strict inclusion criteri, completed Trils 3 or 4, nd elected to enroll in the ension Study 9 Men ge, yers (rnge) 9.1 (6-12) 8.7 (6-12) 8.9 (6-12) Rre dverse events my not hve been detected 11 Men percent predicted FEV 1 (rnge) 91.4 ( ) 88.8 (48.9.6) 90.7 ( ) Men swet chloride, mmol/l (rnge) ( ) ( ) ( ) ADDITIONAL DISCLOSURES The Tril 4 efficcy results nd the ension Study re not included in the pproved full Prescribing Informtion, nd the FDA did not consider either study in pproving (lumcftor/ivcftor) Men LCI 2.5 score (rnge) Men BMI z-score (rnge) 10.3 ( ) (-1.93 to 2.35) 14 (-3.24 to 1.54) ( ) (-2.51 to 1.73) The ension Study my not meet the FDA definition of n dequte nd well-controlled study due to its study design At bseline in Tril 4, 97.1% of ptients treted with hd bnorml LCI 2.5 ( 7.5); men percent predicted FEV 1 ws ,13 Ages Study Designs PATIENTS FROM TRIALS 3 AND 4 WERE ELIGIBLE TO ENROLL IN THE EXTENSION STUDY Of 262 eligible ptients from Trils 3 nd 4, 240 (91.6%) enrolled in the ension Study 9 96 previously received plcebo nd 143 previously received Use in Ptients With Advnced Liver Disese Worsening of liver function, including heptic encephlopthy, in ptients with dvnced liver disese hs been reported. Liver function decompenstion, including liver filure leding to deth, hs been reported in CF ptients with pre-existing cirrhosis with portl hypertension while receiving. Use with cution in ptients with dvnced liver disese nd only if the benefits re expected to outweigh the risks. If is used in these ptients, they should be closely monitored fter the initition of tretment nd the dose should be reduced Dt re reported for 239 ptients who received t lest 1 dose of 9 Limittions nd Disclosures/ Bseline Chrcteristics 14 15

9 Sfety profile: Trils 3, 4, nd the ension Study Limittions nd Disclosures/ Bseline Chrcteristics DISCONTINUATIONS DUE TO ADVERSE EVENTS Tril 3: 3.4% (n=2); due to elevted liver trnsminses (1) nd rsh (1) 7 Tril 4: 3% (n=3) in the (lumcftor/ivcftor) group due to respirtion bnorml (1) nd elevted trnsminses (2); 2% (n=2) in the plcebo groupboth were due to elevted trnsminses 2 ension Study: 3.8% (n=9); Plcebo " : urticri nd hot flush (1), elevted AST, ALT (4), utoimmune heptitis (1), nd CF heptic disese (1). " : gstrointestinl disorder (bdominl pin dirrhe/vomiting) (1), FEV 1 decresed, respirtion bnorml, sthm (1) 15 SERIOUS ADVERSE REACTIONS Tril 3: 6.9% (n=4); included infective pulmonry excerbtion (2), ileus (1), nd elevted liver trnsminse levels (1) 7 Tril 4: 13% (n=13) in the group hd serious dverse events, of which 2 (1 drug interction nd 1 obstructive irwy disorder) were considered tretment relted. 11% (n=11) in the plcebo group hd serious dverse events, of which 3 (1 DIOS nd 2 elevted minotrnsferses) were considered tretment relted 2 ension Study: 30.2% (n=29) of ptients in the plcebo " group nd 30.1% (n=43) in the " group hd t lest 1 serious dverse event. 8 hd serious dverse events considered relted to study drug. Infective pulmonry excerbtions of cystic fibrosis occurred in 15.6% (n=15) of ptients in the plcebo " group nd 23.8% (n=34) of ptients in the " group % (n=2) of ptients hd t lest 1 dverse event of elevted trnsminses. The overll nture nd incidence of liver events were consistent with Trils 3 nd 4 3.8% (n=9) of ptients hd ctrcts/lens opcities, which were not considered visully significnt nd did not led to study drug interruption or discontinution. All lens findings were either present t Tril 3 or 4 bseline, resolved with continued tretment, or hd confounding risk fctors (e.g., corticosteroid use or fmily history) There ws 1 cse of utoimmune heptitis tht ws ssessed s severe nd relted to study drug No cliniclly importnt trends were observed on electrocrdiogrphy, pulse oximetry, ophthlmologic exmintions, or vitl signs Plese see pge 14 for Limittions nd Disclosures of Trils 3, 4, nd the ension Study These trils were conducted in different ptient popultions nd re not ment to be comprtive PARAMETER PCS/CATEGORICAL CRITERIA Liver-relted dverse rections TRIAL 3 24 WEEKS n/n (%) 7 TRIAL 3 24 WEEKS n/n (%) 1,7 TRIAL 4 24 WEEKS n/n (%) 16 ALT or AST Plcebo In Trils 3 nd 4 nd the ension Study, no ptients hd n increse in totl bilirubin levels >2 x ULN 1,11,15,16 In the ension Study, 3 ptients hd other liver-relted events, including 2 dverse events of heptitis nd 1 serious dverse event of utoimmune heptitis 15 TRIAL 4 24 WEEKS n/n (%) 2,16 Plcebo EXTENSION STUDY n/n (%) 15 g EXTENSION STUDY n/n (%) 15 g Plcebog >8 x ULN 3/57 (5.3) 1/103 (1.0) 2/101 (2.0) 5/143 (3.5) 4/96 (4.2) >5 x ULN 5/57 (8.8) 5/103 (4.9) 3/101 (3.0) 9/143 (6.3) 7/96 (7.3) >3 x ULN 11/57 (19.3) 13/103 (12.6) 8/101 (7.9) 27/143 (18.9) 17/96 (17.7) Discontinution due to trnsminse elevtions Potentilly Cliniclly Significnt (PCS) Lbortory Tests 1/57 (1.8) 2/103 (1.9) 2/101 (2.0) 0/143 (0) 4/96 (4.2) Respirtory dverse rections Incidence of Respirtory Symptom-Relted Adverse Rections Plcebog Totl incidence 2/58 (3.0) 11/103 (11) 9/101 (9) 21/143 (14.7) 23/96 (24.0) Dyspne 1/58 (1.7) 5/103 (5) 5/101 (5) 4/143 (2.8) 6/96 (6.3) Respirtion bnorml 1/58 (1.7) 6/103 (6) 4/101 (4) 7/143 (4.9) 7/96 (7.3) Chest discomfort 0/58 (0) 0/103 (0) 1/101 (1) 2/143 (1.4) 3/96 (3.1) Number of subjects with t lest one mesurement during the period from initition of study drug to 28 dys following lst dose. 7 DIOS, distl intestinl obstruction disorder. Sfety 16 17

10 Sfety profile: Trils 3, 4, nd the ension Study (cont) COMMON ADVERSE REACTIONS IN TRIAL 3 Most frequently observed tretment-emergent dverse events in 10% of ptients 17 Tril 3 Sfety Set. TEAE, tretment-emergent dverse event. TRIAL 3 24 WEEKS n=58 Any TEAEs, n (%) 55 (94.8) Cough 29 (50.0) Infective pulmonry excerbtion 12 (20.7) Nsl congestion 12 (20.7) Hedche 12 (20.7) Abdominl pin upper 8 (13.8) Sputum incresed 8 (13.8) ALT incresed 7 (12.1) Pyrexi 6 (10.3) Vomiting 6 (10.3) Abdominl pin 6 (10.3) Ftigue 6 (10.3) Nuse 6 (10.3) COMMON ADVERSE REACTIONS IN TRIAL 4 Most frequently observed tretment-emergent dverse events in 5% of ptients in the rm nd 3% higher thn plcebo 16 n=103 TRIAL 4 b 24 WEEKS Plcebo n=101 Any TEAEs, n (%) 98 (95.1) 98 (97.0) Productive cough 18 (17.5) 6 (5.9) Nsl congestion 17 (16.5) 8 (7.9) Orophryngel pin 15 (14.6) 10 (9.9) Hedche 13 (12.6) 9 (8.9) Abdominl pin upper 13 (12.6) 7 (6.9) Sputum incresed 11 (10.7) 2 (2.0) Rhinorrhe 10 (9.7) 5 (5.0) Rsh 6 (5.8) 1 (1.0) b Tril 4 Sfety Set. COMMON ADVERSE REACTIONS IN THE EXTENSION STUDY Most frequently observed tretment-emergent dverse events in 10% of ptients 15 g n=143 EXTENSION STUDY Plcebog n=96 Any TEAEs, n (%) 142 (99.3) 94 (97.9) Cough 91 (63.6) 64 (66.7) Infective pulmonry excerbtion 75 (52.4) 43 (44.8) Pyrexi 45 (31.5) 27 (28.1) Upper respirtory trct infection 36 (25.2) 13 (13.5) Nsl congestion 34 (23.8) 21 (21.9) Orophryngel pin 32 (22.4) 18 (18.8) Vomiting 30 (21.0) 15 (15.6) Bcteril test positive 30 (21.0) 16 (16.7) Hedche 29 (20.3) 26 (27.1) Rhinorrhe 24 (16.8) 13 (13.5) ALT incresed 22 (15.4) 23 (24.0) Abdominl pin upper 22 (15.4) 20 (20.8) Nsophryngitis 21 (14.7) 16 (16.7) Virl upper respirtory trct infection 21 (14.7) 15 (15.6) Productive cough 19 (13.3) 15 (15.6) Sputum incresed 18 (12.6) 7 (7.3) Abdominl pin 17 (11.9) 19 (19.8) AST incresed 17 (11.9) 15 (15.6) Sinusitis 17 (11.9) 8 (8.3) Dirrhe 16 (11.2) 8 (8.3) Constiption 15 (10.5) 11 (11.5) Nuse 13 (9.1) 11 (11.5) Plese see pge 14 for Limittions nd Disclosures of Trils 3, 4, nd the ension Study Sfety Sfety profile in Trils 3 nd 4 ws similr to tht observed in ptients ge 12 yers nd older (see pges 32-34)

11 Improvements in lung function (LCI 2.5 ) through 24 weeks LCI 2.5 results for the ension Study Lung Function TRIAL 4 STATISTICALLY SIGNIFICANT IMPROVEMENT THROUGH WEEK 24 VS PLACEBO 2 EXTENSION STUDY LCI 2.5 CHANGES 19 Primry Endpoint: Absolute Chnge in LCI 2.5 From Bseline Through Week 24 2 Men Absolute Chnge in LCI 2.5 From Bseline Through ension Week 96 19, Absolute Chnge in LCI 2.5 LS Men (95% CI) (n=103) (P<0.0001) Bseline Dy 15 Week 4 Week 16 Week 24 Plcebo (n=101) -1.1 POINT Absolute Chnge From Bseline in LCI 2.5 LS Men (95% CI) Dy 1 Dy 15 Wk 4 Wk 24 (95% CI -1.49, -0.65) Plcebo Wk 48 (n=133) (n=101) Wk 96 n Plcebo n Adpted from Rtjen F et l. Lncet Respir Med. 2017;5(7): , with permission from Elsevier. Bseline ws from Tril 3 or Within-group LS men bsolute chnge in LCI 2.5 from bseline through Week 24 ws 0.1 (95% CI -0.2 to 0.3) for plcebo vs -1.0 (95% CI -1.3 to -0.8) for (lumcftor/ivcftor) 2,18 LCI is still considered n explortory endpoint in clinicl trils 18 Improvements in lung function re represented by negtive chnge in LCI 2 The ension Study included ptients from Tril 3, where LCI ws n explortory endpoint in subgroup (n=27) 7 g: point (95% CI -1.25, -0.45) LS men chnge from bseline 19, Plcebog: point (95% CI -1.33, -0.38) LS men chnge from bseline 19, Plese see pge 14 for Limittions nd Disclosures of Trils 3, 4, nd the ension Study Liver-relted Events Serious dverse rections relted to elevted trnsminses hve been reported in ptients with CF receiving. In some instnces, these elevtions hve been ssocited with concomitnt elevtions in totl serum bilirubin LS, lest squres. Liver-relted Events (cont) It is recommended tht ALT, AST, nd bilirubin be ssessed prior to inititing (lumcftor/ivcftor), every 3 months during the first yer of tretment, nd nnully therefter. For ptients with history of ALT, AST, or bilirubin elevtions, more frequent monitoring should be considered. Ptients who develop incresed ALT, AST, or bilirubin should be closely monitored until the bnormlities resolve Dosing should be interrupted in ptients with ALT or AST greter thn 5 x upper limit of norml (ULN) when not ssocited with elevted bilirubin. Dosing should lso be interrupted in ptients with ALT or AST elevtions greter thn 3 x ULN when ssocited with bilirubin elevtions greter thn 2 x ULN. Following resolution of trnsminse elevtions, consider the benefits nd risks of resuming dosing 20 21

12 Lung function (ppfev 1 ) through 24 weeks Lung Function Lung function (ppfev 1 ) results for the ension Study ppfev 1 TRIAL 3 ppfev 1 AT WEEK 24 (PART OF THE SAFETY ASSESSMENT) % point LS men bsolute chnge in ppfev % point LS men bsolute chnge in ppfev 1 from Week 24 t Week 26 (wshout) 7 EXTENSION STUDY ppfev 1 CHANGES 19 Men Absolute Chnge in ppfev 1 From Bseline Through ension Week 96 19, TRIAL 4 IMPROVEMENT IN ppfev 1 THROUGH WEEK 24 VS PLACEBO Plcebo (n=161) (n=101) Absolute Chnge in ppfev 1 (% points), LS Men (95% CI) Other Secondry Endpoint: Men Absolute Chnge in Percent Predicted FEV 1 From Bseline Through Week 24 2 (n=103) Plcebo (n=101) -5 Bseline Dy 15 Week 4 Week 8 Week 16 Week 24 Absolute Chnge From Bseline in ppfev 1 LS Men (95% CI) Dy 1 Dy 15 Wk 4 Wk 8 Wk 16 Wk 24 Wk 36 Wk 48 Wk 60 Wk 72 Wk 84 Wk 96 Bseline ws from Tril 3 or Adpted from Rtjen F et l. Lncet Respir Med. 2017;5(7): , with permission from Elsevier. +2.4% LS men bsolute improvement in ppfev 1 from bseline through Week 24 compred to plcebo 2 Power for secondry endpoints ws limited. Anlysis of secondry endpoints ws not djusted for multiplicity 2 Respirtory Events Respirtory events (e.g., chest discomfort, dyspne, nd respirtion bnorml) were observed more commonly in ptients during initition of (lumcftor/ivcftor) compred to those who received plcebo. These events hve led to drug discontinution nd cn be serious, prticulrly in ptients with dvnced lung disese (percent predicted FEV 1 (ppfev 1 ) <40). Clinicl experience in ptients with ppfev 1 <40 is limited, nd dditionl monitoring of these ptients is recommended during initition of therpy g: +3.1% point (95% CI 1.0, 5.1) LS men chnge from bseline 19, Plcebog: +0.0% point (95% CI -2.7, 2.7) LS men chnge from bseline 19, Plese see pge 14 for Limittions nd Disclosures of Trils 3, 4, nd the ension Study 22 23

13 Reductions in swet chloride through 24 weeks (phrmcodynmics) Swet chloride results for the ension Study (phrmcodynmics) Swet chloride TRIAL 3 SWEAT CHLORIDE WAS REDUCED AT WEEK 24 7 Absolute Chnge in Swet Chloride (mmol/l), Men (95% CI) Phrmcodynmics Assessment: Within-Group Absolute Chnge From Bseline in Swet Chloride Concentrtion 7 (n=58) mmol/l mmol/l -36 Wshout -40 Bseline Dy 15 Wk 4 Wk mmol/l LS men within-group improvement t Week 24 7 Wshout: mmol/l LS men within-group bsolute chnge from Week 24 t Week 26 7 EXTENSION STUDY SWEAT CHLORIDE RESULTS 19 Absolute Chnge in Swet Chloride From Bseline Through ension Week 96 19, Absolute Chnge From Bseline in Swet Chloride LS Men (95% CI) Plcebo (n=161) (n=101) Swet Chloride TRIAL 4 EARLY AND SUSTAINED REDUCTION IN SWEAT CHLORIDE THROUGH WEEK 24 VS PLACEBO 2,20 Absolute Chnge in Swet Chloride (mmol/l), LS Men (95% CI) Other Secondry Endpoint: Absolute Chnge From Bseline in Swet Chloride by 2,20 (n=103) Bseline Dy 15 Wk 4 Wk 16 Wk 24 Plcebo (n=101) Adpted from Rtjen F et l. Lncet Respir Med. 2017;5(7): , with permission from Elsevier mmol/l tretment difference in the verge bsolute chnge in swet chloride t Dy 15 nd Week 4 (secondry endpoint) mmol/l LS men bsolute chnge in swet chloride from bseline through Week 24 2,20 There ws no direct correltion between decrese in swet chloride levels nd improvement in lung function (percent predicted FEV 1 ) 1 Power for secondry endpoints ws limited. Anlysis of secondry endpoints ws not djusted for multiplicity 2-30 Dy 1 Dy 15 Bseline ws from Tril 3 or Wk 4 Wk 24 Wk 96 g: mmol/l (95% CI -25.5, -20.3) LS men chnge from bseline 19, Plcebog: mmol/l (95% CI -26.3, -19.3) LS men chnge from bseline 19, Plese see pge 14 for Limittions nd Disclosures of Trils 3, 4, nd the ension Study Effect on Blood Pressure Incresed blood pressure hs been observed in some ptients treted with (lumcftor/ ivcftor). Blood pressure should be monitored periodiclly in ll ptients being treted with Ctrcts Cses of non-congenitl lens opcities hve been reported in peditric ptients treted with nd ivcftor, component of. Although other risk fctors were present in some cses (such s corticosteroid use nd exposure to rdition), possible risk ttributble to ivcftor cnnot be excluded. Bseline nd follow-up ophthlmologicl exmintions re recommended in peditric ptients inititing tretment with 24 25

14 BMI through 24 weeks BMI results for the ension Study BMI TRIAL 3 RESULTS FOR BMI kg/m 2 LS men bsolute chnge in BMI from bseline t Week 24 7 EXTENSION STUDY BMI RESULTS THROUGH EXTENSION WEEK TRIAL 4 BMI RESULTS THROUGH 24 WEEKS 2 Absolute Chnge in BMI (kg/m 2 ), LS Men Secondry Endpoint: Absolute Chnge From Bseline in BMI by 2, (n=103) Bseline Dy 15 Wk 4 Wk 8 Wk 16 Wk 24 Adpted from Rtjen F et l. Lncet Respir Med. 2017;5(7): , with permission from Elsevier. Plcebo (n=101) Within-group BMI increse t Week 24 ws 0.4 kg/m 2 for (lumcftor/ivcftor) nd 0.3 kg/m 2 for plcebo 2 Power for secondry endpoints ws limited. Anlysis of secondry endpoints ws not djusted for multiplicity 2 Drug Interctions Substrtes of CYP3A Lumcftor is strong inducer of CYP3A. Administrtion of my decrese systemic exposure of medicinl products tht re substrtes of CYP3A, which my decrese therpeutic effect. Codministrtion with sensitive CYP3A substrtes or CYP3A substrtes with nrrow therpeutic index is not recommended my substntilly decrese hormonl contrceptive exposure, reducing their effectiveness nd incresing the incidence of menstrution-ssocited dverse rections, e.g., menorrhe, dysmenorrhe, menorrhgi, menstrul irregulr. Hormonl contrceptives, including orl, injectble, trnsderml, nd implntble, should not be relied upon s n effective method of contrception when co-dministered with Absolute Chnge From Bseline in BMI (kg/m 2 ) LS Men (95% CI) Absolute Chnge From Bseline in BMI Through ension Week 96 19, Dy 1 Dy 15 Bseline ws from Tril 3 or Wk 4 Wk 8 Wk 16 Wk 24 Wk 36 Plcebo Wk 48 Wk 60 (n=161) (n=101) Wk 72 g: kg/m 2 (95% CI 1.56, 1.99) chnge from bseline 19, Plcebog: kg/m 2 (95% CI 1.77, 2.31) chnge from bseline 19, Wk 84 Wk 96 Plese see pge 14 for Limittions nd Disclosures of Trils 3, 4, nd the ension Study Drug Interctions (cont) Strong CYP3A Inducers Ivcftor is substrte of CYP3A4 nd CYP3A5 isoenzymes. Use of with strong CYP3A inducers, such s rifmpin, significntly reduces ivcftor exposure, which my reduce the therpeutic effectiveness of. Therefore, co-dministrtion with strong CYP3A inducers is not recommended BMI 26 27

15 CFQ-R Respirtory Domin score (lumcftor/ivcftor) results RESULTS FOR CFQ-R RESPIRATORY DOMAIN SCORE SAFETY PROFILE 1 BMI CFQ-R Respirtory Domin Tril 3: +5.4 point (95% CI 1.4, 9.4) within-group men bsolute chnge from bseline through Week 24 7 Tril 4: +2.5 point (95% CI -0.1, 5.1) LS men tretment difference vs plcebo through Week 24. CFQ-R Respirtory Domin score ws ssessed s secondry endpoint 2 Within-group LS men bsolute chnge ws +5.5 points (95% CI 3.4, 7.6) for (lumcftor/ivcftor) nd +3.0 points (95% CI 1.0, 5.0) for plcebo Power for secondry endpoints ws limited. Anlysis of secondry endpoints ws not djusted for multiplicity ension Study: +7.4 point (95% CI 4.8, 10.0) increse from bseline through ension Week 96 in the g group nd +6.6 point (95% CI 3.1, 10.0) increse in the plcebog group 19 Ctrcts Cses of non-congenitl lens opcities hve been reported in peditric ptients treted with nd ivcftor, component of. Although other risk fctors were present in some cses (such s corticosteroid use nd exposure to rdition), possible risk ttributble to ivcftor cnnot be excluded. Bseline nd follow-up ophthlmologicl exmintions re recommended in peditric ptients inititing tretment with Adverse Rections Serious dverse rections, whether considered drug-relted or not by the investigtors, tht occurred more frequently in ptients treted with included pneumoni, hemoptysis, cough, incresed blood cretine phosphokinse, nd trnsminse elevtions. These occurred in 1% or less of ptients The most common dverse rections in ptients ge 12 yers nd older in Phse 3 trils (Trils 1 nd 2) occurring in 5% of ptients treted with (N=369) vs plcebo (N=370) nd t rte higher thn plcebo were dyspne, nsophryngitis, nuse, dirrhe, upper respirtory trct infection, ftigue, respirtion bnorml, blood cretine phosphokinse incresed, rsh, fltulence, rhinorrhe, nd influenz The sfety profile in ptients ge 6 through 11 yers from n open-lbel Phse 3 tril (Tril 3; N=58) nd plcebo-controlled Phse 3 tril (Tril 4; ptients treted with, N=103 vs plcebo, N=101) ws similr to tht observed in Trils 1 nd 2. Additionl common dverse rections were reported in Tril 4, but were not reported in Trils 1 nd 2. The dverse rections in Tril 4 tht occurred in 5% of ptients treted with with n incidence of 3% higher thn plcebo included: productive cough, nsl congestion, hedche, bdominl pin upper, nd sputum incresed. The sfety profile in ptients ge 2 through 5 yers from n open-lbel Phse 3 tril (Tril 6; N=60) ws similr to tht in ptients ged 6 yers nd older SAFETY PROFILE +2.5 PERCENTAGE POINTS within-group (prt of the sfety ssessment) 7, mmol/l within-group (phrmcodynmic ssessment) 7,,b +0.6 kg/m2 within-group (secondry endpoint) POINTS within-group (secondry endpoint) PATIENTS AGE 6 THROUGH 11 YEARS WERE STUDIED IN TRIALS 3 AND 4 1,2 TRIAL 3 (OPEN-LABEL SAFETY) Serious dverse rections included infective pulmonry excerbtions, ileus, nd elevted liver trnsminses 7 Most common dverse events (>10%) included cough, nsl congestion, infective pulmonry excerbtion, hedche, sputum incresed, bdominl pin upper, elevted lnine minotrnsferse levels, bdominl pin, nuse, vomiting, ftigue, nd pyrexi 7 TRIAL 3 (OPEN-LABEL SAFETY) TRIAL 4 (PLACEBO CONTROLLED) Serious dverse rections in the group included drug interction nd obstructive irwys disorder 2 Most common dverse events ( 5% for nd lso 3% higher thn plcebo) included productive cough, nsl congestion, orophryngel pin, sputum incresed, rhinorrhe, bdominl pin upper, hedche, nd rsh 16 SUMMARY OF OTHER RESULTS LS men bsolute chnge from bseline LCI 2.5 ppfev1 SWEAT CHLORIDE BMI CFQ-R RESPIRATORY DOMAIN TRIAL 4 (PLACEBO CONTROLLED) POINTS (P<0.0001) vs plcebo (primry endpoint) 2 PERCENTAGE POINTS vs plcebo (other secondry endpoint) 2 * mmol/l vs plcebo (secondry endpoint) 2,20 * +0.1 kg/m2 vs plcebo (secondry endpoint) 2 * +2.5 POINTS vs plcebo (secondry endpoint) 2 * EXTENSION STUDY 239 ptients continued for n dditionl 96 weeks. See pges for more informtion 9 ADDITIONAL LIMITATIONS AND DISCLOSURES The Tril 4 efficcy results nd the ension Study were not included in the pproved full Prescribing Informtion, nd the FDA did not consider either study in pproving The ension Study my not meet the FDA definition of n dequte nd well-controlled study due to its study design Plese see pge 14 for limittions nd disclosures of Trils 3, 4, nd the ension Study CFQ-R Respirtory Domin/ Ages Summry The results for percent predicted FEV 1 nd swet chloride re bsed on n uncontrolled, open-lbel study, nd therefore, hypothesis testing cnnot determine whether within-rm chnges were due to drug effect. There ws no direct correltion between decrese in swet chloride levels nd improvement in lung function (percent predicted FEV 1 ). 1 b Bseline is defined s the verge of the mesurements t screening nd on Dy 1 (predose) in Tril * Power for secondry endpoints in Tril 4, including key secondry endpoints, ws limited. Anlysis of secondry endpoints ws not djusted for multiplicity

16 12+ (lumcftor/ivcftor) studied in ptients ge 12 yers nd older 1,21-24 Trils 1 nd 2 in ptients ge 12 yers nd older (lumcftor/ivcftor) improved nd sustined lung function nd other key clinicl outcomes 1,21 TRIAL 1 Phse 3, Rndomized, Double-blind 24-WEEK TREATMENT lumcftor 400 mg/ivcftor 250 mg q12h (n=182) TRIAL 2 Phse 3, Rndomized, Double-blind 24-WEEK TREATMENT lumcftor 400 mg/ivcftor 250 mg q12h (n=187) In ech tril, hierrchicl testing procedure ws performed within ech ctive tretment rm for primry nd secondry endpoints vs plcebo. For n endpoint to be significnt, both it nd ll previous tests hd to chieve P ,21 The shded boxes in the tble below indicte which endpoints were sttisticlly significnt s confirmed by the hierrchicl testing procedure. Other efficcy mesures were not considered sttisticlly significnt The pooled nlysis for efficcy ws not pre-specified nd did not correct for multiple comprisons 1,21 TRIAL 1 1,21 TRIAL 2 1,21 POOLED 21 All ptients remined on currently prescribed CF therpies PRIMARY ENDPOINT Absolute chnge in ppfev 1 from bseline t Week 24 SELECTED SECONDARY ENDPOINTS Listed in order evluted by sttisticl nlyses hierrchy: Reltive chnge in ppfev 1, bsolute chnge in BMI, bsolute chnge in CFQ-R Respirtory Domin score, proportion of ptients with 5% reltive chnge in ppfev 1, nd number of pulmonry excerbtions POOLED ANALYSIS The sfety of ws evluted bsed on prespecified pooled nlysis A seprte pooled nlysis for efficcy ws not prespecified nd did not correct for multiple comprisons. Seprte nlyses of Trils 1 nd 2 were conducted to evlute efficcy KEY INCLUSION CRITERIA 12 yers old Confirmed CF dignosis Cliniclly stble F508del homozygous ppfev 1 40 to 90 t screening KEY EXCLUSION CRITERIA Plcebo (n=184) Plcebo (n=187) History of coloniztion with orgnisms such s Burkholderi cenocepci, Burkholderi dolos, or Mycobcterium bscessus 3 or more bnorml liver function tests (ALT, AST, AP, GGT 3 x ULN, or totl bilirubin 2 x ULN) 368 ptients received lumcftor 600 mg qd/ivcftor 250 mg q12h. The focus of the following dt is the pproved dose of : lumcftor 400 mg/ivcftor 250 mg q12h. 23 PRIMARY ENDPOINT Absolute chnge in percent predicted FEV 1 t Week 24 (percentge points) b KEY SECONDARY ENDPOINTS Reltive chnge in percent predicted FEV 1 t Week 24 (percentge) b Absolute chnge in BMI t Week 24 (kg/m 2 ) Absolute chnge in CFQ-R Respirtory Domin score t Week 24 (points) Proportion of ptients with 5% reltive chnge in percent predicted FEV 1 t Week 24 b Number of pulmonry excerbtions through Week 24 c Tretment difference (95% CI) Tretment difference (95% CI) Tretment difference (95% CI) Tretment difference (95% CI) (n=182) 2.6 (1.2, 4.0) P= (1.9, 6.8) P= (-0.1, 0.3) 1.5 (-1.7, 4.7) Plcebo (n=184) (n=187) b Assessed s the verge of the tretment effects t the Week 16 nd Week 24 time points. 1 Plcebo (n=187) (n=369) Plcebo (n=371) c A pulmonry excerbtion ws defined s new or chnge in ntibiotic therpy (IV, inhled, or orl) ssocited with 4 or more of the following 12 prespecified sinopulmonry signs/symptoms: chnge in sputum; new or incresed hemoptysis; incresed cough; incresed dyspne; mlise, ftigue, or lethrgy; temperture >38 C (100.4 F); norexi or weight loss; sinus pin or tenderness; chnge in sinus dischrge; chnge in physicl chest exm; decrese in pulmonry function by 10%; rdiogrphic chnges indictive of pulmonry infection. 21 IV, intrvenous. 3.0 (1.6, 4.4) P< (2.7, 7.8) P< (0.2, 0.5) P= (-0.3, 6.0) 2.8 (1.8, 3.8) 4.8 (3.0, 6.6) 0.2 (0.1, 0.4) 2.2 (0.0, 4.5) % 37% 22% 41% 23% 39% 22% Odds rtio (95% CI) No. of events (rte per 48 weeks) Rte rtio (95% CI) 2.1 (1.3, 3.3) 73 (0.7) 0.7 (0.5, 0.9) 112 (1.1) 2.4 (1.5, 3.7) 79 (0.7) 0.6 (0.4, 0.8) 139 (1.2) 2.2 (1.6, 3.1) 152 (0.7) 0.6 (0.5, 0.8) Use in Ptients With Advnced Liver Disese Worsening of liver function, including heptic encephlopthy, in ptients with dvnced liver disese hs been reported. Liver function decompenstion, including liver filure leding to deth, hs been reported in CF ptients with pre-existing cirrhosis with portl hypertension while receiving. Use with cution in ptients with dvnced liver disese nd only if the benefits re expected to outweigh the risks. If is used in these ptients, they should be closely monitored fter the initition of tretment nd the dose should be reduced 251 (1.1) Ages 12+ Study Designs 30 31

17 Trils 1 nd 2 in ptients ge 12 yers nd older Sfety demonstrted in >1100 ptients in two Phse 3 trils Ages 12+ Study Designs THE OVERALL SAFETY PROFILE OF (LUMACAFTOR/IVACAFTOR) IS BASED ON POOLED DATA FROM TRIALS 1 AND 2 1 Discontinutions due to dverse events 1 5%; plcebo 2% Serious dverse rections 1 Serious dverse rections, whether considered drug-relted or not by the investigtors, tht occurred more frequently in ptients treted with included those below. These occurred in 1% or less of ptients: Pneumoni Hemoptysis Incresed blood cretine phosphokinse Cough Trnsminse elevtions LIVER-RELATED ADVERSE REACTIONS 1 In Trils 1 nd 2, the incidence of mximum trnsminse (ALT or AST) levels >8, >5, nd >3 x ULN ws similr between ptients treted with (lumcftor/ivcftor) nd those who received plcebo Three ptients who received hd liver-relted serious dverse rections, including two reported s trnsminse elevtions nd one s heptic encephlopthy, compred to none in the plcebo group Of these three, one hd elevted trnsminses (>3 x ULN) ssocited with bilirubin elevtion >2 x ULN. Following discontinution or interruption of, trnsminses decresed to <3 x ULN Among six ptients with pre-existing cirrhosis nd/or portl hypertension who received, worsening liver function with incresed ALT, AST, bilirubin, nd heptic encephlopthy ws observed in one ptient The event occurred within 5 dys of the strt of dosing nd resolved following discontinution of RESPIRATORY ADVERSE REACTIONS In Trils 1 nd 2, the incidence of respirtory symptom-relted dverse rections (i.e., chest discomfort, dyspne, nd respirtion bnorml) ws more common in ptients treted with (22%) compred to ptients who received plcebo (14%) 1 Respirtion bnorml (chest tightness): (9%) vs plcebo (6%) Dyspne: (13%) vs plcebo (8%) The incidence of these dverse rections ws more common in ptients treted with with lower pre-tretment FEV 1 Most respirtory symptom-relted dverse events occurred within the first week of tretment nd resolved within 2 weeks 21 During 24-week, open-lbel, Phse 3b clinicl tril in 46 ptients ged 12 yers nd older (Tril 5) with dvnced lung disese (ppfev 1 <40) [men ppfev t bseline (rnge: 18.3 to 42.0)], the incidence of respirtory symptom relted dverse rections ws 65% 1 MENSTRUAL ABNORMALITIES 1 In Trils 1 nd 2, the incidence of combined menstrul bnormlity dverse rections (e.g., menorrhe, dysmenorrhe, menorrhgi, menstrul irregulr) ws more common in femle ptients treted with (10%) compred to plcebo (2%) These events occurred more frequently in the subset of femle ptients treted with who were using hormonl contrceptives (27%) compred to those not using hormonl contrceptives (3%) Trils 1 nd 2 Sfety INCREASED BLOOD PRESSURE 1 In Trils 1 nd 2, dverse rections relted to increses in blood pressure (e.g., hypertension, blood pressure incresed) were reported in 1.1% (4/369) of ptients treted with nd in no ptients who received plcebo The proportion of ptients who experienced systolic blood pressure vlue >140 mm Hg or distolic blood pressure >90 mm Hg on t lest two occsions ws 3.6% nd 2.2%, respectively, in ptients treted with compred with 1.6% nd 0.5% in ptients who received plcebo 32 33

18 Trils 1 nd 2 in ptients ge 12 yers nd older Common dverse rections Distinctive pckging for ech dosge strength ADVERSE REACTIONS IN 5% OF PATIENTS TREATED WITH (lumcftor/ivcftor) AND AT A HIGHER RATE THAN PLACEBO 1 (lumcftor/ivcftor) TABLETS Adverse Rection (Preferred Term) N=369 (%) Plcebo N=370 (%) Dyspne 48 (13) 29 (8) Nsophryngitis 48 (13) 40 (11) Nuse 46 (13) 28 (8) Dirrhe 45 (12) 31 (8) Upper respirtory trct infection 37 (10) 20 (5) Ftigue 34 (9) 29 (8) Respirtion bnorml 32 (9) 22 (6) Blood cretine phosphokinse incresed 27 (7) 20 (5) Rsh 25 (7) 7 (2) Fltulence 24 (7) 11 (3) Rhinorrhe 21 (6) 15 (4) Influenz 19 (5) 8 (2) ORAL GRANULES Not ctul size. Reported s chest tightness. 21 Trils 1 nd 2 Sfety Not ctul size

19 Recommended dose for (lumcftor/ivcftor) Dosge djustments for (lumcftor/ivcftor) Dosge Forms 1 Recommended Dose 1 Tblets Dose 1 Orl Grnules Dose 1 For ptients ge 2 to <6 yers, the recommended dose is weight bsed Heptic Impirment Not ctul size. Orl Grnules <14 kg: One pcket contining lumcftor 100 mg/ ivcftor 125 mg every 12 hours 14 kg: One pcket contining lumcftor 150 mg/ ivcftor 188 mg every 12 hours Severe impirment (Child-Pugh Clss C) b Moderte impirment (Child-Pugh Clss B) Mild impirment (Child-Pugh Clss A) 1 tblet in the morning nd 1 tblet in the evening, or less frequently 2 tblets in the morning nd 1 tblet in the evening 1 pcket in the morning or less frequently No dose in the evening 1 pcket in the morning every dy nd 1 pcket in the evening every other dy No dose djustment required For ptients ge 6 yers nd older CYP3A Inhibitors Tblets Age yers: 2 tblets (ech contining lumcftor 100 mg/ivcftor 125 mg) every 12 hours Age 12+ yers: 2 tblets (ech contining lumcftor 200 mg/ivcftor 125 mg) every 12 hours Inititing in ptients lredy tking strong CYP3A inhibitor (e.g., itrconzole) c First Week 1 tblet dily After First Week First Week After First Week Continue with the full recommended dily dose s prescribed 1 pcket every other dy Continue with the full recommended dily dose s prescribed Not ctul size. Inititing CYP3A inhibitors in ptients lredy tking d No dose djustment required 14 kg 31 lbs. orl grnules nd tblets should be tken with ft-contining food 1 Dose interruptions of while tking strong CYP3A inhibitors If is interrupted for more thn 1 week nd then reinitited while tking strong CYP3A inhibitors, reduce dose to 1 tblet dily or 1 pcket every other dy for the first week of tretment reinitition. Following this period, continue with the full recommended dily dose s prescribed. A sfe nd efficcious dose of for peditric ptients less thn 2 yers of ge hs not been estblished. The use of (orl grnules) in children under the ge of 2 yers is not recommended 1 See pge 38 for dditionl informtion on dministering orl grnules Ptients should continue tking ll of their prescribed CF therpies with 1 b Use with cution fter weighing the risks nd benefits of tretment. 1 c Additionl exmples include ketoconzole, posconzole, voriconzole, telithromycin, nd clrithromycin. 1 d No dose djustment is recommended when used with moderte or wek CYP3A inhibitors. 1 Missed dose of orl grnules or tblets 1 If 6 hours hve pssed: Advise ptient to tke the dose with ft-contining food If >6 hours hve pssed: Advise ptient to skip tht dose nd resume the norml schedule for the following dose. A double dose should not be tken to mke up for the forgotten dose Dosing nd Administrtion 36 37

20 How to dminister (lumcftor/ivcftor) orl grnules 1 PREPARATION 1 Cregiver should hold the pcket with the perfortion on top, shke the pcket gently to settle the grnules, nd ter or cut the pcket open long the perfortion Cregiver should mix ll grnules into 1 tespoon (5 ml) of soft food or liquid Food or liquid should be t or below room temperture Exmples of soft foods or liquids include: 2 ADMINISTRATION 1 After mixing, cregiver should give within 1 hour Pureed fruits or pplesuce Cregiver should mke sure the child finishes the dose completely Ter here Flvored yogurt or pudding + Milk or juice References: 1. [prescribing informtion]. Boston, MA: Vertex Phrmceuticls Incorported; August Rtjen F, Hug C, Mrigowd G, et l. Efficcy nd sfety of lumcftor nd ivcftor in ptients ged 6 11 yers with cystic fibrosis homozygous for F508del-CFTR: rndomised, plcebo-controlled phse 3 tril. Lncet Respir Med. 2017;5(7): Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-HQ ; Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-HQ ; Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-HQ (2); Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-HQ (2); Mill CE, Rtjen F, Mrigowd G, Liu F, Wltz D, Rosenfeld M; On behlf of the VX Prt B Investigtor Group. Lumcftor/ivcftor in ptients ged yers with cystic fibrosis homozygous for F508del-CFTR. Am J Respir Crit Cre Med. 2017;195(7): Dt on file. Vertex Phrmceuticls, Incorported. Boston, MA. VXR-US (2); Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. DOF-REF-1101; Chilvers M et l. An open-lbel extension study of lumcftor/ivcftor therpy in ptients ged yers with cystic fibrosis homozygous for F508del-CFTR. Poster nd bstrct presented t: 40th Europen Cystic Fibrosis Conference; Seville, Spin; June 10, Chilvers M et l. Sfety nd efficcy of lumcftor/ivcftor (LUMA/IVA) in ptients ged 6 yers with CF homozygous for F508del phse 3 extension study. Poster nd bstrct presented t: 31st Annul North Americn Cystic Fibrosis Conference; Indinpolis, Indin; November 2-4, Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-HQ ; Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-HQ ; Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-US ; Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. DOF-REF-1103; Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-US ; Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-HQ ; Kent L, Reix P, Innes JA, et l. Lung clernce index: evidence for use in clinicl trils in cystic fibrosis. J Cyst Fibros. 2014;13(2): Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. DOF-REF-1102; Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-HQ (1); Winwright CE, Elborn JS, Rmsey BW, et l. TRAFFIC nd TRANSPORT Study Groups. Lumcftor-ivcftor in ptients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3): A Phse 3 Rollover Study of Lumcftor in Combintion With Ivcftor in Subjects 12 Yers nd Older With Cystic Fibrosis. CliniclTrils.gov. show/nct Updted My 12, Accessed Mrch 19, Konstn MW, McKone EF, Moss RB, et l. Assessment of sfety nd efficcy of long-term tretment with combintion lumcftor nd ivcftor therpy in ptients with cystic fibrosis homozygous for the F508del-CFTR muttion (PROGRESS): phse 3, extension study. Lncet Respir Med. 2017;5(2): Konstn MW, McKone EF, Moss RB, et l. Assessment of sfety nd efficcy of long-term tretment with combintion lumcftor nd ivcftor therpy in ptients with cystic fibrosis homozygous for the F508del-CFTR muttion (PROGRESS): phse 3, extension study. Lncet Respir Med. 2017;5(2)(suppl1-28): UC Dvis Children s Hospitl. How to help your child tke medicine. Ptient_nd_Fmily_Eduction_A_to_Z/PDFs/HowToHelpTkeMedicine.pdf. Accessed Mrch 19, Dt on file. Vertex Phrmceuticls Incorported. Boston, MA. VXR-HQ ; GIVE WITH FAT-CONTAINING FOOD 1 Food tht contins ft must be tken just before or fter the orl grnules dose Exmples of ft-contining foods include: Eggs Avocdo Nuts Butter Penut butter Cheese pizz Whole-milk diry products (e.g., whole milk, cheese, nd yogurt) It is importnt tht ptients consume the entire orl grnules mixture with ech dose 1 PALATABILITY OF ORAL GRANULES Children my find the tste of the orl grnules to be bitter Mixing the orl grnules with soft foods or liquids tht re sweet or rich, such s pudding or chocolte suce, my help with the tste 25,26 Refer your ptients to.com for more informtion on dministering orl grnules

21 sfety profile in ptients ge 2 yers nd older 12+ SAFETY PROFILE 1108 PATIENTS AGE 12 YEARS AND OLDER WERE STUDIED IN TRIALS 1 AND 2 1 Serious dverse rections in Trils 1 nd 2, whether considered drug-relted or not by the investigtors, tht occurred more frequently in ptients treted with included pneumoni, hemoptysis, cough, incresed blood cretine phosphokinse, nd trnsminse elevtions. These occurred in 1% or less of ptients The most common dverse rections in Trils 1 nd 2 occurring in 5% of ptients treted with (N=369) vs plcebo (N=370) nd t higher rte thn plcebo were dyspne, nsophryngitis, nuse, dirrhe, upper respirtory trct infection, ftigue, respirtion bnorml, blood cretine phosphokinse incresed, rsh, fltulence, rhinorrhe, nd influenz SAFETY PROFILE 262 PATIENTS AGE 6 THROUGH 11 YEARS WERE STUDIED IN TRIALS 3 AND 4 1,2 The sfety profile of in children 6 through 11 yers of ge ws similr to tht in ptients 12 yers nd older 1 Additionl common dverse rections were reported in Tril 4, but were not reported in Trils 1 nd 2. The dverse rections in Tril 4 tht occurred in 5% of ptients treted with with n incidence of 3% higher thn plcebo included: productive cough, nsl congestion, hedche, bdominl pin upper, nd sputum incresed SAFETY (PRIMARY ENDPOINT) 60 PATIENTS AGE 2 THROUGH 5 YEARS WERE STUDIED IN TRIAL 6 (OPEN-LABEL) 1 The sfety profile ws similr to tht in ptients ged 6 yers nd older 1 Plese see pge 5 for Limittions of Tril 6 nd pge 14 for Limittions nd Disclosures of Trils 3 nd 4 is mnufctured for Vertex Phrmceuticls Incorported., the logo, Vertex, nd the Vertex tringle logo re registered trdemrks of Vertex Phrmceuticls Incorported. All other trdemrks referenced herein re the property of their respective owners Vertex Phrmceuticls Incorported VXR-US (v2.0) 03/2019