1216:
averaging 78% of normal at baseline. The people in the trial were randomized to receive either ivacaftor or placebo for eight weeks. This was followed by a four to eight week washout period, then each group received the opposite treatment from what it received in the first part of the trial. At week 8, the people on treatment with ivacaftor experienced an average absolute improvement in FEV1 of 13.8%, but there was a strong dependence of the efficacy on the exact mutation that a patient had. The detailed data for different mutation types is shown in the U.S. package insert.
990:(12.8% versus 9.6% on placebo), dizziness (9.2% versus 1.0% on placebo), rash (12.8% versus 6.7% on placebo), upper respiratory tract reactions (including upper respiratory tract infection, nasal congestion, pharyngeal erythema, oropharyngeal pain, rhinitis, sinus congestion, and nasopharyngitis) (63.3% versus 50.0% on placebo), headache (23.9% versus 16.3% on placebo) and bacteria in sputum (7.3% versus 3.8% on placebo). One patient in the ivacaftor group reported a serious adverse reaction: abdominal pain.
704:
681:
31:
3155:
2409:
2365:
2168:
2124:
2014:
1906:
1859:
1749:
1535:
1050:
unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose in the fed state. The apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The mean (±SD) of CL/F for the 150 mg dose was 17.3 (8.4) L/h in healthy subjects at steady state.
1137:
Vertex said it would make the medication available free to patients in the United States with no insurance and a household income of under $ 150,000. In 2012, 24 US doctors and researchers involved in the development of the medication wrote to Vertex to protest the price of the medication, which had
1129:
and relied upon by Vertex in its cystic fibrosis drug discovery programs. The company responded in an email that "while publicly funded academic research provided important early understanding of the cause of cystic fibrosis, it took Vertex scientists 14 years of their own research, funded mostly by
1117:
per year, roughly similar to the price of other medications for extremely rare diseases. In the first nine months of its second year on the market (2014), ivacaftor sales were $ 339M, representing 54% of Vertex's product sales revenue. During the same period, total drug development expenses were $
1202:
The first trial was performed in adults having baseline respiratory function (FEV1) between 32% and 98% of normal for persons of similar age, height, and weight. The baseline average was 64%. Improvement in FEV1 was rapid and sustained. At the end of 48 weeks, people treated with ivacaftor had on
958:
Symkevi is indicated in a combination regimen with ivacaftor 150 mg tablets for the treatment of people with cystic fibrosis (CF) aged twelve years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in
1215:
A third clinical trial examined the efficacy of ivacaftor in people with cystic fibrosis due to G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutations. This trial, which included 39 people of age greater than six years, used a crossover design. The people in the trial had FEV1
1049:
Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the faeces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as
1040:
data indicate that ivacaftor is primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not
1133:
The Cystic
Fibrosis Foundation, a non-profit organization dedicated to improving healthcare for people with cystic fibrosis, provided $ 150 million of the funding for the development for ivacaftor in exchange for royalty rights in the event that the medication was successfully developed and
1138:
been set at about $ 300,000 per year. In the UK, the company provided the medication free for a limited time for certain patients, then left the hospitals to decide whether to continue to pay for it for those patients. UK agencies estimated the cost per quality adjusted life year (
910: (D). G551D is characterized by a dysfunctional CFTR protein on the cell surface. In the case of G551D, the protein is trafficked to the correct area, the epithelial cell surface, but once there the protein cannot transport chloride through the channel. Ivacaftor, a CFTR
930:(CFTR) protein: E56K, G178R, S549R, K1060T, G1244E, P67L, E193K, G551D, A1067T, S1251N, R74W, L206W, G551S, G1069R, S1255P, D110E, R347H, D579G, R1070Q, D1270N, D110H, R352Q, S945L, R1070W, G1349D, R117C, A455E, S977F, F1074L, R117H, S549N, F1052V, D1152H.
1198:
Of the approximately 70,000 cases of cystic fibrosis worldwide, 4% (~3,000) are due to a mutation called G551D. The safety and efficacy of ivacaftor for the treatment of cystic fibrosis in patients with this mutation was examined in two clinical trials.
901:
Cystic fibrosis is caused by any one of several defects in the CFTR protein, which regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus. One such defect is the G551D mutation, in which the amino acid
1206:
In a second trial conducted in children age six to 11, the average improvement in FEV1 was an absolute increase of 12.5% in the ivacaftor group at 48 weeks, compared to a very slight decline in the placebo group.
1999:
2083:
914:, improves the transport of chloride through the ion channel by binding to the channels directly to induce a non-conventional mode of gating which in turn increases the probability that the channel is open.
1734:
2559:
1554:"Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner"
1203:
average an absolute increase in FEV1 of 10.4%, vs. a decline of 0.2% in the placebo group. Pulmonary exacerbations were reduced by about half in the ivacaftor group relative to the placebo group.
333:
2957:
959:
the cystic fibrosis transmembrane conductance regulator (CFTR) gene: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272 26A→G, and 3849+10kbC→T.
2537:
986:
The most common adverse reactions experienced by patients who received ivacaftor in the pooled placebo-controlled Phase III studies were abdominal pain (15.6% versus 12.5% on placebo),
773:
207:
1134:
commercialized. In 2014, the
Foundation sold these royalty rights for $ 3.3 billion. The Foundation has stated that it intends to spend these funds in support of further research.
1965:
258:
2817:
Bobadilla JL, Macek M, Fine JP, Farrell PM (June 2002). "Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening".
831:
927:
860:
2234:
1003:
Ivacaftor is a "potentiator" of CFTR, meaning it increases the probability that the defective channel will be open and allow chloride ions pass through the channel pore.
1143:
1987:
2950:
1722:
1891:
1844:
122:
2350:
2394:
1161:
had called a "fair price" for taxpayers". The negotiations took 16 months and it was estimated that around 20 Ontarians required the medication at the time.
787:
1935:
2563:
2943:
2754:
2773:
2153:
2097:
173:
2672:
2545:
2066:
1810:
815:
InChI=1S/C24H28N2O3/c1-23(2,3)16-11-17(24(4,5)6)20(27)12-19(16)26-22(29)15-13-25-18-10-8-7-9-14(18)21(15)28/h7-13,27H,1-6H3,(H,25,28)(H,26,29)
1175:
Delay in agreement on a price for Vertex to charge national health plans led to patient group protests in Wales, England, and
Australia.
2735:
2603:
Cohen D, Raftery J (February 2014). "Paying twice: questions over high cost of cystic fibrosis drug developed with charitable funding".
1346:
1957:
898:
per year, which has led to criticism of the high cost. The combination drug lumacaftor/ivacaftor was approved by the FDA in July 2015.
2647:
1711:
3185:
807:
203:
87:
2238:
890:
and is the first medication that treats the underlying cause rather than the symptoms of the disease. It was approved by the U.S.
3111:
2298:
876:
2328:
2268:
2031:
1482:
1449:
1296:
451:
318:
154:
2993:
2475:
O'Sullivan BP, Orenstein DM, Milla CE (October 2013). "Pricing for orphan drugs: will the market bear what society cannot?".
2186:
2698:
3210:
1126:
3145:
2084:"Phase 3 Study of VX-770 Shows Marked Improvement in Lung Function Among People with Cystic Fibrosis with G551D Mutation"
1450:"Orkambi- lumacaftor and ivacaftor tablet, film coated Orkambi- lumacaftor and ivacaftor granule prescribing information"
2388:
2354:
2207:
2147:
2103:
1993:
1929:
1885:
1838:
1728:
1080:
891:
580:
2888:
2876:
1879:
1832:
660:
2427:
190:
2454:
1771:"Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects"
3190:
1411:
McPhail GL, Clancy JP (April 2013). "Ivacaftor: the first therapy acting on the primary cause of cystic fibrosis".
1122:
1063:
887:
2382:
863:(CFTR) gene (primarily the G551D mutation), who account for 4–5% cases of cystic fibrosis. It is also included in
1923:
1664:"Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis"
1518:
1340:
1087:
168:
3195:
2787:
529:
955:
Symdeko is indicated to treat people aged six and older who have two copies of the F508del mutation in CFTR.
2141:
1259:
244:
2358:
2109:
699:
2581:
1150:
1059:
883:
864:
649:
400:
3200:
3175:
2988:
2578:"FDA Approves Kalydeco (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis"
1154:
1098:
520:
1066:
and is the first medication that treats the underlying cause rather than the symptoms of the disease.
3103:
2980:
1616:
1094:
934:
872:
868:
420:
676:
475:
251:
2967:
2842:
2628:
2432:
2212:
1603:
Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, et al. (November 2009).
1393:
1125:
in its development and the contribution made by fundamental scientific research performed by the
218:
2577:
2511:
3180:
3054:
2834:
2620:
2492:
1792:
1693:
1644:
1585:
1428:
1385:
629:
569:
370:
357:
345:
104:
1335:
1297:"Kalydeco- ivacaftor tablet, film coated Kalydeco- ivacaftor granule prescribing information"
3205:
2826:
2612:
2484:
1988:"FDA expands approval of treatment for cystic fibrosis to include patients ages 6 and older"
1782:
1683:
1675:
1634:
1624:
1575:
1565:
1513:
1420:
1377:
716:
484:
392:
48:
1121:
An editorial in JAMA called the price of ivacaftor "exorbitant", citing the support by the
589:
3159:
2935:
938:
923:
856:
410:
2864:
703:
680:
2736:"Protests at Birmingham Hospital as cystic fibrosis sufferer is denied life-saving drug"
1620:
3069:
1723:"FDA expands approved use of Kalydeco to treat additional mutations of cystic fibrosis"
1688:
1663:
1639:
1604:
1580:
1553:
2290:
2086:(Press release). Cystic Fibrosis Foundation. 23 February 2011 – via PR Newswire.
3169:
2924:
2912:
2900:
2413:
2369:
2320:
2260:
2172:
2128:
2018:
1910:
1863:
1753:
1605:"Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770"
1539:
1381:
1264:
1190:
The clinical trials used in the regulatory approval of ivacaftor are described here.
907:
692:
509:
146:
2846:
1710:
Cystic
Fibrosis Foundation: FDA Approves Ivacaftor for 23 Additional CFTR Mutations
1397:
3117:
3014:
2971:
2632:
1169:
1158:
301:
296:
291:
286:
281:
276:
271:
266:
1424:
2321:"Kalydeco 150 mg film-coated tablets - Summary of Product Characteristics (SmPC)"
1679:
1233:
132:
3059:
3049:
1113:
per year, which has led to criticism of the high cost. The cost of ivacaftor is
1017:
963:
911:
140:
2774:"NICE gives initial thumbs-down to Vertex's CF combo med Orkambi, citing costs"
1609:
Proceedings of the
National Academy of Sciences of the United States of America
3107:
967:
949:
852:
749:
560:
2716:
2488:
1787:
1770:
1168:
began covering the medication in July 2014, and in
September the province of
3083:
3044:
3024:
3019:
3009:
2291:"Kalydeco 75mg granules sachets - Summary of Product Characteristics (SmPC)"
2261:"Kalydeco 50mg granules sachets - Summary of Product Characteristics (SmPC)"
1629:
1570:
1368:
Jones AM, Helm JM (October 2009). "Emerging treatments in cystic fibrosis".
433:
126:
2838:
2624:
2496:
1796:
1697:
1648:
1589:
1432:
1389:
1172:
became the third province to include it in its provincial medication plan.
894:(FDA) in January 2012. It is one of the most expensive drugs, costing over
2788:"FAQs about the Cause, Diagnosis, Treatment of Cystic Fibrosis & More"
22:
3122:
3034:
3029:
2676:
1487:
1454:
1301:
1033:
987:
971:
942:
540:
185:
2560:"CF Foundation Royalty Sale Will Be Transformational for People with CF"
549:
3039:
2830:
2538:"CF Foundation Cashes Out on Kalydeco in $ 3.3B Sale to Royalty Pharma"
1165:
1037:
1021:
975:
903:
495:
2755:"Kalydeco breakthrough: Plea for life-saving medicine proves a winner"
2616:
1016:
Ivacaftor is approximately 99% bound to plasma proteins, primarily to
30:
3127:
2191:
640:
2795:
1118:
458M, most of which was spent on cystic fibrosis-related research.
609:
3132:
3078:
2235:"Summary Basis of Decision (SBD): Kalydeco - 2012 - Health Canada"
1157:
and the manufacturer negotiated for what "Ontario Health
Minister
772:
763:
620:
2412:
This article incorporates text from this source, which is in the
2368:
This article incorporates text from this source, which is in the
2171:
This article incorporates text from this source, which is in the
2127:
This article incorporates text from this source, which is in the
2017:
This article incorporates text from this source, which is in the
1909:
This article incorporates text from this source, which is in the
1862:
This article incorporates text from this source, which is in the
1752:
This article incorporates text from this source, which is in the
1538:
This article incorporates text from this source, which is in the
1093:
Lumacaftor/ivacaftor was approved by the FDA in July 2015, under
2455:"Vertex Pharmaceuticals 10-Q, Quarter ending September 30, 2014"
1139:
600:
466:-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
376:
351:
163:
2939:
1483:"Symdeko- tezacaftor and ivacaftor kit prescribing information"
364:
197:
180:
974:
for the treatment of people with cystic fibrosis who have the
172:
78:
2098:"FDA approves Kalydeco to treat rare form of cystic fibrosis"
2673:"Saskatchewan to cover $ 300K cystic fibrosis drug Kalydeco"
665:
327:
229:
60:
54:
2717:"Cystic fibrosis: New drug Kalydeco refused for Welsh NHS"
2512:"Cystic Fibrosis: Charity and Industry Partner for Profit"
952:/ivacaftor with ivacaftor sold as Symdeko and as Symkevi.
926:
in people having one of several specific mutations in the
1552:
Eckford PD, Li C, Ramjeesingh M, Bear CE (October 2012).
795:
O=C\2c1c(cccc1)N/C=C/2C(=O)Nc3cc(O)c(cc3C(C)(C)C)C(C)(C)C
69:
340:
2067:"Kalydeco: Annex I: Summary of product characteristics"
937:, in a single pill, which is used to treat people with
838:
2032:"Trikafta- elexacaftor, tezacaftor, and ivacaftor kit"
948:
Ivacaftor is also included in the combination product
3143:
1142:) at between £335,000 and £1,274,000 —well above the
1090:(EMA) and Canada and across some European countries.
962:
Ivacaftor is available in a combination product with
933:
Ivacaftor is also included in a combination product,
879:
which are used to treat people with cystic fibrosis.
88:
72:
66:
51:
1109:
It is one of the most expensive drugs, costing over
1024:. Ivacaftor does not bind to human red blood cells.
75:
57:
3092:
3068:
3002:
2979:
2061:
2059:
2057:
2055:
2053:
1874:
1872:
928:
cystic fibrosis transmembrane conductance regulator
861:
cystic fibrosis transmembrane conductance regulator
761:
748:
715:
710:
691:
659:
639:
619:
599:
579:
559:
539:
528:
519:
494:
474:
442:
432:
419:
409:
399:
391:
317:
312:
257:
243:
217:
153:
139:
121:
113:
103:
63:
42:
37:
1458:. U.S. National Library of Medicine. 15 July 2019
1144:National Institute for Health and Care Excellence
3093:Other agents for treating respiratory depression
2351:"FDA approves new treatment for cystic fibrosis"
2108:(Press release). 31 January 2012. Archived from
1291:
1289:
1287:
1285:
1283:
1032:Ivacaftor is extensively metabolised in humans.
508:
1477:
1475:
1473:
1444:
1442:
1330:
1328:
1326:
1324:
1322:
1320:
483:
1508:
1506:
202:
2951:
2648:"OHIP to cover cystic fibrosis drug Kalydeco"
2142:"Drug Approval Package: Kalydeco (ivacaftor)"
1764:
1762:
8:
2383:"Orkambi (lumacaftor/ivacaftor) Oral Tablet"
1182:cost $ 259,000 a year in the United States.
1130:the company, before the drug won approval."
189:
21:
2580:(Press release). Cambridge, Massachusetts:
1775:Therapeutic Advances in Respiratory Disease
1234:"Ivacaftor (Kalydeco) Use During Pregnancy"
906: (G) in position 551 is replaced with
384:In general: ℞ (Prescription only)
2958:
2944:
2936:
2428:"F.D.A. Approves New Cystic Fibrosis Drug"
1083:(FDA) approved ivacaftor in January 2012,
702:
679:
568:
29:
2699:"Plea for Kalydeco drug to be introduced"
1786:
1769:Kuk K, Taylor-Cousar JL (December 2015).
1687:
1638:
1628:
1579:
1569:
1149:The medication was not covered under the
588:
2925:"Elexacaftor, Tezacaftor, and Ivacaftor"
1924:"Symdeko (tezacaftor/ivacaftor) Tablets"
859:in people with certain mutations in the
3150:
1225:
922:Ivacaftor is used for the treatment of
812:
792:
675:
548:
456:
145:
693:
20:
2397:from the original on 21 November 2019
2331:from the original on 21 November 2019
2301:from the original on 21 November 2019
2271:from the original on 21 November 2019
2187:"The Most Important New Drug Of 2012"
2156:from the original on 21 November 2019
2002:from the original on 11 December 2019
1968:from the original on 21 November 2019
1958:"Summary Basis of Decision - Symdeko"
1938:from the original on 11 December 2019
1894:from the original on 21 November 2019
1847:from the original on 21 November 2019
1737:from the original on 21 November 2019
1668:Current Opinion in Pulmonary Medicine
1349:from the original on 21 November 2019
1041:considered pharmacologically active.
648:
628:
131:
7:
2895:. U.S. National Library of Medicine.
2883:. U.S. National Library of Medicine.
2871:. U.S. National Library of Medicine.
1811:"Orkambi (lumacaftor and ivacaftor)"
1662:Sloane PA, Rowe SM (November 2010).
300:
290:
280:
270:
2889:"Ivacaftor regimen with Tezacaftor"
2877:"Ivacaftor mixture with lumacaftor"
1558:The Journal of Biological Chemistry
608:
499:
2357:(FDA). 2 July 2015. Archived from
1180:the combination medication Orkambi
14:
3153:
2407:
2363:
2166:
2122:
2012:
1904:
1880:"Drug Trials Snapshots: Symdeko"
1857:
1833:"Drug Trials Snapshots: Orkambi"
1747:
1533:
1382:10.2165/11318500-000000000-00000
877:elexacaftor/tezacaftor/ivacaftor
733:
727:
47:
1998:(Press release). 21 June 2019.
1153:plan until June 2014, when the
1086:Soon afterwards so too did the
820:Key:PURKAOJPTOLRMP-UHFFFAOYSA-N
2994:Dipalmitoylphosphatidylcholine
1733:(Press release). 17 May 2017.
1260:"Kalydeco Product information"
739:
721:
16:Cystic fibrosis treatment drug
1:
2772:Wasserman E (23 March 2016).
2734:Lockley M (29 October 2012).
2536:Fidler B (19 November 2014).
2426:Pollack A (31 January 2012).
1425:10.1358/dot.2013.49.4.1940984
1127:National Institutes of Health
978:mutation or other mutations.
2753:Swain E (23 December 2013).
2389:Food and Drug Administration
2355:Food and Drug Administration
2148:Food and Drug Administration
2104:Food and Drug Administration
2072:. European Medicines Agency.
1994:Food and Drug Administration
1930:Food and Drug Administration
1886:Food and Drug Administration
1839:Food and Drug Administration
1729:Food and Drug Administration
1680:10.1097/MCP.0b013e32833f1d00
1081:Food and Drug Administration
892:Food and Drug Administration
2646:Ferguson R (20 June 2014).
1058:Ivacaftor was developed by
882:Ivacaftor was developed by
3227:
2913:"Tezacaftor and Ivacaftor"
2901:"Lumacaftor and Ivacaftor"
2525:– via MedPage Today.
1123:Cystic Fibrosis Foundation
1064:Cystic Fibrosis Foundation
888:Cystic Fibrosis Foundation
711:Chemical and physical data
2516:Milwauke Journal-Sentinel
2206:Nocera J (18 July 2014).
1519:European Medicines Agency
1341:European Medicines Agency
1088:European Medicines Agency
1018:alpha 1-acid glycoprotein
828:
803:
783:
447:
28:
3186:Chloride channel openers
2510:Fauber J (19 May 2013).
2489:10.1001/jama.2013.278129
1788:10.1177/1753465815601934
1062:in conjunction with the
886:in conjunction with the
2893:Drug Information Portal
2881:Drug Information Portal
2869:Drug Information Portal
1630:10.1073/pnas.0904709106
1571:10.1074/jbc.M112.393637
865:combination medications
3112:elexacaftor/tezacaftor
3003:Respiratory stimulants
2582:Vertex Pharmaceuticals
2353:(Press release). U.S.
1060:Vertex Pharmaceuticals
884:Vertex Pharmaceuticals
2989:Colfosceril palmitate
1345:. 17 September 2018.
1155:Government of Ontario
3211:Tert-butyl compounds
2566:on 27 December 2014.
2393:. 21 November 2019.
2208:"The $ 300,000 Drug"
1151:Ontario Drug Benefit
1095:breakthrough therapy
935:lumacaftor/ivacaftor
873:tezacaftor/ivacaftor
869:lumacaftor/ivacaftor
428:12 hrs (single dose)
2759:Manning River Times
2548:on 4 February 2015.
2361:on 26 January 2018.
1621:2009PNAS..10618825V
1615:(44): 18825–18830.
1564:(44): 36639–36649.
1523:. 17 September 2018
1097:status and under a
1070:Society and culture
360:(Prescription only)
336:(Prescription only)
25:
2968:respiratory system
2831:10.1002/humu.10041
2798:on 25 October 2006
2433:The New York Times
2327:. 30 August 2019.
2297:. 30 August 2019.
2267:. 30 August 2019.
2213:The New York Times
1178:As of March 2016,
945:mutation in CFTR.
3191:CYP3A4 inhibitors
3141:
3140:
2617:10.1136/bmj.g1445
2584:. 31 January 2012
2483:(13): 1343–1344.
2152:. 13 March 2012.
2038:. 29 January 2020
1964:. 15 April 2019.
1934:. 13 March 2018.
1376:(14): 1903–1910.
1240:. 9 November 2019
1028:Biotransformation
846:
845:
774:Interactive image
661:CompTox Dashboard
380:
368:
355:
343:
331:
233:
200:
183:
166:
3218:
3158:
3157:
3156:
3149:
2981:Lung surfactants
2960:
2953:
2946:
2937:
2932:
2920:
2908:
2896:
2884:
2872:
2851:
2850:
2814:
2808:
2807:
2805:
2803:
2794:. Archived from
2784:
2778:
2777:
2769:
2763:
2762:
2750:
2744:
2743:
2731:
2725:
2724:
2713:
2707:
2706:
2695:
2689:
2688:
2686:
2684:
2679:. 28 August 2014
2669:
2663:
2662:
2660:
2658:
2652:The Toronto Star
2643:
2637:
2636:
2600:
2594:
2593:
2591:
2589:
2574:
2568:
2567:
2562:. Archived from
2556:
2550:
2549:
2544:. Archived from
2533:
2527:
2526:
2524:
2522:
2507:
2501:
2500:
2472:
2466:
2465:
2463:
2461:
2451:
2445:
2444:
2442:
2440:
2423:
2417:
2411:
2410:
2406:
2404:
2402:
2379:
2373:
2367:
2366:
2362:
2347:
2341:
2340:
2338:
2336:
2317:
2311:
2310:
2308:
2306:
2287:
2281:
2280:
2278:
2276:
2257:
2251:
2250:
2248:
2246:
2241:on 6 August 2014
2237:. Archived from
2231:
2225:
2224:
2222:
2220:
2203:
2197:
2196:
2182:
2176:
2170:
2169:
2165:
2163:
2161:
2138:
2132:
2126:
2125:
2121:
2119:
2117:
2112:on 18 March 2016
2094:
2088:
2087:
2080:
2074:
2073:
2071:
2063:
2048:
2047:
2045:
2043:
2028:
2022:
2016:
2015:
2011:
2009:
2007:
1984:
1978:
1977:
1975:
1973:
1954:
1948:
1947:
1945:
1943:
1920:
1914:
1908:
1907:
1903:
1901:
1899:
1890:. 7 March 2018.
1876:
1867:
1861:
1860:
1856:
1854:
1852:
1843:. 30 July 2015.
1829:
1823:
1822:
1820:
1818:
1807:
1801:
1800:
1790:
1766:
1757:
1751:
1750:
1746:
1744:
1742:
1719:
1713:
1708:
1702:
1701:
1691:
1659:
1653:
1652:
1642:
1632:
1600:
1594:
1593:
1583:
1573:
1549:
1543:
1537:
1536:
1532:
1530:
1528:
1510:
1501:
1500:
1498:
1496:
1479:
1468:
1467:
1465:
1463:
1446:
1437:
1436:
1408:
1402:
1401:
1365:
1359:
1358:
1356:
1354:
1332:
1315:
1314:
1312:
1310:
1293:
1278:
1277:
1275:
1273:
1256:
1250:
1249:
1247:
1245:
1230:
1181:
1164:The province of
1116:
1112:
1007:Pharmacokinetics
999:Pharmacodynamics
897:
842:
841:
834:
776:
756:
741:
735:
729:
723:
706:
695:
684:
683:
669:
667:
652:
632:
612:
592:
572:
552:
532:
512:
502:
501:
487:
424:
378:
375:
366:
363:
353:
350:
342:
339:
329:
326:
304:
294:
284:
274:
231:
228:
210:
199:
196:
193:
182:
179:
176:
165:
162:
149:
135:
95:
91:
85:
84:
81:
80:
77:
74:
71:
68:
65:
62:
59:
56:
53:
33:
26:
24:
3226:
3225:
3221:
3220:
3219:
3217:
3216:
3215:
3196:Cystic fibrosis
3166:
3165:
3164:
3154:
3152:
3144:
3142:
3137:
3088:
3064:
2998:
2975:
2964:
2923:
2911:
2899:
2887:
2875:
2863:
2860:
2855:
2854:
2816:
2815:
2811:
2801:
2799:
2786:
2785:
2781:
2776:. FiercePharma.
2771:
2770:
2766:
2752:
2751:
2747:
2740:Birmingham Mail
2733:
2732:
2728:
2721:BBC News Online
2715:
2714:
2710:
2697:
2696:
2692:
2682:
2680:
2671:
2670:
2666:
2656:
2654:
2645:
2644:
2640:
2602:
2601:
2597:
2587:
2585:
2576:
2575:
2571:
2558:
2557:
2553:
2535:
2534:
2530:
2520:
2518:
2509:
2508:
2504:
2474:
2473:
2469:
2459:
2457:
2453:
2452:
2448:
2438:
2436:
2425:
2424:
2420:
2408:
2400:
2398:
2381:
2380:
2376:
2364:
2349:
2348:
2344:
2334:
2332:
2319:
2318:
2314:
2304:
2302:
2289:
2288:
2284:
2274:
2272:
2259:
2258:
2254:
2244:
2242:
2233:
2232:
2228:
2218:
2216:
2205:
2204:
2200:
2184:
2183:
2179:
2167:
2159:
2157:
2140:
2139:
2135:
2123:
2115:
2113:
2096:
2095:
2091:
2082:
2081:
2077:
2069:
2065:
2064:
2051:
2041:
2039:
2030:
2029:
2025:
2013:
2005:
2003:
1986:
1985:
1981:
1971:
1969:
1956:
1955:
1951:
1941:
1939:
1922:
1921:
1917:
1905:
1897:
1895:
1878:
1877:
1870:
1858:
1850:
1848:
1831:
1830:
1826:
1816:
1814:
1809:
1808:
1804:
1768:
1767:
1760:
1748:
1740:
1738:
1721:
1720:
1716:
1709:
1705:
1661:
1660:
1656:
1602:
1601:
1597:
1551:
1550:
1546:
1534:
1526:
1524:
1512:
1511:
1504:
1494:
1492:
1481:
1480:
1471:
1461:
1459:
1448:
1447:
1440:
1410:
1409:
1405:
1367:
1366:
1362:
1352:
1350:
1336:"Kalydeco EPAR"
1334:
1333:
1318:
1308:
1306:
1305:. 25 April 2019
1295:
1294:
1281:
1271:
1269:
1268:. 25 April 2012
1258:
1257:
1253:
1243:
1241:
1232:
1231:
1227:
1222:
1213:
1211:Other mutations
1196:
1188:
1179:
1114:
1110:
1107:
1099:priority review
1077:
1072:
1056:
1047:
1030:
1014:
1009:
1001:
996:
984:
982:Adverse effects
939:cystic fibrosis
924:cystic fibrosis
920:
895:
857:cystic fibrosis
837:
835:
832:(what is this?)
829:
824:
821:
816:
811:
810:
799:
796:
791:
790:
779:
754:
744:
738:
732:
726:
687:
663:
655:
635:
615:
595:
575:
555:
535:
515:
498:
490:
470:
467:
455:
454:
422:
401:Protein binding
393:Pharmacokinetic
387:
308:
246:
239:
220:
213:
93:
89:
86:
50:
46:
17:
12:
11:
5:
3224:
3222:
3214:
3213:
3208:
3203:
3198:
3193:
3188:
3183:
3178:
3168:
3167:
3163:
3162:
3139:
3138:
3136:
3135:
3130:
3125:
3120:
3115:
3096:
3094:
3090:
3089:
3087:
3086:
3081:
3075:
3073:
3070:5-HT4 receptor
3066:
3065:
3063:
3062:
3057:
3052:
3047:
3042:
3037:
3032:
3027:
3022:
3017:
3012:
3006:
3004:
3000:
2999:
2997:
2996:
2991:
2985:
2983:
2977:
2976:
2965:
2963:
2962:
2955:
2948:
2940:
2934:
2933:
2921:
2909:
2897:
2885:
2873:
2859:
2858:External links
2856:
2853:
2852:
2825:(6): 575–606.
2819:Human Mutation
2809:
2779:
2764:
2745:
2726:
2708:
2690:
2664:
2638:
2595:
2569:
2551:
2528:
2502:
2467:
2446:
2418:
2374:
2342:
2312:
2282:
2252:
2226:
2198:
2177:
2133:
2089:
2075:
2049:
2023:
1979:
1949:
1915:
1868:
1824:
1802:
1781:(6): 313–326.
1758:
1714:
1703:
1674:(6): 591–597.
1654:
1595:
1544:
1514:"Symkevi EPAR"
1502:
1491:. 11 June 2019
1469:
1438:
1419:(4): 253–260.
1413:Drugs of Today
1403:
1360:
1316:
1279:
1251:
1224:
1223:
1221:
1218:
1212:
1209:
1195:
1194:G551D mutation
1192:
1187:
1184:
1106:
1103:
1076:
1073:
1071:
1068:
1055:
1052:
1046:
1043:
1029:
1026:
1013:
1010:
1008:
1005:
1000:
997:
995:
992:
983:
980:
919:
916:
855:used to treat
844:
843:
826:
825:
823:
822:
819:
817:
814:
806:
805:
804:
801:
800:
798:
797:
794:
786:
785:
784:
781:
780:
778:
777:
769:
767:
759:
758:
752:
746:
745:
742:
736:
730:
724:
719:
713:
712:
708:
707:
697:
689:
688:
686:
685:
677:DTXSID00236281
672:
670:
657:
656:
654:
653:
645:
643:
637:
636:
634:
633:
625:
623:
617:
616:
614:
613:
605:
603:
597:
596:
594:
593:
585:
583:
577:
576:
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563:
557:
556:
554:
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545:
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536:
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533:
525:
523:
517:
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514:
513:
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492:
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472:
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458:
450:
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448:
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430:
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417:
416:
413:
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403:
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389:
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386:
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382:
373:
361:
348:
337:
323:
321:
315:
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310:
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306:
263:
261:
255:
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247:administration
241:
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194:
177:
159:
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137:
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129:
119:
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115:
111:
110:
107:
101:
100:
44:
40:
39:
35:
34:
15:
13:
10:
9:
6:
4:
3:
2:
3223:
3212:
3209:
3207:
3204:
3202:
3199:
3197:
3194:
3192:
3189:
3187:
3184:
3182:
3179:
3177:
3174:
3173:
3171:
3161:
3151:
3147:
3134:
3131:
3129:
3126:
3124:
3121:
3119:
3116:
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3109:
3105:
3101:
3098:
3097:
3095:
3091:
3085:
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3080:
3077:
3076:
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3061:
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3056:
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3051:
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3046:
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3036:
3033:
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3028:
3026:
3023:
3021:
3018:
3016:
3013:
3011:
3008:
3007:
3005:
3001:
2995:
2992:
2990:
2987:
2986:
2984:
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2973:
2969:
2961:
2956:
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2949:
2947:
2942:
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2926:
2922:
2918:
2914:
2910:
2906:
2902:
2898:
2894:
2890:
2886:
2882:
2878:
2874:
2870:
2866:
2862:
2861:
2857:
2848:
2844:
2840:
2836:
2832:
2828:
2824:
2820:
2813:
2810:
2797:
2793:
2792:CF Foundation
2789:
2783:
2780:
2775:
2768:
2765:
2760:
2756:
2749:
2746:
2741:
2737:
2730:
2727:
2723:. 8 May 2013.
2722:
2718:
2712:
2709:
2704:
2700:
2694:
2691:
2678:
2674:
2668:
2665:
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2639:
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2579:
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2414:public domain
2396:
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2370:public domain
2360:
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2173:public domain
2155:
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2129:public domain
2111:
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2068:
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2027:
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2019:public domain
2001:
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1989:
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1962:Health Canada
1959:
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1933:
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1911:public domain
1893:
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1864:public domain
1846:
1842:
1840:
1834:
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1813:. CenterWatch
1812:
1806:
1803:
1798:
1794:
1789:
1784:
1780:
1776:
1772:
1765:
1763:
1759:
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1754:public domain
1736:
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1540:public domain
1522:
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1265:Health Canada
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989:
981:
979:
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951:
946:
944:
941:who have the
940:
936:
931:
929:
925:
917:
915:
913:
909:
908:aspartic acid
905:
899:
893:
889:
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827:
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751:
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720:
718:
714:
709:
705:
701:
698:
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694:ECHA InfoCard
690:
682:
678:
674:
673:
671:
662:
658:
651:
650:ChEMBL2010601
647:
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631:
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622:
618:
611:
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567:
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