COSY NMR PREDICT
Ivacaftor (trade name Kalydeco, developed as VX-770) is a drug approved for patients with a certain mutation of cystic fibrosis, which accounts for 4–5% cases of cystic fibrosis. Ivacaftor was developed by Vertex Pharmaceuticals in conjunction with theCystic Fibrosis Foundation and is the first drug that treats the underlying cause rather than the symptoms of the disease. Called “the most important new drug of 2012”, and “a wonder drug” it is one of the most expensive drugs, costing over US$300,000 per year, which has led to criticism of Vertex for the high cost.
Ivacaftor (VX-770, Kalydeco) is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively
Ivacaftor is a white to off-white crystalline solid. It is freely soluble in methylethyl ketone/water mixture, soluble in 2-methyl tetrahydrofuran and PEG 400, slightly soluble in methanol, acetone and ethanol and practically insoluble in water and buffers with pH 1.0 – 7.0. The active substance shows polymorphism. Mixture of two major crystalline neat polymorphic forms (B and C) is obtained when manufactured by the commercial manufacturing process described. Form C is the most thermodynamically stable neat form. The polymorphic form is not of concern during the synthesis of the active substance, as the active substance is fully dissolved during manufacture of the finished product…………http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002494/WC500130766.pdf
Quality by Design (QbD) approach has been used in product and process development of ivacaftor. For the active substance synthesis, a combination of multivariate analyses and range-finding studies was used to define a design space for each step. All parameters with a potential impact on critical quality attributes (CQAs) of the active substance were identified and thoroughly investigated. The Applicant has proposed a combination of proven acceptable ranges (PARs) and design spaces (DSs) for the manufacturing process of the active substance. Design spaces have been developed at small laboratory scales (0.5-20 g) and the scale-up to production levels (100 kg) is wide (x 5000, x 10.000…).
Cystic fibrosis is caused by any one of several defects in a protein, cystic fibrosis transmembrane conductance regulator (CFTR), 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 glycine (G) in position 551 is replaced with aspartic acid (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 potentiator, 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.
The cost of ivacaftor is $311,000 per year, roughly similar to the price of other drugs for extremely rare diseases. In the first 9 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, drug development expenses were $458M, most of which was spent on cystic fibrosis-related research.
An editorial in JAMA called the price of ivacaftor “exorbitant”, citing the support by the Cystic Fibrosis Foundation in its development and the contribution made by fundamental scientific research performed by the National Institutes of Health 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 the company, before the drug won approval.”
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 drug was successfully developed and 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.
Vertex said it would make the drug 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 drug wrote to Vertex to protest the price of the drug, which had been set at about $300,000 per year. In the UK, the company provided the drug 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 (QALY) at between £335,000 and £1,274,000 —well above the National Institute for Health and Care Excellence thresholds.
The drug was not covered under the Ontario Drug Benefit plan until June 2014 when the Province of Ontario and the manufacturer negotiated for what “Ontario Health MinisterDeb Matthews had called a “fair price” for taxpayers”. The negotiations took 16 months and it was estimated that around 20 Ontarians required the drug at the time.
NMR GRAPH FROM NET
1H NMR PREDICT
13C NMR PREDICT
1H NMR PREDICT VIA NMRDB
13C NMR VIA NMRDB
(0.2 g, 71%). 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 11.82 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.84−7.78 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.56−7.45 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H).
HRMS-ESI (m/z): [M + H]+ calcd for C24H28N2O3, 393.2178; found, 393.2164.
VERTEX PHARMACEUTICALS INCORPORATED Patent: US2008/90864 A1, 2008 ; Location in patent: Page/Page column 8; 9 ;
Heterocycles, , vol. 89, # 4 p. 1035 – 1040
US2011/230519 A1, ;
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- “Phase 3 Study of VX-770 Shows Marked Improvement in Lung Function Among People with Cystic Fibrosis with G551D Mutation”. Press Release. Cystic Fibrosis Foundation. 2011-02-23.
- “The Most Important New Drug Of 2012 – Forbes”.
- “The $300,000 Drug – NYTimes.com”.
- Eckford PD, Li C, Ramjeesingh M, Bear CE (October 2012). “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”. J. Biol. Chem. 287 (44): 36639–49.doi:10.1074/jbc.M112.393637. PMID 22942289.
- Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P (November 2009).“Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770”.Proc. Natl. Acad. Sci. U.S.A. 106 (44): 18825–30. doi:10.1073/pnas.0904709106.PMC 2773991. PMID 19846789.
- Sloane PA, Rowe SM (November 2010). “Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis”. Curr Opin Pulm Med 16(6): 591–7. doi:10.1097/MCP.0b013e32833f1d00. PMID 20829696.
- “pi.vrtx.com” (PDF).
- “FAQs about the Cause, Diagnosis, Treatment of Cystic Fibrosis & More | CF Foundation”.
- 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”.Hum. Mutat. 19 (6): 575–606. doi:10.1002/humu.10041. PMID 12007216.
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- Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW (November 2010). “Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation”. N. Engl. J. Med. 363(21): 1991–2003. doi:10.1056/NEJMoa0909825. PMC 3148255. PMID 21083385.
- “Kalydeco: Annex I: Summary of product characteristics” (PDF). European Medicines Agency.
- “pi.vrtx.com” (PDF).
- “F.D.A. Approves New Cystic Fibrosis Drug”. New York Times. January 31, 2012. Retrieved 2015-02-10.
- “Vertex Pharmaceuticals 10-Q, Quarter ending September 30, 2014”. Retrieved2015-02-10.
- Brian P. O’Sullivan; David M. Orenstein; Carlos E. Milla (October 2, 2013). “Viewpoint: Pricing for Orphan Drugs: Will the Market Bear What Society Cannot?”. JAMA. 310 (13): 1343–1344. doi:10.1001/jama.2013.278129.
- “Cystic Fibrosis: Charity and Industry Partner for Profit”. MedPage Today. May 19, 2013. Retrieved 2015-02-10.
- “CF Foundation Cashes Out on Kalydeco in $3.3B Sale to Royalty Pharma | Xconomy”.
- “CF Foundation Royalty Sale Will Be Transformational for People with CF”.
- “FDA Approves KALYDECO™ (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis” (Press release). Cambridge, Massachusetts: Vertex Pharmaceuticals. 2012-01-31. Retrieved 2014-02-01.
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- Ferguson, Rob (June 20, 2014). “OHIP to cover cystic fibrosis drug Kalydeco”. The Toronto Star. Retrieved June 20, 2014.
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- FAQs About VX-770 from the Cystic Fibrosis Foundation
|US4556658 *||Apr 24, 1984||Dec 3, 1985||Bayer Aktiengesellschaft||7-Amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acids and antibacterial agents containing these compounds|
|US4822801 *||Oct 20, 1986||Apr 18, 1989||Warner-Lambert Company||4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents|
|US20060074075 *||Jun 24, 2005||Apr 6, 2006||Sara Hadida-Ruah||Modulators of ATP-binding cassette transporters|
|US20100267768 *||Mar 19, 2010||Oct 21, 2010||Vertex Pharmaceuticals Incorporated||Process for making modulators of cystic fibrosis transmembrane conductance regulator|
|US20110064811 *||Dec 28, 2006||Mar 17, 2011||Patricia Hurter||Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide|
|Systematic (IUPAC) name|
|Licence data||US FDA:link|
|Biological half-life||12 hrs (single dose)|
|CAS Registry Number||873054-44-5|
|Molecular mass||392.490 g/mol|
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//////Ivacaftor, Kalydeco, VX-770