Ceritinib

Ceritinib is an anaplastic lymphoma kinase (ALK) inhibitor primarily used for the treatment of ALK positive metastatic NSCLC.{{cite web|url=https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/zykadia.pdf |title=Prescribing data |website=www.pharma.us.novartis.com |access-date=12 June 2019}}{{cite journal | vauthors = Deeks ED | title = Ceritinib: a Review in ALK-Positive Advanced NSCLC | journal = Targeted Oncology | volume = 11 | issue = 5 | pages = 693–700 | date = October 2016 | pmid = 27699584 | doi = 10.1007/s11523-016-0460-7 | s2cid = 24118254 }} Previously, it was only indicated for patients who had developed resistant to crizotinib, another ALK inhibitor, but has since had its usage expanded to serve as a primary option for metastatic NSCLC.{{cite web|url=https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-ceritinib-nsclc|title=FDA Expands Ceritinib Approval for Lung Cancer|date=27 June 2017|website=National Cancer Institute}}

Serious adverse effects include gastrointestinal toxicity, hepatotoxicity, interstitial lung disease, prolonged QT syndrome, hyperglycemia, bradycardia, and pancreatitis.{{cite journal | vauthors = Au TH, Cavalieri CC, Stenehjem DD | title = Ceritinib: A primer for pharmacists | journal = Journal of Oncology Pharmacy Practice | volume = 23 | issue = 8 | pages = 602–614 | date = December 2017 | pmid = 27738095 | doi = 10.1177/1078155216672315 | s2cid = 12034087 | doi-access = free }}

The most commonly reported side effects were diarrhea, nausea, elevated liver enzymes, vomiting, abdominal pain, fatigue, decreased appetite, and constipation.

Ceritinib is both a substrate and potent inhibitor of the enzyme CYP3A4, so medications that have affinity for this enzyme may interact with ceritinib.{{Cite book | title = Therapeutic Strategies to Overcome ALK Resistance in Cancer | editor = Luc Friboulet | volume = 13 | series = Cancer Sensitizing Agents for Chemotherapy | date = 2021 | page = 31}}

Ceritinib is a tyrosine kinase inhibitor that selectively and potently inhibits anaplastic lymphoma kinase (ALK). In normal physiology, ALK functions as a key step in the development and function of nervous system tissue. However, chromosomal translocation and fusion give rise to an oncogenic form of ALK that has been implicated in progression of NSCLC. Ceritinib thus acts to inhibit this mutated enzyme and stop cell proliferation, ultimately halting cancer progression.{{cite web|title=Analplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer|url=https://www.uptodate.com/contents/anaplastic-lymphoma-kinase-alk-fusion-oncogene-positive-non-small-cell-lung-cancer|website=UpToDate|publisher=Wolters Kluwer|access-date=30 October 2017}} Because ceritinib is considered a targeted cancer therapy, an FDA-approved test is required to determine which patients are candidates for ceritinib. This test, developed by Roche, is the VENTANA ALK (D5F3) CDx Assay and is used to identify ALK-positive NSCLC patients who would benefit from ceritinib treatment.{{cite web|url=https://diagnostics.roche.com/global/en/news-listing/2017/roche-announces-fda-approval-of-companion-diagnostic-to-identify.html|title=Roche announces FDA approval of companion diagnostic to identify ALK-positive non-small cell lung cancer patients|website=diagnostics.roche.com|access-date=12 June 2019|archive-date=26 April 2019|archive-url=https://web.archive.org/web/20190426195802/https://diagnostics.roche.com/global/en/news-listing/2017/roche-announces-fda-approval-of-companion-diagnostic-to-identify.html|url-status=dead}}

Researchers first identified the ALK fusion gene in 1994. Several years later, Novartis Pharmaceuticals Corporation, began working towards development of targeted ALK inhibitors. In April 2014, the FDA granted accelerated approval for ceritinib when used for ALK-positive NSCLC patients who have progressed on or are intolerant to crizotinib (Xalkori, Pfizer, Inc.). This rapid approval was determined from a multi-center clinical trial in which 163 patients who had disease progression or were intolerant to crizotinib received oral ceritinib 750 mg once daily. This trial demonstrated an objective response rate (ORR) of 44% and a median duration of response (DOR) of 7.1 months, both of which were favorable compared to the worsening or failed use of crizotinib.{{cite journal | vauthors = Khozin S, Blumenthal GM, Zhang L, Tang S, Brower M, Fox E, Helms W, Leong R, Song P, Pan Y, Liu Q, Zhao P, Zhao H, Lu D, Tang Z, Al Hakim A, Boyd K, Keegan P, Justice R, Pazdur R | title = FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer | journal = Clinical Cancer Research | volume = 21 | issue = 11 | pages = 2436–2439 | date = June 2015 | pmid = 25754348 | doi = 10.1158/1078-0432.CCR-14-3157 | doi-access = free }}

In February 2017, the FDA accepted a supplement New Drug Application for ceritinib and granted Priority Review for expanded use of ceritinib. Specifically, it became a first-line therapy option for metastatic NSCLC with ALK-positive tumors. Additionally, the FDA also gave Breakthrough Therapy designation to the drug for ALK-positive metastatic NSCLC that has metastasized to the brain.{{cite web|url=https://www.novartis.com/news/media-releases/novartis-drug-zykadia-receives-fda-priority-review-first-line-use-patients-alk|title=Novartis drug Zykadia receives FDA Priority Review for first-line use in patients with ALK+ metastatic NSCLC|website=Novartis|access-date=1 November 2017|archive-date=26 April 2019|archive-url=https://web.archive.org/web/20190426155720/https://www.novartis.com/news/media-releases/novartis-drug-zykadia-receives-fda-priority-review-first-line-use-patients-alk|url-status=dead}} This new designation resulted from the ASCEND-4 clinical trial, which was a randomized, phase III study that compared the use of ceritinib to standard-of-care platinum-based chemotherapy treatments. Median progression-free survival was 16.6 months for ceritinib (n=189) versus 8.1 months in the chemotherapy-treated patients (n=187).{{cite journal | vauthors = Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, Geater SL, Orlov S, Cortinovis D, Yu CJ, Hochmair M, Cortot AB, Tsai CM, Moro-Sibilot D, Campelo RG, McCulloch T, Sen P, Dugan M, Pantano S, Branle F, Massacesi C, de Castro G | title = First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study | journal = Lancet | volume = 389 | issue = 10072 | pages = 917–929 | date = March 2017 | pmid = 28126333 | doi = 10.1016/s0140-6736(17)30123-x | s2cid = 4739527 }}

Zykadia is manufactured by Novartis.{{cite web|url=https://www.us.zykadia.com/globalassets/products2.com/zykadia/pdf/crt-1132590-zykadia-branded-brochure.pdf |title=Brochure |website=www.us.zykadia.com |access-date=12 June 2019}} Created in 1996 from a merger between Ciba-Geigy and Sandoz, Novartis is a global corporation based out of Basel, Switzerland.{{cite web|title=Novartis Company History|url=https://www.novartis.com/about-us/who-we-are/novartis-company-history|website=Novartis Global|access-date=3 November 2017|archive-date=7 November 2017|archive-url=https://web.archive.org/web/20171107030240/https://www.novartis.com/about-us/who-we-are/novartis-company-history|url-status=dead}} Over 155 countries worldwide have Novartis products available for use.{{cite web|url=https://www.novartis.com/investors/novartis-annual-reporting-suite|title=Novartis Annual Reporting Suite|website=Novartis}} Financial data from 2016 reveals net sales of $48.5 billion for the Swiss company.

Novartis divides its shares into two major market exchanges: the ordinary shares (NOVN SW) trade in the Six Swiss Exchange while the American Depositary Receipts (NVS US) trade in the New York Stock Exchange.{{cite web|url=https://www.novartis.com/investors/share-data-analysis/share-overview|title=Share Overview|website=Novartis}} Nominees, fiduciaries, and ADR depositary make up the bulk of registered shareholders of Novartis stock while individual shareholders make up the lowest percentage.{{cite web|url=https://www.novartis.com/investors/share-data-analysis/share-ownership|title=Share Ownership|website=Novartis}}

Originally launched in 2014, Zykadia sales for Fiscal Year 2016 reached $91 million.{{cite web |url=https://www.novartis.com/sites/www.novartis.com/files/2017-01-interim-financial-report-en.pdf |title=Interim financial report |date=2017 |website=www.novartis.com |access-date=12 June 2019 |archive-date=4 December 2020 |archive-url=https://web.archive.org/web/20201204063447/https://www.novartis.com/sites/www.novartis.com/files/2017-01-interim-financial-report-en.pdf |url-status=dead }} While this is substantially less than several of their other pharmaceuticals, the new indication introduced in 2017 should result in increased sales of the drug. GlobalData predicts ceritinib sales to exceed $127million by 2025, while sustaining a compounded annual growth rate of 10.7%.{{cite magazine|url=https://drug-dev.com/nsclc-market-global-drug-forecast-market-analysis-to-2025/|title=NSCLC MARKET – Global Drug Forecast & Market Analysis to 2025| vauthors = Xuan C, Gunduz V |magazine=Drug Development & Delivery|issue=November–December 2016}}

Novartis currently owns twelve patents on Zykadia.{{cite web|url=https://www.pharmacompass.com/patent-expiry-expiration/zykadia|title=Zykadia - Patents - Expiry - Expiration - Dates|website=PharmaCompass.com}} The patents relate to different structures{{clarify|reason=What is the vague term "different structures" referring to? A chemical compound only has one chemical structure.|date=April 2019}} of the chemical compound as well as methodologies for manufacturing the drug. For example, one patent examines the structure of pyrimidines and their use in treatment of neoplastic diseases.{{cite web|title=US Patent No.: 7964592|url=https://www.lens.org/images/patent/US/7964592/B2/US_7964592_B2.pdf|website=PharmaCompass|access-date=1 November 2017}} Others examine the composition of protein kinase inhibitors.{{cite web|title=US No.: 8399450|url=https://www.lens.org/lens/patent/US_8399450_B2|website=PharmaCompass|access-date=1 November 2017}} The most recent patents are specific the methodologies of using ALK inhibitors.{{cite web|title=US No.: 8703787|url=https://www.lens.org/lens/patent/US_8703787_B2|website=PharmaCompass|access-date=1 November 2017}}

Ceritinib is also sold under the brand name Spexib in some countries by Novartis.{{cn|date=April 2024}}

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Category:4-Piperidinyl compounds

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Category:Drugs developed by Novartis