Rucaparib

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Rucaparib
Rucaparib.svg
Clinical data
Pronunciation /rˈkæpərɪb/ roo-KAP-ə-rib
Trade names Rubraca
Synonyms AG014699
Routes of
administration
By mouth (tablets)
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Bioavailability 30–45% (Tmax = 1.9 hours)
Protein binding 70% (in vitro)
Metabolism Liver (primarily CYP2D6; 1A2 and 3A4 to a lesser extent)
Biological half-life 17–19 hours[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C19H18FN3O
Molar mass 323.37 g·mol−1
3D model (JSmol)

Rucaparib (brand name Rubraca /rˈbrɑːkə/ roo-BRAH-kə, code name AG 014699) is a PARP inhibitor used as an anti-cancer agent. Rucaparib is a first-in-class pharmaceutical drug targeting the DNA repair enzyme poly-ADP ribose polymerase-1 (PARP-1). It was discovered as part of a collaboration between scientists working at the Northern Institute of Cancer Research and Medical School of Newcastle University and Agouron Pharmaceuticals in San Diego, California.[2] It is being developed by Clovis Oncology.

In December 2016, the U.S. FDA granted an accelerated approval for use in cases of pretreated advanced ovarian cancer.[3]

It can be taken orally in tablet form.[1][4]

Biological effects[edit]

Rucaparib inhibits "the contraction of isolated vascular smooth muscle, including that from the tumours of cancer patients. It also reduces the migration of some cancer and normal cells in culture."[5]

Mechanism of action[edit]

As a PARP inhibitor, rucaparib is expected to be more effective in the 9% of pancreatic cancers with a BRCA mutation (BRCA1 or BRCA2).[6]

Regulatory Information[edit]

Clinical Trials[edit]

In 2013, a total of 106 patients from six different countries were enrolled into phase II trial (ARIEL2) to evaluate the activity of the investigational drug in women with platinum-sensitive advanced ovarian, fallopian tube, or primary peritoneal cancer. By 2015, the initial data from ARIEL2 were presented at ASCO, representing breakthrough therapy designation. of 106 patients in the study, 52 of the subjects did not show any adverse event, such as death or disease progression.Of these 52 patients, 18 subjects discontinued treatment for personal reasons.[7]

In the first quarter of 2016, the marketing applications were submitted in order to prove of the treatment of advanced ovarian cancer in women with deleterious BRCA mutation–positive (BRCAmut+). In June 2016, an NDA was filed with the FDA and the PDUFA date assigned for February 2017. However, surprisingly, rucaparib was granted fast-track status and was approved by the FDA in December 2016 as monotherapy treatment of mentioned patients who have been treated ≥2 prior chemotherapies. Furthermore, the FDA also approved the FoundationFocus CDxBRCA Test as the first next-generation sequencing (NGS)-based companion diagnostic to identify the most potent ovarian cancer patients who responded to rucaparib therapy.[8]

After the FDA approval, TRITON2 and TRITON3 mCRPC studies were initiated in order to determine how patients with prostate cancer will respond to the rucaparib drug. The studies for these two trials are still going on and the estimated dates for the first results are raging between 2019 through 2022.[9]

The ARIEL3 and ARIEL4 are two randomized, double-blind phase III studies. The ARIEL3 study was designed to evaluate the effect of the investigational agent as a maintenance treatment for the advanced platinum-sensitive ovarian cancer patients versus placebo after their response to ≥2 prior chemotherapies. The top-line results from the study were presented at the ESMO 2017 congress and right after that, it was published in the Lancet journal in September 2017. The findings showed significant improvement in progression-free survival (PFS) in patients treated with Rubraca than placebo. Recently, in October 2017, a supplemental sNDA for the rucaparib ARIEL3 maintenance treatment has been submitted to the FDA.[10]

The ARIEL4 trial is still going on to evaluate how patients will best respond to treatment with rucaparib versus chemotherapy. The estimated data collection date for primary outcome measurement will be in June 2022.[11]

Commercialization[edit]

Rucaparib is a prescription medicine being commercialized under the brand name Rubraca® by a biopharmaceutical company called Clovis Oncology, Inc. (NASDAQ: CLVS). The highest goal of the company is the discovery, development, and commercialization of novel anti-tumor drugs.[12]They believe that “ Delivering the right treatment to the right patient is the future of cancer therapy," said Patrick J. Mahaffy, President and CEO of Clovis.[13]

Commercial Aspects

The Clovis has reported a significant net loss since its inception, but during 2017 they had a transition to profitability relying on the revenues from their only marketed drug, Rubraca. In January 2017, the company has sold 5,750,000 shares ($41.00 per share) and their net proceeds were $221.2 million. Moreover, in June 2017 they sold 3,920,454 shares ($88.00 per share) with net proceeds of $324.9 million. The goal of the company is to spend the mentioned net proceeds of the offering for marketing and sales expenses associated with Rubraca.[14]

In June 2011, Pfizer announced an agreement with Clovis Oncology Inc. that permits the company to defer the milestone payments payable upon regulatory approval of an NDA. The Clovis has also been licensed from AstraZeneca in April 2012 to develop the rucaparib medicine for certain methods of treatment of patients with PARP inhibitors. In the first quarter of 2017, Clovis paid $0.75 million milestone payment to Pfizer. The company has also been committed to pay a $20.0 million milestone payment upon the FDA approval. However, Clovis has agreed to pay $3.0 million extra within 18 months in the hope of making a significant profit by selling Rubraca.[15]

Intellectual Property

There are a total of eight patent from the US Patent and Trademark Office (USPTO) and one NDA for the marketed rucaparib.[16]

The patents are related to the production methods, using methods, high dosage strength tablets, formulations, and multiple salt/polymorphic forms of the drug, with expiration dates between 2022-2035. For instance, the invention directed to the composition of matter will be expired in 2020 and the camsylate salt/polymorph patent family which is licensed from the Pfizer will be expired in 2031. Additional patent applications are still pending in the United States or Europe in various jurisdictions that, if issued, would have expiration dates ranging from 2029 through 2033.[17]

See also[edit]

References[edit]

  1. ^ a b "Rubraca (rucaparib) Tablets, for Oral Use. Full Prescribing Information" (PDF). Clovis Oncology, Inc. Boulder, CO 80301. Retrieved 20 December 2016. 
  2. ^ White, AW; Almassy, R; Calvert, AH; Curtin, NJ; Griffin, RJ; Hostomsky, Z; Maegley, K; Newell, DR; Srinivasan, S; Golding, BT (2 November 2000). "Resistance-Modifying Agents. 9. Synthesis and Biological Properties of Benzimidazole Inhibitors of the DNA Repair Enzyme Poly(ADP-ribose) Polymerase". Journal of Medicinal Chemistry. 43 (22): 4084–97. doi:10.1021/jm000950v. PMID 11063605. 
  3. ^ Bankhead, C (December 19, 2016). "PARP Inhibitor Gets FDA Nod for Ovarian Cancer". MedPage Today, LLC. Retrieved 20 December 2016. 
  4. ^ "Cancer Research Launches New Drug Trial". netdoctor.co.uk. Hearst Magazines UK. Retrieved 20 December 2016. 
  5. ^ http://www.qub.ac.uk/schools/SchoolofPharmacy/Filestore/Filetoupload,121186,en.pdf
  6. ^ Rucaparib shows clinical benefit in pancreatic cancer patients with BRCA mutation. June 2016
  7. ^ "Clovis Oncology Presents Data from Phase 2 Studies of Rucaparib in Advanced Ovarian Cancer and Pancreatic Cancer at 2016 ASCO Annual Meeting",http://www.businesswire.com/news/home/20160606005594/en/Clovis-Oncology-Presents-Data-Phase-2-Studies
  8. ^ "Rucaparib", https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm533891.htm
  9. ^ "CURRENT CLOVIS CLINICAL TRIALS INVESTIGATING RUCAPARIB", http://clovisoncology.com/files/Clovis_Oncology_Clinical_Trial_Fact_Sheet_FINAL_1.pdf
  10. ^ "[http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)32440-6.pdf Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3):a randomised, double-blind, placebo-controlled, phase 3 trial]",Robert L Coleman et al., (October 2017), Lancet 2017, 390: 1949–61, doi.org/10.1016/S0140-6736(17)32440-6
  11. ^ "CLOVIS ONCOLOGY TO PRESENT COMPREHENSIVE DATASET FROM SUCCESSFUL ARIEL3 CLINICAL TRIAL PROGRAM AT 2017 ESMO CONGRESS",http://ir.clovisoncology.com/phoenix.zhtml?c=247187&p=irol-newsArticle&ID=2297323
  12. ^ "Rucaparib: First Global Approval" ,Drugs, Yahiya Y. Syed, 2017, Volume 77, P. 585
  13. ^ "Delivering the right treatment to the right patient is the future of cancer therapy" ,http://clovisoncology.com/files/Clovis_Oncology_Clinical_Trial_Fact_Sheet_FINAL_1.pdf
  14. ^ "Clovis Oncology (CLVS)FORM 10-Q" ,https://www.sec.gov/Archives/edgar/data/1466301/000155837017005797/clvs-20170630x10q.htm
  15. ^ "Financial Reports SEC Filings" ,http://phx.corporate-ir.net/phoenix.zhtml?c=247187&p=irol-sec
  16. ^ "What is the patent landscape for Rubraca, and what generic Rubraca alternatives are available?" ,https://www.drugpatentwatch.com/p/tradename/RUBRACA
  17. ^ "CLOVIS ONCOLOGY, INC. filed this Form S-3ASR on 01/03/2017" ,http://ir.clovisoncology.com/mobile.view?c=247187&v=202&d=3&id=aHR0cDovL2FwaS50ZW5rd2l6YXJkLmNvbS9maWxpbmcueG1sP2lwYWdlPTExMzAxODk1JkRTRVE9MSZTRVE9NyZTUURFU0M9U0VDVElPTl9QQUdFJmV4cD0mc3Vic2lkPTU3

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