Chemistry:Nepafenac

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Nepafenac, sold under the brand name Nevanac among others, is a nonsteroidal anti-inflammatory drug (NSAID), usually sold as a prescription eye drop 0.1% solution (Nevanac) or 0.3% solution (Ilevro). It is used to treat pain and inflammation associated with cataract surgery.[1] Nepafenac is a prodrug of amfenac, an inhibitor of COX-1 and COX-2 activity.[2][3]

Medical uses

Nepafenac is indicated for use in the treatment of pain and inflammation following cataract surgery.[1][4][5][6]

In the European Union nepafenac is also indicated for the reduction in the risk of postoperative macular edema associated with cataract surgery in people with diabetes.[6]

Pharmacology

Mechanism of action

Nepafenac is an NSAID, thought to be a prodrug of amfenac after conversion by ocular tissue hydrolases after penetration via the cornea.[4][5] Amfenac, like other NSAIDs, is thought to inhibit cyclooxygenase action.[4][5]

Adverse events

Side effects include headache; runny nose; pain or pressure in the face; nausea; vomiting; and dry, itchy, sticky eyes.[7] Serious side effects include red or bloody eyes; foreign body sensation in the eye; sensitivity to light; decreased visual acuity; seeing specks or spots; teary eyes; or eye discharge or crusting.[7]

Regulatory

Nevanac

On February 25, 2005, Alcon filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for Nevanac 0.1%.[8] Results from the two trials referenced in the NDA (Phase 2/3 study C-02-53; Phase 3 study C-03-32) have not been published.[9] Study C-02-53 consisted of 228 patients across 10 centers in the United States.[10] Study C-03-32 consisted of 522 patients across 22 centers in the United States.[10] The efficacy results presented were confirmed in a study published in 2007.[11]

Nevanac was approved by the FDA on August 19, 2005, with application number 021–862.[12]

Ilevro

An NDA for Ilevro was filed on December 15, 2011.[13] In a one-month study, no new toxicities arose in the new formulation of nepafenac.[14] Safety and efficacy information was derived from the previous Nevanac application.[14] In June 2010, a confirmatory study began (Study C09055) consisting of over 2000 patients from 49 US sites and 37 European sites.[15][16] A second phase 3 trial (Study C11003) was conducted in a population of 1,342 patients at 37 sites across the United States which failed to demonstrate superiority over Nevanac in an altered dosing regimen.[15]

Ilevro was approved by the FDA on October 16, 2012, with application number 203–491.[17]

Commercialization

Both Nevanac and Ilevro are manufactured and sold by Alcon, Inc.[4][5] Alcon is currently a division of Novartis International AG, which is primarily based out of Switzerland.[18] Alcon, Inc. also holds locations in both Switzerland and the United States.[19] The company has gone through several name changes, from Alcon Laboratories, Inc. to Alcon Universal, Ltd., to Alcon, Inc.[19]

Nevanac entered the market in 2005 as a product of Alcon, at the time a subsidiary of Nestlé.[20] On April 6, 2008, Novartis agreed to purchase approximately 74 million shares of Alcon from Nestlé at $143.18 per share.[20] On January 4, 2010, Novartis agreed to purchase all remaining shares of Alcon from Nestlé, totalling 156 million shares or 77% of the shares in the company.[20] At the time of the purchase, a proposal for a merger under Swiss merger law was given to the Alcon board of directors.[20] The merger was agreed upon on December 15, 2010, making Alcon "the second largest division within Novartis."[20] The merger was completed on April 8, 2011.[21]

Ilevro was launched by Alcon on January 21, 2013.[22] In 2014 and 2015, net sales by Alcon grew, contributed to in part by the increased volume in sales of Ilevro.[23][24][25] That financial year, Novartis reported $18 billion in total financial debt.[23] That figure has grown steadily since. In 2016, Novartis reported a total debt of $23.8 billion,[26] up from the $21.9 billion reported in 2015 [25] and the $20.4 billion reported in 2014.[24] As of May 2017, Novartis is estimated to be worth $193.2 billion.[27]

On January 27, 2016, Alcon was moved to become a branch of the Innovative Medicines Division at Novartis.[26] Early in 2016, Alcon formed agreements with both TrueVision and PowerVision, and acquired Transcend Medical.[26] As of January 2017, Novartis is weighing options for Alcon in the business structure.[26]

Commercial risks

Alcon faced declining growth in 2016, having faced challenges in development and marketing of new products.[26]

Marketing

Novartis maintains a detailing unit geared toward health professionals consisting of over 3,000 employees within the United States and an additional 21,000 worldwide.[26] Novartis is also seeking to expand direct-to-consumer advertising and entrance into specialty product markets.[26] Novartis also notes the influence of position and preference on US Centers for Medicare & Medicaid formularies in expanding their market value.[26]

Nepafenac, Nevanac, and Ilevro are all absent from the 2016 Annual Report issued from Novartis.[26]

Intellectual property

There are currently[when?] seven U.S. patents filed that are directly associated with the modernized formulations of nepafenac, all stemming from Novartis.[28] There are three patents associated with Nevanac that are still[when?] active[29] and four associated with Ilevro.[30] The earliest patent related to the modern formulations of nepafenac was approved on June 11, 2002, after being filed in 1999, by Bahram Asgharian.[31] A patent was filed by Warren Wong, associated with Alcon, Inc. based out of Fort Worth, Texas, on December 2, 2005, for aqueous suspensions of nepafenac.[32] Another patent for a nepafenac-based drug was filed on May 8, 2006, by Geoffrey Owen, Amy Brooks, and Gustav Graff.[33] A patent was filed by Masood A. Chowhan and Huagang Chen on February 9, 2007, and approved on May 24, 2011,[34] followed closely by a patent filed by Warren Wong on September 23, 2010, and approved on December 6, 2011.[35] Masood A. Chowhan, Malay Ghosh, Bahram Asgharian, and Wesley Wehsin Han filed another patent on December 1, 2010, and approved on December 30, 2014.[36] The most recent[when?] patent was filed by Masood A. Chowhan, Malay Ghosh, Bahram Asgharian, and Wesley Weshin Han on November 12, 2014, and approved on May 30, 2017.[37] These patents are in effect until dates ranging between July 17, 2018, and March 31, 2032.[30]

Novartis also maintains patents on nepafenac in 26 countries outside the United States.[38]

References

  1. ↑ 1.0 1.1 Nepafenac Monograph
  2. ↑ Drugbank: Nepafenac
  3. ↑ "Effect of preoperative use of topical prednisolone acetate, ketorolac tromethamine, nepafenac and placebo, on the maintenance of intraoperative mydriasis during cataract surgery: a randomized trial". Indian Journal of Ophthalmology 60 (4): 277–81. July 2012. doi:10.4103/0301-4738.98705. PMID 22824596. 
  4. ↑ 4.0 4.1 4.2 4.3 "Nevanac- nepafenac suspension/ drops". 9 September 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3ad48650-75e3-4c74-9302-01b0088f164e. 
  5. ↑ 5.0 5.1 5.2 5.3 "Ilevro- nepafenac suspension". 9 September 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6c212466-ff8d-ecfc-ede2-ef8bdcaaf114. 
  6. ↑ 6.0 6.1 "Nevanac EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/nevanac. 
  7. ↑ 7.0 7.1 "Nepafenac Ophthalmic". U.S. National Library of Medicine. https://medlineplus.gov/druginfo/meds/a606007.html. 
  8. ↑ "Nevanac Approval Package". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021862s000_Nevanac_approv.pdf. 
  9. ↑ "Topical ophthalmic NSAIDs: a discussion with focus on nepafenac ophthalmic suspension". Clinical Ophthalmology 2 (2): 355–68. June 2008. doi:10.2147/opth.s1067. PMID 19668727. 
  10. ↑ 10.0 10.1 "Nevanac Statistical Review". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021862s000_Nevanac_statr.pdf. 
  11. ↑ "Nepafenac ophthalmic suspension 0.1% for the prevention and treatment of ocular inflammation associated with cataract surgery". Journal of Cataract and Refractive Surgery 33 (1): 53–8. January 2007. doi:10.1016/j.jcrs.2006.08.043. PMID 17189793. 
  12. ↑ "Drug Approval Package: Nevanac (Nepafenac) Ophthalmic Suspension NDA #021862". January 6, 2005. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021862s000_NevanacTOC.cfm. 
  13. ↑ "Ilevro Approval Package". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203491Orig1s000Approv.pdf. 
  14. ↑ 14.0 14.1 "203491 Pharmacology Review". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203491Orig1s000PharmR.pdf. 
  15. ↑ 15.0 15.1 "Ilevro Statistical Review". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203491Orig1s000StatR.pdf. 
  16. ↑ Confirmatory Study Nepafenac 0.3%. U.S. National Library of Medicine. 29 November 2012. https://clinicaltrials.gov/ct2/show/NCT01109173. Retrieved October 31, 2017. 
  17. ↑ "Drug Approval Package: Nepafenac Ophthalmic Suspension, 0.3% NDA #203491". April 8, 2013. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203491_nepafenac_toc.cfm. 
  18. ↑ "About Us". https://www.novartis.com/about-us. 
  19. ↑ 19.0 19.1 "Nevanac Administrative Documents and Correspondence". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021862s000_Nevanac_admincorres.pdf. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 "Alcon Annual Report 2010". United States Securities and Exchange Commission. https://www.sec.gov/Archives/edgar/data/1167379/000116737911000037/acl20f2010.pdf. 
  21. ↑ "Alcon Form 15". United States Securities and Exchange Commission. https://www.sec.gov/Archives/edgar/data/1167379/000110465911021611/a11-7954_41512b.htm. 
  22. ↑ "Alcon Launches ILEVRO™ (nepafenac ophthalmic suspension) 0.3%, a New Non-Steroidal Anti-Inflammatory Drug, for the Treatment of Pain and Inflammation Associated with Cataract Surgery". https://www.alcon.com/news/media-releases/alcon-launches-ilevro-nepafenac-ophthalmic-suspension-03-new-non-steroidal-anti. 
  23. ↑ 23.0 23.1 "Form 20-F". United States Securities and Exchange Commission. https://www.sec.gov/Archives/edgar/data/1114448/000104746914000415/a2217883z20-f.htm. 
  24. ↑ 24.0 24.1 "Form 20-F". United States Securities and Exchange Commission. https://www.sec.gov/Archives/edgar/data/1114448/000104746915000433/a2222787z20-f.htm. 
  25. ↑ 25.0 25.1 "Form 20F". United States Securities and Exchange Commission. https://www.sec.gov/Archives/edgar/data/1114448/000104746916009872/a2227040z20-f.htm. 
  26. ↑ 26.0 26.1 26.2 26.3 26.4 26.5 26.6 26.7 26.8 "Form 20-F". United States Securities and Exchange Commission. https://www.sec.gov/Archives/edgar/data/1114448/000104746917000338/a2230622z20-f.htm. 
  27. ↑ "Novartis on the Forbes Top Multinational Performers List". https://www.forbes.com/companies/novartis/. 
  28. ↑ "Nepafenac". PharmaCompass. https://www.pharmacompass.com/patent-expiry-expiration/nepafenac. 
  29. ↑ "Generic Nevanac Availability". https://www.drugs.com/availability/generic-nevanac.html. 
  30. ↑ 30.0 30.1 "Generic Ilevro Availability". https://www.drugs.com/availability/generic-ilevro.html. 
  31. ↑ "United States Patent Application: 6403609". http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/6403609. 
  32. ↑ "United States Patent Application: 0060122277". http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20060122277.PGNR.. 
  33. ↑ "United States Patent Application: 0060257487". http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=/netahtml/PTO/srchnum.html&r=1&f=G&l=50&s1=20060257487.PGNR.. 
  34. ↑ "United States Patent: 7947295". http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/7947295. 
  35. ↑ "United States Patent: 8071648". http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/8071648. 
  36. ↑ "United States Patent: 8921337". http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/8921337. 
  37. ↑ "United States Patent: 9662398". http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/9662398. 
  38. ↑ "Nepafenac - Generic Drug Details". thinkBiotech LLC. https://www.drugpatentwatch.com/p/generic-api/nepafenac. 



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