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Imatinib

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{{drugbox | verifiedrevid = 459451238 | IUPAC_name = 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide | image = Imatinib2DACS.svg | width = 300 | image2 = Imatinib3Dan.gif | width2 = 250 | tradename = Gleevec, Glivec | Drugs.com = Monograph | MedlinePlus = a606018 | licence_EU = Glivec | licence_US = IMATINIB | pregnancy_AU = D | pregnancy_US = D | legal_AU = S4 | legal_CA = Rx-only | legal_UK = POM | legal_US = Rx-only | routes_of_administration = Oral

| bioavailability = 98% | protein_bound = 95% | metabolism = Hepatic (mainly CYP3A4-mediated) | elimination_half-life = 18 hours (imatinib)
40 hours (active metabolite) | excretion = Faecal (68%) and renal (13%)

| CASNo_Ref =  checkY | CAS_number_Ref =  checkY | CAS_number = 152459-95-5 | CAS_supplemental =
220127-57-1 (mesilate) | ATC_prefix = L01 | ATC_suffix = XE01 | PubChem = 5291 | DrugBank_Ref =  checkY 

| DrugBank = DB00619

| ChemSpiderID_Ref =  checkY | ChemSpiderID = 5101 | UNII_Ref =  checkY | UNII = BKJ8M8G5HI | KEGG_Ref =  checkY | KEGG = D08066 | ChEBI_Ref =  checkY | ChEBI = 45783 | ChEMBL_Ref =  checkY | ChEMBL = 941

| C=29 | H=31 | N=7 | O=1 | molecular_weight = 493.603 g/mol
589.7 g/mol (mesilate) | smiles = Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)NC(=O)c4ccc(cc4)CN5CCN(CC5)C | InChI = 1/C29H31N7O/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34) | InChIKey = KTUFNOKKBVMGRW-UHFFFAOYAJ | StdInChI_Ref =  checkY | StdInChI = 1S/C29H31N7O/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34) | StdInChIKey_Ref =  checkY | StdInChIKey = KTUFNOKKBVMGRW-UHFFFAOYSA-N }} Imatinib (INN), marketed by Novartis as Gleevec (Canada, South Africa and the USA) or Glivec (Australia, Europe and Latin America), and sometimes referred to by its investigational name STI-571, is a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).[1]

Like all tyrosine-kinase inhibitors, imatinib works by preventing a tyrosine kinase enzyme, in this case BCR-Abl, from phosphorylating subsequent proteins and initiating the signalling cascade necessary for cancer growth and survival, thus preventing the growth of cancer cells and leading to their death by apoptosis.[2] Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form of targeted therapy—only cancer cells are killed through the drug's action.[3] In this regard, imatinib was one of the first cancer therapies to show the potential for such targeted action, and is often cited as a paradigm for research in cancer therapeutics.[4]

Imatinib has been cited as the first of the exceptionally expensive cancer drugs, costing $92,000 a year. Doctors and patients complain that this is excessive, given that its development costs have been recovered many times over, and that the costs of synthesizing the drug are orders of magnitude lower. In the USA, the patent protecting the active principle will expire on 4 January 2015 while the patent protecting the beta crystal form of the active principal ingredient will expire on 23 May 2019.[5]

The developers of imatinib were awarded the Lasker Award in 2009 and the Japan Prize in 2012.[6][7]

Medical uses

Imatinib is used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies.

Chronic myelogenous leukemia

The U.S. Food and Drug Administration (FDA) has approved imatinib as first-line treatment for Philadelphia chromosome-positive CML, both in adults and children. The drug is approved in multiple Philadelphia chromosome-positive cases of CML, including after stem cell transplant, in blast crisis, and newly diagnosed.[8]

Gastrointestinal stromal tumors

The FDA first granted approval for advanced GIST patients in 2002. On 1 February 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence.[9] The drug is also approved in unresectable KIT-positive GISTs.[8]

Other

The FDA has approved imatinib for use in adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), myelodysplastic/ myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements, aggressive systemic mastocytosis without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.[8] On 25 January 2013, Gleevec was approved for use in children with Ph+ ALL.[10]

For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, early research has shown potential for using the c-KIT tyrosine kinase blocking properties of imatinib.[11][12][13][14]

Experimental

One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-KIT.[15]However, since imatinib binds to tyrosine kinases when they are in the inactive configuration and the D816V mutant of c-KIT is constitutively active, imatinib does not inhibit the kinase activity of the D816V mutant of c-KIT. Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis.

Imatinib may also have a role in the treatment of pulmonary hypertension. It has been shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertension.[16] In systemic sclerosis, the drug has been tested for potential use in slowing down pulmonary fibrosis. In laboratory settings, imatinib is being used as an experimental agent to suppress platelet-derived growth factor (PDGF) by inhibiting its receptor (PDGF-Rβ). One of its effects is delaying atherosclerosis in mice without[17] or with diabetes.[18]

Mouse animal studies have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur.[19]

In vitro studies identified that a modified version of imatinib can bind to gamma-secretase activating protein (GSAP), which selectively increases the production and accumulation of neurotoxic beta-amyloid plaques. This suggests molecules that target at GSAP and are able to cross blood–brain barrier are potential therapeutic agents for treating Alzheimer's disease.[20]Another study suggests that imatinib may not need to cross the blood–brain barrier to be effective at treating Alzheimer's, as the research indicates the production of beta-amyloid may begin in the liver. Tests on mice indicate that imatinib is effective at reducing beta-amyloid in the brain.[21] It is not known whether reduction of beta-amyloid is a feasible way of treating Alzheimer's, as an anti-beta-amyloid vaccine has been shown to clear the brain of plaques without having any effect on Alzheimer symptoms.[22]

A formulation of imatinib with a cyclodextrin (Captisol) as a carrier to overcome the blood–brain barrier is also currently considered as an experimental drug for lowering and reversing opioid tolerance. Imatinib has shown reversal of tolerance in rats.[23] Imatinib is an experimental drug in the treatment of desmoid tumor or aggressive fibromatosis.

Contraindications and cautions

The only known contraindication to imatinib is hypersensitivity to imatinib.[24] Cautions include:[25]

  • Hepatic impairment, such as in the elderly.
  • Risk of severe CHF or left ventricular dysfunction, especially in patients with comorbidities
  • Pregnancy, risk of embryo-foetal toxicity.
  • Risk of fluid retention
  • Risk of growth stunting in children or adolescents

Adverse effects

See also: List of adverse effects of imatinib
bcr-abl kinase (green), which causes CML, inhibited by imatinib (red; small molecule).

The most common side effects include feeling sick (nausea), diarrhea, headaches, leg aches/cramps, fluid retention, visual disturbances, itchy rash, lowered resistance to infection, bruising or bleeding, loss of appetite;[26] weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), and edema.[27]

Severe congestive cardiac failure is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium.[28]

If imatinib is used in prepubescent children, it can delay normal growth, although a proportion will experience catch-up growth during puberty.[29]

Interactions

Its use is advised against in patients on strong CYP3A4 inhibitors such as clarithromycin, chloramphenicol, ketoconazole, ritonavir and nefazodone due to its reliance on CYP3A4 for metabolism.[25] Likewise it is a CYP3A4, CYP2D6 and CYP2C9 inhibitor and hence concurrent treatment with substrates of any of these enzymes may increase plasma concentrations of said drugs.[25]

Overdose

Medical experience with imatinib overdose is limited and treatment is purely supportive.[30] Dialysis is unlikely to be helpful seeing how highly plasma protein-bound imatinib is.[30] Symptoms of minor overdose include:

  • Nausea
  • Vomiting
  • Diarrhea
  • Rash
  • Erythema
  • Oedema
  • Swelling
  • Fatigue
  • Muscle spasms
  • Thrombocytopenia
  • Pancytopenia
  • Abdominal pain
  • Headache
  • Decreased appetite

Symptoms of moderate overdose include:[30]

  • Weakness
  • Myalgia
  • Increased CPK
  • Increased bilirubin
  • Gastrointestinal pain

Whereas symptoms of one single severe overdose include:[30]

  • Nausea
  • Vomiting
  • Abdominal pain
  • Pyrexia
  • Facial swelling
  • Neutrophil count decreased
  • Increased transaminases

Mechanism of action

Mechanism of action of imatinib
Mechanism of action of imatinib
Imatinib
Drug mechanism
Crystallographic structure of tyrosine-protein kinase ABL (rainbow colored, N-terminus = blue, C-terminus = red) complexed with imatinib (spheres, carbon = white, oxygen = red, nitrogen = blue).[31]
Therapeutic usechronic myelogenous leukemia
Biological targetABL, c-kit, PDGF-R
Mechanism of actionTyrosine-kinase inhibitor
External links
ATC codeL01XE01
PDB ligand idSTI: PDBe, RCSB PDB
LIGPLOT1iep

Imatinib is a 2-phenyl amino pyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.

There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain inabl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factorreceptor).

In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.

The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively.[32] This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.[33]

Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other known tyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl.[34] Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions.[35]

The Bcr-Abl pathway has many downstream pathways including the Ras/MapK pathway, which leads to increased proliferation due to increased growth factor-independent cell growth. It also affects the Src/Pax/Fak/Rac pathway. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion. The PI/PI3K/AKT/BCL-2 pathway is also affected. BCL-2 is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival. The last pathway that Bcr-Abl affects is the JAK/STAT pathway, which is responsible for proliferation.[36]

Pharmacokinetics

Imatinib is rapidly absorbed when given by mouth, and is highly bioavailable: 98% of an oral dose reaches the bloodstream. Metabolism of imatinib occurs in the liver and is mediated by several isozymes of the cytochrome P450 system, including CYP3A4 and, to a lesser extent, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. The main metabolite, N-demethylated piperazine derivative, is also active. The major route of elimination is in the bile and feces; only a small portion of the drug is excreted in the urine. Most of imatinib is eliminated as metabolites; only 25% is eliminated unchanged. The half-lives of imatinib and its main metabolite are 18 and 40 hours, respectively. It blocks the activity of Abelson cytoplasmic tyrosine kinase (ABL), c-Kit and the platelet-derived growth factor receptor (PDGFR). As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases. Imatinib has been reported to be an effective treatment for FIP1L1-PDGFRalpha+ mast cell disease, hypereosinophilic syndrome, and dermatofibrosarcoma protuberans.[37]

Interactions

Since imatinib is mainly metabolised via the liver enzyme CYP3A4, substances influencing the activity of this enzyme change the plasma concentration of the drug. An example of a drug that increases imatinib activity and therefore side effects by blocking CYP3A4 is ketoconazole. The same could be true of itraconazole, clarithromycin, grapefruit juice, among others. Conversely, CYP3A4 inductors like rifampicin and St. John's Wort reduce the drug's activity, risking therapy failure. Imatinib also acts as an inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma concentrations of a number of other drugs like simvastatin, ciclosporin, pimozide, warfarin, metoprolol, and possibly paracetamol. The drug also reduces plasma levels of levothyroxin via an unknown mechanism.[27]

As with other immunosuppressants, application of live vaccines is contraindicated because the microorganisms in the vaccine could multiply and infect the patient. Inactivated and toxoid vaccines do not hold this risk, but may not be effective under imatinib therapy.[38]

History

File:Time cover on Glivec 28 May 2001.png

Imatinib was invented in the late 1990s by scientists at Ciba-Geigy (which merged with Sandoz in 1996 to become Novartis), in a team led by biochemist Nicholas Lydon and that included Elisabeth Buchdunger and Jürg Zimmerman[39] and its use to treat CML was driven by oncologist Brian Druker of Oregon Health & Science University (OHSU).[40] Other major contributions to imatinib development were made by Carlo Gambacorti-Passerini, a physician scientist and hematologist at University of Milano Bicocca, Italy, John Goldman at Hammersmith Hospital in London, UK, and later on by Charles Sawyers of Memorial Sloan-Kettering Cancer Center.[41]Druker led the clinical trials confirming its efficacy in CML.[42]

Imatinib was developed by rational drug design. After the Philadelphia chromosome mutation and hyperactive bcr-abl protein were discovered, the investigators screened chemical libraries to find a drug that would inhibit that protein. With high-throughput screening, they identified 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib.[43]

A Swiss patent application was filed on imanitib and various salts on in April of 1992, which was then filed in the EU, the US, and other countries in March and April of 1993.[44][45] and in 1996 United States and European patent offices issued patents listing Jürg Zimmerman as the inventor.[46][47]

In July 1997, Novartis filed a new patent application in Switzerland on the beta crystalline form of imatinib mesylate (the mesylatesalt of imatinib). The "beta crystalline form" of the molecule is a specific polymorph of imatinib mesylate; a specific way that the individual molecules pack together to form a solid. This is the actual form of the drug sold as Gleevec/Glivec; a salt (imatinib mesylate) as opposed to a free base, and the beta crystalline form as opposed to the alpha or other form.[48]: 3 and 4  In 1998, Novartis filed international patent applications claiming priority to the 1997 filing.[49][50] A United States patent was granted in 2005.[51]

Both Novartis US patents mentioned here - the one on the freebase form of imatinib, and the one on the beta crystalline form of imatinib mesylate - are listed by Novartis along with others in the FDA's Orange Book entry for Gleevec.[52]

The first clinical trial of Gleevec took place in 1998 and the drug received FDA approval in May 2001, only two and a half months after the new drug application was submitted.[39][53] On the same month it made the cover of TIME magazine as a "bullet" to be used against cancer. Druker, Lydon and Sawyers received the Lasker-DeBakey Clinical Medical Research Award in 2009 for "converting a fatal cancer into a manageable chronic condition".[41]

During the FDA review, the tradename of the drug for the US market was changed from "Glivec" to "Gleevec" at the request of the FDA, to avoid confusion with Glyset, a diabetes drug.[54][55][56]

Costs

A box of 400-milligram Glivec tablets (Novartis), as sold in Germany.

In 2013, more than 100 cancer specialists published a letter in Blood saying that the prices of many new cancer drugs, including imatinib, are so high that U.S. patients couldn't afford them, and that the level of prices, and profits, was so high as to be immoral.[57][58] They stated that in 2001, imatinib was priced at $30,000 a year, which was based on the price of interferon, then the standard treatment, and that at this price Novartis would have recouped its initial development costs in two years. They stated that after unexpectedly becoming a blockbuster, Novartis increased the price to $92,000 per year in 2012, with annual revenues of $4.7 billion. Other doctors have complained about the cost.[59][60][61]

Prices for a 100 mg pill of Gleevec internationally range from $20 to $30,[62] although generic imatinib is cheaper, as low as $2 per pill.[63]

Patent litigation in India

Main article: Novartis v. Union of India & Others

Novartis fought a seven year, controversial battle to patent Gleevec in India, and took the case all the way to the Indian Supreme Court. The patent application at the center of the case was filed by Novartis in India in 1998, after India had agreed to enter the World Trade Organization and to abide by worldwide intellectual property standards under the TRIPS agreement. As part of this agreement, India made changes to its patent law; the biggest of which was that prior to these changes, patents on products were not allowed, while afterwards they were, albeit with restrictions. These changes came into effect in 2005, so Novartis' patent application waited in a "mailbox" with others until then, under procedures that India instituted to manage the transition. India also passed certain amendments to its patent law in 2005, just before the laws came into effect.[64]

The patent application[65][50] claimed the final form of Gleevec (the beta crystalline form of imatinib mesylate).[66]: 3  In 1993, during the time India did not allow patents on products, Novartis had patented imatinib, with salts vaguely specified, in many countries but could not patent it in India.[67][68] The key differences between the two patent applications, were that 1998 patent application specified the counterion(Gleevec is a specific salt - imatinib mesylate) while the 1993 patent application did not claim any specific salts nor did it mention mesylate, and the 1998 patent application specified the solid form of Gleevec - the way the individual molecules are packed together into a solid when the drug itself is manufactured (this is separate from processes by which the drug itself is formulated into pills or capsules) - while the 1993 patent application did not. The solid form of imatinib mesylate in Gleevec is beta crystalline.[69]

As provided under the TRIPS agreement, Novartis applied for Exclusive Marketing Rights (EMR) for Gleevec from the Indian Patent Office and the EMR was granted in November 2003.[70] Novartis made use of the EMR to obtain orders against some generic manufacturers who had already launched Gleevec in India.[71] Novartis set the price of Gleevec at USD 2666 per patient per month; generic companies were selling their versions at USD 177 to 266 per patient per month.[72] Novartis also initiated a program to assist patients who could not afford its version of the drug, concurrent with its product launch.[73]

When examination of Novartis' patent application began in 2005, it came under immediate attack from oppositions initiated by generic companies that were already selling Gleevec in India and by advocacy groups. The application was rejected by the patent office and by an appeal board. The key basis for the rejection was the part of Indian patent law that was created by amendment in 2005, describing the patentability of new uses for known drugs and modifications of known drugs. That section, Paragraph 3d, specified that such inventions are patentable only if "they differ significantly in properties with regard to efficacy."[74][71] At one point, Novartis went to court to try to invalidate Paragraph 3d; it argued that the provision was unconstitutionally vague and that it violated TRIPS. Novartis lost that case and did not appeal.[75] Novartis did appeal the rejection by the patent office to India's Supreme Court, which took the case.

The Supreme Court case hinged on the interpretation of Paragraph 3d. The Supreme Court issued its decision in 2013, ruling that the substance that Novartis sought to patent was indeed a modification of a known drug (the raw form of imatinib, which was publicly disclosed in the 1993 patent application and in scientific articles), that Novartis did not present evidence of a difference in therapeutic efficacy between the final form of Gleevec and the raw form of imatinib, and that therefore the patent application was properly rejected by the patent office and lower courts.[76]

Although the court ruled narrowly,[77] and took care to note that the subject application was filed during a time of transition in Indian patent law,[78] the decision generated widespread global news coverage and reignited debates on balancing public good with monopolistic pricing, innovation with affordability etc.[79][80][81]

Had Novartis won and gotten its patent issued, it could not have prevented generics companies in India from continuing to sell generic Gleevec, but it could have obligated them to pay a reasonable royalty under a grandfather clause included in India's patent law.[82][83]

Synthesis

Imatinib synthesis.[84]

See also

References

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  31. ^ PDB: 1IEP​; Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J (August 2002). "Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571)" (PDF). Cancer Res. 62 (15): 4236–43. PMID 12154025.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  33. ^ Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L (February 2003). "Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias". Lancet Oncol. 4 (2): 75–85. doi:10.1016/S1470-2045(03)00979-3. PMID 12573349.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  34. ^ Deininger MW, Druker BJ (September 2003). "Specific targeted therapy of chronic myelogenous leukemia with imatinib". Pharmacol. Rev. 55 (3): 401–23. doi:10.1124/pr.55.3.4. PMID 12869662.
  35. ^ Vigneri P, Wang JY (February 2001). "Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase". Nat. Med. 7 (2): 228–34. doi:10.1038/84683. PMID 11175855.
  36. ^ Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD (May 2007). "Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia". Nature Reviews Cancer. 7 (5): 345–56. doi:10.1038/nrc2126. PMID 17457302.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  39. ^ a b Staff, Innovation.org (a project of the Pharmaceutical Research and Manufacturers of America)The Story of Gleevec
  40. ^ Claudia Dreifus for the New York Times. November 2, 2009 Researcher Behind the Drug Gleevec
  41. ^ a b A Conversation With Brian J. Druker, M.D., Researcher Behind the Drug Gleevec by Claudia Dreifus, The New York Times, 2 November 2009
  42. ^ Gambacorti-Passerini C (2008). "Part I: Milestones in personalised medicine—imatinib". Lancet Oncology. 9 (600): 600. doi:10.1016/S1470-2045(08)70152-9. PMID 18510992.
  43. ^ Druker BJ, Lydon NB (January 2000). "Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia". J. Clin. Invest. 105 (1): 3–7. doi:10.1172/JCI9083. PMC 382593. PMID 10619854.
  44. ^ U.S. patent 5,521,184
  45. ^ Seehere for worldwide filings]
  46. ^ US Patent 5,521,184
  47. ^ [1]
  48. ^ Staff, European Medicines Agency, 2004.EMEA Scientific Discussion of Glivec
  49. ^ Note: The Indian patent application, which became the subject of litigation in India that gathered a lot of press, does not appear to be publicly available. However according to documents produced in the course of that litigation (page 27), "The Appellant’s application under the PCT was substantially on the same invention as had been made in India."
  50. ^ a b Published PCT application WO1999003854
  51. ^ US Patent 6,894,051
  52. ^ FDA Orange Book; Patent and Exclusivity Search Results from query on Appl No 021588 Product 001 in the OB_Rx list.
  53. ^ Novartis press release, May 10, 2001. [http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=5838 FDA approves Novartis' unique cancer medication Glivec®
  54. ^ Cohen MH et al. Approval Summary for Imatinib Mesylate Capsules in the Treatment of Chronic Myelogenous Leukemia Clin Cancer Res May 2002 8; 935
  55. ^ Margot J. Fromer for Oncology Times. December 2002. What’s in a Name? Quite a Lot When It Comes to Marketing & Selling New Cancer Drugs
  56. ^ Novartis Press Release. April 30 2001Novartis Oncology Changes Trade Name of Investigational Agent Glivec(TM) to Gleevec(TM) in the United States
  57. ^ Experts in Chronic Myeloid Leukemia. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts Blood. 2013 May 30;121(22):4439-42. PMID 23620577
  58. ^ Andrew Pollack for the New York Times, April 25, 2013 Doctors Denounce Cancer Drug Prices of $100,000 a Year
  59. ^ Schiffer CA (July 2007). "BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia". N. Engl. J. Med. 357 (3): 258–65. doi:10.1056/NEJMct071828. PMID 17634461.
  60. ^ As Pills Treat Cancer, Insurance Lags Behind, By ANDREW POLLACK, New York Times, 14 April 2009
  61. ^ Living With a Formerly fatal Blood Cancer, By JANE E. BRODY, New York Times, 18 January 2010
  62. ^ Patented Medicine Review Board (Canada). Report on New Patented Drugs – Gleevec.
  63. ^ "pharmacychecker.com". pharmacychecker.com. Retrieved 3 April 2013.
  64. ^ Gardiner Harris and Katie Thomas for the New York Times. April 1 2013 Top court in India rejects Novartis drug patent
  65. ^ Note: The Indian patent application No.1602/MAS/1998 does not appear to be publicly available. However according to the decision of the IPAB on 26 June 2009 (page 27) discussed below, "The Appellant’s application under the PCT was substantially on the same invention as had been made in India."
  66. ^ Staff, European Medicines Agency, 2004. EMEA Scientific Discussion of Glivec
  67. ^ US Patent 5,521,184
  68. ^ EP0564409
  69. ^ Indian Supreme Court Decision paragraphs 5-6
  70. ^ Novartis v UoI, para 8-9
  71. ^ a b Shamnad Basheer for Spicy IP March 11, 2006First Mailbox Opposition (Gleevec) Decided in India
  72. ^ Staff, LawyersCollective. September 6, 2011[http://www.lawyerscollective.org/news/archived-news-a-articles/126-novartis-case-background-and-update-supreme-court-of-india-to-recommence-hearing.html Novartis case: background and update – Supreme Court of India to recommence hearing
  73. ^ R. Jai Krishna and Jeanne Whalen for the Wall Street Journal. April 1, 2013Novartis Loses Glivec Patent Battle in India
  74. ^ Intellectual Property Appellate Board decision dated 26 June 2009, p 149
  75. ^ W.P. No.24759 of 2006
  76. ^ "Supreme Court rejects bid by Novartis to patent Glivec".
  77. ^ Novartis v UoI, Para 191
  78. ^ Novartis v UoI, Para 24-25
  79. ^ "How the Indian judgment will reverberate across the world".
  80. ^ "Patented drugs must be priced smartly".
  81. ^ Patent with a purpose, Prof. Shamnad Basheer, Indian Express, 3 April 2013
  82. ^ Kevin Grogan for PharmaTimes. February 27, 2012 Novartis explains stance over India patent law challenge
  83. ^ Berne Declaration. May 8, 2007 Short questions and answers about the court case initiated by Novartis in India
  84. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/0960-894X(96)00197-7, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/0960-894X(96)00197-7 instead.
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