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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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FDA grants priority review to Pharmacyclics drug
ibrutinib
FDA grants priority review to Pharmacyclics drug
Pharmacyclics is getting a priority review of its blood cancer treatment by federal regulators. A priority review shortens a drug evaluation by the U.S. Food and Drug Administration from 10 months to six. The acceptance of the application triggers a $75 million milestone payment to Pharmacyclics from Johnson & Johnson’s Janssen unit.
Ibrutinib (USAN[1]), also known as PCI-32765, is an experimental drug candidate for the treatment of various types of cancer. It is an orally-administered, selective and covalent inhibitor of the enzyme Bruton tyrosine kinase (Btk).[2][3][4] Ibrutinib is currently under development by Pharmacyclics, Inc and Johnson & Johnson’s Janssen Pharmaceutical division for B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and multiple myeloma.[6][7][8]. Ibrutinib was first designed and synthesized at Celera Genomics by Zhengying Pan, who along with a team of chemists and biologists reported in 2007 a structure-based approach for creating a series of small molecules that inactivate BTK through covalent binding to cysteine-481 near the ATP binding domain of BTK[2]. These small molecules irreversibly inhibited BTK by using a Michael acceptor for binding to the target cysteine. In April 2006, Pharmacyclics acquired Celera’s small molecule BTK inhibitor discovery program, which included a compound, PCI-32765 (known as compound 13 in the Pan et al paper) that was subsequently chosen for further preclinical development based on the discovery of anti-lymphoma properties in vivo [5]. Since 2006, Pharmacyclics’ scientists have advanced the molecule into clinical trials and identified specific clinical indications for the drug. [2][3][4] [5] [6][7][8] It also has potential effects against autoimmune arthritis.[9]
Clinical trials
It has given good results in two phase II clinical trials.[10]
Mechanism
In preclinical studies on chronic lymphocytic leukemia (CLL) cells, ibrutinib has been reported to promote apoptosis, inhibit proliferation, and also prevent CLL cells from responding to survival stimuli provided by the microenvironment.[11] In this study, treatment of activated CLL cells with ibrutinib resulted in inhibition of Btk tyrosine phosphorylation and also effectively abrogated downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. Additionally, ibrutinib inhibited proliferation of CLL cells in vitro, effectively blocking survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement and stromal cell contact.
In early clinical studies, the activity of ibrutinib has been described to include a rapid reduction in lymphadenopathy accompanied by a transient lymphocytosis, suggesting that the drug might have direct effects on cell homing or migration to factors in tissue microenvironments.[12]
Ibrutinib has been reported to reduce CLL cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor.[13][14] Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumor microenvironments.
References
- ^ Statement on a Nonproprietary Name Adopted by the USAN Council
- ^ Pan, Z; Scheerens, H; Li, SJ; Schultz, BE; Sprengeler, PA; Burrill, LC; Mendonca, RV; Sweeney, MD et al. (2007). “Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase”. ChemMedChem 2 (1): 58–61. doi:10.1002/cmdc.200600221. PMID 17154430.
|displayauthors=suggested (help) - ^ Celera Genomics Announces Sale of Therapeutic Programs to Pharmacyclics
- ^ United States patent 7514444
- ^ Honigberg, LA; Smith, AM; Sirisawad, M; Verner, E; Loury, D; Chang, B; Li, S; Pan, Z; Thamm, DH; Miller, RA; Buggy (2010). “The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy”. Proceedings of the National Academy of Sciences of the United States of America 107 (29): 13075–80. doi:10.1073/pnas.1004594107. PMID 20615965. Unknown parameter
|firs11=ignored (help) - ^ Janssen Biotech, Inc. Announces Collaborative Development and Worldwide License Agreement for Investigational Anti-Cancer Drug, PCI-32765
- ^ Clinical trials involve PCI-32765
- ^ Clinical trials involve ibrutinib
- ^ Chang, BY; Huang, MM; Francesco, M; Chen, J; Sokolove, J; Magadala, P; Robinson, WH; Buggy, JJ (2011). “The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells”. Arthritis Research & Therapy 13 (4): R115. doi:10.1186/ar3400. PMID 21752263.
- ^ Good News Continues for Ibrutinib in CLL. 8 Dec 2012
- ^ Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, Flynn J, Jones J, Blum KA, Buggy J.J., Hamdy A, Johnson AJ, Byrd JC. (2011) Bruton’s tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 117: 6287-6296
- ^ The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study.J Clin Oncol 30, 2012 (suppl; abstr 6507)
- ^ Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O’Brien S, Chiorazzi N, Burger JA. (2012) The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 119: 1182-1189.
- ^ de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, Spaargaren M. (2012) The clinically active BTK inhibitor PCI-32765 targets B-cell receptor (BCR)- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 119: 2590-2594.
External links
- BTK inhibitor PCI-32765, National Cancer Institute Drug Dictionary
Citrus And Statins
bergamottin
Citrus And Statins. —Citrus And Statins “” “How Foods and Drugs Collide” provided my first knowledge that 5-geranoxy psoralen (bergamottin) had been identified as the active agent in grapefruit juice implicated in interfering with the so-called statin drugs
( C&ENCitrus And Statins, Sept. 27, page 55 William L. Stanley Carmel, Calif. /articles/88/i49/Citrus-Statins.html 20101206 88 49 /magazine/88/8849.html /departments/letters.html Citrus And Statins Letters Citrus And Statins Chemical & Engineering News Citrus And Statins ACS 2009 IRS Form 990 Available The American Chemical Society’s 2009 Form 990 is now available on ACS’s website.
Chemical & Engineering News, 88(49), December 06, 2010 [Letters] you will have to pay a fee or subscribe
free info from net
Bergamottin is a natural furanocoumarin found principally in grapefruit juice. It is also found in the oil of bergamot orange, from which it was first isolated and from which its name is derived. To a lesser extent, bergamottin is also present in the essential oils of other citrus fruits. Along with the chemically related compound 6′,7′-dihydroxybergamottin, it is believed to be responsible for thegrapefruit juice effect in which the consumption of the juice affects the metabolism of a variety of pharmaceutical drugs.[1]
Chemistry
Chemically, bergamottin and dihydroxybergamottin are linear furanocoumarins functionalized with side chains derived fromgeraniol. They are inhibitors of some isoforms of the cytochrome P450 enzyme, particularly CYP3A4.[2] This prevents oxidative metabolism of certain drugs by the enzyme, resulting in an elevated concentration of drug in the bloodstream.
Normally, the grapefruit juice effect is considered to be a negative interaction, and patients are often warned not to consume grapefruit or its juice when taking medication. However, some current research is focused on the potential benefits of cytochrome P450 inhibition.[3] Bergamottin, dihydroxybergamottin, or synthetic analogs may be developed as drugs that are targeted to increase the oral bioavailability of other drugs. Drugs that may have limited use because they are metabolized by CYP3A4 may become viable medications when taken with a CYP3A4 inhibitor because the dose required to achieve a necessary concentration in the blood would be lowered.[4]
Biosynthesis of bergamottin
Bergamottin is derived from components originating in the shikimate pathway.[5] The biosynthesis of this compound starts with the formation of the demethylsuberosin (3) product which is formed via the alkylation of the umbelliferone (2) compound.[6] The alkylation of the umbelliferone is initiated with the use of dimethylallyl pyrophosphate, more commonly known as DMAPP. The cyclization of an alkyl group occurs to form marmesin (4), which is done in the presence of NADPH and oxygen along with a cytochrome P450 monooxygenase catalyst.[7] This process is then repeated twice more, first to remove the hydroxyisopropyl substituent from marmesin (4) to form psoralen (5), and then to add a hydroxyl group to form bergaptol (6).[8] Bergaptol (6) is next methylated with SAM, S-Adenosyl methionine, to form bergapten (7). The final step in this biosynthesis is the attachment of a GPP, or geranyl pyrophosphate, to the newly methylated bergapten (7) to form the target molecule bergamottin (8).
References
- ^ David G. Bailey, J. Malcolm, O. Arnold, J. David Spence (1998). “Grapefruit juice-drug interactions”. Br J Clin Pharmacol 46 (2): 101–110. doi:10.1046/j.1365-2125.1998.00764.x.PMC 1873672. PMID 9723817.
- ^ Basavaraj Girennavar, Shibu M. Poulose, Guddadarangavvanahally K. Jayaprakasha, Narayan G. Bhat and Bhimanagouda S. Patila (2006). “Furocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes”. Bioorganic & Medicinal Chemistry 14 (8): 2606–2612. doi:10.1016/j.bmc.2005.11.039. PMID 16338240.
- ^ E. C. Row, S. A. Brown, A. V. Stachulski and M. S. Lennard (2006). “Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4”. Org. Biomol. Chem. 4(8): 1604–1610. doi:10.1039/b601096b. PMID 16604230.
- ^ Christensen, Hege; Asberg, Anders; Holmboe, Aase-Britt; Berg, Knut Joachim (2002). “Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers”. European Journal of Clinical Pharmacology 58 (8): 515–520. doi:10.1007/s00228-002-0516-8. PMID 12451428.
- ^ Dewick, P. Medicinal Natural Products:A Biosynthetic Approach, 2nd ed., Wiley&Sons: West Sussex, England, 2001, p 145.
- ^ Bisagni, E. Synthesis of psoralens and analogues. J. Photochem. Photobiol. B. 1992, 14, 23-46.
- ^ Voznesensky, A. I.; Schenkman, J. B. The cytochrome P450 2B4-NADPH cytochrome P450 reductase electron transfer complex is not formed by charge-pairing. J. Biol. Chem. 1992, 267, 14669-14676.
- ^ Kent, U. M.; Lin, H. L.; Noon, K. R.; Harris, D. L.; Hollenberg, P. F. Metabolism of bergamottin by cytochromes P450 2B6 and 3A5. J. Pharmacol. Exp. Ther. 2006, 318, 992-1005
Catalyst’s Firdapse Gets FDA ‘Breakthrough’ Designation
amifampridine
used as phosphate salt
Catalyst Pharmaceutical Partners Receives Breakthrough Therapy Designation From FDA for Firdapse(TM) for the Treatment of LEMS
CORAL GABLES, Fla., Aug. 27, 2013 (GLOBE NEWSWIRE) — Catalyst Pharmaceutical Partners, Inc. (Nasdaq:CPRX), a specialty pharmaceutical company focused on the development and commercialization of novel prescription drugs targeting rare (orphan) neuromuscular and neurological diseases, today announced that its investigational product
Firdapse(TM) (amifampridine phosphate) has received “Breakthrough Therapy Designation” by the U.S. Food and Drug Administration (FDA) for the symptomatic treatment of patients with Lambert-Eaton Myasthenic Syndrome (LEMS). Firdapse(TM) is Catalyst’s investigational therapy that is being evaluated for the treatment of the debilitating symptoms associated with LEMS, including muscle weakness.
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http://www.pharmalive.com/catalysts-firdapse-gets-fda-breakthrough-designation
3,4-Diaminopyridine (or 3,4-DAP) is an organic compound with the formula C5H3N(NH2)2. It is formally derived from pyridine by substitution of the 3 and 4 positions with an amino group.
With the International Nonproprietary Name amifampridine, it is used as a drug, predominantly in the treatment of a number of rare muscle diseases. In Europe, the phosphate salt of amifampridine has been licenced as Firdapse (BioMarin Pharmaceutical) in 2010 as an orphan drug
ATORVASTATIN SYNTHESIS
atorvastatin
Atorvastatin (INN) /əˌtɔrvəˈstætən/, marketed by Pfizer as a calcium salt under the trade name Lipitor,[1] is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms. Like all statins, atorvastatin works by inhibitingHMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body.
Atorvastatin was first synthesized in 1985 by Bruce Roth of Parke-Davis Warner-Lambert Company (since acquired by Pfizer). The best selling drug in pharmaceutical history, sales of Lipitor since it was approved in 1996 exceed US$125 billion, and the drug has topped the list of best-selling branded pharmaceuticals in the world for nearly a decade.[2] When Pfizer’s patent on Lipitor expired on November 30, 2011,[3] generic atorvastatin became available in the United States, initially manufactured only by generic drugmakers Watson Pharmaceuticals and India’s Ranbaxy Laboratories. Prices for the generic version did not drop to the level of other generics—$10 or less for a month’s supply—until other manufacturers were able to supply the drug in May 2012.[4]
| Atorvastatin calcium, YM-548, CI-981, Prevencor, Tahor, Lipibec, Torvast, Sortis, Lipitor | |
| (3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxyheptanoic acid calcium salt (2:1) | |
| 134523-03-8, 134523-00-5 (free acid), 110862-48-1 (free acid (R*,R*)-isomer) | |
| 2-C33-H34-F-N2-O5.Ca | |
| 1155.35 | |
| Alzheimer’s Dementia, Treatment of , Cardiovascular Drugs, Cognition Disorders, Treatment of, Immunologic Neuromuscular Disorders, Treatment of, Lipoprotein Disorders, Treatment of , Metabolic Drugs, Multiple Sclerosis, Agents for, Neurologic Drugs, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HMG-CoA Reductase Inhibitors, TNFSF6 Expression Inhibitors | |
| Launched-1997 | |
| Jouveinal (Originator), Pfizer (Originator), Almirall Prodesfarma (Licensee), Syncro (Licensee), Yamanouchi (Licensee), Stanford University (Codevelopment) |
| SYNTHESISTrans-6-[2-(3- or 4-carboxamido-substd. pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis | |
| Roth, B.D. (Pfizer Inc.) | |
| EP 0247633; US 4681893 | |
 |
|
1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl 2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 C in acetic anhydride giving 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX), which is finally treated first with NaOH in methanol/water, and then with CaCl2 or calcium acetate. |
|
- “Pfizer product promotion page (Liptor)”. Retrieved 2011-12-05.
- “Lipitor becomes world’s top-selling drug”. Crain’s New York Business. 2011-12-28.
- CNN Wire Staff (November 30, 2011). “Lipitor loses patent, goes generic”. CNN. Retrieved November 18, 2012.
- NeLM, June 2012: Price to UK National Health Service for 28 tablets from £3.25 (10mg) to £10.00 (80mg).
- “Atorvastatin Calcium”. Drugs.com. Retrieved 3 April 2011.
Further reading
- “Highlights of prescribing information” (pdf). Lipitor (atorvastatin calcium) Tablets for oral administration. Pfizer. 2009-06-01. Retrieved 2011-10-26.
- Maggon K (June 2005). “Best-selling human medicines 2002-2004”. Drug Discov. Today 10 (11): 739–42. doi:10.1016/S1359-6446(05)03468-9. PMID 15922927.
- Roth BD (2002). “The discovery and development of atorvastatin, a potent novel hypolipidemic agent”. Prog Med Chem. Progress in Medicinal Chemistry 40: 1–22. doi:10.1016/S0079-6468(08)70080-8. ISBN 978-0-444-51054-9. PMID 12516521.
- Simons J (2003-01-20). “The $10 Billion Pill Hold the fries, please. Lipitor, the cholesterol-lowering drug, has become the bestselling pharmaceutical in history. Here’s how Pfizer did it”. Fortune. Retrieved 2011-10-26.
- Winslow R (2000-01-24). “The Birth of a Blockbuster: Lipitor’s Route out of the Lab”. The Wall Street Journal. Retrieved 2011-10-26.
- “Ann Arbor chemist wins national award for drug discovery”. ScienceBlog. American Chemical Society. 2003-03-01. Retrieved 2011-10-26.
- Rowe A (2008-08-20). “Meet the Guy Who Invented Lipitor”. Wired Science. Wired.com. Retrieved 2011-10-26.
- Bernstein M (2008-08-16). “Chemical Society To Honor ‘Heroes Of Chemistry’ During National Meeting”. Medical News Today. Retrieved 2011-10-26.
- He L (2003-09-27). “Bruce D. Roth, Pfizer Inc, USA”. Chinese Academy of Sciences·Institute of Process Engineering. Retrieved 2011-10-26.
External links
- Atorvastatin bound to proteins in the PDB
- Lipitor.com – manufacturer’s site
- MedlinePlus Drug information: Atorvastatin (Systemic) – information from USP DI Advice for the Patient
- U.S. National Library of Medicine: Drug Information Portal – Atorvastatin
| An improved synthesis of 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for atorvastatin synthesis | |
| Radl, S.; et al. | |
| Tetrahedron Lett 2002,43(11),2087 | |
 |
|
The 6-cyanohexanoic ester (VII), intermediate in the synthesis of 180072 (see intermediate (XLI) in scheme no. 18007204a) has been obtained as follows: the reaction of 1,6-heptadien-4-ol (I) with BuLi, CO2, and I2 in THF gives the cyclic carbonate (II), which is treated with Ts-OH in acetone to yield the acetonide (III). The reaction of the iodine atom of (III) with KCN in hot DMSO affords the nitrile (IV), which is oxidized at the terminal double bond with OsO4 and NaIO4, or O3 and Me2S, to provide the carbaldehyde (V). The oxidation of (V) with CrO3/H2SO4 in acetone gives the carboxylic acid (VI), which is finally esterified with tert-butanol by means of DCC and DMAP in dichloromethane, yielding the target ester intermediate (VII). |
|
Lipitor industrial production shown below (TL, 1985, 2951; TL, 1992, 2279; 2283)
Divided into two fragments. Primary amine fragment iso-ascorbic acid as a starting material (stereoisomer of vitamin C) in the system. 1,4 – dione as a starting material isobutyrylacetanilide fragment, obtained by the Stetter reaction, the reaction of benzoin conjugated version Michael addition. Diketone related primary amine with a substituted pyrrole ring obtained five, after deprotection and salt formation Lipitor.
Atorvastatin of IC50-0.025μM, its RR configuration is as high IC50-0.007μM (SS configuration IC50-0.44μM).
Initially synthesized as shown above (JMC, 1991, 357).
Which polysubstituted pyrrole ring by the Munchnone of 1,3-dipolar [3 +2] cycloaddition get.
Big boost for Incyte as Jakafi shines in PhII
ruxolitinib
Top-line results from a Phase II trial showed that its JAK inhibitor Jakafi (ruxolitinib), in combination with Roche’s Xeloda (capecitabine), improved survival in some patients with recurrent or treatment refractory advanced pancreatic cancer
http://www.pharmatimes.com/Article/13-08-
22/Big_boost_for_Incyte_as_Jakafi_shines_in_PhII.aspx
Ruxolitinib (trade names Jakafi and Jakavi, by Incyte Pharmaceuticals and Novartis) is a drug for the treatment of intermediate or high-risk myelofibrosis, a type of bone marrow cancer.It is also being investigated for the treatment of other types of cancer (such as lymphomas and pancreatic cancer), for polycythemia vera, and for plaque psoriasis.
The phase III Controlled Myelofibrosis Study with Oral JAK Inhibitor-I (COMFORT-I) and COMFORT-II trials showed significant benefits by reducing spleen size, relieving debilitating symptoms, and improving overall survival.
Mechanism of action
Ruxolitinib is a Janus kinase inhibitor with selectivity for subtypes 1 and 2 of this enzyme.
Side effects
Immunologic side effects have included herpes zoster (1.9%) and case reports of opportunistic infections.[10] Metabolic side effects have included weight gain (7.1%). Laboratory abnormalities have included alanine transaminase (ALT) abnormalities (25.2%), aspartate transaminase (AST) abnormalities (17.4%), and elevated cholesterol levels (16.8%).
Legal status
In November 2011, ruxolitinib was approved by the USFDA for the treatment of intermediate or high-risk myelofibrosis based on results of the COMFORT-I and COMFORT-II Trials.
Some analysts believe this to be a potential blockbuster drug.[3] As of the end of March 2012, and according to an Incyte spokesman, approximately 1000 physicians had prescribed the drug in the United States, out of a total 6500 hematologists and oncologists nationwide.
The US Food and Drug Administration had approved Incyte’s Jakafi (ruxolitinib) to treat patients with the bone marrow disease myelofibrosis (MF). Jakafi is the first and only drug granted license specifically for the treatment of the rare blood cancer.
Jakafi approved by FDA to treat rare bone marrow disease
Posted By Edward Su On November 17th, 2011
MF is a rare, potentially life-threatening blood cancer with limited treatment methods. Patients with the bone marrow disoder, characterized by bone marrow failure, enlarged spleen (splenomegaly), suffer from the symptoms of fatigue, night sweats and pruritus, poor quality of life, weight loss and shortened survival. The US drug firm Incyte estimates the disease affects about 16,000-18,500 people in the USA. Currently, the disease is treated with chemotherapy or bone marrow transplant.
Incyte’s Jakafi, the first drug to reach market from the Wilmington-based drug company, was approved by the FDA as a twice-a-day pill for the treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF. The US regulators reviewed Jakafi under its priority review program for important new therapies.
The approval of Jakafi was based on the results from two clinical studies involved 528 patients with the disease. Patients in the Jakafi treatment arm experienced a significant reduction in the size of their spleen as well as a 50 percent decrease in symptoms, including pain, discomfort and night sweats.
Jakafi, generically known as ruxolitinib, works by blocking JAK1 and JAK2 enzymes associated with the disease. The company has co-developed the drug with Novartis as part of their collaboration signed in 2009. The Swiss drug firm has the rights to market Jakafi in other countries.
“The availability of Jakafi is a significant medical advancement for people living with myelofibrosis, a debilitating disease,” said Paul A. Friedman, M.D., President and Chief Executive Officer of Incyte. “This milestone marks a tremendous achievement for Incyte because a scientific discovery from our research laboratories has become the first JAK inhibitor to reach the market and provide a clinical benefit to patients.”
Richard Pazdur, director of the Office of Hematology and Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said that Jakafi “represents another example of an increasing trend in oncology where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways”.
Incyte says Jakafi will be available next week, and the drug will cost $7,000 per month, or $84,000 for a year’s supply for insured patients. The company plans to provide Jakafi free to uninsured patients and will offer co-pay assistance to patients with financial need.
(JAK1, JAK2) inhibitor, developed by the Incyte Corporation, trade name Jakafi.
Ruxolitinib synthetic route as shown below. 4 – bromo-pyrazole ( 1 ) with ethyl vinyl ether ( 2 ) to protect, and then with a Grignard reagent to a halogen – exchanged with isopropyl magnesiumpinacol ester ( 3 ) quenching to obtain 4 . Compound 5 is obtained consisting of hydrogen is protected 6 , and then with a boronic acid ester 4 Suzuki coupling occurs under acidic conditions after removal of the protecting group pyrazolyl 7 , 7 and α, β-unsaturated aldehyde 8 chiral catalyst 9 of under the catalysis of asymmetric Michael addition to give ( R ) -10 (90% EE). ( R) -10 , after reaction with ammonia to obtain an imine oxidation with iodine nitrile 11 , respectively, with different conditions for the final removal of the protecting group to afford Ruxolitinib.
FDA Accepts Nuvo’s New Drug Application for Review
Nuvo Research Inc. announced that its U.S. licensee for PENNSAID@ (diclofenac sodium topical solution) 1.5% w/w and PENNSAID 2% (diclofenac sodium topical solution) 2% w/w,
Mallinckrodt has advised that the U.S. Food and Drug Administration has accepted for filing and review the New Drug Application (NDA) for PENNSAID 2% submitted by Mallinckrodt on August 7, 2013.
Oncopeptides Testing Melflufen in Europe
Oncopeptides AB, a company working to enhance oncology therapies, announced that the first patient has been dosed as part of a phase 2 study in multiple myeloma patients with its drug candidate melflufen (previously called J1). The trial is an open-label phase 2 study, designed to determine the level of efficacy of melflufen in combination with dexamethasone, for late stage, relapsing or relapsing/refractory patients
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Diabetes Drug Trial Moves to Israel
Oramed Pharmaceuticals Inc., a developer of oral drug delivery systems, announced that it has initiated patient recruitment for a new clinical trial of its orally ingestible insulin capsule, ORMD-0801 for patients with type 1 diabetes mellitus (T1DM) in Israel.
Ajay Piramal’s 20-20 game planThree years after selling its generics business to Abbott, the group is ready with a new strategy on becoming a $20-billion company by 2020
Twenty is an important number for Ajay Piramal, founder of thePiramal Group. Whether it is the target of 20 per cent annual growth or the goal of taking market capitalisation to $20 billion by 2020, the number is key in his scheme of things.
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Novartis Muscle Drug Bimagrumab Gets Breakthrough Status
immunoglobulin G1-lambda2, anti-[Homo sapiens ACVR2B (activin
A receptor type IIB, ActR-IIB)], Homo sapiens monoclonal antibody;
gamma1 heavy chain (1-445) [Homo sapiens VH (IGHV1-2*02
(91.80%) -(IGHD)-IGHJ5*01 [8.8.8] (1-115) -IGHG1*03 (CH1 (116-
213), hinge (214-228), CH2 L1.3>A (232), L1.2>A (233) (229-338),
CH3 (339-443), CHS (444-445)) (116-445)], (218-216′)-disulfide with
lambda light chain (1′-217′) [Homo sapiens V-LAMBDA (IGLV2-
23*02 (90.90%) -IGLJ2*01) [9.3.11] (1′-111′) -IGLC2*01 (112′-217′)];
dimer (224-224”:227-227”)-bisdisulfide
myostatin inhibitor
bimagrumab immunoglobuline G1-lambda2, anti-[Homo sapiens ACVR2B
(récepteur type IIB de l’activine A, ActR-IIB)], Homo sapiens
anticorps monoclonal;
chaîne lourde gamma1 (1-445) [Homo sapiens VH (IGHV1-2*02
(91.80%) -(IGHD)-IGHJ5*01 [8.8.8] (1-115) -IGHG1*03 (CH1 (116-
213), charnière (214-228), CH2 L1.3>A (232), L1.2>A (233) (229-
338), CH3 (339-443), CHS (444-445)) (116-445)], (218-216′)-
disulfure avec la chaîne légère lambda (1′-217′) [Homo sapiens
V-LAMBDA (IGLV2-23*02 (90.90%) -IGLJ2*01) [9.3.11] (1′-111′) –
IGLC2*01 (112′-217′)]; dimère (224-224”:227-227”)-bisdisulfure
inhibiteur de la myostatine
inmunoglobulina G1-lambda2, anti-[Homo sapiens ACVR2B
(receptor tipo IIB de la activina A, ActR-IIB)], anticuerpo monoclonal
de Homo sapiens;
cadena pesada gamma1 (1-445) [Homo sapiens VH (IGHV1-2*02
(91.80%) -(IGHD)-IGHJ5*01 [8.8.8] (1-115) -IGHG1*03 (CH1 (116-
213), bisagra (214-228), CH2 L1.3>A (232), L1.2>A (233) (229-338),
CH3 (339-443), CHS (444-445)) (116-445)], (218-216′)-disulfuro con
la cadena ligera lambda (1′-217′) [Homo sapiens V-LAMBDA
(IGLV2-23*02 (90.90%) -IGLJ2*01) [9.3.11] (1′-111′) -IGLC2*01
(112′-217′)]; dímero (224-224”:227-227”)-bisdisulfuro
inhibidor de la miostatina
1356922-05-8
Heavy chain / Chaîne lourde / Cadena pesada
QVQLVQSGAE VKKPGASVKV SCKASGYTFT SSYINWVRQA PGQGLEWMGT 50
INPVSGSTSY AQKFQGRVTM TRDTSISTAY MELSRLRSDD TAVYYCARGG 100
WFDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE 150
PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV 200
NHKPSNTKVD KRVEPKSCDK THTCPPCPAP EAAGGPSVFL FPPKPKDTLM 250
ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV 300
VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP 350
PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG 400
SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK 445
Light chain / Chaîne légère / Cadena ligera
QSALTQPASV SGSPGQSITI SCTGTSSDVG SYNYVNWYQQ HPGKAPKLMI 50
YGVSKRPSGV SNRFSGSKSG NTASLTISGL QAEDEADYYC GTFAGGSYYG 100
VFGGGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT 150
VAWKADSSPV KAGVETTTPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCQV 200
THEGSTVEKT VAPTECS 217
Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro
Intra-H 22-96 142-198 259-319 365-423
22”-96” 142”-198” 259”-319” 365”-423”
Intra-L 22′-90′ 139′-198′
22”’-90”’ 139”’-198”’
Inter-H-L 218-216′ 218”-216”’
Inter-H-H 224-224” 227-227”
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación
H CH2 N84.4
Bimagrumab
http://www.who.int/medicines/publications/druginformation/innlists/PL108_Final.pdf
Novartis announced that the US Food and Drug Administration (FDA) has granted breakthrough therapy designation to BYM338 for sporadic inclusion body myositis (sIBM). This designation is based on the results of a phase 2 proof-of-concept study that showed BYM338 substantially benefited patients with sIBM compared to placebo.
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Novartis receives FDA breakthrough therapy designation for BYM338 (bimagrumab) for sporadic inclusion body myositis (sIBM)
• Designation highlights potential of BYM338 to address an unmet medical need in a serious disease
• If approved, BYM338 has the potential to be the first treatment for sIBM patients
• BYM338 is the third Novartis investigational treatment this year to receive a breakthrough therapy designation by the FDA, highlighting Novartis’ leadership in the industry in breakthrough therapy designations
Bimagrumab (BYM338) is a human monoclonal antibody developed by Novartis to treat pathological muscle loss and weakness. On August 20, 2013 it was announced that bimagrumab was granted breakthrough therapy designation for sporadic inclusion body myositis(sIBM) by US Food and Drug Administration.[1]
- “Novartis receives FDA breakthrough therapy designation for BYM338 (bimagrumab) for sporadic inclusion body myositis (sIBM)”. Retrieved 20 August 2013.
World Health Organization (2012). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 108” (PDF). WHO Drug Information 26(4)
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