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CTI BioPharma receives Israeli approval for aggressive B-cell non-Hodgkin’s lymphoma therapy

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Chemical structure for CTK0H5262

 

 

Pixantrone.svg

Pixantrone

BBR-2778 , CTK0H5262

 

  • Pixolti
  • Pixuvri
  • UNII-P0R64C4CR9

 

An immunosuppressant.

144510-96-3 [RN]

5,8-Bis((2-aminoethyl)amino)-2-aza-anthracene-9,10-dione

6,9-Bis((2-aminoethyl)amino)benz(g)isoquinoline-5,10-dione

5,8-Bis((2-aminoethyl)amino)-2-aza-anthracene-9,10-dione

6,9-Bis((2-aminoethyl)amino)benz(g)isoquinoline-5,10-dione

CTI BioPharma receives Israeli approval for aggressive B-cell non-Hodgkin’s lymphoma therapy

CTI BioPharma has obtained Israeli Ministry of Health’s approval for Pixuvri (pixantrone), as a monotherapy to treat adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma who have received up to three previous courses of treatment.

The company also announced that the Dutch Healthcare Authority and the College voor zorgverzekeringen of the Netherlands have approved funding for Pixuvri as an add-on drug for patients who need a third or fourth-line treatment option for aggressive B-cell lymphoma.

Tel Aviv University faculty of medicine Dr Abraham Avigdor said: “The approval of PIXUVRI in Israel provides patients with aggressive B-cell NHL who have failed second or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side-effects.

 

read at

http://www.pharmaceutical-technology.com/news/newscti-biopharma-receives-israeli-approval-aggressive-b-cell-non-hodgkins-lymphoma-therapy-4321986?WT.mc_id=DN_News

 

Pixantrone
Pixantrone.svg
Identifiers
CAS number  144510-96-3
PubChem 134019
ChemSpider 118174 Yes
KEGG D05522 Yes
ChEMBL CHEMBL167731 Yes
ATC code L01DB11
Jmol-3D images Image 1
Properties
Molecular formula C17H19N5O2
Molar mass 325.365 g/mol
Appearance Blue solid
Pharmacology
Routes of
administration
Intravenous
Elimination
half-life
9.5–17.5 hours
Excretion Fecal (main route of excretion) and renal (4–9%)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)

Pixantrone dimaleate [USAN]

CAS  144675-97-8

Molecular Formula

  • C17-H19-N5-O2.2C4-H4-O4

Molecular Weight

  • 441.4417
  • Benz(g)isoquinoline-5,10-dione, 6,9-bis((2-aminoethyl)amino)-, (2Z)-2-butenedioate (1:2)

On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin’s B-cell lymphoma (NHL). Pixantrone is a cytotoxic aza-anthracenedione that directly alkylates DNA-forming stable DNA adducts and cross-strand breaks. The recommended dose of pixantrone is 50 mg/m2 administered on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician’s best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects with pixantrone were bone marrow suppression (particularly of the neutrophil lineage) nausea, vomiting, and asthenia. This article summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu).

 

 

Pixantrone (rINN; trade name Pixuvri) is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewertoxic effects on cardiac tissue.[1] It acts as a topoisomerase II poison and intercalating agent.[2][3] The code name BBR 2778 refers topixantrone dimaleate, the actual substance commonly used in clinical trials.[4]

 

 

History

Anthracyclines are important chemotherapy agents. However, their use is associated with irreversible and cumulative heart damage. Investigators have attempted to design related drugs that maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines.[5] Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.[1]

Random screening at the US National Cancer Institute of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant anti-tumor activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone, which also exhibited marked anti-tumor activity[5] Mitoxantrone was considered as an analog of doxorubicin with less structural complexity but with a similar mode of action. In clinical studies, mitoxantrone was shown to be effective against numerous types of tumors with less toxic side effects than those resulting from doxorubicin therapy. However, mitoxantrone was not totally free of cardiotoxicity. A number of structurally modified analogs of mitoxantrone were synthesized and structure-activity relationship studies made.[5] BBR 2778 was originally synthesized by University of Vermont researchers Miles P. Hacker and Paul A. Krapcho[5] and initially characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the Boehringer Mannheim Italia Research Center, Monza, and University of VermontBurlington.[4]Other studies have been completed at the University of Texas M. D. Anderson Cancer CenterHouston, the Istituto Nazionale Tumori,Milan, and the University of Padua.[2][6][4] In the search for novel heteroanalogs of anthracenediones, it was selected as the most promising compound. Toxicological studies indicated that BBR 2778 was not cardiotoxic, and US patents are held by the University of Vermont. An additional US patent application was completed in June 1995 by Boehringer Mannheim, Italy.[5]

Novuspharma, an Italian company, was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-La Roche, and BBR 2778 was developed as Novuspharma’s leading anti-cancer drug, pixantrone.[7] A patent application for the injectable preparation was filed in May 2003.[8]

In 2003, Cell Therapeutics, a Seattle biotechnology company, acquired pixantrone through a merger with Novuspharma.[9]

Clinical trials

Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics.[10] phase III clinical trials of pixantrone have been completed.[11][12] Pixantrone is being studied as an antineoplastic for different kinds of cancer, including solid tumors and hematological malignancies such as non-Hodgkin lymphomas.

Animal studies demonstrated that pixantrone does not worsen pre-existing heart muscle damage, suggesting that pixantrone may be useful in patients pretreated with anthracyclines. While only minimal cardiac changes are observed in mice given repeated cycles of pixantrone, 2 cycles of traditional anthracyclines doxorubicin or mitoxantrone result in marked or severe heart muscle degeneragion.[1]

Clinical trials substituting pixantrone for doxorubicin in standard first-line treatment of patients with aggressive non-Hodgkin’s lymphoma, had a reduction in severe side effects when compared to patients treated with standard doxorubicin-based therapy. Despite pixantrone patients receiving more treatment cycles, a three-fold reduction in the incidence of severe heart damage was seen as well as clinically significant reductions in infections and thrombocytopenia, and a significant reduction in febrile neutropenia. These findings could have major implications for treating patients with breast cancer, lymphoma, and leukemia, where debilitating cardiac damage from doxorubicin might be prevented.[13]Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.[14]

The completed phase II RAPID trial compared the CHOP-R regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab to the same regimen, but substituting Doxorubicin with Pixantrone. The objective was to show that Pixantrone was not inferior to Doxorubicin and less toxic to the heart.[15]

Pixantrone was shown to have potentially reduced cardiotoxicity and demonstrated promising clinical activity in these phase II studies in heavily pretreated non-Hodgkin lymphomapatients.[14]

The pivotal phase III EXTEND (PIX301) randomized clinical trial studied pixantrone to see how well it works compared to other chemotherapy drugs in treating patients with relapsed non-Hodgkin’s lymphoma.[16] The complete response rate in patients treated with pixantrone has been significantly higher than in those receiving other chemotherapeutic agents for treatment of relapsed/refractory aggressive non-Hodgkin lymphoma.[14]

Administration

It can be administered through a peripheral vein rather than a central implanted catheter as required for other similar drugs.[8][14]

Regulatory approval

U.S. Food and Drug Administration

The FDA granted fast track designation for pixantrone in patients who had previously been treated two or more times for relapsed or refractory aggressive NHL. Study sponsor Cell Therapeutics announced that Pixantrone achieved the primary efficacy endpoint. The minutes of the Oncologic Drugs Advisory Committee meeting of March 22, 2010[17]show that this had not in fact been achieved with statistical significance and this combined with major safety concerns lead to the conclusion that the trial was not sufficient to support approval. In April 2010 the FDA asked for an additional trial.[18]

European Medicines Agency

On May 5, 2009, Pixantrone became available in Europe on a Named-Patient Basis. A named-patient program is a compassionate use drug supply program under which physicians can legally supply investigational drugs to qualifying patients. Under a named-patient program, investigational drugs can be administered to patients who are suffering from serious illnesses prior to the drug being approved by the European Medicines Evaluation Agency. “Named-patient” distribution refers to the distribution or sale of a product to a specific healthcare professional for the treatment of an individual patient. In Europe, under the named-patient program the drug is most often purchased through the national health system.[19] In 2012 pixantrone received conditional marketing authorization in the European Union as Monotherapy to Treat Adult Patients with Multiply Relapsed or Refractory Aggressive Non-Hodgkin B-Cell Lymphomas.

Research

Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis.[20] Pixantrone has a similar mechanism of action as mitoxantrone on the effector function of lymphomonocyte B and T cells in experimental allergic encephalomyelitis but with lower cardiotoxicity. Pixantrone inhibits antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production.[21] Clinical trials are currently ongoing in Europe.

Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats,[22] and in vitro cell viability experiments indicated that Pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity, a mechanism implicated in Alzheimer’s disease.[23]

 

http://www.chemdrug.com/databases/8_0_mhpyqlxgrykqdwig.html

3,4-Pyridinedicarboxylic acid (I) was converted to the cyclic anhydride (II) upon heating with acetic anhydride. Friedel-Crafts condensation of anhydride (II) with p-difluorobenzene (III) in the presence of AlCl3 gave rise to a mixture of two regioisomeric keto acids, (IV) and (V). Cyclization of this mixture in fuming sulfuric acid at 140 C generated the benzoisoquinoline (VI) (1,2). Subsequent displacement of the fluorine atoms of (VI) with ethylenediamine ( VII) in pyridine provided the target bis (2-aminoethylamino) derivative, which was finally converted to the stable dimaleate salt. Alternatively, ethylenediamine (VII) was protected as the mono-N-Boc derivative (VIII) by treatment with Boc2O. Condensation of the difluoro compound (VI) with the protected ethylenediamine (VIII) furnished (IX). The Boc groups of (IX) were then removed by treatment with trifluoroacetic acid. After adjustment of the pH to 4.2 with KOH, treatment with maleic acid provided BBR-2778.

J Med Chem1994,37, (6): 828

SEE MORE

http://www.chemdrug.com/databases/8_0_mhpyqlxgrykqdwig.html

References

  1.  Cavalletti E, Crippa L, Mainardi P, Oggioni N, Cavagnoli R, Bellini O, Sala F. (2007). “Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone”. Invest New Drugs. 25 (3): 187–95. doi:10.1007/s10637-007-9037-8PMID 17285358.
  2. De Isabella P, Palumbo M, Sissi C, Capranico G, Carenini N, Menta E, Oliva A, Spinelli S, Krapcho AP, Giuliani FC, Zunino F. (1995). “Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives”. Mol Pharmacol. 48 (1): 30–8.PMID 7623772.
  3.  Evison BJ, Mansour OC, Menta E, Phillips DR, Cutts SM (2007). “Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent”Nucleic Acids Res. 35 (11): 3581–9. doi:10.1093/nar/gkm285PMC 1920253.PMID 17483512.
  4.  Krapcho AP, Petry ME, Getahun Z, Landi JJ Jr, Stallman J, Polsenberg JF, Gallagher CE, Maresch MJ, Hacker MP, Giuliani FC, Beggiolin G, Pezzoni G, Menta E, Manzotti C, Oliva A, Spinelli S, Tognella S (1994). “6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5,10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: synthesis and antitumor evaluations”. J Med Chem. 37 (6): 828–37. doi:10.1021/jm00032a018PMID 8145234.
  5.  US patent 5587382, Krapcho AP, Hacker MP, Cavalletti E, Giuliani FC, “6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity”, issued 1996-12-24, assigned to Boehringer Mannheim Italia, SpA
  6.  Zwelling LA, Mayes J, Altschuler E, Satitpunwaycha P, Tritton TR, Hacker MP. (1993). “Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II”. Biochem Pharmacol. 46 (2): 265–71. doi:10.1016/0006-2952(93)90413-QPMID 8394077.
  7.  Borchmann P, Reiser M (May 2003). “Pixantrone (Novuspharma)”. IDrugs 6 (5): 486–90. PMID 12789604.
  8.  EP patent 1503797, Bernareggi A, Livi V, “Injectable Pharmaceutical Compositions of an Anthracenedione Derivative with Anti-Tumoral Activity”, published 2003-11-27, issued 2008-09-29, assigned to Cell Therapeutics Europe S.R.L.
  9.  Pollack, Andrew (2003-06-17). “Company News; Cell Therapeutics Announces Plan To Buy Novuspharma”The New York Times. Retrieved 2010-05-22.
  10. Jump up^ Mosby’s Medical Dictionary, 8th edition. © 2009, Elsevier. “definition of antineoplastic antibiotic”. Free Online Medical Dictionary, Thesaurus and Encyclopedia. Retrieved 2012-01-31.
  11. Jump up^ “NCT00088530”BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). ClinicalTrials.gov. Retrieved 2012-01-31.
  12.  “NCT00551239”Fludarabine and Rituximab With or Without Pixantrone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma. ClinicalTrials.gov. 2012-01-31. Retrieved 2012-01-31.
  13. “Pixantrone Combination Therapy for First-line Treatment of Aggressive Non-Hodgkin’s Lymphoma Results in Reduction in Severe Toxicities Including Heart Damage When Compared to Doxorubicin-based Therapy”Press Release. Retrieved 2012-01-31.
  14. Jump up to:a b c d Engert A, Herbrecht R, Santoro A, Zinzani PL, Gorbatchevsky I (September 2006). “EXTEND PIX301: a phase III randomized trial of pixantrone versus other chemotherapeutic agents as third-line monotherapy in patients with relapsed, aggressive non-Hodgkin’s lymphoma”. Clin Lymphoma Myeloma 7 (2): 152–4.doi:10.3816/CLM.2006.n.055PMID 17026830.
  15. Jump up^ “NCT00268853”A Trial in Patients With Diffuse Large-B-cell Lymphoma Comparing Pixantrone Against Doxorubicin. ClinicalTrials.gov. Retrieved 2012-01-31.
  16. Jump up^ “NCT00101049”BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). ClinicalTrials.gov. Retrieved 2012-01-31.
  17. Jump up^ Vesely N, Eckhardt SG (2010-03-22). “NDA 022-481 PIXUVRI (pixantrone dimaleate) injection” (pdf). Summary Minutes of the Oncologic Drugs Advisory Committee. United States Food and Drug Administration. Retrieved 2012-01-31.
  18. Jump up^ “Cell Therapeutics Formally Appeals FDA’s Nonapprovable Ruling for Pixantrone”. GEN News. 2010-12-03.
  19. Jump up^ “Pixantrone Now Available in Europe on a Named-Patient Basis”. Retrieved 2012-01-31.
  20. Jump up^ Gonsette RE, Dubois B (August 2004). “Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity”. J. Neurol. Sci. 223(1): 81–6. doi:10.1016/j.jns.2004.04.024PMID 15261566.
  21. Jump up^ Mazzanti B, Biagioli T, Aldinucci A, Cavaletti G, Cavalletti E, Oggioni N, Frigo M, Rota S, Tagliabue E, Ballerini C, Massacesi L, Riccio P, Lolli F (November 2005). “Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis”. J. Neuroimmunol. 168 (1-2): 111–7.doi:10.1016/j.jneuroim.2005.07.010PMID 16120465.
  22. Jump up^ Ubiali F, Nava S, Nessi V, Longhi R, Pezzoni G, Capobianco R, Mantegazza R, Antozzi C, Baggi F (February 2008). “Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats”. J. Immunol. 180 (4): 2696–703. PMID 18250482.
  23. Jump up^ Colombo R, Carotti A, Catto M, Racchi M, Lanni C, Verga L, Caccialanza G, De Lorenzi E (April 2009). “CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity”. Electrophoresis 30(8): 1418–29. doi:10.1002/elps.200800377PMID 19306269.

 

 

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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