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Pixantrone

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Pixantrone
Names
IUPAC name
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
Identifiers
3D model (JSmol)
  • C1=CC(=C2C(=C1NCCN)C(=O)C3=C(C2=O)C=NC=C3)NCCN
Properties
C17H19N5O2
Molar mass 325.365 g/mol
Pharmacology
Intravenous
Pharmacokinetics:
9.5–17.5 hours
Fecal (main route of excretion) and renal (4–9%)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Pixantrone (rINN, codenamed BBR2778) is an immunosuppressant drug, an analogue of mitoxantrone with less toxic effects on cardiac tissue.[1]

It acts as a topoisomerase II poison and intercalating agent.[2]

History

Numerous investigators have attempted to design related drugs which maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines[3].

Random screening of a vast number of compounds provided by the Allied Chemical Company, at the US National Cancer Institute, led to the discovery of ametantrone as having significant antitumor activity. Further investigation regarding the rational development of analogs of ametantrone through structure-activity studies of some substituted aminoalkyl aminoanthraquinones led to the synthesis of mitoxantrone which exhibited marked antitumor activity[4].

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 far 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].

In the search for novel heteroanalogs of anthracenediones, 6,9-bis[(2-aminoethyl-amino]-benzo[g]isoquinoline-5,10-dione dimaleate (BBR 2778), was selected as the most promising compound. Toxicological studies indicated that BBR 2778 was not cardiotoxic, and a patent application was filed in June 1995[6].

BBR 2778 was characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the University of Vermont, Burlington, and Anderson Cancer Center, Houston, TX Department of Medical Oncology, M.D. Anderson Cancer Center, Houston, TX, and at the Division of Experimental Oncology in the Istituto Nazionale Tumori, Milan, Italy.[7][8][9]

Novuspharma, an Italian company, was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-LaRoche to exploit the R&D team's proven track record in product development. BBR 2778 was developed as Novuspharma's leading anti-cancer drug, pixantrone[10]. A patent application for the injectable preparation was filed in May 2003 [11]. In June 2003 Cell Therapeutics, a Seattle biotechnology company, acquired Pixantrone when it purchased Novuspharma. [12]

Uses

Anthracyclines are important oncotherapeutics; however, their use is associated with irreversible and cumulative heart damage. Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy. [13] It also can be administered through a peripheral vein rather than a central implanted catheter as required for other drugs in this class[14].

Cancer

It 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. [13]

Clinical trials substituting pixantrone for doxorubicin in standard first-line treatment of patients with aggressive non-Hodgkin's lymphoma (NHL), had a reduction in severe (grade 3/4) 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 (LVEF decline >15 percent) 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. [15]

Multiple Sclerosis

The potential efficacy in multiple sclerosis of immunosuppressants used in cancer therapy has received attention. However, no human trial results have yet been published. Pixantrone could be studied for it's ability to effect potent immunosuppression in MS similar to treatments of MS with mitoxantrone, but with potentially less cardiotoxicity. Suggestions that early administration of potent immunosuppressants is definitely more effective than approved immunomodulators [16] such as interferon beta-1a[2] to delay or even reverse disability progression will need to be newly compared to the successful immunomodulator Fingolimod, which may demonstrate [17] the superiority of immunomodulation.

Experimental Autoimmune Encephalomyelitis

It is as potent as mitoxantrone in animal models of multiple sclerosis. [18] 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[1].

Myasthenia Gravis

Pixantrone reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats.[19]

Alzheimer's disease

In vitro cell viability experiments indicated that pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity. Soluble and toxic oligomers of A beta protein have been identified as the true neurotoxic species involved in Alzheimer's disease. [20]

Clinical Research

Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics.[21] As of 2009, phase III clinical trials of pixantrone are underway.[22][23]

Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates. [24] The completed phase II RAPID (PIX203) trial compared the standard 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 CHOP-R and less toxic to the heart. [25] Pixantrone was shown to have potentially reduced cardiotoxicity and demonstrated promising clinical activity in these phase II studies in heavily pretreated non-Hodgkin lymphoma patients. [26]

A Potential Treatment for non-Hodgkin’s Lymphoma

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. [27] 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[28].

Pixantrone (n=70) Control (n=70) P value
Complete Response (CR/CRu) 20% (14) 5.7% (4) p=0.021
Overall Response Rate (ORR) 37% (26) 14.3% (10) p=0.003

Table 1. Response Rates and Number of Responses in treatement of non-Hodgkin lymphoma[29]

Regulatory Approval Process

U.S. Food and Drug Administration

Study sponsor Cell Therapeutics announced that Pixantrone achieved the primary efficacy endpoint, and in April 2009 began a rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for pixantrone to treat relapsed or refractory aggressive NHL. They will request priority review by FDA. The FDA granted fast track designation for pixantrone in third-line (or more) treatment of relapsed or refractory aggressive NHL[30].

European Medicines Evaluation 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[31].

Impact

"Our experience with pixantrone has been positive with patients achieving a complete response where such a result was not achievable with other treatments," said Prof. Pier Luigi Zinzani, M.D., Institute of Hematology and Oncology, University of Bologna. "I am pleased that it is now available on a named-patient basis as it has the potential to address a significant unmet need in this heavily pretreated patient population." [32]

"Pixantrone is an important new treatment with impressive remission and progression-free survival data," said Dr. Raul Herbrecht of Strasbourg University Hospital in France. "This drug is also important because it meets an unmet medical need for this group of patients. I have been impressed by the good tolerance and efficacy of pixantrone since the first clinical trial we had with this drug in our department. We obtained excellent results in salvage therapy of non-Hodgkin's lymphoma in heavily pretreated patients and several years later some of our patients are still in complete response. These positive results have been confirmed in further studies," Dr Herbrecht added. [33]

References

  1. ^ a b Mazzanti B, Biagioli T, Aldinucci A; et al. (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.2005.07.010. PMID 16120465. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid16120465" was defined multiple times with different content (see the help page).
  2. ^ 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/gkm285. PMC 1920253. PMID 17483512.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ http://www.freepatentsonline.com/5587382.html United States Patent 5587382 6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity
  4. ^ http://www.freepatentsonline.com/5587382.html United States Patent 5587382 6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity
  5. ^ http://www.freepatentsonline.com/5587382.html United States Patent 5587382 6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity
  6. ^ http://www.freepatentsonline.com/5587382.html United States Patent 5587382 6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity
  7. ^ De Isabella P, Palumbo M, Sissi C, Capranico G, Carenini N, Menta E, Oliva A, Spinelli S, Krapcho AP, Giuliani FC; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  8. ^ 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. PMID 8394077.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Krapcho AP, Petry ME, Getahun Z, Landi JJ Jr, Stallman J, Polsenberg JF, Gallagher CE, Maresch MJ, Hacker MP, Giuliani FC; et al. (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. PMID 8145234. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  10. ^ http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/06-24-2002/0001752386
  11. ^ http://www.freepatentsonline.com/EP1503797.html
  12. ^ http://www.nytimes.com/2003/06/17/business/company-news-cell-therapeutics-announces-plan-to-buy-novuspharma.html?sec=health
  13. ^ a b 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. PMID 17285358.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ http://news.prnewswire.com/DisplayReleaseContent.aspx?ACCT=104&STORY=/www/story/05-15-2009/0005026831
  15. ^ http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/07-11-2007/0004623260 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
  16. ^ Gonsette RE (2007). "Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis". Expert Opin Pharmacother. 8 (8): 1103–16. PMID 17516874.
  17. ^ http://www.novartis.com/newsroom/media-releases/en/2009/1309396.shtml
  18. ^ Gonsette RE, Dubois B (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.2004.04.024. PMID 15261566.
  19. ^ Ubiali F, Nava S, Nessi V, et al. Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats. J Immunol. 2008 Feb 15;180(4):2696-703.
  20. ^ Electrophoresis. 2009 Apr;30(8):1418-29. CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity. Colombo R, Carotti A, Catto M, Racchi M, Lanni C, Verga L, Caccialanza G, De Lorenzi E.
  21. ^ http://www.survivorship.cancer.gov/Templates/db_alpha.aspx?CdrID=322132
  22. ^ BBR 2778 for Relapsed, Aggressive Non-Hodgkin's Lymphoma (NHL). ClinicalTrials.gov (2007-08-30). Retrieved on 2007-11-06.
  23. ^ Fludarabine and Rituximab With or Without Pixantrone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma. ClinicalTrials.gov (2007-10-25). Retrieved on 2007-11-06.
  24. ^ http://www.abstract.asco.org/AbstView_65_35306.html
  25. ^ http://clinicaltrials.gov/ct2/show/NCT00268853 A Trial in Patients With Diffuse Large-B-Cell Lymphoma Comparing Pixantrone Against Doxorubicin (RAPID) Retrieved on 2009-05-16
  26. ^ http://www.abstract.asco.org/AbstView_65_35306.html Randomized phase III trial of pixantrone compared with other chemotherapeutic agents for third-line single-agent treatment of relapsed aggressive non-Hodgkin's lymphoma. J Clin Oncol 27:15s, 2009 (suppl; abstr 8523)
  27. ^ Pixantrone or Other Chemotherapy Drugs in Treating Patients With Relapsed Non-Hodgkin's Lymphoma. ClinicalTrials.gov (2007-10-25). Retrieved on 2007-11-06.
  28. ^ http://www.abstract.asco.org/AbstView_65_35306.html
  29. ^ http://www.abstract.asco.org/AbstView_65_35306.html
  30. ^ http://www.celltherapeutics.com/pixantrone
  31. ^ http://news.prnewswire.com/DisplayReleaseContent.aspx?ACCT=104&STORY=/www/story/05-05-2009/0005019037
  32. ^ http://news.prnewswire.com/DisplayReleaseContent.aspx?ACCT=104&STORY=/www/story/05-05-2009/0005019037
  33. ^ http://www.reuters.com/article/pressRelease/idUS69825+10-Feb-2009+PRN20090210
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