Pixantrone

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. Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.{{cite journal |vauthors=Cavalletti E, Crippa L, Mainardi P, Oggioni N, Cavagnoli R, Bellini O, Sala F |title=Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone |journal=Invest New Drugs. |volume=25 |issue=3 |pages=187–95 |year=2007 |pmid=17285358 |doi=10.1007/s10637-007-9037-8|s2cid=20933712 }}

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 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. BBR 2778 was originally synthesized by University of Vermont researchers Miles P. Hacker and Paul A. Krapcho{{ cite patent | country = US | number = 5587382 | status = patent | title = 6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity | pubdate = | gdate = 24 December 1996 | fdate = 1995-06-06 | pridate = | inventor = Krapcho AP, Hacker MP, Cavalletti E, Giuliani FC | assign1 = Boehringer Mannheim Italia, SpA }} 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 Vermont, Burlington. Other studies have been completed at the University of Texas M. D. Anderson Cancer Center, Houston, the Istituto Nazionale Tumori, Milan, and the University of Padua.{{cite journal |vauthors=De Isabella P, Palumbo M, Sissi C, Capranico G, Carenini N, Menta E, Oliva A, Spinelli S, Krapcho AP, Giuliani FC, Zunino F |title=Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives |journal=Mol. Pharmacol. |volume=48 |issue=1 |pages=30–8 |year=1995 |pmid=7623772}}{{cite journal |vauthors=Zwelling LA, Mayes J, Altschuler E, Satitpunwaycha P, Tritton TR, Hacker MP |title=Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II |journal=Biochem. Pharmacol. |volume=46 |issue=2 |pages=265–71 |year=1993 |pmid=8394077 |doi=10.1016/0006-2952(93)90413-Q}} 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.

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.{{cite journal |vauthors=Borchmann P, Reiser M | title = Pixantrone (Novuspharma) | journal = IDrugs | volume = 6 | issue = 5 | pages = 486–90 |date=May 2003 | pmid = 12789604 }} A patent application for the injectable preparation was filed in May 2003.{{ cite patent | country = EP | number = 1503797 | status = patent | title = Injectable Pharmaceutical Compositions of an Anthracenedione Derivative with Anti-Tumoral Activity | pubdate = 27 November 2003 | gdate = 2008-09-29 | fdate = 2003-09-05 | pridate = 2002-05-16 | inventor = Bernareggi A, Livi V | assign1 = Cell Therapeutics Europe S.R.L. }}

In 2003, Cell Therapeutics, a Seattle biotechnology company, acquired pixantrone through a merger with Novuspharma.{{cite news| url=https://www.nytimes.com/2003/06/17/business/company-news-cell-therapeutics-announces-plan-to-buy-novuspharma.html?sec=health | work=The New York Times | title=Company News; Cell Therapeutics Announces Plan To Buy Novuspharma | first=Andrew | last=Pollack | date=17 June 2003 | access-date=22 May 2010}}

Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics.{{cite web | url = http://medical-dictionary.thefreedictionary.com/antineoplastic+antibiotic | title = definition of antineoplastic antibiotic | author = Mosby's Medical Dictionary, 8th edition. © 2009, Elsevier. | publisher = Free Online Medical Dictionary, Thesaurus and Encyclopedia | access-date = 31 January 2012 }} phase III clinical trials of pixantrone have been completed.{{cite web | url = http://clinicaltrials.gov/ct/show/NCT00088530 | title = NCT00088530 | work = BBR 2778 for Relapsed, Aggressive Non-Hodgkin's Lymphoma (NHL) | publisher = ClinicalTrials.gov | access-date = 31 January 2012 }}{{cite web | url = http://clinicaltrials.gov/ct/show/NCT00551239 | title = NCT00551239 | date = 31 January 2012 | work = Fludarabine and Rituximab With or Without Pixantrone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma | publisher = ClinicalTrials.gov | access-date = 31 January 2012 }} 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 degeneration.

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.{{cite press release | url = http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/07-11-2007/0004623260 | title = 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 | work = Press Release | access-date = 31 January 2012 }} Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.

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.{{cite web | url = http://clinicaltrials.gov/ct2/show/NCT00268853 | title = NCT00268853 | work = A Trial in Patients With Diffuse Large-B-cell Lymphoma Comparing Pixantrone Against Doxorubicin | publisher = ClinicalTrials.gov | access-date = 31 January 2012 }}

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.{{cite journal |vauthors=Engert A, Herbrecht R, Santoro A, Zinzani PL, Gorbatchevsky I | title = 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 | journal = Clin Lymphoma Myeloma | volume = 7 | issue = 2 | pages = 152–4 |date=September 2006 | pmid = 17026830 | doi = 10.3816/CLM.2006.n.055 }}

The phase III EXTEND (PIX301) randomized clinical trial studied pixantrone to see how well it works compared to other chemotherapy drugs in treating participants with relapsed non-Hodgkin's lymphoma.{{cite web | url = http://clinicaltrials.gov/ct/show/NCT00101049 | title = NCT00101049 | work = BBR 2778 for Relapsed, Aggressive Non-Hodgkin's Lymphoma (NHL) | publisher = ClinicalTrials.gov | access-date = 31 January 2012 }} The complete response rate in pixantrone treated with pixantrone has been significantly higher than in those receiving other chemotherapeutic agents for treatment of relapsed/refractory aggressive non-Hodgkin lymphoma.

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

The US Food and Drug Administration (FDA) granted fast track designation for pixantrone in people who had previously been treated two or more times for relapsed or refractory aggressive Non-Hodgkin's Lymphoma. Study sponsor Cell Therapeutics announced that pixantrone achieved the primary efficacy endpoint. The minutes of the Oncologic Drugs Advisory Committee meeting of 22 March 2010{{cite web | url = https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM207638.pdf | title = NDA 022-481 PIXUVRI (pixantrone dimaleate) injection |vauthors=Vesely N, Eckhardt SG | date = 22 March 2010 | work = Summary Minutes of the Oncologic Drugs Advisory Committee | publisher = United States Food and Drug Administration | access-date = 31 January 2012 }} 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.{{cite news | url = http://www.genengnews.com/gen-news-highlights/cell-therapeutics-formally-appeals-fda-s-nonapprovable-ruling-for-pixantrone/81244332/ | title = Cell Therapeutics Formally Appeals FDA's Nonapprovable Ruling for Pixantrone | date = 3 December 2010 | publisher = GEN News }}

In May 2009, pixantrone became available in the European Union 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 individuals. Under a named-patient program, investigational drugs can be administered to people 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. In the European Union, under the named-patient program the drug is most often purchased through the national health system.{{cite web| url =http://news.prnewswire.com/DisplayReleaseContent.aspx?ACCT=104&STORY=/www/story/05-05-2009/0005019037| title =Pixantrone Now Available in Europe on a Named-Patient Basis| archive-date =1 October 2009| access-date =31 January 2012| url-status =dead| archive-url =https://web.archive.org/web/20091001154001/http://news.prnewswire.com/DisplayReleaseContent.aspx?ACCT=104}}

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.{{cite journal | vauthors = Péan E, Flores B, Hudson I, Sjöberg J, Dunder K, Salmonson T, Gisselbrecht C, Laane E, Pignatti F | title = The European Medicines Agency review of pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin's B-cell lymphomas: summary of the scientific assessment of the committee for medicinal products for human use | journal = The Oncologist | volume = 18 | issue = 5 | pages = 625–33 | date = 2013 | pmid = 23615696 | pmc = 3662855 | doi = 10.1634/theoncologist.2013-0020 }}{{cite web | title=Pixuvri EPAR | website=European Medicines Agency | date=31 May 2012 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/pixuvri | access-date=12 July 2024}} The authorization expired in July 2024, after the holder decided not to renew.

Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis.{{cite journal |vauthors=Gonsette RE, Dubois B | title = Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity | journal = J. Neurol. Sci. | volume = 223 | issue = 1 | pages = 81–6 |date=August 2004 | pmid = 15261566 | doi = 10.1016/j.jns.2004.04.024 | s2cid = 35170743 }} 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.{{cite journal |vauthors=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 | title = Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis | journal = J. Neuroimmunol. | volume = 168 | issue = 1–2 | pages = 111–7 |date=November 2005 | pmid = 16120465 | doi = 10.1016/j.jneuroim.2005.07.010 | s2cid = 32913479 }} Clinical trials are currently ongoing in Europe.

Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats,{{cite journal |vauthors=Ubiali F, Nava S, Nessi V, Longhi R, Pezzoni G, Capobianco R, Mantegazza R, Antozzi C, Baggi F | title = Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats | journal = J. Immunol. | volume = 180 | issue = 4 | pages = 2696–703 |date=February 2008 | pmid = 18250482 | doi = 10.4049/jimmunol.180.4.2696| doi-access = free }} 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.{{cite journal |vauthors=Colombo R, Carotti A, Catto M, Racchi M, Lanni C, Verga L, Caccialanza G, De Lorenzi E | title = CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity | journal = Electrophoresis | volume = 30 | issue = 8 | pages = 1418–29 |date=April 2009 | pmid = 19306269 | doi = 10.1002/elps.200800377 | s2cid = 6594113 }}

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