Pixantrone
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Pixantrone ( rINN; trade name Pixuvri) is an experimental antineoplastic (anti-cancer) drug, an analogue of
mitoxantrone Mitoxantrone (INN, BAN, USAN; also known as Mitozantrone in Australia; trade name Novantrone) is an anthracenedione antineoplastic agent. Uses Mitoxantrone is used to treat certain types of cancer, mostly acute myeloid leukemia. It improves th ...
with fewer
toxic Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
effects on
cardiac The heart is a muscular organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrients to the tissu ...
tissue. It acts as a
topoisomerase II Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of Adenosine triphosphate, ATP, unlike Type I topoisomerase. In this process, t ...
poison and
intercalating agent In biochemistry, intercalation is the insertion of molecules between the planar bases of deoxyribonucleic acid (DNA). This process is used as a method for analyzing DNA and it is also the basis of certain kinds of poisoning. There are several ...
. The code name BBR 2778 refers to pixantrone dimaleate, the actual substance commonly used in clinical trials.


History

Anthracycline Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from '' Streptomyces peucetius'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, b ...
s are important
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
agents. However, their use is associated with irreversible and cumulative
heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
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. Random screening at the US
National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant
anti-tumor Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cu ...
activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of
mitoxantrone Mitoxantrone (INN, BAN, USAN; also known as Mitozantrone in Australia; trade name Novantrone) is an anthracenedione antineoplastic agent. Uses Mitoxantrone is used to treat certain types of cancer, mostly acute myeloid leukemia. It improves th ...
, which also exhibited marked anti-tumor activity Mitoxantrone was considered as an analog of
doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...
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 and initially characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the Boehringer Mannheim Italia Research Center,
Monza Monza (, ; ; , locally ; ) is a city and ''comune'' (municipality) on the Lambro, River Lambro, a tributary of the Po (river), River Po, in the Lombardy region of Italy, about north-northeast of Milan. It is the capital of the province of Mo ...
, and
University of Vermont The University of Vermont and State Agricultural College, commonly referred to as the University of Vermont (UVM), is a Public university, public Land-grant university, land-grant research university in Burlington, Vermont, United States. Foun ...
, Burlington. Other studies have been completed at the University of Texas M. D. Anderson Cancer Center,
Houston Houston ( ) is the List of cities in Texas by population, most populous city in the U.S. state of Texas and in the Southern United States. Located in Southeast Texas near Galveston Bay and the Gulf of Mexico, it is the county seat, seat of ...
, the Istituto Nazionale Tumori,
Milan Milan ( , , ; ) is a city in northern Italy, regional capital of Lombardy, the largest city in Italy by urban area and the List of cities in Italy, second-most-populous city proper in Italy after Rome. The city proper has a population of nea ...
, and the
University of Padua The University of Padua (, UNIPD) is an Italian public research university in Padua, Italy. It was founded in 1222 by a group of students and teachers from the University of Bologna, who previously settled in Vicenza; thus, it is the second-oldest ...
. 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 F. Hoffmann-La Roche AG, commonly known as Roche (), is a Swiss multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on ...
, and BBR 2778 was developed as Novuspharma's leading anti-cancer drug, pixantrone. A patent application for the injectable preparation was filed in May 2003. In 2003,
Cell Therapeutics Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a d ...
, a
Seattle Seattle ( ) is the most populous city in the U.S. state of Washington and in the Pacific Northwest region of North America. With a population of 780,995 in 2024, it is the 18th-most populous city in the United States. The city is the cou ...
biotechnology company, acquired pixantrone through a merger with Novuspharma.


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. phase III
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s of pixantrone have been completed. Pixantrone is being studied as an antineoplastic for different kinds of
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
, including solid tumors and hematological malignancies such as
non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...
s. 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. Previous treatment options for multiply relapsed aggressive
non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...
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. Pixantrone was shown to have potentially reduced cardiotoxicity and demonstrated promising clinical activity in these phase II studies in heavily pretreated
non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...
patients. 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. 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 Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...
.


Administration

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


Society and culture


Legal status


US Food and Drug Administration

The US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(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 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.


European Medicines Agency

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. 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. The authorization expired in July 2024, after the holder decided not to renew.


Research

Pixantrone is as potent as mitoxantrone in animal models of
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
. 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. Clinical trials are currently ongoing in Europe. Pixantrone also reduces the severity of experimental autoimmune
myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...
in Lewis rats, 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 Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
.


References

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