Pixantrone (
rINN
Rinn is a municipality in the district of Innsbruck-Land in the Austrian state of Tyrol located 6 km southeast of Innsbruck. The village was mentioned in documents as “Runne” in 1250 for the first time.
Population
Climate
Climate typ ...
; trade name Pixuvri)
is an experimental
antineoplastic (anti-cancer) drug, an
analogue of
mitoxantrone 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 subs ...
effects on
cardiac
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
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 ATP, unlike Type I topoisomerase. In this process, these enzymes change th ...
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'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder canc ...
s are important
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
agents. However, their use is associated with irreversible and cumulative
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
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
An alliance is a relationship among people, groups, or sovereign state, states that have joined together for mutual benefit or to achieve some common purpose, whether or not explicit agreement has been worked out among them. Members of an alli ...
led to the discovery of
ametantrone as having significant
anti-tumor
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothera ...
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
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, and
University of Vermont
The University of Vermont (UVM), officially the University of Vermont and State Agricultural College, is a public land-grant research university in Burlington, Vermont. It was founded in 1791 and is among the oldest universities in the United ...
,
Burlington.
Other studies have been completed at
the University of Texas M. D. Anderson Cancer Center,
Houston
Houston (; ) is the most populous city in Texas, the most populous city in the Southern United States, the fourth-most populous city in the United States, and the sixth-most populous city in North America, with a population of 2,304,580 i ...
, the
Istituto Nazionale Tumori,
Milan
Milan ( , , Lombard: ; it, Milano ) is a city in northern Italy, capital of Lombardy, and the second-most populous city proper in Italy after Rome. The city proper has a population of about 1.4 million, while its metropolitan city h ...
, and the
University of Padua
The University of Padua ( it, Università degli Studi di Padova, UNIPD) is an Italian university located in the city of Padua, region of Veneto, northern Italy. The University of Padua was founded in 1222 by a group of students and teachers from ...
.
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.
A patent application for the injectable preparation was filed in May 2003.
In 2003,
Cell Therapeutics, a
Seattle
Seattle ( ) is a seaport city on the West Coast of the United States. It is the seat of King County, Washington. With a 2020 population of 737,015, it is the largest city in both the state of Washington and the Pacific Northwest regio ...
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 participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
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 abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, including solid tumors and
hematological malignancies
Tumors of the hematopoietic and lymphoid tissues (American English) or tumours of the haematopoietic and lymphoid tissues (British English) are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are al ...
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 tirednes ...
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 tirednes ...
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 tirednes ...
patients.
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.
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
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 tirednes ...
.
Administration
It can be administered through a peripheral vein rather than a central implanted catheter as required for other similar drugs.
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
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
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.
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.
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 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.
References
{{Chemotherapeutic agents
Topoisomerase inhibitors
Quinones
Amines
Quinolines
Heterocyclic compounds with 3 rings
DNA intercalaters
Enones