Pixantrone
Encyclopedia
Pixantrone
is an experimental antineoplastic drug, an analogue
of mitoxantrone
with fewer toxic effects on cardiac tissue. It acts as a topoisomerase II poison and intercalating agent. The code name BBR 2778 refers to pixantrone dimaleate, the actual substance commonly used in clinical trials.
s are important chemotherapy
agents; however, their use is associated with irreversible and cumulative heart
damage. Investigators have attempted to design related drugs which 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
of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant antitumor
activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone
which also exhibited marked antitumor 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 http://www.patentstorm.us/patents/5587382.html 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
. 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. A 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 biotechnology company, acquired pixantrone through a merger with Novuspharma.
As of 2009, phase III clinical trial
s of pixantrone are underway.
Pixantrone is being studied as an antineoplastic for different kinds of cancer
, including solid tumors and hematological malignancies such as non-Hodgkin lymphoma
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 degeneragion.
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
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
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
.
.
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
.
is an experimental antineoplastic drug, an analogue
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of mitoxantrone
Mitoxantrone
Mitoxantrone is an anthracenedione antineoplastic agent.-Uses:It is used in the treatment of certain types of cancer, mostly metastatic breast cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma...
with fewer toxic effects on cardiac tissue. It acts as a topoisomerase II poison and intercalating agent. The code name BBR 2778 refers to pixantrone dimaleate, the actual substance commonly used in clinical trials.
History
AnthracyclineAnthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var...
s are important chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
agents; however, their use is associated with irreversible and cumulative heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
damage. Investigators have attempted to design related drugs which 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
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant antitumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone
Mitoxantrone
Mitoxantrone is an anthracenedione antineoplastic agent.-Uses:It is used in the treatment of certain types of cancer, mostly metastatic breast cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma...
which also exhibited marked antitumor activity Mitoxantrone was considered as an analog of doxorubicin
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
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 http://www.patentstorm.us/patents/5587382.html and initially characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the Boehringer Mannheim Italia Research Center, Monza
Monza
Monza is a city and comune on the river Lambro, a tributary of the Po, in the Lombardy region of Italy some 15 km north-northeast of Milan. It is the capital of the Province of Monza and Brianza. It is best known for its Grand Prix motor racing circuit, the Autodromo Nazionale Monza.On June...
, and University of Vermont
University of Vermont
The University of Vermont comprises seven undergraduate schools, an honors college, a graduate college, and a college of medicine. The Honors College does not offer its own degrees; students in the Honors College concurrently enroll in one of the university's seven undergraduate colleges or...
, Burlington
Burlington, Vermont
Burlington is the largest city in the U.S. state of Vermont and the shire town of Chittenden County. Burlington lies south of the U.S.-Canadian border and some south of Montreal....
. Other studies have been completed at the University of Texas M. D. Anderson Cancer Center
The University of Texas M. D. Anderson Cancer Center
The University of Texas MD Anderson Cancer Center is one of the nation's original three comprehensive cancer centers established by the National Cancer Act of 1971. It is both a degree-granting academic institution and a cancer treatment and research center located at the Texas Medical Center in...
, Houston, the Istituto Nazionale Tumori, Milan
Milan
Milan is the second-largest city in Italy and the capital city of the region of Lombardy and of the province of Milan. The city proper has a population of about 1.3 million, while its urban area, roughly coinciding with its administrative province and the bordering Province of Monza and Brianza ,...
, and the University of Padua
University of Padua
The University of Padua is a premier Italian university located in the city of Padua, Italy. The University of Padua was founded in 1222 as a school of law and was one of the most prominent universities in early modern Europe. It is among the earliest universities of the world and the second...
. 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. A 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
Hoffmann-La Roche
F. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
, 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 biotechnology company, acquired pixantrone through a merger with Novuspharma.
Uses
Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics.As of 2009, phase III clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s of pixantrone are underway.
Pixantrone is being studied as an antineoplastic for different kinds of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, including solid tumors and hematological malignancies such as non-Hodgkin lymphoma
Non-Hodgkin lymphoma
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
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 degeneragion.
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
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
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
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
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
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
.
Administration
It can be administered through a peripheral vein rather than a central implanted catheter as required for other similar drugs..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. A New Drug Application for pixantrone is under review by the U.S. Food and Drug Administration for Pixantrone to treat relapsed or refractory aggressive NHL.. 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.Research
Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosisMultiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
.
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
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
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
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.