Mifamurtide
Encyclopedia
Mifamurtide is a drug against osteosarcoma
, a kind of bone cancer
mainly affecting children and young adults, which is lethal in about a third of cases. The drug was approved in Europe in March 2009.
) in the early 1980s and sold to Jenner Biotherapies in the 1990s. In 2003, IDM Pharma bought the rights and developed it further. IDM Pharma was acquired by Takeda along with mifamurtide in June 2009.
Mifamurtide had already been granted orphan drug
status by the U.S. Food and Drug Administration (FDA) in 2001, and the European Medicines Agency
(EMA) followed in 2004. It was approved in the 27 European Union
member states plus Iceland, Liechtenstein and Norway via a centralized marketing authorization in March 2009. The drug was denied approval by the FDA in 2007.Mifamurtide (Mepact) has been licensed by the EMA since March, 2009.
, resectable
osteosarcoma following complete surgical removal in children, adolescents and young adults, aged two to 30 years. Osteosarcoma is a type of bone cancer diagnosed in about 1,000 individuals in Europe and the USA per year, most under the age of 30. The drug is used in combination with post-operative, multi-agent chemotherapy
to kill remaining cancer cells and so help improve a patient's chance of overall survival.
In a phase III clinical trial
in about 800 newly diagnosed osteosarcoma patients, mifamurtide was combined with the chemotherapeutic agents doxorubicin
and methotrexate
, with or without cisplatin
and ifosfamide
. The mortality
could be lowered by 30% versus chemotherapy plus placebo
. Six years after the treatment, 78% of patients were still alive. This equals an absolute risk reduction of 8% (p
=0.03).
(ca. 90%), vomiting, fatigue and tachycardia
(ca. 50%), infection
s, anaemia, anorexia
, headache, diarrhoea and constipation
(>10%).
, nasopharynx
, and thyroid
. The terminal half-life is 18 hours. In patients receiving a second treatment after 11–12 weeks, no accumulation effects were observed.
(MDP), the smallest naturally-occurring immune stimulatory component of cell walls from Mycobacterium
species. It has similar immunostimulatory effects as natural MDP with the advantage of a longer half-life in plasma.
NOD2
is a pattern recognition receptor
which is found in several kinds of white blood cell
s, mainly monocytes and macrophages. It recognises muramyl dipeptide, a component of the cell wall of bacteria
. Mifamurtide simulates a bacterial infection by binding to NOD2, activating white cells. This results in an increased production of TNF-α, interleukin 1, interleukin 6
, interleukin 8
, interleukin 12
and other cytokine
s, as well as ICAM-1
. The activated white cells attack cancer cells, but not, at least in vitro
, other cells.
Consequently, the combination of mifamurtide with these types of drugs is contraindicated. However, mifamurtide can be co-administered with low doses of NSAIDs. There is no evidence to suggest that mifamurtide interacts with the studied chemotherapeutics, or with the cytochrome P450 system.
Mifamurtide is muramyl tripeptide
phosphatidylethanolamine
(MTP-PE), a synthetic analogue of muramyl dipeptide. The side chains of the molecule give it a longer elimination half-life than the natural substance. Being a phospholipid
, it accumulates in the lipid bilayer
of the liposomes in the infusion.
-L-alanine with N-hydroxysuccinimide
, followed by a condensation with 2-aminoethyl-2,3-dipalmitoyl
glycerylphosphoric acid in triethylamine
(Et3N). A different approach (shown right) uses N-acetylmuramyl-L-alanyl-D-isoglutamine, hydroxysuccinimide and alanyl-2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid; that is, the alanine is introduced in the second step instead of the first.
Osteosarcoma
Osteosarcoma is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid...
, a kind of bone 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...
mainly affecting children and young adults, which is lethal in about a third of cases. The drug was approved in Europe in March 2009.
History
The drug was invented by Ciba-Geigy (now NovartisNovartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
) in the early 1980s and sold to Jenner Biotherapies in the 1990s. In 2003, IDM Pharma bought the rights and developed it further. IDM Pharma was acquired by Takeda along with mifamurtide in June 2009.
Mifamurtide had already been granted orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
status by the U.S. Food and Drug Administration (FDA) in 2001, and the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(EMA) followed in 2004. It was approved in the 27 European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
member states plus Iceland, Liechtenstein and Norway via a centralized marketing authorization in March 2009. The drug was denied approval by the FDA in 2007.Mifamurtide (Mepact) has been licensed by the EMA since March, 2009.
Indications
Mifamurtide is indicated for the treatment of high-grade, non-metastasizingMetastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
, resectable
Segmental resection
Segmental resection is a surgical procedure to remove part of an organ or gland. It may also be used to remove a tumor and normal tissue around it. In lung cancer surgery, segmental resection refers to removing a section of a lobe of the lung.- External links :* entry in the public domain NCI...
osteosarcoma following complete surgical removal in children, adolescents and young adults, aged two to 30 years. Osteosarcoma is a type of bone cancer diagnosed in about 1,000 individuals in Europe and the USA per year, most under the age of 30. The drug is used in combination with post-operative, multi-agent chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
to kill remaining cancer cells and so help improve a patient's chance of overall survival.
In a 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...
in about 800 newly diagnosed osteosarcoma patients, mifamurtide was combined with the chemotherapeutic agents 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....
and methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
, with or without cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
and ifosfamide
Ifosfamide
Ifosfamide is a nitrogen mustard alkylating agent used in the treatment of cancer.It is sometimes abbreviated "IFO".-Uses:It is given as a treatment for a variety of cancers, including:...
. The mortality
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
could be lowered by 30% versus chemotherapy plus placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. Six years after the treatment, 78% of patients were still alive. This equals an absolute risk reduction of 8% (p
P-value
In statistical significance testing, the p-value is the probability of obtaining a test statistic at least as extreme as the one that was actually observed, assuming that the null hypothesis is true. One often "rejects the null hypothesis" when the p-value is less than the significance level α ,...
=0.03).
Adverse effects
In a clinical study, mifamurtide was given to 332 subjects (half of whom were under age of 16) and most side effects were found to be mild to moderate in nature. Most patients experience fewer adverse events with subsequent administration. Common side effects include feverFever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
(ca. 90%), vomiting, fatigue and tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
(ca. 50%), infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s, anaemia, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, headache, diarrhoea and constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
(>10%).
Pharmacokinetics
After application of the liposomal infusion, the drug is cleared from the plasma within minutes and is concentrated in lung, liver, spleenSpleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, nasopharynx
Nasopharynx
The nasopharynx is the uppermost part of the pharynx. It extends from the base of the skull to the upper surface of the soft palate; it differs from the oral and laryngeal parts of the pharynx in that its cavity always remains patent .-Lateral:On its lateral wall is the pharyngeal ostium of the...
, and thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
. The terminal half-life is 18 hours. In patients receiving a second treatment after 11–12 weeks, no accumulation effects were observed.
Pharmacodynamics
Mifamurtide is a fully synthetic derivative of muramyl dipeptideMuramyl dipeptide
Muramyl dipeptide is a peptidoglycan constituent of both Gram positive and Gram negative bacteria. It is composed of N-acetylmuramic acid linked by its lactic acid moiety to the N-terminus of an L-alanine D-isoglutamine dipeptide.-See also:* Dipeptide...
(MDP), the smallest naturally-occurring immune stimulatory component of cell walls from Mycobacterium
Mycobacterium
Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy...
species. It has similar immunostimulatory effects as natural MDP with the advantage of a longer half-life in plasma.
NOD2
NOD2
Nucleotide-binding oligomerization domain-containing protein 2 also known as caspase recruitment domain-containing protein 15 or inflammatory bowel disease protein 1 is a protein that in humans is encoded by the NOD2 gene located on chromosome 16. NOD2 plays an important role in the immune system...
is a pattern recognition receptor
Pattern recognition receptor
Pattern recognition receptors are a primitive part of the immune system. They are proteins expressed by cells of the innate immune system to identify pathogen-associated molecular patterns , which are associated with microbial pathogens or cellular stress, as well as damage-associated molecular...
which is found in several kinds of white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s, mainly monocytes and macrophages. It recognises muramyl dipeptide, a component of the cell wall of bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. Mifamurtide simulates a bacterial infection by binding to NOD2, activating white cells. This results in an increased production of TNF-α, interleukin 1, interleukin 6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, interleukin 8
Interleukin 8
Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...
, interleukin 12
Interleukin 12
Interleukin 12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells in response to antigenic stimulation.-Gene and structure:...
and other cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s, as well as ICAM-1
ICAM-1
ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system...
. The activated white cells attack cancer cells, but not, at least in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
, other cells.
Interactions
- Theoretical considerations suggest that calcineurin inhibitors like ciclosporinCiclosporinCiclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
and tacrolimusTacrolimusTacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
might interact with mifamurtide because of their effect on macrophages. - High-dose NSAIDs block the mechanism of mifamurtide in vitro.
Consequently, the combination of mifamurtide with these types of drugs is contraindicated. However, mifamurtide can be co-administered with low doses of NSAIDs. There is no evidence to suggest that mifamurtide interacts with the studied chemotherapeutics, or with the cytochrome P450 system.
Chemistry
Tripeptide
A tripeptide is a peptide consisting of three amino acids joined by peptide bonds.Examples of tripeptides are:*Eisenin is a peptide with immunological activity that is isolated from the Japanese marine alga, Eisenia bicyclis, which more commonly is known as, Arame*GHK-Cu is a human copper binding...
phosphatidylethanolamine
Phosphatidylethanolamine
Phosphatidylethanolamine is a lipid found in biological membranes. It is synthesized by the addition of CDP-ethanolamine to diglyceride, releasing CMP. S-adenosyl methionine can subsequently methylate the amine of phosphatidyl ethanolamine to yield phosphatidyl choline.Cephalin is a phospholipid,...
(MTP-PE), a synthetic analogue of muramyl dipeptide. The side chains of the molecule give it a longer elimination half-life than the natural substance. Being a phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
, it accumulates in the lipid bilayer
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
of the liposomes in the infusion.
Synthesis
One method of synthesis (shown left) is based on N,N-dicyclohexylcarbodiimide (DCC) assisted esterification of N-acetylmuramyl-L-alanyl-D-isoglutaminylIsoglutamine
Isoglutamine or α-glutamine is an amino acid which is derived from glutamic acid by substituting the carboxyl group in position 1 with an amide group...
-L-alanine with N-hydroxysuccinimide
N-Hydroxysuccinimide
N-Hydroxysuccinimide is a compound with a molecular weight of 115.09 and a melting point of 95 °C.As it is slightly acidic, it is an irritant to skin, eyes and mucous membranes....
, followed by a condensation with 2-aminoethyl-2,3-dipalmitoyl
Palmitic acid
Palmitic acid, or hexadecanoic acid in IUPAC nomenclature, is one of the most common saturated fatty acids found in animals and plants. Its molecular formula is CH314CO2H. As its name indicates, it is a major component of the oil from palm trees . Palmitate is a term for the salts and esters of...
Triethylamine
Triethylamine is the chemical compound with the formula N3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine, for which TEA is also a common abbreviation....
(Et3N). A different approach (shown right) uses N-acetylmuramyl-L-alanyl-D-isoglutamine, hydroxysuccinimide and alanyl-2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid; that is, the alanine is introduced in the second step instead of the first.