Carfilzomib
Encyclopedia
Carfilzomib is a tetrapeptide
epoxyketone and a selective proteasome inhibitor
. It is an analog of epoxomicin
.
Clinical trials for carfilzomib continue under Onyx Pharmaceuticals
, which acquired Proteolix in 2009. In January 2011, the U.S. FDA granted carfilzomib fast-track status
, allowing Onyx to initiate a rolling submission of its new drug application for carfilzomib.
-like activity of the 20S proteasome, an enzyme that degrades unwanted cellular proteins. Inhibition of proteasome-mediated proteolysis results in a build-up of polyubiquinated proteins, which may cause cell cycle arrest, apoptosis
, and inhibition of tumor growth.
showed promising results.
A single-arm, phase 2 trial of carfilzomib in patients with relapsed and refractory multiple myeloma showed that single-agent carfilzomib had durable responses in 36 percent of the 257 patients evaluated.
In another phase 2 trial of patients with relapsed and/or refractory multiple myeloma, carfilzomib in combination with lenalidomide and dexamethasone demonstrated an overall response rate of 78 percent. Researchers found carfilzomib could be administered over a period of 14-23 months with no new or overlapping toxicities.
In a phase 2 trial, carfilzomib had a 53 percent overall response rate among patients with relapsed and/or refractory multiple myeloma who had not previously received bortezomib
. This study also found prolonged carfilzomib treatment is well-tolerated with approximately 22 percent of patients continuing treatment beyond one year.
In phase 2 trials of carfilzomib, the most common grade 3 or higher treatment-emergent adverse events were thrombocytopenia
, anemia, lymphoenia, neutropenia, pneumonia, fatigue and hyponatremia.
A phase 3 trial comparing carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma is ongoing.
Tetrapeptide
A tetrapeptide is a peptide consisting of four amino acids joined by peptide bonds. Many tetrapeptides are pharmacologically active, often showing affinity and specificity for a variety of receptors in protein-protein signaling...
epoxyketone and a selective proteasome inhibitor
Proteasome inhibitor
Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Proteasome inhibitors are being studied in the treatment of cancer.-Examples:...
. It is an analog of epoxomicin
Epoxomicin
Epoxomicin is a naturally occurring selective proteasome inhibitor with anti-inflammatory activity. It was originally discovered in 1992. Injected, it can induce Parkinson's-like symptoms in rats.Derivatives of epoxomicin include carfilzomib....
.
Discovery and Early Development
Carfilzomib was discovered and advanced to multiple Phase 1 and 2 clinical trials, including a pivotal Phase 2 clinical trial designed to seek accelerated approval, by Proteolix, Inc.Proteolix, Inc.
Proteolix, Inc., was a private biotechnology company with headquarters in South San Francisco, California. Proteolix focused primarily on the proteasome as a therapeutic target. Its lead product candidate, carfilzomib , is a tetrapeptide epoxyketone...
Clinical trials for carfilzomib continue under Onyx Pharmaceuticals
Onyx Pharmaceuticals
Onyx Pharmaceuticals Inc. is a biopharmaceutical company headquartered in South San Francisco, California. The company develops and markets medicines for the treatment of cancer. Onyx was founded in 1992 by Frank McCormick Ph.D., FRS...
, which acquired Proteolix in 2009. In January 2011, the U.S. FDA granted carfilzomib fast-track status
FDA Fast Track Development Program
The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days...
, allowing Onyx to initiate a rolling submission of its new drug application for carfilzomib.
Mechanism
Carfilzomib irreversibly binds to and inhibits the chymotrypsinChymotrypsin
Chymotrypsin is a digestive enzyme that can perform proteolysis. Chymotrypsin preferentially cleaves peptide amide bonds where the carboxyl side of the amide bond is a tyrosine, tryptophan, or phenylalanine. These amino acids contain an aromatic ring in their sidechain that fits into a...
-like activity of the 20S proteasome, an enzyme that degrades unwanted cellular proteins. Inhibition of proteasome-mediated proteolysis results in a build-up of polyubiquinated proteins, which may cause cell cycle arrest, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, and inhibition of tumor growth.
Clinical trials
A phase 2 trial for multiple myelomaMultiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
showed promising results.
A single-arm, phase 2 trial of carfilzomib in patients with relapsed and refractory multiple myeloma showed that single-agent carfilzomib had durable responses in 36 percent of the 257 patients evaluated.
In another phase 2 trial of patients with relapsed and/or refractory multiple myeloma, carfilzomib in combination with lenalidomide and dexamethasone demonstrated an overall response rate of 78 percent. Researchers found carfilzomib could be administered over a period of 14-23 months with no new or overlapping toxicities.
In a phase 2 trial, carfilzomib had a 53 percent overall response rate among patients with relapsed and/or refractory multiple myeloma who had not previously received bortezomib
Bortezomib
Bortezomib is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma...
. This study also found prolonged carfilzomib treatment is well-tolerated with approximately 22 percent of patients continuing treatment beyond one year.
In phase 2 trials of carfilzomib, the most common grade 3 or higher treatment-emergent adverse events were thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
, anemia, lymphoenia, neutropenia, pneumonia, fatigue and hyponatremia.
A phase 3 trial comparing carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma is ongoing.