Carfilzomib 868540-17-4

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. 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.

Mechanism

Carfilzomib irreversibly binds to and inhibits the chymotrypsin-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. 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.