Carfilzomib, CAS number 868540-17-4, is a late-stage, selective next-generation proteasome inhibitor for patients with multiple myeloma. Developed by Onyx, carfilzomib has the ability to irreversibly bind to and inhibit the chymotrypsin-like activity of the 20S proteasome, which is an enzyme that degrades unwanted cellular proteins. The subsequent inhibition of the proteasome-mediated proteolysis creates a build-up of polyubiquinated proteins. This build up may cause apoptosis, cell cycle arrest and even inhibit tumor growth. LGM Pharma is a provider of the API carfilzomib for research and development.
With a fast track status given to Onyx for a rolling submission of carfilzomib by the FDA in January 2011, two Stage 3 clinical trials are underway. The first of the Stage 3 trials, known as ASPIRE, is an international and randomized trial. This trial combines carfilzomib with lenalidomide and low-dose dexamethasone, versus lenalidomide and low-dose dexamethasone alone, as a potential treatment for relapsed patients with multiple myeloma. The second of the Stage 3 trials is deemed FOCUS. This study of carfilzomib as a single agent in the relapsed and refractory setting is designed to support a regulatory filing in Europe. Additional ongoing clinical studies in patients with multiple myeloma are also underway, including a carfilzomib Phase 1b/2 study for patients with advanced solid tumors.
Previous trials include a single-arm, Phase 2 trial in patients with relapsed and refractory multiple myeloma. Carfilzomib, as a single-agent showed a positive response in this trial of 257 patients, with a 36% response rate. In another Phase 2 trial of patients with refractory multiple myeloma carfilzomib was combined with lenalidomide and dexamethasone. The durable response rate of 78% led researchers to initiate the current Stage 3 study, ASPIRE.
Clinical trials have shown carfilzomib to be effective when administered for periods of 14-23 months, with no overlapping or new incidence of toxicity. While 22% of patients in Phase 2 trials tolerated treatment well for over a year, adverse effects have been noted. Patients receiving grade 3 or higher treatment showed treatment emergent effects including thrombocytopenia, anemia, lymphoenia, neutropenia, pneumonia, fatigue and hyponatremia. However, current studies show carfilzomib to have a positive safety profile, including low rates of neuropathy.
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