On May 13, 2003, the U.S. Food and Drug Administration (FDA) granted accelerated approval for bortezomib (formerly PS-341), Velcade^® for Injection (Millenium Pharmaceuticals; Cambridge, MA), for use as a single agent for the treatment of patients with multiple myeloma after two prior therapies and progressing on their most recent therapy. In 1998, Millennium Pharmaceuticals, submitted an Investigational New Drug Application for bortezomib and in January, 2003, a New Drug Application (NDA) was filed. At the time of the NDA submission, melphalan, cyclophosphamide, and carmustine had been FDA approved for myeloma treatment, and pamidronate and zoledronate were approved for reducing skeletal-related events.

The clinical development of bortezomib followed preclinical observations of its ability to inhibit reversibly the proteolytic (chymotryptic) activity of the proteasome complex in mammalian cells. Inhibition of the intracellular protein degradation pathway (proteasome) alters the levels of numerous intracellular signaling and regulatory proteins as well as other proteins and, in some fashion, then alters the regulation of cellular processes that may lead to growth arrest or apoptosis.

Recovery of proteasome activity was nearly complete by 48–72 hours following bortezomib dosing in preclinical models. At present, the relationship between these or other intracellular effects of bortezomib and the clinical results is uncertain. In the future, pharmacodynamic correlations (proteasome inhibition and/or other proteomic measures) in patients may provide more accurate dosing than the current toxicity end points.

Accelerated approval is a mechanism to accelerate patients’ access to drugs; it also carries the requirement that the applicant study the drug further, to verify and describe its clinical benefit with the expectation that the accelerated approval can be converted to full approval. These requirements may be addressed in the form of “phase IV commitments” agreed to by the company at the time of the accelerated approval.

Thus, concurrent with accelerated approval, a clear development plan for the product should be under way. For bortezomib, the sponsor will characterize the pharmacokinetics as a single agent in patients with myeloma and in patients with hepatic and renal impairments. Drug-drug cytochrome interactions will be examined further, and follow-up to characterize the frequency, severity, and reversibility of the peripheral neuropathy will be undertaken. Also, new studies will compare bortezomib with dexamethasone in relapsed and in previously untreated myeloma patients.