Proteolix/Onyx Pharmaceuticals: Kyprolis approval is bad news for Velcade

Kyprolis, the multiple myeloma treatment from Proteolix and Onyx Pharmaceuticals, has received US approval a full week before the date set for the FDA's decision. With its high response rate and acceptable toxicity profile, Kyprolis will pose a serious threat to Velcade's position in the myeloma market.

The early approval comes after the recent recommendation of the drug by the FDA's Oncologic Drugs Advisory Committee (ODAC). The regulator's decision is based on results from the pivotal Phase II 003A1 study, with consideration of data from eight additional Phase I and Phase II studies. The target population of Kyprolis (carfilzomib) is patients with refractory or relapsed multiple myeloma who have received at least two prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. This indication and treatment setting currently have a poor prognosis and limited treatment options.

The Phase II 003A1 study was an open-label, multicenter, single-arm trial which enrolled 266 patients. Kyprolis was found to induce an overall response rate (ORR) of 22.9%, with a median duration of response of 7.8 months. Kyprolis also maintains efficacy in patients who were refractory to Velcade (bortezomib; Takeda/Johnson & Johnson) in their last treatment regimen (ORR 18.3%), and in patients who were double refractory to Velcade and Revlimid (lenalidomide; Celgene) (ORR 15.4%). Additionally, Kyprolis is not associated with the dose-limiting peripheral neuropathy that is a debilitating side effect of other multiple myeloma treatment options.

The FDA previously released a briefing paper in which it expressed significant concerns about Kyprolis's potential toxicity. In the 003A1 study, seven patients (2.6%) died due to severe cardiac adverse effects, while cardiac toxicity may have also played a role in the deaths of another three patients (1.1%). In addition, two patients (0.8%) died due to adverse effects associated with hepatic toxicity. However, ODAC concluded that the cardiac-related toxicities present an acceptable level of risk in highly refractory patients lacking alternative treatment options.

Kyprolis will now directly compete with blockbuster Velcade in the proteasome inhibitor market. Despite its approval as a third-line treatment, the lower levels of peripheral neuropathy associated with Kyprolis may attract physicians to use it off-label in earlier lines of therapy. In addition, Onyx Pharmaceuticals has initiated a Phase III head-to-head trial to investigate the efficacy of Kyprolis against Velcade in the second-line setting. Johnson & Johnson will be waiting anxiously for the results of this study, which may significantly impact Velcade's current dominance of this treatment setting.