Editor

Favorable Phase IIb results disclosed last week with Onyx Pharmaceuticals Inc.'s carfilzomib added more than 20 percent to the company's shares, and enthusiasm on Wall Street was well founded, but some unanswered questions about the data likely must wait until the American Society of Hematology meeting in early December.

The first peek at results from the trial known as 003-A1 with carfilzomib, a next-generation proteasome inhibitor, gave onlookers renewed faith in Emeryville, Calif.-based Onyx, hobbled by the fizzle of the Phase III NEXUS trial of Nexavar (sorafenib) as a first-line non-small-cell lung cancer treatment. Nexavar performed well in progression free survival, but failed to show statistically significant improvement in overall survival when combined with gemcitabine and cisplatin vs. chemotherapy. (See BioWorld Today, July 15, 2010.)

In 003-A1, patients with relapsed-refractory multiple myeloma given carfilzomib as a single agent turned up an overall response rate of 24 percent, with a median duration of response of 7.4 months and no new or unexpected toxicities. The results stack up nicely alongside such results as those in the SUMMIT trial with Velcade (bortezomib) from Cambridge, Mass.-based Millennium Pharmaceuticals Inc., which showed a 28 percent overall response rate and a 12-month duration of response. (See BioWorld Today, Dec. 10, 2002.)

Velcade is one of the drugs that participants in the 003-A1 may have failed in order to become eligible. The study tested 266 heavily pretreated patients with relapsed-refractory MM who got at least two prior therapies, such as Velcade, Revlimid (lenalidomide, Celgene Corp.) or thalidomide, an alkylating agent, glucocorticoids or an anthracycline. Patients enrolled were refractory to their last treatment regimen.

But that was in 2002, and more therapeutic options since have become available for MM - some patients are even treated again with Velcade after relapsing during the first round. Some of carfilzomib's 24 percent response rate could have come from patients who previously responded to Velcade, but whether or to what degree, won't be known until ASCO. If most of the patients in 003-A1 who did well on carfilzomib had responded to Velcade, the results may be seen as less thrilling, as Leerink Swann analyst Howard Liang pointed out in a research report. What's more, Leerink's consultation with opinion leaders in MM suggest they "have not been supportive" of carfilzomib. Liang maintains a "market perform" rating on Onyx's shares.

Carfilzomib drove the fall 2009 buyout by Onyx of South San Francisco-based Proteolix Inc. in a deal valued as high as $851 million. Onyx needed to beef up its pipeline to bridge the gap between approved cancer drug Nexavar (sorafenib) and two early stage in-licensed programs, and found just what it wanted in Proteolix and carfilzomib. (See BioWorld Today, Aug. 10, 2009.)

Nexavar brings up another possible problem for Onyx, though the compound seems to be doing well so far. Onyx's partner Bayer AG, of Leverkusen, Germany, reported second-quarter worldwide revenues of $236 million, but "even with carfilzomib's emergence as an increasingly important revenue driver," the challenges ahead for Nexavar "could negate any upside to an early carfilzomib approval," wrote analyst Christopher Raymond of Robert Baird & Co. in a research report.

Quarter-over-quarter growth in the U.S. totaled 11 percent, with revenues of $59.7 million, and results outside the U.S., especially in the Asia Pacific region, also satisfying. Revenues in Japan of $33 million rose about 14 percent quarter over quarter, but Onyx gets only about a 7 percent royalty there, as compared with the half-and-half profit split in other areas. In China, revenues rose about 38 percent to $15.2 million. Growth in the U.S., though, was largely dependent on price hikes of 7.5 percent in January and 9.3 percent in July, as other agents take market share away and physicians in Asia - surveyed by Baird - are "far from encouraging" in their lack of enthusiasm, Raymond wrote.