Although Amgen Inc.'s top-line data from TRINOVA-1, the first of three Phase III trials evaluating trebananib, also known as AMG 386, proved positive in ovarian cancer with regard to progression-free survival (PFS), whether this will be enough for approval remains in question.

The company reported that a statistically significant difference was observed in PFS, with a 34 percent knock-down in the risk of disease progression or death (hazard ratio = 0.66, 95 percent confidence interval, 0.57, 0.77, p < 0.001), and a median PFS of 7.2 months in the trebananib arm vs. 5.4 months in the control arm.

Although an early imbalance of deaths favoring the control arm was observed, there was an overall favorable OS trend for trebananib in a pre-planned interim analysis, the company said. More studies with the compound in ovarian cancer, TRINOVA-2 and TRINOVA-3, will not be available until the 2015-2016 time frame.

Analysts speculated that the Thousand Oaks, Calif.-based company would wait for the maturity of overall survival (OS) data next year to file for marketing clearance – and even this might not be enough.

"Avastin [bevacizumab, Roche AG] is case in point that survival benefit might be needed for U.S. approval, even in diseases as dire as ovarian cancer (as PFS is not fully shown to drive survival in this indication)," wrote RBC Capital Markets analyst Michael Yee in a research report.

In platinum-resistant patients undergoing a Phase III trial, Avastin plus chemotherapy almost doubled PFS, but failed to win approval in the U.S., though the European Union gave clearance there, which could mean a lower regulatory bar, Yee noted.

While TRINOVA-1, testing trebananib plus paclitaxel vs. placebo plus paclitaxel in recurrent tumors, met its primary endpoint in PFS, dropouts because of adverse events (AEs) amounted to more than in Phase II trials, but the dose in the Phase III experiment was higher, too. The most frequently reported AEs were localized edema, nausea and alopecia. In the trebananib arm, the discontinuation rate was 20 percent, as compared to 7 percent among control patients.

TRINOVA-2 is designed to find out whether trebananib plus pegylated liposomal doxorubicin (PLD) is superior to placebo plus PLD as measured by PFS in recurrent epithelial ovarian, primary peritoneal or fallopian-tube cancer.

TRINOVA-3 is facing off trebananib with placebo in combination with paclitaxel and carboplatin in first-line epithelial ovarian, primary peritoneal or fallopian tube cancer.

Trebananib binds to angiopoietin-1 and -2 (Ang1 and Ang2) and inhibits their interaction with the Tie2 receptor. Ang1 and Ang2 each mediate separate actions upon binding with Tie2, with Ang1 impacting vessel quality and Ang2 influencing vessel quantity. The angiopoietins are also involved in forming new lymphatic vessels, allowing tumors to metastasize.

About 22,240 new cases of ovarian cancer will be diagnosed in the U.S. this year, with more than 70 percent of patients showing up with advanced disease at diagnosis. Disease will recur in up to 80 percent of them, who will eventually die from their tumors.

Amgen Buys Rights to a Heart Drug in Japan

In other news from Amgen, the company is expanding its 2006 deal with Cytokinetics Inc., of South San Francisco, for omecamtiv mecarbil for heart failure to include Japan, which was not included in the original deal. (See BioWorld Today, Jan. 4, 2007.)

Cytokinetics will get $25 million, including a nonrefundable license fee of $15 million and $10 million from purchase of common stock by Amgen – 8.4 million shares at about $1.18 each. Amgen owns 7.3 percent of Cytokinetics, which could also collect pre-commercialization milestone payments of up to $50M and royalties on sales in Japan. The firm's stock (NASDAQ:CYTK) closed Wednesday at $1.40, up 13 cents, after trading as high as $1.49.

Cowen analyst Simos Simeonidis, in a research report, called the development a "clear positive for Cytokinetics on a number of fronts. First off, and most importantly, the decision to expand the agreement will be interpreted by investors as Amgen having a favorable view of the molecule, overall, and the upcoming ATOMIC-AHF Phase IIb data, specifically."

Also, Amgen with partner Astrazeneca plc, of London, said they will unveil data from a Phase II study with brodalumab, a human monoclonal antibody targeting the IL-17 receptor for psoriatic arthritis at the 2013 European League Against Rheumatism meeting in Madrid this week. Based on those data, the companies plan to advance the compound into Phase III trials for the same indication next year.

In the spring of 2012, the pair entered a deal to jointly develop and commercialize five monoclonal antibodies from Amgen's inflammation portfolio, including brodalumab (then known as AMG 827). Astrazeneca needed the deal especially, having just lost patent protection for its $4 billion-plus antipsychotic drug Seroquel (quetiapine fumarate) and having just seen its diabetes drug dapagliflozin rejected by the FDA. The pharma giant's depression drug TC-5214 had fizzled in Phase III trials. (See BioWorld Today, April 16, 2012.)

Amgen's stock (NASDAQ:AMGN) closed Wednesday at $96.37, down $1.56.