Biotech Values

[DewDiligence]

AMGN’s Xgeva (denosumab) Increases PFS in CRPC

[This is the first phase-3 trial for Xgeva in *prevention* rather than treatment of bone mets. Unlike the phase-3 trials in bone-met treatment reported previously, where the comparator was Zometa and the primary endpoint was time to first skeletal event (usually a fracture), the phase-3 prevention trial reported in this PR had placebo as the comparator and the primary endpoint was bone-met-progression-free survival, defined as the time to either death or metastasis to the bone. (Please see the fourth row the table in #msg-51295923.)

The hazard ratio for PFS was 0.85 with a p-value of 0.03, so the efficacy ought to be good enough for FDA approval even though there was no statsig benefit in overall survival (a secondary endpoint). However, regarding the dreaded ONJ side effect, the PR says that the rate was higher in the Xgeva arm than in the placebo arm and that “the yearly rate of ONJ in the XGEVA-treated group was similar to what has been observed in prior XGEVA trials.” The vagueness of this language might indicate a problem.]

http://finance.yahoo.com/news/XGEVA-Denosumab-Significantly-prnews-2515773001.html?x=0&.v=1

›XGEVA (Denosumab) Significantly Improved Bone Metastasis-Free Survival in Men With Prostate Cancer

• Pivotal Phase 3 '147 Study Meets Primary Endpoint

• First Bone-Targeted Therapy to Delay the Onset of Bone Metastases in Patients with Prostate Cancer

Monday December 13, 2010, 5:52 pm

THOUSAND OAKS, Calif., Dec. 13, 3010 /PRNewswire-FirstCall/ -- Amgen (Nasdaq:AMGN) today announced top-line results from a Phase 3 trial evaluating XGEVA™ (denosumab) versus placebo in 1,432 men with castrate-resistant prostate cancer. The trial, known as the '147 study, demonstrated that XGEVA significantly improved median bone metastasis-free survival by 4.2 months (HR=0.85, 95 percent CI 0.73-0.98, p=0.03) compared to placebo (primary endpoint), and significantly improved time to first occurrence of bone metastases (secondary endpoint). Overall survival was similar between the XGEVA and placebo groups (secondary endpoint).

Overall rates of adverse events and serious adverse events were generally similar between XGEVA and placebo, with hypocalcemia and osteonecrosis of the jaw (ONJ) observed at increased frequencies in the XGEVA arm. The yearly rate of ONJ in the XGEVA-treated group was similar to what has been observed in prior XGEVA trials. [This kind of language is usually not a good sign.]

"Our data demonstrate that XGEVA, which antagonizes the RANK Ligand axis, limits the ability of tumors to colonize bone, an important finding for men at risk for bone metastases and their healthcare providers," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "We look forward to presenting these landmark data at an upcoming medical conference."

The RANK Ligand pathway, first discovered by Amgen scientists in the mid-1990s, is believed to play a central role in cancer-induced bone destruction, regardless of cancer type. Data suggest that in bone metastasis, the invasion of cancer is facilitated by bone destruction. Hence, increased bone resorption due to increased RANK Ligand expression appears to augment bone metastasis.

XGEVA is a fully human monoclonal antibody that binds to RANK Ligand, a protein essential for the formation, function and survival of osteoclasts (the cells that break down bone). XGEVA prevents RANK Ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and halting release of growth factors, making the environment less conducive to tumor growth.

About Study '147

Study '147 was a randomized, placebo-controlled, multi-center Phase 3 study comparing the treatment effect of XGEVA with placebo on prolonging bone metastasis-free survival in men with hormone-refractory (castrate-resistant) prostate cancer with rapidly-rising PSA levels who had no bone metastases at baseline. The primary endpoint of the trial was time to first occurrence of bone metastasis or death from any cause, with secondary endpoints including time to first occurrence of bone metastasis (excluding death) and overall survival.‹