Replies to post #109240 on Biotech Values

[DewDiligence]

FDA Approves AMGN's Xgeva for Bone Metasases

[This WSJ piece contains some bullish sales forecasts for Xgeva and says the annual US price will be $20K.]

http://online.wsj.com/article/SB10001424052748704410404575623530026654838.html

›NOVEMBER 18, 2010, 11:04 P.M. ET
By THOMAS GRYTA

NEW YORK—Amgen Inc. received Food and Drug Administration approval for bone drug denosumab's use in helping prevent bone complications in cancer patients with solid tumors whose disease has spread to the bone.

The drug, to be called Xgeva, is the same as approved osteoporosis treatment Prolia, but is used at a much higher dose than Prolia and is seen adding more than $1 billion in annual sales. The approval is important for the Thousand Oaks, Calif., biotech giant, which has seen various aspects of its business come under pressure in recent years and is looking for denosumab's various uses to invigorate its profit growth.

Although it is approved for a broad range of solid cancers, the drug is not indicated for use in patients with multiple myeloma and other blood cancers, according to an FDA spokeswoman.

UBS analyst Matthew Roden recently said that Wednesday's expanded approval was widely priced into Amgen shares, with minimal share reaction expected.

Mr. Roden believes the skeletal-related event use of Xgeva represents the largest overall market opportunity for the drug, with global sales in the area potentially growing to more $2.5 billion by 2015.

In a potential additional use for the drug, key data are expected by year-end to show whether the drug prevents prostate cancer from actually spreading to the bone [see the fourth row of table in #msg-51295923], something that could add billions of dollars more in annual sales.

In advanced cancer, the disease often invades bones. The spread can weaken and destroy bone, which can lead to fractures, spinal cord compression and the need for more aggressive therapy, including surgery [not to mention early death from complications of one or more of the above].

Prolia was approved in June in the U.S. after an initial rejection last year that came with a request for more information. Prolia is given twice a year, while Xgeva is given monthly at a higher dose.

A monthly dose of Xgeva will cost about $1,650, coming to about $20,000 a year, which is almost twice the price of Novartis AG's Zometa, its main competition, that costs about $844 per dose given every three to four weeks.

Amgen believes the drug is more attractive than Zometa because of its effectiveness data, and it is given as a shot under the skin compared with Zometa's administration through intravenous infusion.

As part of its sales strategy related to prostate cancer patients, Amgen plans to target urologists because they don't typically have the necessary equipment for such infusions.

The company will also target oncologists using experience gained from selling other drugs used in cancer patients including Aranesp, Vectibix, Neupogen and Neulasta.

The application for the expanded use—which was more than 1.5 million pages long—was filed in mid-May and given priority review status by the agency, giving the drug a six-month review.

The application was supported with data from three late-stage trials that included almost 6,000 patients and tested the drug against Zometa.

In the breast cancer and prostate cancer studies, the drug was superior to Zometa [see first two rows of #msg-51295923]. But a third trial, in all types of solid tumors excluding breast and prostate cancer and including a type of blood cancer called multiple myeloma, met its main goal of showing it was equally effective, or "non-inferior," to Zometa, but missed a secondary goal of showing superiority.

Overall, the trials showed comparable side effects to Zometa.

Amgen has submitted similar regulatory application in areas including Europe, Australia and Canada.‹

[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.‹

[DewDiligence]

CHMP approves AMGN’s Xgeva for treatment of bone mets (i.e. prevention of skeletal-related events in patients with bone mets):

http://finance.yahoo.com/news/Amgen-Receives-CHMP-Positive-prnews-3364941121.html?x=0&.v=1

Rubber-stamping by the EU Commission will follow in 2-3 months.

Xgeva was approved in the US in this indication in Nov 2010 (#msg-56882220). AMGN plans to submit an sBLA for prevention of bone mets in CRPC during 1H11.

[DewDiligence]

AMGN submits Xgeva sBLA for prevention of PCa bone mets:

http://finance.yahoo.com/news/Amgen-Submits-Application-to-prnews-2107233735.html?x=0&.v=1

This is an sBLA (rather than an ordinary BLA) because Xgeva is already approved for preventing skeletal-related events in patients who have bone mets (#msg-56882220).

The newly sought indication corresponds to the fourth row in the table in #msg-57938233.

An sBLA for preventing bone mets in metastatic breast cancer will be submitted much later, pending data from the phase-3 trial (see fifth row in #msg-57938233).