Phase 3 Trial Shows Denosumab Delayed Skeletal Related Events in Advanced Cancer Patients With Bone Metastases

Update: Prolia (denosumab) Now FDA Approved - June 1, 2010

THOUSAND OAKS, Calif., Sept. 21 /PRNewswire-FirstCall/ -- Amgen (NASDAQ: AMGN) today announced detailed results from a Phase 3 trial evaluating denosumab administered subcutaneously versus Zometa (zoledronic acid) administered as an intravenous infusion in the treatment of bone metastases in 1,776 advanced cancer patients with solid tumors (not including breast and prostate cancer) or multiple myeloma. These results were presented today at the 2009 ECCO 15 - ESMO 34 European Multidisciplinary Congress in Berlin, Germany (Abstract Number: 20LBA).

For the primary endpoint of this study, the median time to first on-study skeletal related event (SRE) (fracture, radiation to bone, surgery to bone, or spinal cord compression) was 20.6 months for those patients receiving denosumab and 16.3 months for those patients receiving Zometa (hazard ratio 0.84, 95 percent CI: 0.71-0.98), which is statistically significant for non-inferiority (p=0.0007). Although numerically greater, the delay in the time to first SRE associated with denosumab was not statistically superior compared to Zometa based upon the statistical testing strategy (adjusted p=0.06) (secondary endpoint). The time to first-and-subsequent SRE was also numerically greater but not statistically superior compared to Zometa (hazard ratio 0.90, 95 percent CI: 0.77-1.04, p=0.14) (secondary endpoint).

"It is encouraging to see denosumab's efficacy in this broad cancer population. There is no need for renal monitoring or dose adjustments due to renal impairment," said David Henry, M.D., clinical professor of Medicine, Pennsylvania Hospital, Philadelphia, PA, United States of America. "Furthermore, the positive results of this study, combined with the convenience of a monthly subcutaneous injection and without the flu-like symptoms associated with Zometa administration, make this an exciting potential treatment option for advanced cancer patients."

Bone metastases, the spread of tumors to the bone, are a serious concern for many advanced cancer patients. When cancer spreads to the bone, the growing cancer cells weaken and destroy the bone around the tumor. This damage can result in a number of serious bone complications, collectively called skeletal related events.

Denosumab also delayed the median time to first on-study SRE or hypercalcemia of malignancy (HCM) compared to Zometa (hazard ratio 0.83, 95 percent CI: 0.71, 0.97; p=0.02). The median time to first on-study SRE or HCM was 19.0 months for denosumab and 14.4 months for Zometa.

Bone destruction is a major cause of pain in approximately 70 percent of patients with metastatic disease. (1) In an exploratory analysis, patients on the denosumab arm reported worsening of pain later than those on the Zometa arm (57 days versus 36 days, respectively).

Adverse events rates (96 percent denosumab, 96 percent Zometa) and serious adverse events (63 percent denosumab, 66 percent Zometa) were similar between groups and were consistent with what has previously been reported for these two agents. Rates of osteonecrosis of the jaw (ONJ) were balanced and infrequent in both treatment groups (10 patients receiving denosumab as compared with 11 patients receiving Zometa). Infectious adverse events were balanced between the two treatment arms, as was overall survival (hazard ratio 0.95, 95 percent CI: 0.83-1.08; p=0.43) and the time to cancer progression (hazard ratio 1.00, 95 percent CI: 0.89, 1.12; p=1.0).

Detailed data from a second Phase 3, head-to-head trial evaluating denosumab versus Zometa will be presented Tuesday, Sept. 22, 2009 at 14:15 - 14:30 Central European Summer Time (CEST) in the Presidential Session of ECCO-ESMO (Abstract #2LBA; presentation embargoed until 12:15 CEST Sept. 22, 2009). In this study of 2,049 patients with advanced breast cancer, denosumab met all primary and secondary endpoints and demonstrated superior efficacy compared to Zometa in the treatment of bone metastases.

Webcast Information

Denosumab data presented at ECCO-ESMO today will be discussed by Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen at the UBS Global Life Sciences Conference in New York this morning at 8:30 a.m. Eastern Time (ET). Live audio of the presentation will be available over the Internet and can be accessed from Amgen's Web site at www.amgen.com, under Investors.

An analyst/investor event will also be held from the Congress on September 24th, at 6:30 a.m. ET to discuss data presented at ECCO-ESMO. A webcast of the event can be found on Amgen's Web site at www.amgen.com, under Investors. The audio webcast will be archived and available for replay for at least 72 hours.

Study Design

This was an international, Phase 3, randomized, double-blind, active-comparator-controlled study comparing denosumab with Zometa in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. Patients enrolled in this event-driven study were randomized in a one-to-one ratio to receive either 120 mg of denosumab subcutaneously every four weeks (Q4W) or Zometa administered intravenously at a dose of 4 mg delivered as a single, 15-minute infusion every four weeks.

In clinical trials thus far to test new medications for bone metastases, treatment success has been measured by whether the bone complications, or SREs, caused by the tumor are reduced or delayed. The primary and secondary endpoints of the denosumab bone metastases studies use a composite endpoint of four SREs - fracture, the need for radiation to bone, the need for bone surgery, and spinal cord compression - to measure the effectiveness of denosumab versus Zometa.

The primary endpoint was to evaluate if denosumab is non-inferior to Zometa with respect to the first on-study SRE in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma and bone metastases. Secondary endpoints were to evaluate if denosumab is superior to Zometa with respect to the first on-study SRE, as well as first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.

About Denosumab and Amgen's Research in Bone Biology

Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, the essential regulator of osteoclasts (the cells that break down bone). With more than 19,000 patients in trials across indications worldwide, the denosumab development program is the largest ever initiated by Amgen. This broad and deep development program demonstrates Amgen's commitment to researching and delivering pioneering medicines to patients with unmet medical needs. Amgen is studying denosumab in numerous tumor types across the spectrum of cancer-induced bone disease. Over 11,000 patients have been enrolled in the denosumab oncology clinical trials, testing the drug for the reduction of SREs in breast cancer patients, for the amelioration of treatment-induced bone loss in patients with breast or prostate cancers, for the prevention of SREs due to the spread of cancer to the bone in patients with multiple myeloma or those suffering from a variety of solid tumors, and for its potential to delay bone metastases in prostate cancer.

Bone Metastases: Impact and Prevalence

Bone metastases, cancer cells that separate from tumors and migrate to bone tissue where they settle and grow, occur in more than 1.5 million people worldwide.(2) With improvements in cancer care, including earlier diagnosis and new treatment options, leading to increases in survival rates(3), the number of patients developing metastatic disease secondary to a primary cancer is increasing. Bone metastases are a significant problem for patients with certain types of advanced cancer, with incidence rates of nearly 100 percent in myeloma patients and as high as 75 percent in solid tumor patients.

With bone metastases the growing cancer cells weaken and destroy the bone around the tumor. The damage the tumor has caused to the bone can result in a number of serious complications, collectively called SREs. These include fracture of a bone, the need for radiation to bone, the need for bone surgery, or spinal cord compression. All are serious complications for advanced cancer patients.

Regardless of the type of underlying cancer, the process by which cancers invade and destroy bones is fundamentally the same. At the center of this destructive process is a protein RANK Ligand that is stimulated by the presence of cancer in the bone.

The economic burden of U.S. patients with bone metastases is significant and was estimated to be $12.6 billion last year.(4) Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE.(5)

About Amgen

Amgen discovers, develops and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.

Forward-Looking Statements

This news release contains forward-looking statements that are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission (SEC) reports filed by Amgen, including Amgen's most recent annual report on Form 10-K and most recent periodic reports on Form 10-Q and Form 8-K. Please refer to Amgen's most recent Forms 10-K, 10-Q and 8-K for additional information on the uncertainties and risk factors related to our business. Unless otherwise noted, Amgen is providing this information as of Sept. 21, 2009 and expressly disclaims any duty to update information contained in this news release.

No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for us to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. We develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products after they are on the market. Our business may be impacted by government investigations, litigation and products liability claims. We depend on third parties for a significant portion of our manufacturing capacity for the supply of certain of our current and future products and limits on supply may constrain sales of certain of our current products and product candidate development.

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The scientific information discussed in this news release relating to new indications for our products is preliminary and investigative and is not part of the labeling approved by the U.S. Food and Drug Administration (FDA) for the products. The products are not approved for the investigational use(s) discussed in this news release, and no conclusions can or should be drawn regarding the safety or effectiveness of the products for these uses. Only the FDA can determine whether the products are safe and effective for these uses. Healthcare professionals should refer to and rely upon the FDA-approved labeling for the products, and not the information discussed in this news release.

ZOMETA is a registered trademark of Novartis Oncology.

*Editors Note: The FDA has provisionally approved the trade name Prolia(TM) for the proposed indications of treatment and prevention of osteoporosis in postmenopausal women, and treatment and prevention of bone loss in patients undergoing hormone ablation for non-metastatic prostate or breast cancer, for which denosumab is administered twice yearly subcutaneously at a 60 mg dose. The Prolia(TM) trade name is only for these indications and may not apply for other indications of denosumab.

  CONTACT: Amgen, Thousand Oaks

  Sabeena Ahmad: +41 (0) 41 369 25 30 (media Europe/Australia)

  Lisa Rooney: +1 (805) 447-6437 (media U.S.)

  Arvind Sood:  +1 (805) 447-1060 (investors)

  (Logo:  http://www.newscom.com/cgi-bin/prnh/20081015/AMGENLOGO)


  1. Cleeland CS, et al. Pain and its treatment in outpatients with

  metastatic cancer. N Engl J Med. 1994: 330:592-596.

  2. Capanna R, Coia LR, Coleman R. et al. eds. Textbook of Bone Metastases.

  Hoboken, NJ: Edition: John Wiley and Sons; 2005:105.

  3. Mundy GR. Metastasis to bone: causes, consequences and therapeutic

  opportunities. Nat Rev Cancer. 2002 Aug;2(8):584-93.

  4. Schulman K and Kohles J. Cancer. 2007;109:2334-2342

  5. GVD/Barber ISPOR 2008 Poster; Schulman 2007; Delea et al. 2006

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Source: Amgen

CONTACT: media Europe/Australia, Sabeena Ahmad, +41 (0) 41 369 25 30, or
media U.S., Lisa Rooney, +1-805-447-6437, or investors, Arvind Sood,
+1-805-447-1060, all of Amgen, Thousand Oaks

Web Site: http://www.amgen.com/
 

Posted: September 2009

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