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Bayer's Stivarga® (regorafenib) Tablets Approved by U.S. FDA for Treatment


WAYNE, N.J. and SOUTH SAN FRANCISCO, Calif., Feb. 25, 2013 /PRNewswire/ -- Intended for U.S. Media Only -- Bayer HealthCare and Onyx Pharmaceuticals, Inc. (NASDAQ: ONXX) announced today that the U.S. Food and Drug Administration (FDA) approved Bayer's Stivarga® (regorafenib) tablets to treat patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.1 Stivarga was approved by the FDA in September 2012 for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.1

(Photo: http://photos.prnewswire.com/prnh/20130225/NY62678 )

"The FDA's decision marks the second approval for Stivarga – first in metastatic colorectal cancer last year and now in locally advanced, unresectable or metastatic GIST, where there is a high unmet medical need for patients who have exhausted all approved treatment options," said Pamela A. Cyrus, MD, Vice President and Head of U.S. Medical Affairs, Bayer HealthCare Pharmaceuticals. "These regulatory milestones underscore Bayer's commitment to deliver effective products for difficult-to-treat cancers."

Stivarga is a Bayer compound developed by Bayer and jointly promoted by Bayer and Onyx in the United States. In 2011, Bayer entered into an agreement with Onyx, under which Onyx receives a royalty on all global net sales of Stivarga in oncology.

The approval of Stivarga in GIST is based on data from the pivotal Phase III GRID (GIST – Regorafenib In Progressive Disease) trial, which showed that Stivarga plus best supportive care (BSC) statistically significantly improved progression-free survival (PFS) compared to placebo plus BSC (HR=0.27 [95% CI 0.19-0.39], p<0.0001) in patients with locally advanced, unresectable or metastatic GIST who have been previously treated with imatinib mesylate and sunitinib malate.1 The median PFS was 4.8 months in the Stivarga arm versus 0.9 months in the placebo arm (p<0.0001). There was no statistically significant difference in overall survival at the time of the planned interim analysis based on 29% of the total events for the final analysis. At the time of disease progression as assessed by central review, the study blind was broken and all patients were offered the opportunity to take Stivarga at the investigator's discretion. Fifty-six (85%) patients randomized to placebo and 41 (31%) patients randomized to Stivarga received open-label Stivarga.1

The most frequently observed adverse drug reactions (= 30%) in Stivarga-treated patients vs. placebo-treated patients in GIST, respectively, were: hand-foot skin reaction (HFSR) / palmar-plantar erythrodysesthesia (PPE), hypertension, asthenia/fatigue, diarrhea, mucositis, dysphonia, infection, decreased appetite and food intake, and rash. The Stivarga label includes a boxed warning citing the risk of hepatotoxicity. Severe and sometimes fatal hepatotoxicity has been observed in clinical trials.1

"While great progress has been made in the treatment of GIST since the introduction of kinase inhibitors as effective therapies for this orphan disease, we have been looking for additional, effective treatments for GIST patients whose disease worsens despite currently approved therapies," said George D. Demetri, MD, Principal Investigator of the GRID study and Director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston, MA. "These data show that regorafenib can slow disease progression in patients who are no longer responding to other approved therapies and may provide another avenue for GIST patients who would otherwise have no FDA-approved treatment option."

About Gastrointestinal Stromal Tumor (GIST)
GIST is the most common form of sarcoma (a type of cancer that develops from certain tissues, like bone or muscle) involving the gastrointestinal tract.2 In the United States, it is estimated that there are approximately 4,000-5,000 new cases of GIST diagnosed each year, of which about 1,500 have already metastasized at diagnosis.2,3 GIST may not cause any symptoms and may be found incidentally when the doctor is looking for other problems.3

About the GRID Study
GRID was a randomized, double-blind, placebo-controlled, multi-center, cross-over Phase III study of regorafenib for the treatment of GIST. It randomized 199 patients who had been previously treated with imatinib mesylate and sunitinib malate. Patients were randomized in a 2:1 ratio to receive either regorafenib plus BSC or placebo plus BSC to evaluate efficacy and safety. Treatment cycles consisted of 160 mg regorafenib (or matching placebo) once daily for three weeks on / one week off plus BSC. Patients continued therapy until disease progression or unacceptable toxicity. The primary endpoint was PFS, and the key secondary outcome measure was OS. The safety and tolerability of the two treatment groups were also compared.4

About Stivarga (regorafenib)
Stivarga is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.1 It is also indicated for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.1

Stivarga is an inhibitor of multiple kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.1

Stivarga was developed under the Fast Track program and received priority review designations for locally advanced, unresectable or metastatic GIST and mCRC from the FDA. These designations are granted by the FDA to expedite the development and review of drugs to treat serious diseases and fill an unmet medical need (fast track), and given to drugs that provide a treatment where no adequate therapy exists (priority review).

For full prescribing information, including BOXED WARNING, visit www.stivarga-us.com. Bayer offers patient assistance through the Bayer REACH® (Resources for Expert Assistance and Care Helpline) program. Patients may contact the REACH Program at 1-866-639-2827 for additional information.

WARNING: HEPATOTOXICITY:

Severe and sometimes fatal hepatotoxicity has been observed in clinical trials.
Monitor hepatic function prior to and during treatment.
Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.
Severe drug-induced liver injury with fatal outcome occurred in 0.3% of 1200 STIVARGA-treated patients across all clinical trials. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm.

Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.

STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% with STIVARGA vs 8% and 3% with placebo in mCRC and GIST patients, respectively. Fatal hemorrhage occurred in 4 of 632 (0.6%) STIVARGA-treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin.

STIVARGA caused an increased incidence of hand-foot skin reaction (HFSR) (also known as palmar-plantar erythrodysesthesia [PPE]) and severe rash, frequently requiring dose modification. The overall incidence was 45% and 67% with STIVARGA vs 7% and 12% with placebo in mCRC and GIST patients, respectively. Incidence of Grade 3 HFSR (17% vs 0% in mCRC and 22% vs 0% in GIST), Grade 3 rash (6% vs <1% in mCRC and 7% vs 0% in GIST), serious adverse reactions of erythema multiforme (0.2% vs 0% in mCRC), and Stevens-Johnson syndrome (0.2% vs 0% in mCRC) was higher in STIVARGA-treated patients. Toxic epidermal necrolysis occurred in 0.17% of 1200 STIVARGA-treated patients across all clinical trials. Withhold STIVARGA, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity.

STIVARGA caused an increased incidence of hypertension (30% vs 8% in mCRC and 59% vs 27% in GIST with STIVARGA vs placebo, respectively). Hypertensive crisis occurred in 0.25% of 1200 STIVARGA-treated patients across all clinical trials. Do not initiate STIVARGA until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension.

STIVARGA increased the incidence of myocardial ischemia and infarction (1.2% with STIVARGA vs 0.4% with placebo). Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) occurred in 1 of 1200 STIVARGA-treated patients across all clinical trials. Confirm the diagnosis of RPLS with MRI and discontinue STIVARGA in patients who develop RPLS.

Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with STIVARGA across clinical trials. In GIST, 2.1% (4/188) of STIVARGA-treated patients developed gastrointestinal fistula or perforation: of these, 2 cases of gastrointestinal perforation were fatal. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.

Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence.

STIVARGA can cause fetal harm when administered to a pregnant woman. Use effective contraception during treatment and up to 2 months after completion of therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from STIVARGA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The most frequently observed adverse drug reactions (=30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

The most frequently observed adverse drug reactions (=30%) in STIVARGA-treated patients vs placebo-treated patients in GIST, respectively, were: HFSR/PPE (67% vs 15%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%).

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. Bayer's oncology franchise now includes two oncology products and several other compounds in various stages of clinical development. Together, these products reflect the company's approach to research, which prioritizes novel targets and pathways with the potential to transform the way that cancer is treated across tumor types and stages of disease.

About Bayer HealthCare Pharmaceuticals Inc.
Bayer HealthCare Pharmaceuticals Inc. is the U.S.-based pharmaceuticals business of Bayer HealthCare LLC, a subsidiary of Bayer AG. Bayer HealthCare is one of the world's leading, innovative companies in the healthcare and medical products industry, and combines the activities of the Animal Health, Consumer Care, Medical Care, and Pharmaceuticals divisions. As a specialty pharmaceutical company, Bayer HealthCare provides products for General Medicine, Hematology, Neurology, Oncology and Women's Healthcare. The company's aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.

About Onyx Pharmaceuticals, Inc.
Based in South San Francisco, California, Onyx Pharmaceuticals, Inc. is a global biopharmaceutical company engaged in the development and commercialization of innovative therapies for improving the lives of people with cancer. The company is focused on developing novel medicines that target key molecular pathways. For more information about Onyx, visit the company's website at www.onyx.com.

STIVARGA® is a trademark of Bayer®. Bayer® and the Bayer Cross® are registered trademarks of Bayer.


Forward-Looking Statement
This news release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer's public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

This news release contains "forward-looking statements" of Onyx within the meaning of the federal securities laws. These forward-looking statements include, without limitation, statements regarding results of clinical development, regulatory processes, safety and commercial potential of Stivarga (regorafenib). These statements are subject to risks and uncertainties that could cause actual results and events to differ materially from those anticipated, including, but not limited to, risks and uncertainties related to: competition; failures or delays in clinical trials or the regulatory process; Onyx or Bayer, as the case may be, may be unsuccessful in launching, maintaining adequate supply of or obtaining reimbursement for Stivarga; market acceptance and the rate of adoption of Stivarga; pharmaceutical pricing and reimbursement pressures; serious adverse side effects, if they are associated with Stivarga; and government regulation. Reference should be made to Onyx's Annual Report on Form 10-K for the year ended December 31, 2011 filed with the Securities and Exchange Commission, as updated by Onyx's subsequent Quarterly Reports on Form 10-Q, under the heading "Risk Factors" for a more detailed description of these and other risks. Readers are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date of this release. Onyx undertakes no obligation to update publicly any forward-looking statements to reflect new information, events, or circumstances after the date of this release except as required by law.

References:

1. STIVARGA Prescribing Information, February 2013.

2. Joensuu H. Gastrointestinal stromal tumor (GIST). Annals of Oncology. 2006 September; Volume 17. Available at http://annonc.oxfordjournals.org/content/17/suppl_10/x280.full.pdf+html . Accessed October 19, 2012.

3. American Cancer Society. Gastrointestinal Stromal Tumor (GIST). (Last Revised 2/1/2012). Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003103-pdf.pdf. Accessed October 12, 2012.

4. Casali, et al. Clinical benefit with regorafenib across subgroups and post progression in patients with advanced gastrointestinal stromal tumors (GIST) after progression on imatinib (IM) and sunitinib (SU): Phase III GRID trial update. 2012 European Society of Medical Oncology; September, 2012. Vienna, Austria.

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