FDA Approves Eovist

FDA Approves Eovist to Detect and Characterize Focal Liver Lesions

First Organ-specific MRI Contrast Agent Approved in the United States in More Than a Decade

WAYNE, N.J., July 08, 2008 /PRNewswire/ -- Bayer HealthCare Pharmaceuticals Inc., a leader in diagnostic imaging, announced today that the U.S. Food and Drug Administration (FDA) has approved Eovist (Gadoxetate Disodium) Injection, a gadolinium-based contrast agent, for intravenous use in T1-weighted magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected focal liver disease. The approval makes Eovist the first organ-specific MRI contrast agent approved in the United States in more than a decade.

"The approval of Eovist in the United States marks a significant achievement in advancing the accurate diagnosis of liver disease," said Douglas Stefanelli, Vice President and General Manager, Diagnostic Imaging, Bayer HealthCare Pharmaceuticals. "This milestone demonstrates Bayer HealthCare Pharmaceuticals' commitment to providing innovative imaging products that can help improve the lives of patients."

Eovist is a paramagnetic MRI contrast agent that combines features of both an extracellular contrast agent and a hepatocyte-specific agent. Eovist is administered via an intravenous, bolus injection and has a dual route of excretion with approximately 50 percent eliminated through the liver and 50 percent eliminated through the kidney. Detection and characterization of malignant and benign focal liver lesions with Eovist may help enhance diagnostic accuracy and increase diagnostic confidence.

"Eovist-enhanced images can provide more comprehensive information about focal liver lesions in a single, short imaging session than was previously available," said Jeffrey Brown, MD, Professor of Radiology, School of Medicine, St. Louis. "With the availability of Eovist, our ability to evaluate patients with benign and malignant focal hepatic lesions will be improved."

The American Cancer Society estimates that 21,370 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the United States during 2008, and the incidence of liver cancer continues to increase.(1) Earlier staging of primary tumors with metastases in the liver, such as colon cancer, may improve treatment decisions and, hence, the survival rate. This year, approximately 110,000 new cases of colon cancer will be diagnosed in the United States.(2)

Stefanelli continued, "With Eovist and Nexavar, Bayer HealthCare Pharmaceuticals is uniquely positioned to help healthcare professionals detect and treat liver cancer." Nexavar (sorafenib), an oral anticancer medicine called a kinase inhibitor, is approved for use in patients with unresectable hepatocellular carcinoma (HCC).

Eovist is marketed by Bayer HealthCare affiliates outside the United States as Primovist and in Japan as EOB Primovist. It was first approved in 2004 in Europe, and with this FDA approval, is now approved in more than 40 countries.

Clinical Trials Summary

Eight-hundred sixteen (816) patients with suspected or known focal liver lesions were enrolled in two of four non-randomized, intrapatient-controlled studies that evaluated predominantly the detection (Studies one and two) or morphological characterization (Studies three and four) of liver lesions. Studies one and two ("detection" studies) enrolled patients who were scheduled for liver surgery. MRI results were compared to a reference standard that consisted of surgical histopathology and the results from intra-operative ultrasound of the liver. The studies assessed the sensitivity of pre-contrast MRI and Eovist-contrasted MRI for the detection of liver lesions when each set of images was compared to the reference.

Studies three and four ("characterization" studies) enrolled patients with known or suspected focal liver lesions, including patients who were not scheduled for liver surgery. MRI results were compared to a reference standard that consisted of surgical histopathology and other prospectively defined criteria. The studies assessed the correctness of liver lesion characterization by pre-contrast MRI and Eovist-contrasted MRI when each set of images was compared to the reference. Lesions were characterized as one of the following choices: hepatocellular carcinoma, cholangiocarcinoma, metastasis, focal lymphoma, adenoma, focal nodular hyperplasia, hemangioma, abscess, focal liver fibrosis, regenerative nodule, focal fat, hydatid cyst, liver cyst, "not assessable," normal, no lesion or "other."

In all four studies, patients underwent a baseline, pre-contrast MRI followed by the administration of Eovist at a dose of 0.025 mmol/kg body weight, with MRI performed immediately (the "dynamic" phase) and at 10 to 20 minutes following Eovist administration (the "hepatocyte" phase). Patients also underwent computerized tomography with contrast examinations of the liver. Pre-contrast MRI and Eovist-contrasted MR images were evaluated in a systematic, randomized, paired and unpaired fashion by three radiologists who were blinded to clinical information. Computed tomography (CT) images were also evaluated by the radiologists in a separate reading session.

Eovist was generally well-tolerated during the trials. The safety database was based on Eovist exposure in 1,755 adult subjects who received a dose that ranged from 0.003 to 0.5 mmol/kg body weight; the majority (N=1,365) received the recommended dose of 0.025 mmol/kg body weight.

Overall, 4.3% of subjects reported one or more drug-related adverse reactions during a follow-up period that, for most subjects, extended more than 24 hours after Eovist administration. These adverse reactions were predominantly of mild to moderate severity. Serious adverse events were reported among six patients and were attributed to underlying conditions or non-MRI procedures. All serious events occurred more than 10 hours following Eovist administration. The most common adverse reactions at the recommended dose were feeling hot, nausea, headache, injection site reaction (pain, burning, coldness, extravasation), dysgeusia (taste abnormality), flushing, parosmia (smell abnormality), dizziness and vomiting.

About Eovist

Eovist is the first gadolinium-based, liver-specific MRI contrast agent approved in the United States. Eovist enhances the T1-weighted signal. Compared to other extracellular fluid gadolinium-chelate contrast agents, Eovist exhibits a low-level binding to plasma proteins. The resulting higher relaxivity accounts for the lower dose. The recommended dose of Eovist is 0.1 mL/kg body weight (0.025 mmol/kg body weight). Based on its structural properties, Eovist is partially taken up by liver cells, thus enhancing healthy liver tissue (parenchymal enhancement). Lesions with no or minimal hepatocyte function (e.g., cysts, metastases, the majority of hepatocellular carcinomas) will remain unenhanced and will therefore be more readily detected and localized. Eovist provides useful diagnostic information at the time immediately after contrast administration (dynamic imaging) and, thus, also supports lesion characterization (i.e., distinction of malignant and benign types of liver lesions). Eovist is marketed by Bayer HealthCare affiliates outside the United States as Primovist and in Japan as EOB Primovist, and is approved in more than 40 countries, including the United States.

For additional information on Eovist, please visit www.Imaging.BayerHealthCare.com or call 1-888.84.BAYER.

Warning: Nephrogenic Systemic Fibrosis

Gadolinium-based contrast agents increase the risk of Nephrogenic Systemic Fibrosis in patients with:

-- acute or chronic severe renal insufficiency (glomerular filtration) rate <30 mL/min/1.73 m2), or

-- acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.

In these patients, avoid the use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any readministration.

As with other contrast media, the possibility of serious or life- threatening anaphylactoid/hypersensitivity reactions with cardiovascular, respiratory and/or cutaneous manifestations should always be considered. The most common adverse reactions observed in clinical trials at the recommended dose included feeling hot, nausea and headache.

Differentiated Mechanism of Nexavar

Nexavar targets both the tumor cell and tumor vasculature. In preclinical studies, Nexavar has been shown to target members of two classes of kinases known to be involved in both cell proliferation (growth) and angiogenesis (blood supply) - two important processes that enable cancer growth. These kinases included Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.

Nexavar is currently approved in more than 40 countries for the treatment of liver cancer and in more than 70 countries for the treatment of patients with advanced kidney cancer. Nexavar is also being evaluated as a single agent or combination treatment in a wide range of cancers, including metastatic melanoma, lung cancer, breast cancer and as an adjuvant therapy for kidney cancer.

Important Safety Considerations For Patients Taking Nexavar

Based on the currently approved U.S. package insert for the treatment of patients with unresectable hepatocellular carcinoma, hypertension may occur early in the course of therapy and blood pressure should be monitored weekly during the first six weeks of therapy and treated as needed. Bleeding with a fatal outcome from any site was reported in 2.4% for Nexavar and 4% in placebo. The incidence of treatment-emergent cardiac ischemia/infarction was 2.7% for Nexavar vs. 1.3% for placebo. Most common adverse events reported with Nexavar in patients with unresectable HCC were diarrhea, fatigue, abdominal pain, weight loss, anorexia, nausea and hand-foot skin reaction. Grade 3/4 adverse events were 45% for Nexavar vs. 32% for placebo. Women of child-bearing potential should be advised to avoid becoming pregnant and advised against breast-feeding. In cases of any severe or persistent side effects, temporary treatment interruption, dose modification or permanent discontinuation should be considered.

For information about Nexavar including U.S. Nexavar prescribing information, visit www.nexavar.com or call 1.866.NEXAVAR (1.866.639.2827).

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, Diabetes Care, and Pharmaceuticals divisions. Bayer HealthCare Pharmaceuticals comprises the following business units: Women's Healthcare, Diagnostic Imaging, General Medicine, which includes Cardiology and Primary Care and Specialty Medicine, which includes Hematology, Oncology and Multiple Sclerosis. The company's aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.

This news release contains forward-looking statements based on current assumptions and forecasts made by Bayer Group 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 our public reports filed with the Frankfurt Stock Exchange and with the U.S. Securities and Exchange Commission (including Form 20-F). The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

(1) American Cancer Society. "What Are the Key Statistics About Liver Cancer?" Available at http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statisti cs_for_liver_cancer_25.asp?sitearea=. Last Accessed on 4/16/08.

(2) American Cancer Society. "Overview: Colon and Rectum Cancer: How Many People Get Colorectal Cancer?" Available at http://www.cancer.org/docroot/CRI/content/CRI_2_2_1X_How_Many_People_Get_Color ectal_Cancer.asp?sitearea=. Last Accessed, 5/16/08.

CONTACT: Joanne Marlin of Bayer HealthCare, +1-973-305-5383

Web site: http://www.Imaging.BayerHealthCare.com/http://www.nexavar.com/

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Posted: July 2008

Eovist (gadoxetate disodium) FDA Approval History

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