U.S. FDA Approves Expanded ZYTIGA® Indication for Treatment of Metastatic Castration-Resistant Prostate Cancer

HORSHAM, Pa., Dec. 10, 2012 /PRNewswire/ -- Janssen announced today that the U.S. Food and Drug Administration (FDA) has approved a broader indication for the oral, once-daily medication ZYTIGA^® (abiraterone acetate). Until now, ZYTIGA with prednisone has only been approved to treat men with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel. With this approval, ZYTIGA, in combination with prednisone, may now be used earlier in the treatment continuum for metastatic castration-resistant disease, before the use of chemotherapy.

ZYTIGA also received a positive opinion for an expanded indication from the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) and is under review by other health authorities worldwide.

"This expanded indication for ZYTIGA helps fill a critical medical need, providing physicians an important tool for treating men with metastatic castration-resistant prostate cancer who have not received chemotherapy," said Charles J. Ryan, M.D., associate professor of clinical medicine at the UCSF Helen Diller Family Comprehensive Cancer Center and lead investigator of the pivotal Phase 3 study on which this approval is based.  "ZYTIGA works by inhibiting the enzyme complex required for the production of androgens in the testes, adrenals and the prostate tumor tissue."

Excluding skin cancer, prostate cancer is the most frequently diagnosed cancer in men in the U.S.  In 2012, the American Cancer Society estimates more than 28,000 men will die from the disease, making it the second leading cause of cancer death behind lung cancer. There are approximately 35,000 new cases of mCRPC each year.

"Over and over, I hear how devastating it is when men and their families learn their metastatic prostate cancer has progressed despite treatment," said Thomas Farrington, president and founder, Prostate Health Education Network (PHEN), a national organization committed to increasing prostate health education and awareness.  "I believe having ZYTIGA as a new therapeutic option before chemotherapy will provide hope for patients with metastatic castration-resistant prostate cancer and their families as they continue to battle the disease."

Janssen Research & Development previously announced that an Independent Data Monitoring Committee (IDMC) unanimously recommended unblinding the Phase 3, randomized, double-blind, placebo-controlled, international study, COU-AA-302, after planned interim analyses found a statistically significant difference in radiographic progression-free survival (rPFS), and median overall survival (OS) for ZYTIGA was longer than the placebo group.  Based on these results, the IDMC also recommended that patients in the control arm be offered treatment with ZYTIGA.

"We are delighted ZYTIGA is now approved for men with metastatic castration-resistant prostate cancer earlier in the course of their disease, before chemotherapy, where there continues to be a need for additional treatment options," said Robert Bazemore, president, Janssen Biotech, Inc.  "We're dedicated to delivering therapeutic options with exceptional services.  ZYTIGAOne™ is our one-to-one support for ZYTIGA, to help make access simple and convenient."

Additional Details from the COU-AA-302 Study
The approval is based on a supplemental New Drug Application (sNDA) that included efficacy and safety results of a Phase 3, randomized, double-blind, placebo-controlled international clinical study, which evaluated ZYTIGA plus prednisone compared to placebo plus prednisone in 1,088 men with mCRPC who had failed androgen deprivation therapy and had not received cytotoxic chemotherapy.

Patients were randomized either to receive ZYTIGA 1,000 milligrams (mg) administered orally once daily plus prednisone 5 mg administered twice daily or placebo plus prednisone 5 mg administered twice daily.  The co-primary endpoints of the study are radiographic progression-free survival (rPFS) and overall survival (OS).  

Results from a pre-specified analysis examining rPFS demonstrated a statistically significant improvement in rPFS in the ZYTIGA plus prednisone arm (ZYTIGA arm) compared to the placebo plus prednisone (control) arm.  The median rPFS in the control arm was 8.28 months but had not yet been reached in the ZYTIGA arm because progression events were occurring more slowly in the ZYTIGA arm compared to the control arm (N=150 vs. 251, respectively).  These results reached statistical significance with a p-value <0.0001 and a hazard ratio (HR) of 0.425 [95% confidence interval (CI): 0.347, 0.522]. 

Additionally, in a separate pre-specified interim analysis, OS was longer for the ZYTIGA arm compared to the control arm with an HR of 0.792: median overall survival was 35.3 months in the ZYTIGA arm versus 30.1 months in the control arm (95% CI: 0.655 - 0.956). The p-value was 0.0151, which did not meet the pre-specified value for statistical significance.

Treatment with ZYTIGA plus prednisone also resulted in significant improvements in secondary study endpoints compared to the control arm.  Specifically, ZYTIGA plus prednisone resulted in improvements in median time to opiate use for cancer pain (the median time in the ZYTIGA arm was not reached and was 23.7 months in the control arm; HR= 0.686; 95% CI: [0.566, 0.833]; p=0.0001); and median time to initiation of cytotoxic chemotherapy for prostate cancer (25.2 months for the ZYTIGA arm vs. 16.8 months for the control arm (HR=0.580; 95% CI: [0.487, 0.691]; p<0.0001).

The most common adverse reactions (greater than or equal to 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (> 20%) are anemia, elevated blood levels of certain tissue enzymes (alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase), high blood levels of triglycerides (hypertriglyceridemia) and cholesterol (hypercholesterolemia), low levels of immune cells called lymphocytes (lymphopenia), hyperglycemia, and low blood levels of phosphorous (hypophosphatemia) and potassium (hypokalemia).

About ZYTIGA
Since its first approval in the U.S. in 2011, ZYTIGA has been approved in more than 65 countries.  More than 40,000 men worldwide have received treatment with it, and it is quickly becoming one of the cornerstones of treatments.

ZYTIGA in combination with prednisone was approved by the U.S. Food and Drug Administration (FDA) in April 2011 for the treatment of men with mCRPC who have received prior chemotherapy containing docetaxel. 

More information about ZYTIGA can be found at www.zytiga.com.

About ZYTIGAOne™ Support
ZytigaOne™ Support provides simplified access to ZYTIGA^®.  ZytigaOne™ Support handles rapid investigation and assessment of patient eligibility and coverage, assistance with the prior authorization process, the coordination with specialty pharmacies to arrange efficient handling and convenient shipment of ZYTIGA^®, immediate and direct access to the ZytigaOne™ Instant Savings Program, referrals to a patient assistance program and identification of alternate sources of funding for eligible patients. ZytigaOne™ Support also offers educational materials and personalized prescription reminders. A personally assigned Care Coordinator provides assistance with insurance coverage questions and navigation. 

The ZytigaOne™ Instant Savings Program provides eligible, commercially insured ZYTIGA^® patients with assistance for out-of-pocket costs.

Indication
ZYTIGA^® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

IMPORTANT SAFETY INFORMATION

Contraindications - ZYTIGA^® (abiraterone acetate) is not indicated for use in women. ZYTIGA^® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess - Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA^® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in study 1) or NYHA Class II to IV heart failure (in study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI) - AI was reported in patients receiving ZYTIGA^® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA^®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity - Monitor liver function and modify, withhold, or discontinue ZYTIGA^® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA^®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA^® treatment and closely monitor liver function.

Increased ZYTIGA^® Exposures with Food - ZYTIGA^® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA^® is taken and for at least one hour after the dose of ZYTIGA^® is taken. Abiraterone C_max and AUC_0-infinity (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions - The most common adverse reactions (greater than or equal to 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Drug Interactions - ZYTIGA^® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. In vitro, ZYTIGA^® inhibits CYP2C8. There are no clinical data on its use with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Based on in vitro data, ZYTIGA^® is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors or inducers on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution during treatment with ZYTIGA^®.

Use in Specific Populations - Do not use ZYTIGA^® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

About Janssen Biotech, Inc.

Janssen Biotech, Inc. redefines the standard of care in immunology, oncology, urology and nephrology. Built upon a rich legacy of innovative firsts, Janssen Biotech has delivered on the promise of new treatments and ways to improve the health of individuals with serious disease. Beyond its innovative medicines, Janssen Biotech is at the forefront of developing education and public policy initiatives to ensure patients and their families, caregivers, advocates and health care professionals have access to the latest treatment information, support services and quality care. For more information on Janssen Biotech, Inc. or its products, visit www.janssenbiotech.com.

Janssen Biotech, Inc. is one of the Janssen Pharmaceutical Companies of Johnson & Johnson, dedicated to addressing and solving some of the most important unmet medical needs in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we work together to bring innovative ideas, products, services and solutions to people throughout the world.  Follow us on Twitter at www.twitter.com/JanssenUS.

About Janssen Research & Development, LLC

Janssen Research & Development, LLC, is headquartered in Raritan, N.J. and has affiliated facilities in Europe, the United States and Asia. Janssen Research & Development is leveraging a combination of internal and external innovation to discover and develop novel medicines and solutions in five distinct therapeutic areas: Neuroscience, Oncology, Immunology, Infectious Diseases and Vaccines, and Cardiovascular and Metabolism. For more information about Janssen Research & Development, LLC visit www.janssenrnd.com.

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