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Biopharmaceuticals Oncology Regulatory

 News Release - November 19, 2012

ZYTIGA(R) Receives Positive Regulatory Recommendation in the European Union for Treatment of Metastatic Castration-Resistant Prostate Cancer before Chemotherapy

BEERSE, Belgium--(Healthcare Sales & Marketing Network)--Janssen-Cilag International NV (Janssen) announced today that the Committee for Medical Products for Human Use (CHMP) of the European Medicines Agency (EMA) has granted a positive opinion recommending approval of the oral, once-daily medication ZYTIGAŽ (abiraterone acetate) for use in combination with prednisone or prednisolone in the treatment of metastatic castration-resistant prostate cancer (mCRPC), in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy and in whom chemotherapy is not yet clinically indicated.1 If endorsed by the European Commission, the recommendation would expand the indication for ZYTIGAŽ, which is currently approved for use in combination with prednisone/prednisolone to treat men with mCRPC whose disease has progressed on or after a docetaxel-based chemotherapy regimen.

In February 2012 an Independent Data Monitoring Committee (IDMC) unanimously recommended unblinding the Phase III COU-AA-302 study2 on which this CHMP recommendation is based after a pre-specified analysis found statistically significant differences in radiographic progression-free survival (rPFS) and a strong trend in overall survival (OS) favouring ZYTIGAŽ. Based on these results, the IDMC also recommended that patients in the control arm be offered treatment with ZYTIGAŽ. Patients in the ZYTIGA arm also demonstrated a statistically significant difference in all the secondary endpoints compared to the control arm.

The CHMP is the committee responsible for the scientific assessment of products seeking centralised marketing authorisation throughout the European Union. The CHMP’s positive opinion is now referred for approval to the European Commission. Janssen anticipates receiving the regulatory decision from the Commission in early 2013.

Jane Griffiths, Company Group Chairman, Janssen Europe, Middle-East, Africa, commented, “This positive opinion brings us a step closer to being able to offer ZYTIGAŽ to advanced cancer patients earlier in the course of their disease and fills a previously unmet medical need. If approved, the expanded indication will provide a welcome new option for patients with castration-resistant prostate cancer. It could not only give men a chance of extended survival, but may also delay the need for chemotherapy and help to improve their quality of life.”

About the COU-AA-302 study2

Study COU-AA-302 is a Phase III, international, randomised, double-blind, placebo controlled study which evaluated ZYTIGAŽ plus prednisone/prednisolone compared to placebo plus prednisone/prednisolone in 1,088 asymptomatic or mildly symptomatic men with mCRPC who had not received prior chemotherapy. Patients were randomised 1:1 to receive either abiraterone acetate (ZYTIGAŽ) 1,000 milligrams (mg) administered orally once daily plus prednisone/prednisolone 5 mg administered twice daily or placebo plus prednisone/prednisolone 5 mg administered twice daily. The co-primary endpoints of the study are radiographic progression-free survival (rPFS) and overall survival (OS).

This is the first randomised study to demonstrate a rPFS benefit and an OS trend in this patient population. The COU-AA-302 results were presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) in June 2012.

The data demonstrated a statistically significant improvement in rPFS in the abiraterone acetate plus prednisone/prednisolone arm (ZYTIGAŽ arm) of the study compared to the placebo plus prednisone/prednisolone (control) arm. The median rPFS in the control arm was 8.3 months but had not yet been reached in the ZYTIGAŽ arm at the time of the final analysis for rPFS (N=251 vs. 150, respectively). These results reached statistical significance with a p value <0.0001 and a hazard Ratio (HR) of 0.43, with a 95% confidence interval (CI): [0.35, 0.52].

Additionally, treatment with ZYTIGAŽ plus prednisone/prednisolone resulted in a longer overall survival than with placebo; HR=0.752; 95% CI: 0.606; 0.934 (median overall survival in the ZYTIGAŽ arm was not reached because progression events occurred more slowly in the ZYTIGAŽ arm compared to the control arm, in which median overall survival was 27.2 months; HR=0.75; 95% CI: [0.61, 0.93], p=0.0097). At the time of the interim analysis, statistical significance was not reached.

Secondary Endpoints2

Treatment with ZYTIGAŽ plus prednisone also demonstrated significant improvements in secondary study endpoints compared to the control arm, specifically, longer time until:

Opiate use for cancer pain: the median time in the ZYTIGAŽ arm was not reached and was 23.7 months in the control arm (HR=0.69; 95% CI: [0.57, 0.83]; p=0.0001).

Initiation of cytotoxic chemotherapy for prostate cancer: 25.2 months for the ZYTIGAŽ arm vs. 16.8 months for the control arm (HR=0.58 [95% CI: 0.49, 0.69]; p<0.0001).

Deterioration in performance status: 12.3 months for the ZYTIGAŽ arm vs. 10.9 months for the control arm (HR=0.82; 95% CI: [0.71, 0.94]; p=0.0053) for an increase in the Eastern Cooperative Oncology Group (ECOG) performance score of one point or more. The ECOG performance score is a standard measure used to assess functional status of a patient and is often used to determine prognosis and appropriate treatment.

PSA progression: 11.1 months for the ZYTIGAŽ arm vs. 5.6 months for the control arm (HR=0.49; 95% CI: [0.42, 0.57], p<0.0001), based on The Prostate Cancer Clinical Trials Working Group (PCWG2) criteria.

Safety Findings2

Patients in the ZYTIGAŽ arm of the study experienced more grade 3 and grade 4 adverse events than those in the control arm, including cardiac disorders (6% vs. 3%) and hypertension (4% vs. 3%), as well as increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (5.4% vs. 0.8% and 3.0% vs. 0.9%, respectively). Fatigue was the most common adverse event observed in the study.

About metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer occurs when cancer has metastasised (spread) beyond the prostate to other parts of the body and the disease progresses despite serum testosterone below castrate levels.3

The prostate is a gland in men that produces part of the seminal fluid and is located around the urethra (under the bladder). In some cases, cancer of the prostate can grow slowly. However, depending on factors including characteristics specific to the patient and the tumour, prostate cancer also can grow very quickly and spread widely.4

In 2008, an estimated 370,000 new cases of prostate cancer were diagnosed in Europe, and nearly 90,000 men died from the disease.5

About ZYTIGAŽ6

Since its approval in 2011, ZYTIGAŽ has been approved in more than 60 countries worldwide, many thousands of men have received treatment with it, and it is quickly becoming one of the cornerstones of our oncology offerings.

ZYTIGAŽ is the only approved therapy that inhibits production of androgen, which fuels prostate cancer growth, via inhibiting the CYP17 enzyme complex present at three sources: the testes, adrenals and the tumour itself.

ZYTIGAŽ in combination with prednisone/prednisolone was approved by the European Medicines Agency (EMA) in September 2011, for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.

ZYTIGAŽ in combination with prednisone was approved by the U.S. Food and Drug Administration (FDA) in April 2011 for the treatment of men with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel.

In June 2012, Janssen simultaneously submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for ZYTIGAŽ and a type II variation to the European Medicines Agency (EMA). Both applications are intended to extend the use of ZYTIGAŽ administered with prednisone or prednisolone to include the treatment of adult men with metastatic castration-resistant prostate cancer who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy and in whom chemotherapy is not yet clinically indicated.

Important Safety Information6

DOSAGE & ADMINISTRATION:

In adults, the recommended dose of ZYTIGAŽ is 1000 mg (4 tablets) single daily dose. It must not be taken with food as this increases systemic exposure to abiraterone (take dose at least two hours after eating; no food for at least one hour post-dose). Tablets should be swallowed whole with water and taken with the recommended dose of prednisone or prednisolone (10 mg daily). In the event of a missed daily dose, treatment should be resumed the following day with the usual daily dose.

Medical castration with LHRH analogue should be continued during treatment in patients not surgically castrated.

Renal impairment: No dose adjustment is required, however caution is advised as there is no previous experience in patients with prostate cancer and severe renal impairment.

Hepatotoxicity: If hepatotoxicity develops (serum ALT or AST above five times the upper limit of normal), stop treatment immediately until liver function returns to baseline; restart ZYTIGAŽ at 500 mg (2 tablets) once daily and monitor serum transaminases at least every two weeks for three months and monthly thereafter (see full prescribing information). If hepatotoxicity recurs at the reduced dose, stop treatment. If severe hepatotoxicity develops (ALT or AST 20 times the upper limit of normal), discontinue ZYTIGAŽ and do not restart.

Hepatic impairment: No dose adjustment is required in mild cases (Child-Pugh Class A). In moderate cases (Child-Pugh Class B) systemic exposure is increased by approximately four times after a single oral dose of 1,000 mg. In moderate cases (Child-Pugh Class B) there is no clinical data for multiple doses and treatment with ZYTIGAŽ should be cautiously assessed and the benefit clearly should outweigh the possible risks. It should not be used in patients with severe hepatic impairment.

CONTRAINDICATIONS:

ZYTIGAŽ is contraindicated in women who are pregnant or may potentially be pregnant, in people hypersensitive to the active substance or any excipients and in people with severe hepatic impairment [Child-Pugh Class C].

SPECIAL WARNINGS & PRECAUTIONS:

Mineralocorticoid excess-related: ZYTIGAŽ may cause hypertension, hypokalaemia and fluid retention due to mineralocorticoid excess from CYP17 inhibition. Reduced incidence and severity is associated with corticosteroid administration. Caution is required in patients whose underlying medical conditions might be compromised by hypertension, hypokalaemia (those on cardiac glycosides), or fluid retention (those with heart failure), severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those with severe renal impairment. Caution is advised in patients with a history of cardiovascular disease. The phase III studies conducted with ZYTIGA excluded patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angin, or a left ventricular ejection fraction below 50% or NYHA Class III or IV heart failure (study 301) or Class II to IV heart failure (study 302). Control of hypertension and correction of hypokalaemia should be done in advance of and during treatment with ZYTIGAŽ. Before treating patients with a significant risk of congestive heart failure (e.g. a history of cardiac failure, uncontrolled hypertension or cardiac events such as ischaemic heart disease) consider obtaining an assessment of cardiac function (e.g. echocardiogram). Before treatment with ZYTIGA, cardiac failure should be treated and cardiac function optimised. Blood pressure, serum potassium and fluid retention should be monitored before treatment and at least monthly thereafter; for patients with significant risk of congestive heart failure, monitor every two weeks for the first three months.

Hepatotoxicity: Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurred in controlled clinical studies. Serum transaminases should be measured before treatment with ZYTIGAŽ and every two weeks for the first three months, and then monthly. If symptoms/signs suggest hepatotoxicity, serum transaminases should be immediately measured. At any time if serum ALT or AST is above five times the upper limit of normal, treatment should be stopped and liver function monitored. Treatment can be restarted after liver function returns to baseline; using a reduced dose (see above). There is no clinical data in patients with active or symptomatic viral hepatitis.

Corticosteroid withdrawal: Adrenocortical insufficiency should be monitored for if prednisone or prednisolone is withdrawn. An increased dose of corticosteroids may be indicated before/during and after a stressful situation. Mineralocorticoid excess should be monitored for if ZYTIGAŽ is continued after corticosteroids withdrawn.

Bone density: Decreased bone density may be accentuated by treatment with ZYTIGAŽ plus glucocorticoid.

Prior use of ketoconazole: Lower response rates to ZYTIGAŽ may occur in patients previously treated with ketoconazole for prostate cancer.

Hyperglycaemia: The use of glucocorticoids could increase hyperglycaemia, therefore blood sugar should be measured frequently in patients with diabetes.

Use with chemotherapy: The safety and efficacy of concomitant use of ZYTIGA with cytotoxic chemotherapy has not been established.

Intolerance to excipients: ZYTIGAŽ should not be taken by patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Sodium content should be taken into account for those on controlled sodium diet.

Potential risks: Anaemia and sexual dysfunction may occur in men with metastatic castration resistant prostate cancer including those undergoing treatment with ZYTIGA.

SIDE EFFECTS:

Most common: urinary tract infection, hypokalaemia, hypertension, peripheral oedema

Common: hypertriglyceridaemia, cardiac failure (including congestive heart failure, left ventricular dysfunction and decreased ejection fraction), angina pectoris, arrhythmia, atrial fibrillation, tachycardia, increased alanine aminotransferase, fractures (includes all fractures with the exception of pathological fracture), dyspepsia, haematuria and rash.

Uncommon: adrenal insufficiency.

Refer to SmPC for other side effects.

FERTILITY/ PREGNANCY/ LACTATION: ZYTIGAŽ should not be used in women. It is not known whether abiraterone or its metabolites are present in semen. A condom is required if the patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sexual activity with a woman of childbearing potential, a condom is required along with another effective contraceptive method. Abiraterone affected fertility in male and female rats, but these effects were fully reversible

INTERACTIONS:

Use ZYTIGAŽ with caution alongside with drugs activated by or metabolised by CYP2D6 particularly when there is a narrow therapeutic index e.g. metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecanide, codeine, Oxycodone and tramadol. Dose reduction for those metabolised by CYP2D6 should be considered. ZYTIGA is an inhibitor of CYP2C8 (in vitro data); Medicinal products metabolised by CYP2C8 include paclitaxel and repaglinide. There are no clinical data on the use of ZYTIGAŽ with drugs that are substrates of CYP2C8. ZYTIGA is CYP3A4 substrate (in vitro data); avoid or use with caution with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g. phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital). Food increases systemic exposure to abiraterone (see above).

About Janssen

The Janssen Pharmaceutical Companies of Johnson & Johnson are dedicated to addressing and solving the most important unmet medical needs of our time, including oncology, immunology, neuroscience, infectious disease, and cardiovascular and metabolic diseases.

Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world.

More information can be found at www.janssen-emea.com

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen- Cilag International NV, any of the Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; challenges to patents; changes in behaviour and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended January 1, 2012. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)

References

1 http://www.ema.europa.eu/docs/en_GB/document_library/ Summary_of_opinion/human/002321/WC500134841.pdf [last accessed November 2012]

2 Ryan C.J et al. Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

3 Hotte SJ, Saad F. Current management of castrate-resistant prostate cancer. Curr Oncol. 2010 September; 17(Supplement 2): S72–S79.

4 Mayo Clinic. “Prostate Cancer.” http://www.mayoclinic.com/health/prostate-cancer/DS00043. [Last accessed November 2012].

5 http://globocan.iarc.fr/factsheet.asp [last accessed November 2012]

6 ZYTIGAŽ summary of product characteristics 2012


Source: Janssen

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