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Supplemental New Biologics License Application Filed for Peginterferon, Ribavirin Combination for Patients With HIV

NUTLEY, N.J., Sept. 2 /PRNewswire/ -- Roche announced today the submission of a supplemental new biologics license application (sBLA) with the U.S. Food and Drug Administration to market Pegasys® (peginterferon alfa-2a) in combination with Copegus® (ribavirin, USP) for the treatment of chronic hepatitis C in patients co-infected with HIV. The indication has been granted fast track status by the FDA, a designation designed to facilitate the development and expedite the review of drugs that address serious, unmet medical needs.

Pegasys is approved for use alone and in combination with Copegus for the treatment of chronic hepatitis C. Pegasys and Copegus are the first hepatitis C medications to be filed for this indication in HIV patients in the U.S. Roche also filed with the European Medicines Agency in May 2004 to market Pegasys and Copegus for co-infected patients in the European Union.

"Hepatitis C has become one of the leading killers of people with HIV today. The filing of Pegasys combination therapy for this indication offers new hope to the 300,000 Americans co-infected with HIV and hepatitis C," said Jeffery Smith, Director, Clinical Research, American Foundation for AIDS Research (amfAR).

Approximately 30 percent of people in the United States with HIV are infected with hepatitis C, a blood-borne virus that attacks the liver. Liver failure resulting from hepatitis C infection is now a major cause of death in people with HIV. Studies have shown that hepatitis C progresses to cirrhosis much more rapidly in people with HIV.

"Pegasys is the only medication in its class to be studied in major multi-center, international trials in co-infected patients and hepatitis B patients. We hope to receive FDA approvals for our co-infection and hepatitis B indications in 2005," said Gary Zieziula, Vice President Commercial Operations. "Roche is committed to high quality science that helps advance the management of viral hepatitis in a broad range of patients, particularly those with unmet needs."

The file submitted to the FDA includes results from APRICOT (AIDS Pegasys Ribavirin International Co-infection Trial), the largest study conducted to date evaluating chronic hepatitis C treatment in patients co-infected with HIV and HCV. APRICOT results were published in the July 29 issue of The New England Journal of Medicine, the fourth Pegasys study to appear in this journal. The results showed that 40 percent of patients treated with Pegasys and Copegus achieved a sustained virological response (SVR). SVR refers to a patient's continued undetectable hepatitis C virus levels in the blood 24 weeks after finishing a course of treatment.

Study Details

The randomized, partially blinded international trial enrolled a total of 860 HCV/HIV co-infected patients in 19 countries. All patients were HCV positive, had compensated liver disease, a CD4+ count greater than 100 cells/mL, and stable HIV disease, with or without antiretroviral therapy. Patients were randomized to 48 weeks of treatment with interferon alfa 2a 3MIU three times a week plus 800 mg/day of ribavirin, 180 mcg of Pegasys once weekly plus placebo, or 180 mcg of Pegasys once weekly with 800 mg/day of Copegus. Sustained virological response (SVR) was assessed at the end of 24 weeks of treatment-free follow up (week 72).

Treatment-related serious adverse events were experienced in 5 percent of patients treated with standard interferon and ribavirin, in 10 percent treated with Pegasys monotherapy and in 8 percent treated with Pegasys and Copegus

About Hepatitis C/HIV Co-infection

While the U.S. National Institutes of Health has recommended that patients who are co-infected with HIV and hepatitis C be considered for hepatitis C treatment, there are currently no therapies approved for the treatment of chronic hepatitis C in HIV infected patients.

HCV and HIV are the two most prevalent blood-borne infections in the United States, and HCV/HIV co-infection is increasingly recognized as a growing public health problem. According to the Centers for Disease Control, hepatitis C has become a major cause of death for people with HIV. In total, approximately 300,000 individuals are estimated to be co-infected in the United States. Chronic HCV affects approximately 2.7 million and HIV affects almost one million Americans.

About Pegasys

Pegasys, a pegylated alpha interferon, and Copegus were approved by the FDA in December 2002 for use in combination for the treatment of adults with chronic hepatitis

C who have compensated liver disease and have not previously been treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis.

Pegasys is dosed at 180mcg as a subcutaneous injection taken once a week. Copegus is available as a 200mg tablet, and is administered orally two times a day as a split dose.

Roche has backed Pegasys with the most extensive clinical research program ever undertaken in hepatitis C, with major studies initiated to advance treatment for hepatitis C patients with unmet needs, including patients co- infected with HIV and HCV, African

Americans, patients with cirrhosis, patients with normal ALT levels, and patients who have failed to respond to previous therapy.

Facts About Pegasys (Peginterferon alfa-2a) in Combination with Copegus

Indication
* Pegasys®, a pegylated alpha interferon, alone or in combination with Copegus® (ribavirin, USP) is indicated for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not previously been treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A).

Dosing and Administration
* Pegasys, a premixed solution, is dosed at 180mcg as a subcutaneous injection once a week. Copegus, available as a 200mg tablet, is administered at 800 to 1200mg taken twice daily as a split dose. The two products are sold separately.

Combination Therapy Clinical Studies
* The two combination therapy pivotal study findings:
* Study 5, published in the March 2, 2004 Annals of Internal Medicine, including 1,284 patients receiving medication, showed that patients with certain genotypes (strains) of the hepatitis C virus should be treated with different dosing regimens of Pegasys and Copegus. The treatment regimens and resulting sustained virological response rates for these groups treated with Pegasys and Copegus therapy were:
* Genotype 1: 48 week duration with 1000 -- 1200mg Copegus: 51 percent
* Genotype non-1: 24 week duration with 800mg Copegus: 82 percent

* Study 4, published in the September 26, 2002 New England Journal of Medicine, including 1,121 patients receiving medication, showed that Pegasys and Copegus combination therapy is a more effective treatment for chronic hepatitis C than interferon alfa-2b and ribavirin. The sustained virological response rate in the Pegasys and Copegus treated patients was 53 percent compared to 44 percent in the interferon alfa- 2b and ribavirin group. Sustained virological response refers to a patient's continued undetectable serum hepatitis C RNA levels 24 weeks after finishing a course of treatment.

Adverse Events
* Alpha interferons, including Pegasys, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping Pegasys therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE EVENTS in complete product information).

* Use with Ribavirin. Ribavirin, including Copegus may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease. Ribavirin is genotoxic, mutagenic, and should be considered a potential carcinogen (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE EVENTS in complete product information).

* Pegasys is contraindicated in patients with hypersensitivity to Pegasys or any of its components, autoimmune hepatitis, and decompensated hepatic disease (Child-Pugh class B and C) before or during treatment with Pegasys. Pegasys is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. Pegasys and Copegus therapy is additionally contraindicated in patients with a hypersensitivity to Copegus or any of its components, women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).

* COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the six months after treatment has concluded. Routine monthly pregnancy test must be performed during this time. If pregnancy should occur during treatment or during six months post-therapy, the patient must be advised of the significant teratogenic risk of Copegus therapy to the fetus. Physicians and patients are strongly encouraged to report any pregnancies that do occur to Roche by calling 1-800-526-6367.

* The most common adverse events reported for Pegasys and Copegus combination therapy, observed in clinical trials (n=451), were fatigue/asthenia (65%), headache (43%), pyrexia (41%), myalgia (40%), irritability/anxiety/nervousness (33%), insomnia (30%), alopecia (28%), neutropenia (27%), nausea/vomiting (25%), rigors (25%), anorexia (24%), injection site reaction (23%), arthralgia (22%), depression (20%), pruritus (19%) and dermatitis (16%).

* Serious adverse events include neuropsychiatric disorders (suicidal ideation and suicide attempt), serious and severe bacterial infections, bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including psoriasis and lupus), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemiccolitis), pancreatitis, and opthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema).

* The complete package inserts for Pegasys and Copegus are available at https://www.gene.com/patients/medicines/pegasys, or by calling 1-877-PEGASYS.

Source: Roche

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