In preclinical toxicology studies in golden Syrian hamsters and rhesus monkeys, administration of Infergen at doses of up to 100 mcg/kg/day was associated with decreased body weight, decreased food consumption, and bone marrow suppression. High-dose chronic exposure at doses of 10 to 100 mcg/kg/day (50- to 500-fold higher than the maximum clinical dose given daily) in rhesus monkeys was not tolerated for greater than 1 month, due to the development of vascular leak syndrome.

Reproductive toxicity studies in pregnant rhesus monkeys and golden Syrian hamsters demonstrated an increase in fetal loss in hamsters treated with Infergen at doses of greater than 150 mcg/kg/day, and in rhesus monkeys at doses of 3 and 10 mcg/kg/day. The Infergen toxicity profile described is consistent with the known toxicity profile of other alfa interferons.⁴

CLINICAL EXPERIENCE: RESPONSE TO INFERGEN

Infergen was studied in an open-label dose escalation study using 3, 6, 9, 12, or 15 mcg administered three times per week (TIW) to patients with compensated liver disease secondary to chronic hepatitis C virus (HCV) infection. The 15 mcg dose was the maximal tolerated dose. All doses demonstrated an acceptable safety profile and preliminary evidence of efficacy.

The efficacy of 3 and 9 mcg doses of Infergen in the treatment of chronic HCV infection was examined in a randomized, double-blind clinical trial involving 704 patients previously untreated with alfa interferon. Patients were 18 years or older, had compensated liver disease, tested positive for HCV RNA, and had elevated serum alanine aminotransferase (ALT) concentrations averaging > 1.5 times the upper limit of normal. Staging of chronic liver disease was confirmed by a liver biopsy taken within 1 year prior to enrollment. Other causes of chronic liver disease were ruled out prior to randomization. Notable exclusion criteria were decompensated liver disease, thyroid abnormality, or history of depression.

Efficacy of Infergen therapy was assessed on an intent to treat basis and was determined by measurement of serum ALT concentrations at the end of therapy (24 weeks) and following 24 weeks of observation after the end of treatment. Serum HCV RNA was also assessed using a quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay with a lower limit of sensitivity of 100 copies/mL. Liver histology was assessed by comparing the histology activity index (HAI) score⁵ of a pretreatment biopsy specimen with the HAI score from a specimen obtained 24 weeks after cessation of interferon therapy.

Patients enrolled in the study were randomized to one of three treatment groups: Infergen at a dose of 3 mcg (n = 232), Infergen at a dose of 9 mcg (n = 232), or Interferon alfa-2b recombinant [IFN alfa-2b, Intron® A (Intron® is a registered trademark of the Schering Corporation)] at a dose of 3 million international units (IU) (approximately 15 mcg) (n = 240). All patients were scheduled to receive their respective interferons SC TIW for 24 weeks (end of treatment). Following treatment, patients were observed for an additional 24 weeks to assess durability of ALT normalization (end of post-treatment observation). In all patients, a complete response was defined as a decrease in serum ALT concentration to at or below the upper limit of normal (48 U/L) at the end of the post-treatment observation period, even if ALT normalization had not been observed at the end of treatment. Complete response was dependent on two consecutive normal serum ALT values determined 4 weeks apart. Reduction of HCV RNA to < 100 copies/mL was measured as a secondary efficacy endpoint (two consecutive measurements).

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