"SILVER SPRING, MD â€” The US Food and Drug Administration (FDA) is updating labeling information for the hepatitis C antivirals ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) and sofosbuvir (Sovaldi, Gilead Sciences) after th"...
Mechanism of Action
Interferons induce pleiotropic biologic responses which include antiviral, antiproliferative, and immunomodulatory effects, regulation of cell surface major histocompatibility antigen (HLA class I and class II) expression and regulation of cytokine expression.
Analysis of INFERGEN-induced cellular products (induction of 2'5' OAS and ß-2 microglobulin) after treatment in these subjects revealed a statistically significant, dose-related increase in the area under the curve (AUC) for the levels of 2'5' OAS or ß-2 microglobulin induced over time. Concentrations of 2'5' OAS were maximal at 24 hours after dosing, while serum levels of ß-2 microglobulin appeared to reach a maximum 24 to 36 hours after dosing. The dose-response relationships observed for 2'5' OAS and ß-2 microglobulin were indicative of biological activity after subcutaneous injection administration of 1 mcg to 9 mcg INFERGEN.
The pharmacokinetic properties of INFERGEN have not been evaluated in patients with chronic hepatitis C. Pharmacokinetic profiles were evaluated in normal, healthy volunteer subjects after subcutaneous injection of 1 mcg, 3 mcg, or 9 mcg INFERGEN. Plasma levels of INFERGEN after subcutaneous injection administration of any dose were too low to be detected by either enzyme-linked immunosorbent assay (ELISA) or by inhibition of viral cytopathic effect.
Patients with creatinine clearance < 50 mL/min should not be treated with ribavirin [see WARNINGS AND PRECAUTIONS: Renal Impairment; Ribavirin Labeling].
Mechanism of Action
Interferon alfacon-1 is a recombinant hybrid protein based on the consensus amino acid sequence of naturally occurring human type-I interferon alphas. Type-I interferons are a family of small protein molecules with molecular weights of 15,000 to 21,000 daltons that are produced and secreted by cells in response to viral infections or to various synthetic and biological inducers. Interferons do not act directly on the virus but bind to the interferon cell-surface receptor leading to the production of several interferon-stimulated gene products. Interferons induce pleiotropic biologic responses which include antiviral, antiproliferative, and immunomodulatory effects, regulation of cell surface major histocompatibility antigen (HLA class I and class II) expression and regulation of cytokine expression.
Antiviral Activity in Cell Culture
The antiviral activity of INFERGEN, alone or in combination with ribavirin, against HCV or HCV-derived replicons in cell culture has not been determined.
HCV genotypes show wide variability in their response to interferon/ribavirin based therapies. Genetic changes associated with the variable response have not been identified. It has been reported that certain regions of the HCV genome, especially a region in the NS5B protein called IFN-sensitive determining region, may play a role in determination of a patient's response to interferon treatment.
The homology between interferon alfacon-1 and other type-I interferons, and the clinical responses for the different HCV genotypes are consistent with cross-resistance.
Animal Toxicology and/or Pharmacology
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 mcg/kg/day to 100 mcg/kg/day (50-fold 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.
Initial Treatment with INFERGEN Monotherapy
The efficacy of INFERGEN monotherapy compared to recombinant human interferon alfa-2b (IFN α-2b) was evaluated in a randomized, double-blind clinical trial involving 704 subjects previously untreated with interferon alpha. Subjects were 18 years or older, had compensated liver disease, tested positive for HCV RNA, and had elevated serum alanine aminotransferase (ALT) averaging greater than 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.
Subjects were treated with INFERGEN 3 mcg (n = 232), 9 mcg (n = 232), or IFN α-2b 3 million international units (MIU) (n = 240), each administered three times per week for 24 weeks and were observed for 24 weeks after the end of treatment. Efficacy was determined by measurement of serum ALT and HCV RNA levels, and changes in liver histology. Serum HCV RNA was assessed using a research-based 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) score of pretreatment and post treatment biopsy specimens. Histologic improvement was defined as having at least a 2-unit decrease in the Knodell HAI score.
Response rates at the end of the observation period are included in Table 6.
Table 6: End of Observation Response Rates
|INFERGEN 9 mcg
n = 232
|IFN α-2b 3 MIUa
n = 240
|HCV RNA negative||9%||8%|
|a 3 MIU IFN α-2b is equivalent to approximately 15 mcg IFN α-2b.|
The 3 mcg INFERGEN dosage arm was substantially less effective with only 3% of subjects achieving end of observation responses.
Subsequent Treatment with INFERGEN Monotherapy
Subsequent treatment with INFERGEN 15 mcg monotherapy for either 24 or 48 weeks was evaluated in an open-label clinical trial of 208 subjects who had failed initial interferon monotherapy. Of the subjects, 64% had failed to normalize ALT during initial treatment (ALT non-responder) and 36% achieved normal ALT levels during initial treatment, but had return of elevated ALT levels during post treatment observation (ALT relapse). Subjects were assessed for normalization of ALT and HCV RNA reduction to ≤ 100 copies/mL at the end of 24 weeks of observation following discontinuation of therapy. Response rates are included in Table 7.
Table 7: End of Observation Response Rates
|All Subjects||Prior ALT Nonresponders||Prior ALT Relapsers|
(n = 101)
(n = 74)
(n = 59)
(n = 33)
(n = 42)
|HCV RNA < 100 copies/mL||9%||22%||4%||12%||21%||36%|
Subsequent Treatment with Combination INFERGEN/Ribavirin
This study (DIRECT Trial/ IRHC-001 and IRHC-002) was a randomized, open-label, multi-center, US-based study comparing the safety and efficacy of two doses of INFERGEN (9 mcg or 15 mcg) administered daily plus ribavirin (1000 mg or 1200 mg weight based dosed) administered daily for 48 weeks to subjects who were nonresponders to previous pegylated interferon plus ribavirin (PegIFN/ribavirin) therapy. Prior non-response was defined as a < 2 log10 decline in viral load (VL) while undergoing at least 12 weeks of previous Peg-IFN/ribavirin therapy with ≥ 80% adherence or a detectable VL at end-of-treatment after completing at least 24 weeks of therapy. Study subjects had a mean age of 50 yrs, 70% were male, mean weight of 89 kg, 19% were African Americans, 65% were Caucasians, 66% had high VL ( ≥ 850,000 IU/mL), 95% were infected with genotype 1, 54% had evidence of bridging fibrosis, 25% had evidence of cirrhosis on biopsy, and 50% had steatosis. Approximately, 80% of the subjects were null responders ( < 2 log10 drop in viral load during their previous Peg-IFN/ribavirin therapy). The median washout period between previous treatment and day 1 of INFERGEN therapy was 448 days (15 months) and 506 days (16.8 months) for the 9 mcg and 15 mcg groups, respectively. The use of hematopoietic growth factors was not permitted in the DIRECT Trial.
In study IRHC-001, 515 subjects were randomized to INFERGEN 9 mcg plus ribavirin (n=171), INFERGEN 15 mcg plus ribavirin (n=172), or no treatment (n=172). In study IRHC-002, 144 subjects in the no treatment arm of study IRHC-001 were re-randomized to either INFERGEN 9 mcg plus ribavirin (n=74) or INFERGEN 15 mcg plus ribavirin (n=70).
Subjects were treated for up to 48 weeks. The primary endpoint was sustained virological response (SVR), defined as undetectable HCV RNA 24 weeks after the end of treatment using a sensitive qualitative assay (TMA LOD < 10 IU/mL). None of the subjects in the no-treatment arm of study IRHC-001 achieved an SVR.
Combined SVR results from IRHC-001 and IRHC-002 according to baseline characteristics are shown in Table 8. Based on these results, INFERGEN 15 mcg is the recommended starting dose.
Table 8: SVR Rates for Subjects Retreated with INFERGEN/ribavirin
|INFERGEN 9 mcg/ribavirin||INFERGEN 15 mcg/ribavirin|
|Overall SVR||5% (13/245)||9% (21/242)|
|Genotype 1||4% (10/231)||6% (15/233)|
|-F0-3||5% (9/181)||7% (12/167)|
|-F4||2% (1/50)||5% (3/66)|
|Other Genotypes||21% (3/14)||67% (6/9)|
|-F0-3||27% (3/11)||75% (6/8)|
|-F4||0% (0/3)||0% (0/1)|
|HCV RNA < 850,000 IU/mL||13% (10/77)||14% (11/78)|
|HCV RNA ≥ 850,000 IU/mL||2% (3/168)||6% (10/163)|
|Caucasian||6% (10/158)||10% (16/158)|
|African American||4% (2/52)||5% (2/42)|
|Other race||3% (1/35)||7% (3/42)|
Last reviewed on RxList: 6/17/2013
This monograph has been modified to include the generic and brand name in many instances.
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