SUMMARY: Pegylated interferon lambda and pegyalted interferon alfa-2a demonstrated similar activity against hepatitis C virus (HCV) for genotype 2 or 3 patients at week 12, and somewhat better early response rates at higher doses in people with genotypes 1 or 4, according to a study presented at the recent American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston. Furthermore, interferon lambda was better tolerated overall, with fewer cases of anemia and less neutrophil loss.

By Liz Highleyman

Interferon lambda (also known as interleukin 29, or IL-29) is a cytokine produced by certain immune system cells in response to viral infection. It uses a different signalling pathway that type I interferons such as interferon alfa -- the standard treatment for hepatitis C. Because interferon lambda uses a receptor that is present on fewer types of cells in the body, it is expected to have better tolerability and cause fewer side effects.

Andrew Muir from Duke University and colleagues conducted a Phase 2 dose-ranging study comparing pegylated interferon lambda versus pegylated interferon alfa as part of combination therapy.

The study included 55 previously untreated chronic hepatitis C patients. They were randomly assigned to receive pegylated interferon lambda at doses of 80, 120, 180, or 240 mcg, or else 180 mcg pegylated interferon alfa-2a (Pegasys), both in combination with ribavirin. Participants initially received a single dose to assess pharmacokinetic parameters, and then after 2 weeks started weekly dosing that continued for 24 weeks for those with HCV genotypes 2 or 3, or 48 weeks for those with hard-to-treat genotypes 1 or 4.

The investigators analyzed safety data through week 12 or the last study visit (for patients who had not yet reached that point) or discontinuation of treatment. Week 12 efficacy data for HCV genotype 2 or 3 patients were reported in the study abstract, while those with genotypes 1 or 4 had not yet reached this time point.

The researchers also looked at the effect of rs12897986 polymorphisms, or genetic variations, in the human IL28B gene, which encodes a form of interferon lambda. People with the C/C gene pattern have been shown to respond better to interferon alfa, those with the T/T pattern respond poorly, and those with C/T fall in between. Here, the distribution (among 48 patients tested) was 15 with C/C and 33 with C/T or T/T (considered as a single group).

Results

	In an intent-to-treat analysis of genotype 2 and 3 patients, virological response rates were similar in the 3 highest interferon lambda dose groups and the interferon alfa arm:
	Interferon lambda 80 mcg: - Week 2: 40%; - Week 4: 60%; - Week 12: 80%. Interferon lambda 120 mcg: - Week 2: 75%; - Week 4: 100%; - Week 12: 100%. Interferon lambda 180 mcg: - Week 2: 60%; - Week 4: 80%; - Week 12: 80%. Interferon lambda 240 mcg: - Week 2: 75%; - Week 4: 100%; - Week 12: 100%. Interferon alfa 180 mcg: - Week 2: 80%; - Week 4: 100%; - Week 12: 100%.
	In an analysis of genotype 1 and 4 patients (who had not been treated as long at the time of the report), early response appeared slightly better in the higher interferon lambda dose groups:
	Interferon lambda 80 mcg: - Week 2: 0%; - Week 4: 0%; Interferon lambda 120 mcg: - Week 2: 29%; - Week 4: 43%; Interferon lambda 180 mcg: - Week 2: 33%; - Week 4: 33%; Interferon lambda 240 mcg: - Week 2: 29%; - Week 4: 43%; Interferon alfa 180 mcg:   - Week 2: 20%; - Week 4: 40%;
	Overall, white patients had higher response rates than blacks (only 1 black participant achieved viral suppression at weeks 2 and 4).
	Looking at the 3 highest interferon lambda dose arms combined, the virological response rates for genotype 1 or 4 patients with the C/C gene pattern was 71% at both week 2 and week 4.
	For genotype 1 or 4 patients with the C/T or T/T patterns, the corresponding response rates were 8% at week 2, rising to 25% by week 4.
	11 participants discontinued therapy ahead of schedule, 4 of them due to adverse events (1 in the interferon lambda and 1 in the interferon alfa arms).
	33% of patients in the interferon lambda arm experienced clinical adverse events of grade 2 (moderate) or higher, compared with 50% of those taking interferon alfa.
	The frequency of grade 2 anemia (hemoglobin ? 10 g/dL) was 10-fold lower in the interferon lambda arm than in the interferon alfa -- 2% vs 20%, respectively.
	Interferon lambda recipients were less likely to require ribavirin dose reduction due to anemia.
	The median decline in neutrophils (immune white blood cells that protect against infections) was 0.86 x 109/L for interferon lambda recipients versus 2.4 x 109/L in the interferon alfa arm.
	Both arms experience ALT/AST liver enzyme increases (20% vs 30% of participants, respectively, in the interferon lambda and interferon alfa arms).
	3 patients receiving interferon lambda (7%) reduced doses due to ALT/AST elevation, while 1 interferon alfa recipient did so due to depression.
	Among interferon lambda recipients, adverse events did not vary according to dose.

Based on these findings, the researchers concluded, "[Pegyalted interferon lambda] is associated with rapid viral decline and is well-tolerated at doses up to 240 mcg, with less hematologic toxicity compared to [pegyalted interferon alfa-2a]."

Response was influenced by race, HCV genotype, and patient gene pattern, they continued. "[Pegyalted interferon lambda] shows promise across a broad range of doses and viral genotypes, and in difficult to treat host genotypes."

Investigator affiliations: Duke University, Durham, NC; Alamo Medical Research, San Antonio, TX; The Liver Institute, Dallas, TX; University of Utah, Salt Lake City, UT; Liver and Intestinal Research Centre, Vancouver, BC, Canada; University of Colorado, Aurora, CO; New York Hospital, New York, NY; Bristol-Myers Squibb, Wallingford, CT; ZymoGenetics, Inc., Seattle, WA; Fundacion de Investigacion de Diego, Santurce, Puerto Rico.

12/10/10

Reference
AJ Muir, E Lawitz, RH Ghalib, and others. Pegylated Interferon Lambda (PEG-IFN-?) Phase 2 Dose-Ranging, Active-Controlled Study in Combination with Ribavirin (RBV) for Treatment-Naive HCV Patients (Genotypes 1, 2, 3 or 4): Safety, Viral Response, and Impact of IL-28B Host Genotype. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 821.

Other Source
Bristol-Myers Squibb. ZymoGenetics and Bristol-Myers Squibb to Present PEG-Interferon Lambda Phase 2a Interim Clinical Trial Results at AASLD 2010. Press release. October 1, 2010.