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Viramidine, substitute for ribavirin: end-of-treatment response in therapy-naïve patients
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Reported by Jules Levin
Robert Gish and Valeant Pharmaceuticals report at this AASLD meeting the end of treatment study results (48 weeks) for HCV+ patients receiving Pegasys plus different doses of Viramidine compared to Pegasys plus ribavirin. Previous 24 week results were reported at EASL, the European liver meeting in the Spring of 2004 and were promising. The reported study evaluates 3 doses of Viramidine. Phase III study is ongoing.
BRIEF SUMMARY: 27% of patients taking RBV reported anemia vs 11% taking 800 mg Viramidine, 2% taking 600 mg Viramidine and 0% taking 400 mg Viramidine. HCV RNA responses appeared similar across all treatment groups at the end-of-treatment (48 weeks) with Pegasys plus Viramidine or RBV. All study patients experienced mean declines in hemoglobin. All patients experienced a set of side effects including fatigue, depression, body aches, irritability, etc (see list below).
At least 180 million people worldwide have the hepatitis C virus (HCV), and 4 million here in the USA. Use of ribavirin in combination with interferon leads to increased rates of Sustained Viral Response. The standard of care includes ribavirin plus peginterferon. However, a significant portion of patients fail to achieve SVR. Adherence plays a role in achieving SVR. Development of hemolytic anemia is a dose-limiting toxicity of ribavirin, and can undermine adherence. Reduction in ribavirin dose can significantly reduce SVR. Most patients starting ribavirin experience a 2-3 g/dL decline in hemoglobin (Hgb) during the first 4 weeks of therapy and an estimated 20% on combination therapy develop anemia (Hgb <10 g/dL). Anemia often prompts RBV dose reduction or discontinuation, which may be associated with lower SVR rates. Anemia development can also be addressed by use of or use of EPO, which can sustain Hgb and relieve fatigue.
Viramidine is a nucleotide analog, a prodrug of RBV, that is preferentially taken up by the liver and rapidly converted to RBV by adenosine deaminase. Pharmacokinetic studies in nonhuman primates revealed that Viramidine-derived RBV is concentrated in the liver at a rate 3 times that seen with native RBV. Higher RBV concentrations in human red blood cells (RBCs) have been correlated with greater declines in Hgb. In RBC, Viramidine-derived RBV concentrations are half that seen with RBV. The use of Viramidine may lower the incidence of anemia & lead to fewer dose reductions and improved outcomes.
The objective of this study is to evaluate the dose of Viramidine that best balances safety and efficacy when combined with a pegylated interferon (Pegasys) in the treatment of HCV.
The study is open-label, randomized, multicenter, and a parallel-group study. 180 treatment-naïve patients were enrolled at 17 sites in the USA. Patients enrolled in the study were stratified only by genotype.
STUDY DESIGN
Patients were randomized to 1 of 4 treatment groups & to 24/48 weeks of treatment (genotype 2/3: 24 weeks; genotype 1/4/5/6: 48 weeks—
Viramidine 400 mg twice daily + Pegasys
Viramidine 600 mg twice daily + Pegasys
Viramidine 800 mg twice daily + Pegasys
Ribavirin 1000/1200 mg per day + Pegasys
There is a typical 24 week followup period.
PATIENT BASELINE DEMOGRAPHICS
| 400 mg | 600 mg | 800 mg | RBV | | n=47 | n=43 | n=45 | n=45 | | Gender, male | 64% | 67% | 56% | 71% | | Age, mean | 47 | 48 | 49 | 49 | | Race- | | | | | | Caucasian | 77% | 58% | 82% | 84% | | Non-caucasian | 23% | 42% | 18% | 16% | | Genotype ¼ | | | | | | Or untypable | 77% | 70% | 73% | 76% | | HCV RNA | | | | | | <2 million c/ml | 30% | 42% | 24% | 27% | | >2 million c/ml | 70% | 58% | 76% | 73% | | HCV RNA, | | | | | | median log copies | 6.6 | 6.4 | 6.6 | 6.5 | | weight, median kg | 78 | 85 | 85 | 78 | | Hgb, median overall g/dL | 15.2 | 15.4 | 15.4 | 15.6 |
RESULTS
PERCENT UNDETECTABLE HCV RNA
OVERALL END-OF-TREATMENT RESPONSE: Intent-To-Treat Analysis
Bayer TMA Assay, sensitivity to 5 IU/mL, 25 copies/ml
400 mg (n=47): 55%
600 mg (n=43): 63%
800 mg (n=45): 56%
RBV 1000/1200 mg (n=45): 62%
END-OF-TREATMENT RESPONSE in GENOTYPE 1, 4 or UNTYPABLE PATIENTS RECEIVING >=80% of PEGASYS DOSE: ITT Analysis
Percent Undetectable HCV RNA
400 mg (n=24): 58%
600 mg (n=23): 70%
800 mg (n=18): 61%
RBV 1000/1200 mg (n=25): 72%
END-OF-TREATMENT RESPONSE in GENOTYPE 2/3 PATIENTS RECEIVING >=80% of PEGASYS DOSE: ITT Analysis
400 mg (n=10): 100%
600 mg (n=12): 92%
800 mg (n=11): 82%
RBV 1000/1200 (n=9): 78%
SAFETY
INCIDENCE OF ANEMIA (Hgb <10 g/dL) at Anytime During Therapy
% of patients with anemia
400 mg: 0% (p<.01 vs RBV)
600 mg: 2% (p<.01 vs RBV)
800 mg: 11% (p>.05 vs RBV)
RBV 1000/1200 mg: 27%
MEAN CHANGE FROM BASELINE Hgb OVER TIME
(Safety Population)
patients in RBV group at week 4, had -3 g/dL; at week 24, -3.5 g/dL, at week 48, -3.7 g/dL
at week 4 patients in the 3 Viramidine dose groups had decline in Hgb of -1.5 g/dL. At week 24, decline was about -2.5 g/dL with slight differences between 3 groups with 400 better than 600 & 800 better than 600. At week 48, patients taking 400mg had -2.5 g/dL decline, patients taking 600mg & 800 mg had -3 g/dL decline.
SUMMARY OF ADVERSE EVENTS LEADING TO DISCONTINUATIONS OR MODIFICATIONS
| 400mg | 600mg | 800mg | RBV | | Dose discontinuation | 5 | 4 | 2 | 2 | | --diarrhea | 1 | 1 | 1 | 0 | | --depression | 0 | 1 | 0 | 1 | | --other | 4 | 2 | 1 | 1 | | dose modifications | 10 | 7 | 12 | 15 | | --anemia | 0 | 0 | 1 | 8 | | --neutropenia | 5 | 4 | 3 | 2 | | --thrombocytopenia | 1 | 1 | 4 | 0 | | --diarrhea | 2 | 0 | 1 | 0 | | --depression | 0 | 0 | 1 | 1 |
VIRAMIDINE SAFETY: Incidence of Common Adverse Events Graded Moderate and severe
| 400mg | 600mg | 800mg | RBV | | Fatigue | 30% | 40% | 36% | 42% | | Insomnia | 17% | 37% | 29% | 16% | | Headache | 32% | 26% | 29% | 24% | | Depression | 13% | 23% | 27% | 31% | | Myalgia | 17% | 19% | 22% | 7% | | Pyrexia | 2% | 16% | 7% | 7% | | Arthralgia | 9% | 16% | 7% | 16% | | Nausea | 9% | 14% | 11% | 18% | | Irritability | 6% | 14% | 16% | 20% | | Diarrhea | 13% | 12% | 13% | 7% |
AUTHOR'S CONCLUSIONS:
Overall, EOT response showed all doses of Viramidine were at least as effective as RBV in the % of patients achieving undetectable HCV RNA.
A comparison of genotype 1 patients who maintained >80% of their PegIFN dose showed that all doses of Viramidine achieved a comparable EOT response.
A comparison of genotype 2/3 patients who maintained at least 80% adherence to PegIFN doses showed that all Viramidine doses achieved a comparable EOT.
No differences were found between treatment groups in the types of common adverse events.
Patients treated with RBV experienced a significantly greater decline in Hgb when compared with each Viramidine group.
The incidence of anemia was significantly lower in the Viramidine groups than the RBV group (4% vs 27,% p<.001).
There was no significant difference in the number of adverse events leading to dose discontinuation or modifications between treatment groups.
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