Reported by Jules Levin
Bon Voyage to Paris!
New 24/48 week study results from a phase II trial of Viramidine were reported at the final session at EASL Sunday morning. Viramidine results in significantly less anemia than ribavirin and if it proves to be as effective in terms of viral response compared to ribavirin Viramidine may be a safer and more tolerable alternative to ribavirin. Global Phase III studies are ongoing.
"Virologic Response and Safety (anemia) Outcomes in Therapy-Naïve Patients Treated for Chronic Hepatitis C with Viramidine in Combination with Pegylated Interferon Alfa-2A"
R.G. Gish1, D. Nelson2, S. Arora3, M.W. Fried4, K.R. Reddy5, Y. Xu6, B. Murphy7, Study Group6
1 California Pacific Medical Center, San Francisco, CA, USA. 2University of Florida, Gainesville FL, USA. 3University of New Mexico, Albuquerque NM, USA. 4University of North Carolina, Chapel Hill, NC, USA. 5Hospital of the University of Pennsylvania, Philadelphia PA, USA. 6 Valeant Pharmaceuticals International, Costa Mesa, CA, USA
Dose-limiting anemia can be a prominent adverse event of therapy with pegylated interferon and ribavirin. This dose-ranging study examined whether viramidine, a liver-targeting prodrug of ribavirin, may be a safer alternative when used in combination with pegylated interferon a-2a (PEG-IFN).
Of 180 HCV therapy-naive patients enrolled in the study, 171 patients received full-dose viramidine (400 mg: n = 47; 600 mg: n = 43; 800 mg: n = 44) versus ribavirin 1000-1200 mg/d (n = 37) in combination with PEG-IFN (Pegasys) 180 µg/wk SC. Patients were predominantly male (64%), Caucasian (76%), and genotype 1 (72%), with a median HCV RNA of 6.5 log10 copies/ml. Analyses assessed the incidence of anemia (hemoglobin <10 g/dl) and HCV RNA levels (Bayer TMA assay; sensitivity to 5 IU/ml) among patients without dose reduction due to anemia to evaluate the intrinsic activity of viramidine versus ribavirin without the confounder of dose modification.
Viramidine Phase 2 Study Design
This trial was open-label, active-controlled, randomized, multicenter, parallel-group, in treatment-naïve patients stratified by genotype only.
Genotype 2/3 received therapy for 24 weeks; genotype 1, 4, 5, 6 for 48 weeks.
There was a 30-day screening period and a 24-week follow-up period.
STUDY OBJECTIVES
To evaluate the dose that best balances safety & efficacy when combined with a peg-IFN alfa-2a (Pegasys) in the treatment of HCV.
Clinical endpoints:
--Incidence of anemia (hemoglobin <10 g/dL)
--Sustained virologic response
--Overall safety profile
INCLUSION CRITERIA
--treatment-naïve adults 18-70
--compensated HCV-related liver disease
--elevated ALT/AST at acreening
--liver biopsy within 3yrs showing histology consistent with chronic HCV infection
--hemoglobin
men: >= 13 g/dL
women: >= 12 g/dL
--body mass index: 18-35 kg/m2
EXCLUSION CRITERIA
--HIV or HBsAg positivity
--previous ribavirin and/or IFN therapy
--history of other types of significant chronic hepatic diseases
--decompensated liver disease
ischemic heart disease
--significant disease in other organ systems
RESULTS
SVR
Bayer TMA Assa; sensitivity to 5 IU/mL, 25 copies/ml
ITT, 95% CI)
OVERALL SVR
Ribavirin (n=45): 44%
Viramidine 800mg (n=45): 29%
Viramidine: 600mg (n=43): 37%
Viramidine 400mg (n=47): 23%
All comparisons with control are Nonsignifucant.
600 mg is the dose used in Phase III.
SVR GENOTYPE 1
(ITT; 95% CI)
Bayer TMA Assay; sensitivity to 5 IU/mL, 25 copies/ml
Ribavirin (n=34): 35%
600mg Viramidine (n=30): 27%
800mg Viramidine (n=33): 18%
400mg Viramidine (n=36): 17%
Relapse rates were:
53% in 600 mg Viramidine
48% ribavirin
69% 800mg Viramidine
71% 400mg Viramidine
SAFETY
INCIDENCE OF ANEMIA (Hb <10 g/dL) anytime during therapy:
27% ribavirin
2% 600mg Viramidine (p<.01 adjusted for multiple comparisons)
11% 800mg Viramidine (p=NS)
0% 400mg Viramidine (p<.001 adjusted for multiple comparisons
PERCENT OF SUBJECTS WITH Hb CHANGE FROM BASELINE >=25%
(evaluable patients)
WEEK 4
5%* 600mg Viramidine
24% ribavirin
0% 400mg Viramidine
9% 800mg Viramidine
END OF TREATMENT
21%* 600mg Viramidine (p<0.05 versus ribavirin control)
47% ribavirin
14% 400mg Viramidine
16%* 800 mg Viramidine
COMMON ADVERSE EVENTS
Graded Moderate to Severe (%)
Key selected AEs:
Fatigue: 42% (Viramidine 400mg), 47% ribavirin
Depression: 26% (600 mg Viramidine), 31% ribavirin
Anemia (NOS): 0% (600mg Viramidine), 24% ribavirin
Insomnia: 40% (600mg Viramidine), 20% ribavirin
Mylagia: 19% (600mg Viramidine), 7% ribavirin
Pyrexia: 16% 600mg Viramidine, 7% ribavirin
Summary of Adverse Events Leading to Dose Discontinuations or Modifications
5 for 600mg Viramidine
2 for ribavirin
Dose mods:
600mg Viramidine: 19%
RBV: 38%
Due to anemia: 2% Viramidine 600mg
RBV: 20%
Asthenia/fatigue: 0% Viramidine; 11% RBV
