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ATOMIC: 97% RVR FOR PSI-7977 + PEG/RBV X 12 WEEK REGIMEN IN HCV GT1: AN END TO RESPONSE-GUIDED THERAPY?
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Speaker:
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Kris Kowdley
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Author:
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K.V. Kowdley1*, E. Lawitz2, I. Crespo3, T. Hassanein4, M. Davis5, M. DeMicco6, D.R. Nelson7, D. Bernstein8, N.H. Afdhal9, I. Jacobson10, J. Vierling11, S. Gordon12, J.K. Anderson13, R.H. Hyland13, R.G. Hindes13, C. Baker13, R. Sorensen13, E. Albanis13, W.T. Symonds13, M.M. Berrey13, ATOMIC Investigators
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Affiliation:
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1Center for Liver Disease, Virginia Mason Medical Center, Seattle, WA, 2Alamo Medical Research, San Antonio, TX, 3Advanced Research Institute, Trinity, FL, 4Southern California Liver Ctr, Coronado, CA, 5South Florida Center of Gastroenterology, Wellington, FL, 6Advanced Clinical Research Institute, Anaheim, CA, 7University of Florida, Gainesville, FL, 8North Shore University Hospital, Manhassett, NY, 9Beth Israel Deaconess Medical Center, Boston, MA, 10Weill Cornell Medical College, New York, NY, 11Baylor College of Medicine, Houston, TX, 12Henry Ford Health Systems, Detroit, MI, 13Pharmasset, Inc, Princeton, NJ, USA. *kris.kowdley@vmmc.org
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Background and aims: PSI-7977, a potent uridine nucleotide analog, has demonstrated >90% SVR in HCV GT1, GT2, or GT3, independent of predictors of poor responsiveness to interferon. ATOMIC was designed to assess a 12-week regimen of once-daily PSI-7977 400 mg + PEG/RBV.
Methods: Treatment-naïve, non-cirrhotic patients with HCV GT1 and HCV RNA ≥50,000 IU/mL were randomized (1:2:3) into one of three treatment arms: A) PSI-7977+PEG/RBVx12wk, B) PSI-7977+ PEG/RBVx24wk, or C) PSI-7977+PEG/RBVx12wk, with re-randomization at Week 12 to PSI-7977 or PSI-7977/RBV. 25 patients with HCV GT4/5/6 could be enrolled into Arm B.
Results: 316 subjects with HCV GT1, 11 with GT4, and 5 with GT6 were enrolled: mean age 50 years, mean BMI 28, 65% male, 10% Black, 20% Hispanic. Mean baseline HCV RNA 6.4 log10 IU/mL and 18% subjects have IL28B genotype TT. At abstract submission, all subjects have received >8 weeks of PSI-7977. Rapid and consistent antiviral suppression was demonstrated, with 259/332 (78%) achieving HCV RNA < LOD (15 IU/mL) by Week 2 and 323/332 (97%) achieving RVR. The two non-RVR subjects had ~5 log10 IU/mL change from baseline. To date, there has been no viral breakthrough during 12-24 weeks of PSI-7977 and no relapse following completion of treatment in 32 subjects who have reached follow-up.
PSI-7977+PEG/RBV was well-tolerated, with 20 overall discontinuations [14/332 (4%) due to AEs]. Frequency and severity of AEs were consistent with the historical safety profile of PEG/RBV and included fatigue (54%), nausea (29%), headache (29%), chills (19%) and insomnia (19%). Six unrelated SAEs have been reported. Grade 3/4 lab abnormalities included 6% Gr3 Hgb (7-8.9g/dL) and 17% Gr3/Gr4 neutropenia (< 750/mm3). Arm C subjects who received PSI-7977/PEG/RBV x 12 wks and were then re-randomized to PSI-7977+/-RBV demonstrated almost immediate return to baseline values in Hgb and ANC, confirming the predominant effect of PEG in hematologic abnormalities.
Conclusion: PSI-7977 400mg QD with PEG/RBV resulted in 97% RVR in HCV GT1, GT4, or GT6. To date no viral breakthrough or relapse has been observed in subjects completing at least 10 weeks of PSI-7977. SVR for 12 and 24-week regimens of PSI-7977/PEG/RBV will be presented.
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