- Email: [email protected]
4A PROTEASE INHIBITORS WITH A HIGH BARRIER TO RESISTANCE
POSTERS 3. PR plus BOC for 44 weeks (BOC/PR48). Primary endpoint was SVR 24 wks post-therapy (Roche TaqMan LLD = 9.3 IU/mL). Results: SVR was numerically higher in patients with G1a (66–73%) compared to G1b (59–64%) in the BOC arms of both studies. Similarly, the number of patients with RAVs was higher with G1a infection and the rate of detectable RAVs in all patients for whom RAV testing was performed was higher in G1a infected subjects in both studies (Table). Conclusions: BOC/PR therapy is associated with a small but consistently higher SVR rate and lower rate of development of RAVs in patients infected with G1b compared to G1a.
fatigue (21/47), diarrhea (18/47), influenza-like illness (17/47), headache (16/47), decreased appetite (15/47), asthenia (13/47), nausea (12/47), and dyspnoea (10/47). ALT elevations were more frequent on the BMS-650032 regimens than placebo, and were most prominent at the two 600 mg dose levels (QD and BID), occurring at approximately 8 to 12 weeks on-treatment. There were 2 Grade 3–4 ALT abnormalities through Week 12, one each receiving 600 mg BID and 600 mg QD, and none at the 200 mg BID dose.
Study
Number of Subjects (%)
200 mg BID N = 12
600 mg BID N = 12
600 mg QD N = 12
N = 11
eRVR RVR cEVR SAE Discontinuations due to AEs
9 (75.0) 10 (83.3) 11 (91.7) 1 (8.3) 0
9 (75.0) 10 (83.3) 10 (83.3) 0 2 (16.7)
11 (91.7) 11 (91.7) 12 (100.0) 1 (8.3) 2 (16.7)
0 0 7 (63.6) 0 1 (9.1)
Genotype
SVR, % (n/N) 48 P/R
SPRINT-2
1a 1b
RESPOND-2
1a 1b
35% (62/177) 41% (51/126) 24% (11/46) 18% (6/34)
RAVs BOC RGT
59% (106/179) 66% (89/134) 53% (50/94) 67% (44/66)
BOC/PR48
62% (147/237) 73% (85/117) 64% (61/96) 71% (43/61)
Subjects with RAVs detected, % (n/N)
Subjects with samples sequenced and RAVs detected, % (n/N)
19% (87/468) 10% (24/232) 16% (31/188) 11% (14/127)
58% (87/151) 48% (24/50) 48% (31/65) 41% (13/41)
1195 BMS-650032, AN NS3 INHIBITOR, IN COMBINATION WITH PEGINTERFERON ALPHA-2A AND RIBAVIRIN IN TREATMENT-NAIVE SUBJECTS WITH GENOTYPE 1 CHRONIC HEPATITIS C INFECTION J.-P. Bronowicki1 , S. Pol2 , P.J. Thuluvath3 , D. Larrey4 , C.T. Martorell5 , V.K. Rustgi6 , D.W. Morris7 , Z. Younes8 , M.W. Fried9 , M. Bourliere10 , C. Hezode11 , O. Massoud12 , G.A. Abrams13 , V. Ratziu14 , A. Thiry15 , C. Llamoso15 , E.A. Hughes15 , R.G. Hindes15 . 1 Service d’H´epatoGastro-Ent´erologie, C.H.U. De Nancy Hˆ opitaux de Brabois – Hˆ opital d’Adultes, Vandoeuvre-l`es-Nancy, 2 Service Hepatologie, Hˆ opital Cochin, Paris, France; 3 Mercy Medical Center, Baltimore, MD, USA; 4 Service d’H´epato-Gastro-Ent´erologie et Transplantations, Hˆ opital Saint-Eloi, Montpellier, France; 5 The Research Institute, Springfield, MA, 6 Metropolitan Research, Fairfax, VA, 7 Healthcare Research Consultants, Tulsa, OK, 8 Gastroenterology Center of The Midsouth, Germantown, TN, 9 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 10 Service d’H´epato-Gastro-Ent´erologie, Hˆ opital Saint-Joseph, Marseille, 11 Service d’H´epato-Gastro-Ent´erologie, Hˆ opital Henri Mondor, Creteil, France; 12 University of Alabama at Birmingham, Birmingham, 13 Alabama Liver & Digestive Specialists, Montgomery, AL, USA; 14 Service d’H´epato-Gastro-Ent´erologie, Groupe Hospitalier Piti´e-Salpˆetri`ere, Paris, France; 15 Clinical Research and Development, Bristol-Myers Squibb, Wallingford, CT, USA E-mail: [email protected] Background: BMS-650032 is a potent, selective inhibitor of HCV NS3 protease with antiviral activity in genotypes 1 and 4 in vitro. BMS-650032 has been studied previously in combination with the BMS-790052 NS5A inhibitor. This ongoing proof-of-concept Phase 2a study evaluated three regimens of BMS-650032 in combination with pegIFNa-2a (Pegasys® ) and RBV (Copegus® ) in patients with genotype 1. Methods: 47 treatment-naive non-cirrhotic patients with genotype 1 HCV infection were randomized (1:1:1:1) and treated with BMS-650032 200 mg BID, 600 mg BID, 600 mg QD or placebo with pegIFNa-2a/RBV for 48 weeks. An unblinded analysis at week 12 evaluated the safety and antiviral activity to support dose selection for further development. The primary endpoint was extended rapid virologic response (eRVR), defined as undetectable HCV RNA (<10 IU/mL) at both Weeks 4 and 12. Results: The eRVR rates were higher in BMS-650032 regimens (75.0% to 91.7%) than placebo (0%). No viral breakthrough was observed up to 12 weeks while receiving BMS-650032. The majority of AEs were consistent with pegIFNa-2a and RBV and included: S472
BMS-650032 Antiviral Activity BMS-650032
Placebo
Conclusion: This study demonstrates that 200 mg BID of BMS650032 for twelve weeks plus pegIFNa-2a and RBV resulted in increased anti-viral activity and no discontinuations. The 200 mg BID dose has been selected for further clinical development. 1196 NOVEL, POTENT, PAN-GENOTYPIC HCV NS3/4A PROTEASE INHIBITORS WITH A HIGH BARRIER TO RESISTANCE B.O. Buckman1 , K. Kossen1 , J.B. Nicholas1 , V. Serebryany1 , D. Ruhrmund1 , R. Rajagopalan1 , S. Misialek1 , L. Hooi1 , N. Aleskovski1 , L. Pan1 , L. Huang1 , C.J. Schaefer1 , S. Rajyaguru2 , S. Le 2 Pogam2 , I. Najera ´ , K. Klumpp2 , S. Seiwert1 . 1 InterMune, Brisbane, CA, 2 Hoffmann La Roche, Nutley, NJ, USA E-mail: [email protected] Background: NS3 protease inhibitors (PIs) have emerged as useful components in HCV treatment regimens. However, these compounds typically display a low barrier to virologic escape and a restricted activity across HCV genotypes. Next generation inhibitors with improvements in these two properties would be highly desirable as components of direct acting antiviral agent (DAA) cocktail therapy. Materials and Methods: Structure-guided rational drug design employing both WT and mutant NS3 proteases was used to design compounds. Results: Building on work we have previously presented at this meeting (J. Hepatol., 50, 2009, S341), a lead series of NS3 protease inhibitors was identified. High potency was observed in biochemical assay against NS3/4A derived from genotypes 1a, 1b, 2a, 3, 4, 5 and 6 (IC50 <4 nM). In biochemical assay against WT or R155K NS3/4A, similar potency (IC50 ≈ 1 nM) and slow off-rate (t1/2 ≥ 4 h) were observed. In HCV replicon assays, equivalent activity was observed against 1a, 1b and R155K-bearing NS3/4A (EC50 ≈ 6 nM, 2 nM and 3 nM, respectively). Resistance in vitro using GT 1a and 1b replicons was mapped to NS3 amino acid residue 168, with no selection of R155K mutant. Pharmacokinetic analysis of lead compounds in rat, dog and monkey suggested QD administration would provide efficacious exposure in humans. The antiviral activity of a lead compound was evaluated in chimeric mice chronically infected with HCV. Following daily 30 mg/kg doses, viral load was driven below the limit of quantification. Conclusions: We report biochemically pan-genotypic NS3/4A PIs that are equally potent against WT and R155K NS3. These inhibitors have pharmacokinetic performance in preclinical species suggestive of QD administration. Evaluation of a lead compound in mice with a chimeric human liver showed rapid and sustained suppression of viral load. Further study of these compounds is warranted.
Journal of Hepatology 2011 vol. 54 | S363–S534
fatigue (21/47), diarrhea (18/47), influenza-like illness (17/47), headache (16/47), decreased appetite (15/47), asthenia (13/47), nausea (12/47), and dyspnoea (10/47). ALT elevations were more frequent on the BMS-650032 regimens than placebo, and were most prominent at the two 600 mg dose levels (QD and BID), occurring at approximately 8 to 12 weeks on-treatment. There were 2 Grade 3–4 ALT abnormalities through Week 12, one each receiving 600 mg BID and 600 mg QD, and none at the 200 mg BID dose.
Study
Number of Subjects (%)
200 mg BID N = 12
600 mg BID N = 12
600 mg QD N = 12
N = 11
eRVR RVR cEVR SAE Discontinuations due to AEs
9 (75.0) 10 (83.3) 11 (91.7) 1 (8.3) 0
9 (75.0) 10 (83.3) 10 (83.3) 0 2 (16.7)
11 (91.7) 11 (91.7) 12 (100.0) 1 (8.3) 2 (16.7)
0 0 7 (63.6) 0 1 (9.1)
Genotype
SVR, % (n/N) 48 P/R
SPRINT-2
1a 1b
RESPOND-2
1a 1b
35% (62/177) 41% (51/126) 24% (11/46) 18% (6/34)
RAVs BOC RGT
59% (106/179) 66% (89/134) 53% (50/94) 67% (44/66)
BOC/PR48
62% (147/237) 73% (85/117) 64% (61/96) 71% (43/61)
Subjects with RAVs detected, % (n/N)
Subjects with samples sequenced and RAVs detected, % (n/N)
19% (87/468) 10% (24/232) 16% (31/188) 11% (14/127)
58% (87/151) 48% (24/50) 48% (31/65) 41% (13/41)
1195 BMS-650032, AN NS3 INHIBITOR, IN COMBINATION WITH PEGINTERFERON ALPHA-2A AND RIBAVIRIN IN TREATMENT-NAIVE SUBJECTS WITH GENOTYPE 1 CHRONIC HEPATITIS C INFECTION J.-P. Bronowicki1 , S. Pol2 , P.J. Thuluvath3 , D. Larrey4 , C.T. Martorell5 , V.K. Rustgi6 , D.W. Morris7 , Z. Younes8 , M.W. Fried9 , M. Bourliere10 , C. Hezode11 , O. Massoud12 , G.A. Abrams13 , V. Ratziu14 , A. Thiry15 , C. Llamoso15 , E.A. Hughes15 , R.G. Hindes15 . 1 Service d’H´epatoGastro-Ent´erologie, C.H.U. De Nancy Hˆ opitaux de Brabois – Hˆ opital d’Adultes, Vandoeuvre-l`es-Nancy, 2 Service Hepatologie, Hˆ opital Cochin, Paris, France; 3 Mercy Medical Center, Baltimore, MD, USA; 4 Service d’H´epato-Gastro-Ent´erologie et Transplantations, Hˆ opital Saint-Eloi, Montpellier, France; 5 The Research Institute, Springfield, MA, 6 Metropolitan Research, Fairfax, VA, 7 Healthcare Research Consultants, Tulsa, OK, 8 Gastroenterology Center of The Midsouth, Germantown, TN, 9 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 10 Service d’H´epato-Gastro-Ent´erologie, Hˆ opital Saint-Joseph, Marseille, 11 Service d’H´epato-Gastro-Ent´erologie, Hˆ opital Henri Mondor, Creteil, France; 12 University of Alabama at Birmingham, Birmingham, 13 Alabama Liver & Digestive Specialists, Montgomery, AL, USA; 14 Service d’H´epato-Gastro-Ent´erologie, Groupe Hospitalier Piti´e-Salpˆetri`ere, Paris, France; 15 Clinical Research and Development, Bristol-Myers Squibb, Wallingford, CT, USA E-mail: [email protected] Background: BMS-650032 is a potent, selective inhibitor of HCV NS3 protease with antiviral activity in genotypes 1 and 4 in vitro. BMS-650032 has been studied previously in combination with the BMS-790052 NS5A inhibitor. This ongoing proof-of-concept Phase 2a study evaluated three regimens of BMS-650032 in combination with pegIFNa-2a (Pegasys® ) and RBV (Copegus® ) in patients with genotype 1. Methods: 47 treatment-naive non-cirrhotic patients with genotype 1 HCV infection were randomized (1:1:1:1) and treated with BMS-650032 200 mg BID, 600 mg BID, 600 mg QD or placebo with pegIFNa-2a/RBV for 48 weeks. An unblinded analysis at week 12 evaluated the safety and antiviral activity to support dose selection for further development. The primary endpoint was extended rapid virologic response (eRVR), defined as undetectable HCV RNA (<10 IU/mL) at both Weeks 4 and 12. Results: The eRVR rates were higher in BMS-650032 regimens (75.0% to 91.7%) than placebo (0%). No viral breakthrough was observed up to 12 weeks while receiving BMS-650032. The majority of AEs were consistent with pegIFNa-2a and RBV and included: S472
BMS-650032 Antiviral Activity BMS-650032
Placebo
Conclusion: This study demonstrates that 200 mg BID of BMS650032 for twelve weeks plus pegIFNa-2a and RBV resulted in increased anti-viral activity and no discontinuations. The 200 mg BID dose has been selected for further clinical development. 1196 NOVEL, POTENT, PAN-GENOTYPIC HCV NS3/4A PROTEASE INHIBITORS WITH A HIGH BARRIER TO RESISTANCE B.O. Buckman1 , K. Kossen1 , J.B. Nicholas1 , V. Serebryany1 , D. Ruhrmund1 , R. Rajagopalan1 , S. Misialek1 , L. Hooi1 , N. Aleskovski1 , L. Pan1 , L. Huang1 , C.J. Schaefer1 , S. Rajyaguru2 , S. Le 2 Pogam2 , I. Najera ´ , K. Klumpp2 , S. Seiwert1 . 1 InterMune, Brisbane, CA, 2 Hoffmann La Roche, Nutley, NJ, USA E-mail: [email protected] Background: NS3 protease inhibitors (PIs) have emerged as useful components in HCV treatment regimens. However, these compounds typically display a low barrier to virologic escape and a restricted activity across HCV genotypes. Next generation inhibitors with improvements in these two properties would be highly desirable as components of direct acting antiviral agent (DAA) cocktail therapy. Materials and Methods: Structure-guided rational drug design employing both WT and mutant NS3 proteases was used to design compounds. Results: Building on work we have previously presented at this meeting (J. Hepatol., 50, 2009, S341), a lead series of NS3 protease inhibitors was identified. High potency was observed in biochemical assay against NS3/4A derived from genotypes 1a, 1b, 2a, 3, 4, 5 and 6 (IC50 <4 nM). In biochemical assay against WT or R155K NS3/4A, similar potency (IC50 ≈ 1 nM) and slow off-rate (t1/2 ≥ 4 h) were observed. In HCV replicon assays, equivalent activity was observed against 1a, 1b and R155K-bearing NS3/4A (EC50 ≈ 6 nM, 2 nM and 3 nM, respectively). Resistance in vitro using GT 1a and 1b replicons was mapped to NS3 amino acid residue 168, with no selection of R155K mutant. Pharmacokinetic analysis of lead compounds in rat, dog and monkey suggested QD administration would provide efficacious exposure in humans. The antiviral activity of a lead compound was evaluated in chimeric mice chronically infected with HCV. Following daily 30 mg/kg doses, viral load was driven below the limit of quantification. Conclusions: We report biochemically pan-genotypic NS3/4A PIs that are equally potent against WT and R155K NS3. These inhibitors have pharmacokinetic performance in preclinical species suggestive of QD administration. Evaluation of a lead compound in mice with a chimeric human liver showed rapid and sustained suppression of viral load. Further study of these compounds is warranted.
Journal of Hepatology 2011 vol. 54 | S363–S534