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Combination Therapy With A Nucleoside Polymerase (R7128) And Protease (R7227/ITMN-191) Inhibitor In HCV: Safety, Pharmacokinetics, And Virologic Results From INFORM-1
E. J. Gane4; S. K. Roberts5; C. A. Stedman6; P. W. Angus7; B. Ritchie8; R. Elston1; D. Ipe1; P. N. Morcos1; I. Najera1; T. Chu1; M. M. Berrey3; W. Z. Bradford2; M. Laughlin1; N. Shulman1; P. F. Smith1
1. Roche, Palo Alto, CA, USA.
2. Intermune, Brisbane, CA, USA.
3. Pharmasset, Princeton, NJ, USA.
4. Auckland Clinical Studies, Auckland, New Zealand.
5. The Alfred, Melbourne, VIC, Australia.
6. Christchurch Clinical Studies, Christchurch, New Zealand.
7. Austin Hospital, Heidelberg, VIC, Australia.
8. Royal Adelaide Hospital, Adelaide, SA, Australia.


INTRODUCTION: HCV regimens of multiple oral direct acting antivirals (DAAs) may offer advantages by enhancing potency, reducing the emergence of resistance, and potentially eliminating the need for PEG-IFN and/or ribavirin. R7128/R7227 is a particularly attractive combination due to the differing mechanisms of action, different routes of elimination, and high barrier to resistance.
METHODS: INFORM-1 is a randomized, double-blind, placebo controlled, ascending dose trial. HCV-infected adults (Genotype 1, Treatment naïve, experienced, and null responder cohorts) received up to 14d oral combination therapy. Two initial groups received low dose monotherapy with R7128 (n=8) 500mg bid or low dose R7227 (n=9) 100mg tid on d1-3, both followed by combination R7128/R7227 on d4-7. Further groups received 14d escalating doses of R7128/R7227. R7128 was given as 500 or 1000mg bid, R7227 either 600 or 900mg bid or 100 or 200mg tid. After completion of 14d R7128/R7227, pts received Pegasys/Copegus (SOC). Safety, viral kinetics, resistance, & PK of R7128/R7227 were evaluated in all subjects.
RESULTS: 63 pts have completed R7128/R7227 dosing, which was well-tolerated with no treatment-related SAEs, dose modifications, or discontinuations reported. The antiviral responses following 14d R7128/R7227 combination are summarized in Table 1. There were no apparent differences in antiviral responses between naïve and experienced pts, between tid or bid R7227 regimens, or between Genotype 1a and 1b pts. Out of 53 pts receiving active R7128/R7227, only 1 experienced viral rebound, defined as > 0.5 log10 increase from nadir; this subject had an end of treatment HCVRNA = 3070 IU/mL, and remains undetectable after 12wks SOC. Final results from all pts will be presented.
CONCLUSION: The combination of R7128/R7227 for up to 14d provided significant antiviral potency in treatment naïve and experienced patients, sustained viral reductions, and appears safe and well-tolerated as a twice daily oral regimen. This promising combination is undergoing further development for the treatment of CHC.

 
 Antiviral Responses with R7128/R7227 Combination Therapy 
 Regimen (R7128mg/R7227mg) 	N 	Patient Population 	HCV RNA 
 Change From Baseline 
 (Log10 IU/mL) 
 Median (range) 	HCV RNA 
 < LLOQ 
 (< 40 IU/mL) 
 N (%) 	HCV RNA 
 < LLOD 
 (< 15 IU/mL) 
 N (%) 
 500/100tid 	8 	Naive 	-3.9 
 (-5.0 to -2.9) 	1/8 
 (13%) 	1/8 
 (13%) 
 500/200 tid 	8 	Naive 	-5.2 
 (-5.5 to -3.1) 	5/8 
 (63%) 	2/8 
 (25%) 
 1000/100tid 	7 	Naive 	-4.8 
 (-5.7 to -4.5) 	5/7 
 (71%) 	2/7 
 (29%) 
 1000/200tid 	8 	Naive 	-4.8 
 (-5.5 to -2.7) 	5/8 
 (63%) 	2/8 
 (25%) 
 1000/600bid 	5	Experienced* 	-4.5 
 (-6.0 to -3.6) 	2/4 
 (50%) 	1/4 
 (25%) 
 *Excluding Null Responders 
 

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