icon-folder.gif   Conference Reports for NATAP  
  58th Annual Meeting of the American Association
for the Study of Liver Diseases
November 2-6, 2007
Boston, MA
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Roche Polymerase Inhibitor Shows Promise In Phase II
  The Pink Sheet DAILY
November 01, 2007
By Jessica Merrill
In a Phase IIa study, 81 percent of hepatitis C patients treated with Roche's investigational nucleoside polymerase inhibitor, R1626, in combination with Pegasys (peginterferon alfa-2a) and Copegus (ribavirin) had undetectable levels of virus after four weeks, the company reported. The data will be presented during the American Association for the Study of Liver Diseases Liver Meeting in Boston Nov. 2-6.
"What has struck everybody is really the potency. The amount of viral load decline of the regimens containing 1626 is beyond what we've seen with any other polymerase inhibitor and on par with even some of the protease inhibitor data we have seen," Senior Medical Director James Thommes said in an interview with "The Pink Sheet" DAILY ahead of AASLD. Although the study was small, enrolling 104 patients and lasting only four weeks, Roche is pursuing development of the polymerase inhibitor in a much larger Phase IIb study that will enroll 500 patients, randomized to seven different treatment arms. That study, POLI 1, is now open.
Several drug makers have recently discontinued development of their polymerase inhibitors, an emerging class of medicines for HCV, due to safety issues. Roche, however, hasn't seen elevated liver enzymes or gastrointestinal side effects with R1626 as some other companies experienced with their non-nucleoside polymerase inhibitors.
One issue that has arisen in early testing with R1626 is neutropenia, an effect Thommes said could be related to coadministration with Pegasys. In the Phase IIb study, Roche will be modifying the dosing of Pegasys to see how that changes the neutropenia effect.
The Phase IIa study evaluated the safety and efficacy of R1626 with Pegasys alone and with Pegasys/Copegus, compared to standard treatment with Pegasys and Copegus alone. The study randomized HCV genotype 1 patients to four different treatment arms: 1,500 mg plus Pegasys; 3,000 mg plus Pegasys; 1,500 mg plus Pegasys and ribavirin; and Pegasys and ribavirin alone. After four weeks, the triple combination arm resulted in the highest percent of patients, 81 percent, with undetectable HCV RNA, with a mean 5.2 log10 reduction. In comparison, 69 percent of patients in the dual high-dose arm had undetectable virus after four weeks, with a mean reduction of 4.5 log10. In the dual low dose arm, 33 percent had undetectable virus with a mean reduction of 3.6 log10. In comparison, only 5 percent of patients achieving undetectable virus and a mean reduction of 2.4 log10 in the Pegasys/ribavirin treatment arm.
Most adverse events were mild or moderate, Roche reported, with incidence of Grade 4 neutropenia being 48 percent, 78 percent, 39 percent and 10 percent in the dual low, dual high, triple low and Pegasys/ribavirin arms, respectively.
Pfizer is another company that is proceeding with development of its non-nucleoside polymerase inhibitor, PF-868,554, which is being studied in a Phase Ib/IIa study (1"The Pink Sheet" DAILY, Sept. 17, 2007).
"The hepatitis C area is very dynamic and changing right now," Thommes said. "I think we're probably on the brink of some potentially very significant changes in how patients are treated."
In addition to R1626, Roche's hepatitis C pipeline includes a second polymerase inhibitor in earlier stage development with Pharmasset, R7128. That candidate is moving into a 28-day Phase I study in HCV patients now and recently received fast track designation from the FDA. Roche is also developing a protease inhibitor with InterMune, ITMN-191, which is currently in Phase Ib testing.
"With our own in-house development program and our collaborative partnerships, we have a very robust pipeline, and we see ourselves as leading the way in developing new treatments for hepatitis C," Thommes said.
Despite the development of new drugs, Pegasys and Copegus will continue to play a role in the treatment of hepatitis C for the foreseeable future, Thommes predicted. "These new compounds are great and have a lot of high potential because they target the virus in a different way than Pegasys and ribavirin, but ... as the data comes out with all these new compounds, they either may have tolerability issues or side effects, and what's very clear even at this early stage of the game, is that a strong backbone of Pegasys and ribavirin will still need to be there," he said.
A high barrier to resistance may contribute to the robust antiviral effect demonstrated by R1626 in HCV genotype 1-infected treatment-naive patients

I. Najera1; S. Le Pogam1; A. Seshaadri1; A. Kosaka1; S. Hu1; H. Kang1; J. Symons1; K. Klumpp1; N. Cammack1 1. Roche Palo Alto LLC, Palo Alto, CA, USA.
R1626, a prodrug of R1479, is a potent inhibitor of HCV replication that has shown maximum mean (median) HCV RNA reductions of up to 3.7 (4.1) log10 following 2 weeks of monotherapy study), and 5.2 log10 following 4 weeks in combination with peginterferon alfa-2a (PEG-IFNα-2a) ± ribavirin (RBV) (phase 2A) in patients infected with HCV genotype 1. In vitro studies have identified NS5B polymerase amino acid substitutions, S96T or S96T/N142T, that result in 4-5-fold reduced sensitivity to R1479 as determined in the replicon assay. These mutations also resulted in a ~95% reduction in replication capacity compared to the wild type replicon. To study resistance development in vivo, phenotypic and genotypic analyses were performed on multiple serum samples from a total of 11 HCV patients treated with R1626 (3 from the monotherapy study and 8 from the combination study), who showed viral rebound before the end of treatment (defined as a sustained ≥ 0.5 log10 increase of viral load above nadir (lowest point), where nadir is a ≥ 0.5 log10 decrease from baseline). All samples tested in the HCV NS5B phenotypic assay were sensitive to inhibition by R1479 to a similar extent as the baseline samples and the 2 reference strains, Con1 and H77. Sequence analysis of the entire NS5B coding region revealed no known R1479 resistance mutations (S96T or S96T/N142T) or any other common amino acid substitutions.
Three patients who failed to respond to R1626 (defined as <0.5 log10 decrease of viral load from baseline) had all received 500 mg of monotherapy. NS5B population sequence analysis and clonal sequence analysis of between 40-106 NS5B polymerase molecular clones for baseline samples of these 3 patients did not reveal pre-existing amino acid substitutions among the quasispecies of these patients that could be responsible for resistance to R1479. These findings are consistent with the sensitivity of these samples to inhibition by R1479 as observed in the phenotypic assay. In addition, sequence analysis demonstrated the absence of known R1479-resistance mutations in baseline samples of all patients who participated in both studies.
In conclusion, there was no evidence for resistance selection to R1626 after 2 weeks of monotherapy or after 4 weeks in combination with PEG-IFNα-2a ± RBV. These findings suggest that there is a high barrier to the development of resistance to R1626 in vivo, that may contribute to the robust antiviral effect of this drug that has been observed in randomized clinical trials.