Results / Silen-C1 Trial B1201335

www.timescolonist.com/story_print.html?id=4542124&sponsor=

[Trish77]

Interesting, Will.  Thanks for posting this.  

These results for a once-daily dosage are encouraging for a PI when adherence becomes all the more important to limit resistance caused by non-adherence which is a greater risk in twice daily or thrice daily medications.

"(Oral Presentation at EASL, Parallel Session: HCV Drug Development, 16:00h-16:15h, Abstract 60) SILEN-C1: Sustained Virologic Response (SVR) and Safety of BI 201335 Combined with Peginterferon Alfa-2a and Ribavirin in Treatment-Naïve Patients with Chronic Genotype-1 HCV Infection

The Phase II SILEN-C1 study results show BI 201335 to have strong antiviral activity, with overall SVR rates reaching 83% in the 240mg once-daily group (plus current SOC). Of the patients achieving extended rapid viral response (eRVR, defined as plasma viral load less than 25 IU/ml at week 4 and undetectable at weeks 8-20), 93% achieved SVR with 24 weeks of SOC (PegIFN/RBV) treatment.

In addition to high efficacy at all dose levels, BI 201335 once daily with SOC also demonstrated good tolerability and safety:

The most frequent dose-dependent adverse events in BI 201335 treatment groupswere mild gastrointestinal disorders, mild rash or photosensitivity and jaundice resulting from isolated unconjugated hyperbilirubinaemia. Average alanine aminotransferase (ALT) improved in all BI 201335 groups compared to placebo. Of note, there was no excess anaemia reported in the active groups compared to SOC. Phase III trials of BI 201335 are in preparation."

Very different results for non-responders but still superior to SVR rates for non-responders with INF/Ribavirin SOC.

"(Oral Presentation at EASL Parallel Session: HCV Drug Development, 17:30h-17:45h, Abstract 66) SILEN-C2: Sustained Virologic Response and Safety of BI 201335 Combined with Peginterferon Alfa-2a and Ribavirin in Chronic HCV Genotype-1 Patients with Non-Response to PegIFN/RBV

The Phase II SILEN-C2 study evaluated the virological response and safety of different doses of BI 201335 in treatment-experienced patients who did not respond to at least 12 weeks of prior treatment with PegIFN/RBV. The results demonstrate that treatment with BI 201335 once daily at 240mg, plus SOC provides high efficacy and good tolerability in this very difficult-to-treat patient population, with 41% achieving SVR. As is seen in SILEN-C1, a 3-day lead in with SOC was associated with decreased viral response. Phase III trials of BI 201335 are in preparation.

The most frequent dose-dependent adverse events in BI 201335 treatment groups were similar to those seen in SILEN-C1. Serious or severe adverse events were reported more frequently in the BI 201335 240mg BID with lead in (LI) group. "

Here's a companion article:

BI 201335, a potent HCV NS3 protease inhibitor, in treatment-naïve and -experienced chronic HCV genotype-1 infection: genotypic and phenotypic analysis of the NS3 protease domain

http://www.natap.org/2009/EASL/EASL_88.htm

"AUTHOR DISCUSSION AND CONCLUSIONS

HCV NS3 variants that confer resistance to BI 201335 were selected during treatment. These substitutions do not alter the sensitivity to PegIFN/RBV, and the majority of treatment-naïve patients with resistant virus subsequently displayed antiviral responses during combination therapy

The predominant GT 1a resistance mutations encoded a R155K substitution, whereas GT 1b virus mainly encoded changes at D168, with valine as a predominant substitution

The differing persistence of BI 201335 resistance mutants in long-term follow-up among samples in this study suggest D168V variants are less fit in the absence of drug pressure than R155K variants"

"In individual longitudinal analysis, the changing proportions of mutant clones during the follow-up to BI 201335 treatment suggest that D168V variants are substantially less fit in the absence of drug pressure than R155K variants

No D168V variants have been detected in any samples from this study beyond Day 84 due to replacement with WT (or other variants), or to virologic response during SOC treatment"

So for Geno 1b, they develop the weaker variants and none detected past Day 84 in trials so far, making results particularly encouraging and resistance issues of less concern with this drug for particularly for Geno 1b, it appears so far if I'm reading that right.

Will be interesting to watch this through Phase III trials and hopefully (likely) they'll continue to evaluate resistance issues.

Thanks again, Will.  Interesting.

Trish