New HCV Drugs Today at EASL 1st Day

New HCV Drugs Today at EASL 1st Day

Thursday April 23, 2009, Copenhagen Denmark
Reported by Jules Levin
So we see very potent protease inhibitors at various stages of development, boceprevir & telaprevir in phase III and others in earlier studies in patients. We are seeing nice potency also in patients with polymerase inhibitors. Of note some of these polymerase inhibitors will be able to be combined, so we can foresee 2 and 3 drug oral regimens that will be in studies soon. Roche is reporting at this meeting the first results from a combination of 2 oral drugs, R7128 the polymerase inhibitor plus ITMN-191 their protease inhibitor. So Roche is the furthest along in a study of 2 oral drugs. For the near future peg/RBV will be used in combinaton therapy with oral drugs. A combination of 2 orals plus peg/RBV will I expect provide SVR rates of 75-90%, and rates in African-Americans may be a little lower but still good. Vertex acquired 3 Virochem NNRTI polymerase inhibtors 2 months ago with one of them VCH-222 showing in early data about I recall 3.50 viral load reductions. So they are planning a study combining VCH-222 plus telaprevir and peg/RBV. Taken together soon to be coming HCV therapy will provide nice SVR or "cure" rates. Combining 2 orals plus peg/RBV should be much more effective in preventing HCV drug resistance from developing and this regimen should be very effective for prior nonresponders, prior null responders, more effective than 1 oral plus peg/RBV. Below is a brief review of study data presented today and I will follow with more detailed studies. At AASLD in Nov 2008 BMS reported initial data in patients for their NS5A inhibitor and this drug looks potent to. There are 2 HCV entry inhibitors being presented here and several cyclophilin inhibitors and a presentation on intravenous silymarin, and there are presentations on nitazoxanide, and there are 2 phase III presentations for albuferon the interferon taken every 2 weeks.

I am writing this report at the first morning of EASL. I am reporting this to you by wireless sponsored by Gilead, the first time EASL has had wireless at the poster session or the conference I think I am in the Schering symposium after sitting through the Roche symposium which was on HBV and Pegasys and based on the effect of Pegasys on HBsAg decline in predicting HBV DNA and HBsAg loss it looks like Pegasys may have a more significant role in HBV therapy. The HCV Late Breaker posters were put up this morning and some interesting results on new HCV drugs were reported. Boerhinger Ingelheim reported for the first time on their new HCV polymerase inhibitor. They reported 5 days oral treatment with BI 207127 800 mg every 8 hours and other lower doses. The 800mg dose showed a 4 og viral load reduction. Two patients developed a rash, they had the highest pk exposures. The only serious adverse event related to the intake of the drug was a moderate generalized erythema with facial involvement. this patient was receiving 800mg every 8 hrs and the SAE resolved within 2 days after discontinuation of the drug lab parameters did not show any relevant changes from baseline. there were no signs of liver, kidney or hematotoxicity. further clinical development is planned. Boerhinger also has a protease inhibitor currently in phase II in patients, they reported initial potency in patients at AASLD in Nov and the drug showed good potency.

Pfizer presented a poster for their NNRTI polymerase inhibitor in combination with pegasys and ribaviin. In previous monotherapy study for 8 days 2 log viral load reduction was seen. Patients received 200, 300 or 500 mg bid in combination with peg/RBV. The drug appeared safe and tolerable. The mean viral load reduction was at day 4 was -0.58 Placebo), and -2.29, -2.72, and -.2.83 for the 3 doses of drug. At day 28, the viral load reductions were -2.10 (placebo), and -4.46, -4.67, and -3.62 for the 3 drug doses. The percent of patients achieving RVR (undetectable HCV RNA by week 4) was 0% (placebo), and 60%, 75% and 63% for the 3 doses of drug.

Merck presented the first data on their protease inhibitor in naives in combination with peg/RBV. Previously at AASLD last year they reported -4.55 log reduction with monotherapy. In this study the about 75% of patients had undetectable viral load at I think it was 4 weeks, I don't have right in front of me but will report it all later. There was GI upset in some patients over the patients who took only peg/RBV. Merck is planning a study in treatment-experienced patients.

Tibotec reported data for the first time on their protease inhibitor TMC435 in combination with pegasys/RBV for 28 days, a total of 40 patients in study receiving placebo or 1 of 3 doses. Previously they reported -4.35 log reduction in monotherapy. In this study mean decreases in viral load were 4.3, 5.5 and 5.3 for 75, 150, and 200 mg once daily. At day 28 4/9 (44%), 7/9 (78%), and 7/10 (70%) of patients achieved <25 IU/Ml undetectable viral load. Of note in this study, the OPERA Study, these patients were treatment-experienced, patients were classified as prior nonresponders and prior relapsers. For nonresponders (6 or 7 patients in each group) receiving 150 mg once daily about 30% had <10 IU/ml and about 65% had <25 IU/ml; for nonresponders receiving 200 mg once daily about 30% achieved <10 IU/ml and about 50% achieved <25 IU/ml; for nonresponders receiving 75 mg qd about 25% achieved <25 with no one achieving <10 IU/ml. For prior relapsers those receiving 150 mg qd 100% achieved. <10 IU/ml (n=3), for those receiving 75 mg qd (n=2) they all achieved <10 IU/ml, for patients in the 200 mg group (n=4) 90% achieved <25 IU/ml and 20% < 10 IU/ml). For these patients who I reported are <25 IU/ml they are between 10 and 25 IU/ml. There were no discontinuations due to safety.Bilirubin elevations were observed in some patients receiving TMC435 (total, direct & indirect), mostly with the 200 mg dose. These elevations were generally mild and reversible in nature. Future studies are planned.

I am sitting in the Schering symposium where they are previewing the results for boceprevir phase II results being presented later today. Of note for patients with RVR 82% receiving 28 weeks therapy in combination with peg/RBV achieve undetectable, I think it is SVR I just saw slide but not sure, and with 48 weeks it is 94%. This is with I recall 4 week peg/RBV lead-in. I will report exact data later today to you.

Schering will be presenting at this meeting SVH900518, a new protease inhibitor that will be boosted with ritonavir, and it will be dosed twice daily, so Schering is saying blood levels with this drug will be higher and their early thinking is they hope it might suppress protease resistance mutations. But this will of course have to be proven in patients. I think they said in the abstract that this PI has some similar mutations as other PIs but the high bood levels may be good enough to suppress PI resistance.