2010/- New Hepatitis C Drug Update

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2010/- New Hepatitis C Drug Update

Direct-Acting Antiviral Drug Update from EASL

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Part One/Two

http://www.hcvadvocate.org/news/newsLetter/2010/advocate0610.html#2

—Liz HighleymanAt the 45th Annual Meeting of the European Association for the Study of the Liver (EASL) in April, researchers presented data on many experimental direct-acting antiviral drug candidates for hepatitis C. Unlike interferon-based therapy, which stimulates the immune system to fight HCV, direct-acting agents interfere with specific steps of the viral lifecycle (for more information see “How Do Targeted Anti-HCV Drugs Work?†in the December 2009 HCV Advocate).This report covers experimental HCV protease inhibitors, which are furthest along in the development pipeline; HCV polymerase inhibitors and all-oral combinations will be covered next issue.Comment: We are changing the way we report on coverage for the EASL conference. Liz Highleyman will be writing up the information released and I will be providing the editorial comments about the drugs discussed in this article. –Alan

FranciscusTelaprevirT. Berg and colleagues presented data from Study 107, an open-label rollover study of Vertex’s NS3/4A HCV protease inhibitor telaprevir that included HCV genotype 1 patients who did not achieve sustained virological response (SVR) in the standard therapy control arms of the Phase 2 PROVE trials. Participants received 750 mg telaprevir three-times-daily for 12 weeks in combination with pegylated interferon alfa-2a (Pegasys) plus ribavirin, then continued standard therapy for 24 weeks (81 patients) or 48 weeks (34 patients), depending on response at week 4.Overall, 59% achieved SVR (undetectable HCV RNA 24 weeks after completion of treatment). Response varied, however, according to type of previous treatment failure. Almost all prior relapsers achieved SVR when retreated for either 24 weeks (96%) or 48 weeks (100%). Partial responders and people with prior viral breakthrough had SVR rates of 60% and 86%,

respectively, when retreated for 24 weeks, though none of the four patients treated for 48 weeks achieved sustained response. The SVR rate for prior null responders was just 17% with 24 weeks retreatment, but rose to 56% at 48 weeks. Among people with rapid virological response (RVR), or undetectable HCV RNA at week 4, SVR rates were higher in all groups. About half of the participants developed skin rash and 9% stopped treatment early due to adverse events.Comments: Telaprevir continues to show impressive results especially in HCV genotype 1 treatment experienced patients—the most difficult to treat This group is the most in need of new therapy so hopefully the larger studies will continue to show high response rates. The study also demonstrates that a 48-week treatment period confirms the need for longer duration of treatment compared to the 24-week treatment duration for treatment naive patients.The high rates of skin rash are an

on-going problem in telaprevir studies, but since only 9% of patients stopped treatment due to all adverse events it would seem that the skin rash is manageable and for most doesn’t lead to discontinuation of therapy. –AFTypes of Non-ResponsePrior null responders: Patients who had a viral load reduction <> 2 log10 at week 12, but who had detectable HCV RNA at week 24Prior relapsers: Patients who had an undetectable viral load during treatment, but had detectable viral load after treatment ended.Prior viral breakthrough: Patients who had undetectable viral load during treatment, but detectable viral load before the end of treatmentIn another trial (Study C208), X. Forns and colleagues found that telaprevir plus pegylated interferon alfa-2a or alfa-2b (Pegasys or PegIntron) and ribavirin produced high SVR rates among previously untreated genotype 1 patients when taken either twice or three times daily (1125 mg

every 12 hours or 750 mg every eight hours). Participants took telaprevir for 12 weeks and continued pegylated interferon/ribavirin through 24 or 48 weeks depending on early response. About two-thirds (68%) had undetectable HCV RNA from week 4 through 20 and stopped therapy at 24 weeks, while 18% required treatment for 48 weeks. SVR rates were high regardless of telaprevir frequency or type of pegylated interferon (85% every eight hours with Pegasys; 81% every eight hours with PegIntron; 83% every 12 hours with Pegasys; and 82% every 12 hours with PegIntron). Again, the most common adverse events were skin rash and pruritus (itching), and 8% discontinued due to adverse events.Comments: This is the same study reported on in the December 2009 HCV Advocate. It is important for a couple of reasons—the SVR rates for telaprevir taken with Pegasys plus ribavirin and telaprevir taken with PegIntron were similar. But the big news is that response rates

with the twice-a-day dose (every 12 hours) were comparable to the three-times-a-day dose. Hopefully, more studies will be conducted because reducing the dosing schedule would be a big advantage in helping with adherence to treatment. –AFFinally, G. and colleagues tested telaprevir in people with HCV genotypes 2 or 3, which respond better to interferon than genotype 1. Study C209 included 49 previously untreated patients randomly assigned to receive telaprevir alone (750 mg every eight hours), telaprevir with Pegasys plus 800 mg ribavirin, or Pegasys/ribavirin with placebo for two weeks; everyone then received standard therapy through week 24.Among genotype 2 patients HCV RNA declined steeply in all treatment arms (-3.7, -5.5, and -4.8 log10 , respectively, at day 15), but the telaprevir monotherapy arm was less likely to achieve SVR (56%, 100%, and 89%, respectively).Among genotype 3 patients, telaprevir monotherapy

demonstrated minimal activity compared with the other arms (-0.5, -4.9, and -4.7 log10 , respectively); SVR rates were also lower (50%, 67%, and 44%, respectively) relative to genotype 2 patients. The investigators concluded that “telaprevir alone has substantial antiviral activity against HCV genotype 2 while its activity against genotype 3 is limited.â€Comments: Although this is a study with a small patient population I believe this is one of the largest (to date) designed to see how well the telaprevir combo performs in people with HCV genotypes 2 and 3. Genotype 2: While the SVR results were higher in the telaprevir combo group compared to the group that received only Pegasys plus ribavirin, the results were not that much better. This could be due to the small patient population so larger studies are needed to find out if the increase in response outweighs the potential risks of subjecting patients to a direct antiviral. Genotype 3: The

results from the genotype 3 arms clearly show no benefit from the use of the triple combination of telaprevir, Pegasys and ribavirin. –AFBoceprevirP. Kwo and colleagues evaluated 206 treatment-naive genotype 1 chronic hepatitis C patients in the Phase 2 SPRINT-1 trial who received PegIntron plus ribavirin for a four-week lead-in period before adding Merck/Schering-Plough’s NS3 HCV protease inhibitor boceprevir (800 mg three times daily) and continuing on triple therapy for an additional 24 or 48 weeks. A majority (64%) had undetectable HCV RNA after four weeks on triple therapy. SVR rates were high, 82% with 28 total weeks of treatment and 94% with 48 total weeks. However, among late responders (18%) who first achieved undetectable viral load after week eight, sustained response was more likely with 48 rather than 28 total weeks (79% vs 21%, respectively). While baseline characteristics could not predict in advance who would respond to

shorter treatment, virological responses during early therapy appear likely to do so, allowing for response-guided therapy, the researchers concluded.Comments: The important finding of this study was that response-guided therapy is important with the boceprevir combo in people who are late responders. Another interesting finding is the 82% SVR with the group that was treated for 28 weeks vs. the 94% in the group that received the combination for 48 weeks. It will be interesting to see the results in the patient populations treated with the boceprevir combo in the phase III study because a larger patient population will give us a much clearer picture of the advantages of 28 vs. 48 weeks of treatment with the boceprevir combo. –AFIn a related analysis, J. Vierling and colleagues reported findings from a long-term follow-up study of boceprevir. They analyzed blood samples from 604 genotype 1 chronic hepatitis C patients in three previous

trials (SPRINT-1 and the PO3659 and PO4887 studies of prior nonresponders); participants were treated with boceprevir at various doses plus PegIntron, with or without ribavirin. During up to three years of follow-up, none of the 290 patients who achieved SVR experienced later relapse. Among all 604 participants, 5% experienced serious adverse events during extended follow-up. Eighteen boceprevir resistance mutations were identified.Comments: The finding of long term response is good news but not unexpected; however, what is interesting is the follow-up on the serious side effects with 5% of the patients experiencing these long term. There have been reports of serious side effects occurring in people but not documented in studies. Hopefully, this issue will be followed for many years in this and other studies to answer the important question of possible long term effects of HCV therapy. –AFDanoprevirA Phase 1b trial confirmed

laboratory findings that the HCV NS3/4A protease inhibitor danoprevir (formerly known as RG7227 and ITMN-191), being developed jointly by Roche and InterMune, is effective at lower doses when boosted with ritonavir (Norvir). Developed as an HIV protease inhibitor, ritonavir interferes with an enzyme (CYP3A) that processes many other drugs, causing those drugs to reach a higher concentration.E. Gane and colleagues conducted a multiple-ascending-dose trial in which 30 treatment-naive genotype 1 patients were randomly assigned to receive ritonavir-boosted danoprevir or placebo in combination with Pegasys plus ribavirin for 15 days. Danoprevir/ritonavir was tested at doses of 100/100 mg twice-daily, 200/100 mg once-daily, and 200/100 mg twice-daily. Patients taking boosted danoprevir were more likely to achieve undetectable HCV viral load (67%, 50%, and 100%, respectively, in the three dosage arms) compared with 20% in the placebo arm and 14% in a

previous trial of 900 mg unboosted danoprevir. Most patients experienced side effects, but these did not show a consistent dose-response effect. Boosted danoprevir is now being tested in prior nonresponders.Comments: These findings are very good news because it shows increased levels of danoprevir when boosted with ritonavir, but without the severe side effects seen in previous studies. –AFBI 201335M. Sulkowski presented results from the Phase 2 SILEN-C2 trial, evaluating Boehringer Ingelheim’s NS3/4A protease inhibitor BI 201335 in combination with standard therapy. This study included 280 genotype 1 prior nonresponders (not including relapsers) randomly allocated to receive 240 mg BI 201335 once-daily, the same BI 201335 dose after a three-day lead-in with Pegasys plus ribavirin, or 240 mg BI 201335 twice-daily after a lead-in; after 24 weeks all participants continued on pegylated interferon/ribavirin alone through week

48.RVR rates were similar in all dose groups (62%, 64%, and 69%, respectively), as were early virological response rates at week 12 (59%, 59%, and 54%, respectively). Viral breakthrough was slightly more common in the two once-daily groups (22%) compared with the twice-daily arm (14%). Skin rash (33%-59%) and jaundice (9%-34%) occurred more often with twice-daily BI 201335; 4% of patients in the once-daily groups and 24% in the twice-daily arm discontinued early due to adverse events. “In treatment-experienced patients, BI 201335 240 mg once-daily appears to offer the best safety/efficacy balance based on this interim analysis,†the researchers concluded.Comments: This study found similar EVR rates among the once-a-day and twice-a-day groups. If these results are confirmed in larger studies this could be a significant improvement in HCV therapy. Currently, the two protease inhibitors (telaprevir and boceprevir) require dosing three

times a day). -AFNarlaprevirJ. de Bruijne and colleagues presented a poster on narlaprevir, the HCV NS3 serine protease inhibitor formerly known as SCH 900518, which is also being tested with ritonavir boosting. This proof-of-concept study included 40 genotype 1 patients (half treatment-naive, half treatment-experienced) who received narlaprevir, with or without ritonavir, or placebo in combination with PegIntron for two weeks, followed by standard of care therapy for 24 or 48 weeks. Treatment naive patients receiving narlaprevir had a high SVR rate of 81%, but treatment-experienced patients did no better than those taking placebo (both 38%).Comments: This small study seems to indicate that narlaprevir may help to increase the SVR rates in treatment-naïve HCV genotype patients. The results in prior relapsers (50%) were beneficial but the low SVR rates in the prior non-responders (17%) indicate no benefit to the addition of

narlaprevir. –AFACH-1625V. Detishin and colleagues presented data from a Phase 1 study of Achillion Pharmaceuticals’ HCV NS3 protease inhibitor ACH-1625. The first two segments of this proof-of-concept study showed that ACH-1625 monotherapy was well-tolerated in healthy HCV negative volunteers at doses up to 2000 mg. The third segment enrolled 18 genotype 1 chronic hepatitis C patients, either treatment-naive or previous relapsers or partial responders, who received ACH-1625 at doses of 500 mg or 600 mg twice-daily or placebo for five days. Maximal viral load declines were -4.3 and -3.9 log10 , respectively, in the 500 mg and 600 mg arms; two people in the 600 mg arm achieved undetectable HCV RNA. Viral load remained suppressed for at least seven days, and an average sustained HCV RNA decline of 2.5 log10 was still apparent at day 12. There were no serious adverse events and no treatment discontinuations for this reason. Additional dose

cohorts have been added to evaluate lower doses and once-daily dosing.Comments: Since EASL, Achillion announced positive results from the additional cohorts finding that the once-a-day dose provided a mean maximal HCV RNA (viral load) reduction of 3.86 log10 . –AFMK-5172S. Carroll and colleagues reported on MK-5172, a second-generation HCV NS3/4A protease inhibitor. Though further back in the development pipeline, MK-5172 is notable for its activity against HCV strains with known NS3/4A and NS5A/B resistance mutations in laboratory and chimpanzee studies. The first clinical trials in humans are underway.Comments: Treatment of potentially resistant strains of HCV could be the focus of the next generation of research as drug induced treatment resistance emerges –AFDirect-Acting Antiviral Drug Update from EASL: Part 2 http://www.hcvadvocate.org/news/newsLetter/2010/advocate0710.html#2—Liz HighleymanThe 45th Annual Meeting of the European Association for the Study of the Liver (EASL) in April featured data on several experimental direct-acting antiviral drugs for hepatitis C. (For more information see “How Do Targeted Anti-HCV Drugs Work?†in the December 2009 HCV Advocate).This report covers HCV polymerase inhibitors, NS4A inhibitors, and all-oral combinations. See last month’s HCV Advocate for coverage of HCV protease inhibitors.Nucleoside Analog RG7128E. Gane and colleagues reported on RG7128, the NS5B polymerase inhibitor being developed by Roche/Genentech and Pharmasset. Polymerase is a viral enzyme needed to copy genetic material. NS5B refers to the segment of the HCV genome that encodes the polymerase. RG7128 is a nucleoside analog, or defective mimic of natural DNA and RNA building

blocks.Researchers looked at RG7128 in combination with pegylated interferon plus ribavirin in 10 chronic hepatitis C patients with HCV genotype 2 and 15 people with genotype 3 who did not achieve sustained response with prior interferon-based therapy; most trials of direct-acting agents have focused on genotype 1, which is hardest to treat. Participants were randomly assigned to receive 1,500 mg RG7128 twice-daily or placebo with pegylated interferon alfa-2a (Pegasys) plus ribavirin for 28 days, followed by standard therapy for an additional 20-44 weeks.HCV viral load decreased by an average of 5.0 log10 IU/mL at week 4 in the RG7128 arm compared with 3.7 log10 in the placebo arm. All but one patient (95%) receiving RG7128 and 60% in the placebo arm achieved rapid virological response, or undetectable HCV RNA at week 4 of therapy. Sustained virological response (SVR) rates 24 weeks after completion of treatment were 65% and 60%,

respectively. Although the standard treatment duration for HCV genotypes 2 and 3 is 24 weeks, this study saw better outcomes for patients who received a longer course of RG7128 triple therapy (SVR 90% with 48 weeks, 67% with 24 weeks, and none who discontinued before 24 weeks). Response rates were similar for genotypes 2 and 3 (63% vs. 67%) and for prior nonresponders and relapsers (60% vs. 70%).Roche/Genentech discontinued development of another nucleoside analog polymerase inhibitor candidate, RG1626 or balapiravir (the prodrug of RG1479), due to safety concerns. A Phase IIb study showed that the drug increased the likelihood of RVR at week 4 and complete early virological response (EVR) at week 12, but caused unexpected loss of neutrophils and lymphocytes¾an effect not seen with other nucleoside polymerase inhibitors.RG7128 + RG7227Gane also reported findings from INFORM-1, the first clinical trial of a combination oral

hepatitis C regimen. This study looked at RG7128 in combination with the protease inhibitor RG7227, now named danoprevir. Combining agents that target different steps of the viral lifecycle may be more potent and make it harder for the virus to develop resistance.INFORM-1 enrolled treatment-naive and treatment-experienced genotype 1 chronic hepatitis C patients. They were randomly assigned to receive RG7128 (500 or 1,000 mg twice-daily) and RG7227 (100 or 200 mg three-times-daily or 600 or 900 mg twice-daily), or else placebo, for 7 or 13 days, after which they continued on pegylated interferon/ribavirin for 24 or 48 weeks.Outcomes were better with higher doses and longer duration of oral therapy. Treatment-naive patients receiving the high doses of both drugs achieved a 5.1 log10 IU/mL decline in HCV RNA by the end of dosing, while prior nonresponders and relapsers saw drops of 4.0-4.9 log10 IU/mL and placebo recipients showed no

significant change. RVR rates were 88% for treatment-naive patients, 38% for prior partial responders or relapsers, and 13% for prior null responders; complete EVR rates at week 12 were 100%, 75%, and 38%, respectively. Among treatment-naive patients who received the high-dose regimen and were followed for 12 weeks after completion of therapy (SVR-12), 44% maintained an undetectable viral load. The researchers concluded that the large initial viral load reduction with RG7128/RG7227 prior to initiating standard therapy enhanced on-treatment and sustained virological response rates.Nucleotide Analogs PSI-7977 and PSI-938Nucleotide analogs are similar to nucleoside analogs but require less processing to make them active in the body. V. Zennou and colleagues from Pharmasset reported results from a laboratory study of two complementary nucleotide polymerase inhibitors, PSI-7977 (a pyrimidine analog) and PSI-938 (a purine analog). The

combination demonstrated additive to synergistic antiviral activity in replicon models of wild-type (non-mutated) HCV and virus with various known resistance mutations. In addition, either PSI-7977 or PSI-938 plus a non-nucleoside polymerase inhibitor led to better viral clearance.After EASL Pharmasset announced findings from a Phase IIa clinical trial of once-daily PSI-7977 in combination with Pegasys plus ribavirin for 28 days. In this study, which included 63 treatment-naive genotype 1 patients, 88% in the PSI-7977 100 mg arm, 94% in the 200 mg arm, and 93% in the 400 mg arm achieved undetectable viral load, significantly higher than the 21% in the placebo arm; safety and tolerability were comparable in the PSI-7977 and placebo arms and no serious adverse events were reported.Non-nucleoside ANA598Anadys Pharmaceuticals presented findings from a Phase II trial of its non-nucleoside polymerase inhibitor ANA598 at EASL, with

follow-up data announced in May. Non-nucleosides also interfere with the HCV polymerase enzyme, but do so by a different mechanism than nucleoside/nucleotide analogs, making the two classes suitable for combination therapy.This ascending-dose study included 90 treatment-naive genotype 1 patients randomly assigned to receive 200 mg or 400 mg ANA598 twice-daily, or else placebo, in combination with Pegasys plus ribavirin for 12 weeks; they then continued on standard therapy for 24 or 48 weeks.Response rates were similar in the 200 mg and 400 mg dose groups, with 73% and 75%, respectively, achieving complete EVR at week 12, compared with 63% in the placebo group. Tolerability was better and the frequency of skin rash was lower in the 200 mg arm, however, and the company will focus on this dose going forward.While the Phase II trial looked at ANA598 in combination with pegylated interferon/ribavirin, Anadys researchers also reported

in vitro data at EASL showing that it demonstrates enhanced activity when combined with other direct-acting agents and retains activity against HCV with mutations conferring resistance to these drugs.Non-nucleoside VX-222M. - and colleagues presented data on Vertex’s non-nucleoside HCV NS5B polymerase inhibitor candidate VX-222. The researchers conducted a Phase Ib/IIa dose-ascending study that included 32 previously untreated genotype 1 chronic hepatitis C patients. Participants were randomly assigned to receive VX-222 at doses of 250 mg, 500 mg, or 750 mg twice-daily, or 1500 mg once-daily, or placebo for three days. They were then offered Pegasys plus ribavirin for 48 weeks.HCV RNA decreased by about 3.0 log10 IU/mL in all VX-222 arms by day 4; the drug was active against both genotypes 1a and 1b. VX-222 was generally safe and well-tolerated with no serious adverse events. Vertex recently announced that it

will test VX-222 in combination with telaprevir, the company’s HCV protease inhibitor, both as an all-oral regimen and in combination with pegylated interferon/ribavirin.Other Non-nucleosidesFilibuvir (PF-00868554) is Pfizer’s non-nucleoside polymerase inhibitor candidate. In a Phase II study, 35 treatment-naive genotype 1 patients were randomly assigned to receive filibuvir at doses of 200 mg, 300 mg, or 500 mg twice-daily, or else placebo, in combination with Pegasys plus weight-adjusted ribavirin for four weeks, then continuing on standard therapy for 44 more weeks.Participants receiving the triple combination had RVR rates of 60%-75% at week 4, compared with none in the placebo arm, with the best results in the 300 mg dose arm. Filibuvir recipients maintained higher response rates at week 12 (up to 88%) and at the end of treatment (up to 75%). However, 20%-50% of filibuvir recipients relapsed after completing therapy,

compared with none in the placebo arm, resulting in similar SVR-12 rates. The researchers suggested longer use of filibuvir may be needed for sustained response; a study of triple therapy for 24 weeks of treatment is underway.BI 207127 is a non-nucleoside polymerase inhibitor being developed by Boehringer Ingelheim. D. Larrey and colleagues conducted a phase I study of 27 treatment-naive and 30 treatment-experienced genotype 1 patients randomly assigned to receive 400 mg, 600 mg, or 800 mg BI 207127, or else placebo, three times daily for 28 days in combination with pegylated interferon plus ribavirin, then continuing on standard therapy.Among treatment-naive participants, the 600 mg and 800 mg BI 207127 doses had similar potency and worked equally well against genotypes 1a and 1b; among treatment-experienced patients, however, those with 1b had better response. All treatment-naive patients and about half of treatment-experienced

patients who received BI 207127 experienced at least a 3.0 log10 IU/mL decrease in HCV RNA; median decreases in the two higher dose groups were about 5.5 log10 for treatment-naive patients and about 4.4 log10 for treatment-experienced patients. BI 207127 combination therapy was generally well-tolerated, but there was one case of serious rash in the 800 mg group.Abbott also presented data on its non-nucleoside polymerase inhibitor ABT-333, and another further back in the pipeline, ABT-072. In a Phase IIa study, 30 genotype 1 hepatitis C patients received ABT-333 or placebo monotherapy for two days followed by the same agents with pegylated interferon plus ribavirin for 26 days. The triple combination produced about a 2.0 log10 greater reduction in viral load than standard therapy alone. Some drug resistance was detected, but this did not appear to compromise continued treatment response.NS4A InhibitorsIn addition to drugs

targeting the HCV NS5B polymerase, researchers are also looking at agents that interfere with the nonstructural NS4A protein; the function of this protein is not fully understood, but it appears to play an important role in HCV replication.S. Pol and colleagues conducted a Phase IIa trial looking at Bristol-Myers Squibb’s NS5A inhibitor BMS-790052. Treatment-naive genotype 1 patients (12 per arm) were randomly assigned to receive BMS-790052 at doses of 3 mg, 10 mg, or 60 mg once-daily, or else placebo, with Pegasys plus ribavirin for 48 weeks. Participants in all BMS-790052 arms had significantly higher response rates than placebo recipients, but the two higher doses were more effective. RVR rates at week 4 were 42% in the 3 mg arm, 92% in the 10 mg arm, and 83% in the 60 mg arm, compared with 8% in the placebo arm. Complete EVR rates at week 12 were 58%, 83%, and 42%, respectively. BMS-700952 was generally safe and

well-tolerated.Presidio Pharmaceuticals is developing another NS5A inhibitor, PPI-461. R. Colonno and colleagues reported that PPI-461 demonstrated potent activity against all HCV genotypes in a replicon model and showed good tolerability and oral bioavailability in animal studies, suggesting the feasibility of once-daily dosing.Idenix and Tibotec Combination TherapyIn an effort to delay the emergence of drug resistance¾and ultimately enable people to use direct-acting agents without interferon¾pharmaceutical companies are now testing combinations of candidates from different drug classes early in the development process.Idenix Pharmaceuticals presented data on agents from multiple classes alone and in combination. J. Lalezari and colleagues evaluated the safety, antiviral activity, and pharmacokinetics of the nucleotide analog polymerase inhibitor IDX184. In a Phase IIa ascending-dose trial, sequential groups of 20

previously untreated genotype 1 patients received IDX184 at doses of 50, 100, 150, or 200 mg once or twice daily, or else placebo, for 14 days; participants also received Pegasys plus ribavirin during the IDX184 dosing period and for 14 days thereafter.After 14 days, HCV viral load decreased by 2.7 log10 IU/mL in the 50 mg once-daily IDX184 arm, 4.0 log10 IU/mL in the 50 mg twice-daily arm, and 4.2 log10 IU/mL in the 100 mg once-daily arm, compared with just 1.2 log10 IU/mL in the placebo arm. By the end of dosing, half the patients in the 50 mg twice-daily and 100 mg once-daily arms achieved undetectable viral load. Most participants experienced viral rebound after the last day of IDX184 dosing, however, even though they remained on pegylated interferon/ribavirin. The drug was generally well-tolerated and no participants discontinued treatment early.M. La Colla and colleagues from Idenix evaluated various two- and three-drug regimens

containing IDX184, the protease inhibitor candidate IDX320, the non-nucleoside polymerase inhibitor IDX375, and a prototype NS5A inhibitor known as IDX-NS5A in a genotype 1b laboratory replicon model. Over three days IDX320 + IDX375 demonstrated additive activity, while IDX320 + IDX-NS5A produced additive to synergistic activity. Triple combinations of IDX184 + IDX320 + either IDX375 or IDX-NS5A produced clear synergistic activity. Over 14 days, IDX184, IDX320, and IDX375 individually produced viral load reductions of about 0.5-1.5 log10 IU/mL. Any two-drug combination demonstrated additive activity, with a reduction of about 2.0 log10; combining all three drugs led to a decrease of nearly 4.0 log10.Researchers from Tibotec likewise tested combinations of the HCV NS3/4A protease inhibitor TMC435 with a nucleoside analog or non-nucleoside polymerase inhibitor in a replicon model. Both combinations showed additive or synergistic antiviral activity

and a higher genetic barrier to resistance than the drugs used alone. The investigators concluded that combining all three agents at low concentrations resulted in a “pronounced reduction in replicon HCV RNA and the most efficient replicon clearance.â€

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