Question | Pages |
Q1: Current treatment approaches Please describe your current treatment approaches to chronic and acute hepatitis C (HCV). In your answer, please include whether and when you are likely to use interferon monotherapy or combination therapy. What percentage of your patients are treated with interferon and in what percentage is the treatment successful? | 4 |
Q2: Unmet needs and treatments in development What are your key unmet needs in HCV treatment? What are the most exciting HCV products in development? What is particularly noteworthy about these agents and how could they impact current approaches to chronic and acute HCV treatment? | 5 |
Appendix A: Abstract/profile 1: Preclinical Characteristics of ITMN-191, an Orally Active Inhibitor of the HCV NS3/4A Protease Nominated for Preclinical Development | 6; 18 |
Q3: Reaction to profile What do you think of ITMN-191, an oral NS3/4A serine protease inhibitor? In your answer, please tell us about the main strengths and weaknesses of the product and how these compare to combination therapy with pegylated interferon and ribavirin. | 6 |
Appendix B: ITMN191 information from the 42nd Annual EASL meeting | 6; 27 |
Appendix C: Abstract/profile 2 | 8; 27 |
Q4: Agent comparison 1 How does ITMN-191 compare to VX-950, an oral NS3-4A serine protease inhibitor currently in development? Please comment of VX-950’s relative strengths and weaknesses and on whether you think the product is more or less promising than ITMN-191. | 8 |
Appendix D: VX-950 information from 42nd EASL meeting | 9; 34 |
Appendix E: Abstract/profile 3 | 10; 35 |
Q5: Agent comparison 2 How does ITMN-191 compare to SCH 503034, an oral NS3/4A serine protease inhibitor currently in development? Please comment on SCH 503034’s relative strengths and weaknesses and on whether you think the product is more or less promising than ITMN-191. | 10 |
Appendix F: Additional information on SCH 503034 | 11; 36 |
Appendix G: Abstract/profile 4 | 12; 36 |
Q6: Agent comparison 3 How does ITMN-191 compare to R1626, a nucleoside analog polymerase inhibitor currently in development? Please comment on R1626’s relative strengths and weaknesses and on whether you think the product is more or less promising than ITMN-191. | 12 |
Appendix H: Abstract/profile 5 | 13; 42 |
Q7: Agent comparison 4 How does ITMN-191 compare to HCV-796, a non-nucleoside NS5B polymerase inhibitor currently in development? Please comment on HCV-796’s relative strengths and weaknesses and on whether you think the product is more or less promising than ITMN-191. Also, HIV specific non nucleoside inhibitors have performed poorly due to high resistance rates; do you see this as a drug class issue? | 13 |
Q8: Potency Consider the following agents: o ITMN-191 (oral NS3-4A serine protease inhibitor) o VX-950 (oral NS3-4A serine protease inhibitor) o SCH 503034 (oral NS3-4A serine protease inhibitor) o R1626 (a nucleoside analog polymerase inhibitor) o HCV-796 (a non-nucleoside NS5B polymerase inhibitor) How do these agents compare in terms of their potency? How significant/clinically important might differences in potency be? Does higher potency necessarily confer a greater benefit or necessarily put one agent at a disadvantage? Please be as detailed and specific in your response as possible. | 13 |
Appendix I: Data comparing drug resistance | 14; 47 |
Q9: Drug resistance Consider potential monotherapy and combination therapies (e.g., with Pegasys) involving the following agents: o ITMN-191 o VX-950 o SCH 503034 o R1626 o HCV-796 How do these agents compare in terms of their potential to produce drug resistant HCV mutations? Which agents appear most promising to you, in terms of their capacity to delay or reduce viral drug resistance? | 14 |
Q10: Toxicity Consider the following agents: o ITMN-191 o VX-950 o SCH 503034 o R1626 o HCV-796 What, if any, safety/tolerability/toxicity concerns might impact the use and adoption of the drugs above? At this stage, which, if any, of the above drugs appears most/least concerning when it comes to drug toxicity? | 16 |
Q11: Stage of development Consider the following: o ITMN-191 (oral NS3-4A serine protease inhibitor): Phase 1a o VX-950 (oral NS3-4A serine protease inhibitor): Phase 2 o SCH 503034 (oral NS3-4A serine protease inhibitor): Phase 2 o R1626 (a nucleoside analog polymerase inhibitor): Phase 2 o HCV-796 (a non-nucleoside NS5B polymerase inhibitor): Phase 2 Comparing ITMN-191 to the other profiled drugs, how important a factor is ITMN’s lag in the drug development cycle? How, if at all, does this impact your enthusiasm for the agent? | 16 |
HCV Discussion - Tier 1 |
 Introduction
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Welcome to this discussion among hepatologists. In this discussion, we will focus on HCV treatments currently in development. These discussions are enhanced when you, as a panelist, not only respond to the posted questions, but also reply to comments made by our moderator and your fellow panelists. We look forward to a lively and interactive discussion. In your participation on this panel, MedPanel expects and requires that you comply with the terms of the Consultant Confidentiality Agreement to which you previously agreed. If you have any questions about the terms of that agreement, please review them through the link provided on your MedPanel home page after you've logged in. Thank you for your time, insight, and consideration. |
Instructions for posting and reading questions and abstracts |
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Q1: Current treatment approaches |
Please describe your current treatment approaches to chronic and acute hepatitis C (HCV). In your answer, please include whether and when you are likely to use interferon monotherapy or combination therapy. What percentage of your patients are treated with interferon and in what percentage is the treatment successful? |
Panelist 4: about 50% of the patients are treated- combination therapy- i no longer rely on monotherapy- about 33% have a sustained response- about 66% respond but later there is relapse when the drug is discontinued |
Panelist 9: I find the response rate in genotype 1 is 50 percent higher in 2 and 3 |
Panelist 10: I have never diagnosed acute hepatitis C. Chronic hepatitis C first requires evaluation for clinical stage and host factors (e.g. depression). If antiviral treatment is feasible, the patient chooses among the reasonable options, usually observation, direct-to-treatment, and liver biopsy for grade and stage. First-time antiviral treatment is always PEG interferon and ribavirin. |
Panelist 10: I never use monotherapy for initial treatment, including for genotypes 2 and 3. Monotherapy is reserved for ribavirin allergic patients, and low-dose chronic maintainance interferon. |
Panelist 9: I treat all patients except decompensated cirrhotics witha pegylated interferon and ribavirin that is those with chronic hepastitis |
Panelist 2: I treat about 40% of patients, always PEG Interferon plus ribavirin |
Panelist 1: Acute Hepatitis C treatment-I will follow RNA levels for 6 months and if infection persists I will initiate combination therapy with Peg-IFN and ribavirin. For chronic Hep C-I will try to treat all patients if they do not my exclusion criteria (active alcohol or drug use, major depression. I will use combination therapy 90% of the time always with interferon. This is successful in 25% of genotype 1 patients. |
Panelist 7: I have no patients on interferon monotherapy. I think the data is clear that combination therapy is better. |
Panelist 7: Approximately 40% of all my hepatitis C patients are on therapy. All of my patients who are on treatment are on combination therapy. |
Panelist 7: Of the patients treated, I am getting about at 80% response for the type 2 and 3s and 33% response for my type 1s. All patients on therapy get combo therapy. |
Panelist 5: I never see an acute hepatitis C as most people. For chronic HCV, monotherapy is used only in patients who can not tolerate or have contraindications to ribavirin. I can recall a patient with sickle cell and many with advanced renal disease. In genotypes 2,3 you probably see response in 80-90% when treated with combination therapy but response in genotype 1 is lower than the 40% reported |
Panelist 8: I do not treat acute HCV. For the chronic HCV, I always start with Copegus and PEgasys. I do not use monotherapy |
Panelist 8: I do not treat acute HCV. For chronic HCV, I will start with Pegasys and copegus. I do not use monotherapy. I treat about 90% of all HCV pts and have about 50% success on ave. |
Panelist 3: I treat chronic hep c with Peg + Ribo Genotype ! for 48 weeks with about a 45% response and other genotypes for 24 weeks with 75-80% complete responses. I have not t4reated acute hep C |
Q2: Unmet needs and treatments in development |
What are your key unmet needs in HCV treatment? What are the most exciting HCV products in development? What is particularly noteworthy about these agents and how could they impact current approaches to chronic and acute HCV treatment? |
Panelist 4: acute hepatitis C is almost never discovered anymore so i only see chronic HCV. Unmet needs are less expensive drugs, oral vs. injection therapy, less side-effects, better efficacy. |
Panelist 10: the prime need is for more often successful therapy for genotype 1. Right behind that is the need for better-tolerated therapy. Better safety, shorter duration, and lower cost would all be desireable. |
Panelist 9: unmet needs are those failures to respond, those with cirrhosis, those with hiv and hep c and those who cannot tolerate therapy |
Panelist 2: We need more effective Rx for Type 1, should get 90% resoponse. Also need oral, easy to administer Rx |
Panelist 1: Unmet needs include treatment for genotype 1 nonresponders. The protease and polymerase inhibitors show promise in the futre but likely in combination with IFN. |
Panelist 7: We still need meds with a lower side effect profile for genotype 1 |
Panelist 5: Unmet needs is the low response to genotype 1 and the long duration of treatment with associated side effects. Protease and polymerase inhibitors seem promising but they are being studied with interferon. |
Panelist 8: I would like to see better SVR rate. I am excited to see the oral formulations |
Panelist 3: better efficacy shorter duration therapy and less side effects. Jury still out but hopefully new protease inhibitors and polymerase inhibitors will be promising |
Panelist 3: There are a number of protease and polymerase inhibitors in pipeline. Albuferon may be a new interferon with less side effects |
Abstract/profile 1: Preclinical Characteristics of ITMN-191, an Orally Active Inhibitor of the HCV NS3/4A Protease Nominated for Preclinical Development |
Q3: Reaction to profile |
What do you think of ITMN-191, an oral NS3/4A serine protease inhibitor? In your answer, please tell us about the main strengths and weaknesses of the product and how these compare to combination therapy with pegylated interferon and ribavirin. |
Panelist 4: sounds very encouraging but this is in very early development-only animal studies to date- if used in humans will it be as efficacious? will there be side-effects? will these be tolerable? many questions needing answers but very encouraging new product |
Panelist 10: I'm not well-acquainted with the specific assays described, and cannot evaluate the abstract summary critically. Taken at face value, the agent is promising, probably as a component or adjuvant therapy, complementary to existing antiviral agents. |
Panelist 9: having an oral agent with a 50 percent response is exciting but hard to believe |
Panelist 1: ITMN-191 appears promising as a treatment for Hep C-strengths include activity againt various mutations, likely to be oral, min CYTO p450 effect. Probably better tolerated than IFN and riba. |
Panelist 5: I am not familiar with the preliminary results |
Panelist 5: It concentrates in the liver and maintains high levels of the drug in the hepatocyte |
Panelist 2: Very encouraging data, need larger studies to confirm |
Panelist 8: I do not have any experience with this medication. However, If it helps to boost SVR when used with PEG interferon and ribavirin, I would use it. |
Panelist 8: I am excited about the data and I think it would be good adjuvent agent for the PEg interferon and Ribavirin combination. |
ITMN191 information from the 42nd Annual EASL meeting |
Please review the document in the new window. If you do not see the window, it may be open and hidden behind other windows, or you may need to click on the highlighted link in the left pane of this window. |
Viral kinetics: Info on ITMN-191 Phase 1a and b studies |
Panelists, the currently running Phase 1a study of ITMN-191 in healthy subjects will conclude in the first half of 2007. ITMN-191 will be evaluated in a Phase 1b randomized, double-blind, placebo controlled, multiple ascending dose study in patients infected with chronic hepatitis C virus. In this study ITMN-191 will be administered to treatment-naive patients for 14 days; the study will also include a cohort of non-responder patients. The product’s manufacturer(s) expect to announce initial viral kinetic results from the Phase 1b trial in the second half of 2007. |
Follow-up ALL: ITMN a promising product? |
According to the discussion, some of ITMN-191’s strengths (based on the information currently available) include its apparent tolerability and potency (including the fact that the drug “concentrates in the liver and maintains high levels of the drug in the hepatocyte”). Is this an accurate assessment of your views? Why or why not? Acknowledging that ITMN-191 is in a very early stage of development and that information on the product’s viral kinetics are not yet available, please tell us why you consider ITMN a promising product. |
Panelist 5: Agree it appears promising with a target for the hepatocyte. Agree it also appears tolerable thus far. |
Panelist 8: Yes! especially with the drug targeting the hepatocyte where it matters the most. |
Panelist 2: The characteristics sound very promising but need more data to show this plays out favorably in Patients. Concentration in the liver could lead to more side effects. |
Panelist 9: its potency and high levels in the hepatocyte are appealing |
Panelist 1: I believe this is an accurate response. Liver concentrations appear high but with good tolerability. |
Panelist 7: High liver levels are good, but there could still be liver toxicity especially in pts taking other drugs that have p450 interactions. |
Panelist 10: to repeat the summary in the document above- toxicology, pharmacokinetic, potency and resistance data are all promising - so far as in vitro data can go. |
Panelist 4: potency is important- tolerability will ultimately determine this drugs fate |
Panelist 3: ITMN maybe a promising product but it is way too early to make assessements other than to say it seems to have efficacy in viral liver cell lines |
Follow-up ALL: Bioavailability in the liver vs. bloodstream |
Panelist 5 notes, “[ITMN-191] concentrates in the liver and maintains high levels of the drug in the hepatocyte.” Meanwhile, panelists 1 and 9 note ITMN-191 would most likely be an oral treatment for HCV. What is the significance of ITMN-191’s bioavailability in the liver (as opposed to the bloodstream)? How might this feature impact ITMN-191 dosing and efficacy? |
Panelist 5: As there is increased liver concentration would expect lower po doses may achieve desired effect with less systemic toxicity. |
Panelist 8: It think high drug concentation at the target organ (i.e the hapatocytes) would provide better effcicacy. |
Panelist 2: This may or may not have clinical significance. We need to await clinical data. |
Panelist 9: by being an oral pill and cooncentrating in the liver it is an ideal candidate foe hepatitis treatment |
Panelist 1: low dosing with high efficacy |
Panelist 10: Specificity in two senses is reported: Uptake (selective? - not stated) by hepatocytes; Little inhibetion of other liver or serum enzymes (I don't know how exhaustive or sufficient the panels were, however). These are useful properties, increasing th separation of therapeutic and toxic doses. |
Panelist 4: the virus is not just in the liver- it is important to get the drug delivered to the liver as it can serve as a reservoir of infection- oral convenience will be important for its use |
Panelist 5: Agree with strengths of potency and ability to concentrate n the liver. In addition, likelihood of resistance (although real) seems diminished. |
Panelist 7: I think it has potential as adjuvant therapy, but I see it as distant 2nd line therapy at best. The results for 1b do not look good |
Panelist 3: too early to say whether this compound is promising but certainly the abstract would suggest that further trials would be warranted |
 Follow-up ALL: Dosing
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What are your thoughts on dosing for ITMN-191? Would you expect a twice-per-day or a three-times-per-day dosing schedule? What, if any, is the signficance of a 2X or 3X dosing schedule on your enthusiasm for the drug? |
Panelist 10: Given its uptake by, and concentration in, hepatocytes, once a day dosing should suffice. |
Panelist 4: I would anticipate once /day dosing based on the data. The more dosing requirements/day, the less compliance by the patients. |
Panelist 1: I would expect twice a day dosing-this is very much preferred over TID for patient compliance |
Panelist 2: I this are of therapy, and the data, once daily dosing should be the goal. Compliance will be greatly diminished with more than twice dail dosing. |
Panelist 9: I would expect once or twice a day dosing based on the data presented |
Panelist 3: the importance of BID or TID dosing relates more importantly to efficacy and side effect issues which are not yet explored in clinical trials |
Panelist 8: The data suggests that once a day dosing would be adequate. 2-3times/day dosing would decrease complaince |
Panelist 3: unclear what this data means in humans and we really cann't compare it to standard of care at this point without further study |
Abstract/profile 2 |
Q4: Agent comparison 1 |
How does ITMN-191 compare to VX-950, an oral NS3-4A serine protease inhibitor currently in development? Please comment of VX-950’s relative strengths and weaknesses and on whether you think the product is more or less promising than ITMN-191. |
Panelist 4: I believe VX950 is more potent and has been already utilized in humans. |
Panelist 10: the data presented are not comparable; the one concerns pharmacokinetic properties (enzyme binding affinity, hepatic uptake etc.), the other concerns viral kinetics. |
Panelist 9: v950 is well tolerated and has been studied in humans. This places it at an advantage over 191 |
Panelist 1: ITMN-191 will likely have less resistance. VX950 strengths include rapid viral suppression but weaknesses include emergence of resistant strains. Not sure which will be better. |
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