Conference Reports for NATAP

EASL 46th Annual Meeting March 30th - April 3rd 2011 Berlin, Germany Back

Brief Recap Report from EASL Liver Conference in Berlin: state of HCV Now- policy, treatment, access       Written by Jules Levin, NATAP   Danka to Berlin & EASL & the deep HCV research & new drug development programs ongoing at many companies. I am leaving Berlin this morning to fly back to NYC & my cat Pixie. Here is a brief recap of this meeting.   This has been a landmark meeting with the leading developments being the oral Late Breaker in the last clinical session late yesterday afternoon where BMS reported 4/11 genotype 1 null responders achieved SVR24 cure with only the 2 oral BMS HCV drugs without peg/rbv - the proof of concept that we can cure at least some patients without peg/rbv, we know now that genotype 1A will not respond as well to therapies coming out in the near future, genotype 1B responds better, in the BMS study and others genotype !a comprised more of the failures. Of the viral failures in that study peg/rbv was quickly added on & all patients responded with undetectable viral load, this was reported in November at AASLD and is equally important. Also, in the study yesterday BMS & Anna Lok reported that using the QUAD therapy of the BMS protease (BMS-650032) + the BMS potent first in class NS5A (BMS-790052) + peg/rbv 9/10 achieved SVR24 cure and the 1 patient had < LLOQ at week 24 post treatment undetectable on retesting 35 days later. BMS reported impressive data on their peg-lambda interferon in a study comparing it to Pegasys with it showing safety benefit and also surprisingly activity benefit as well, the program is moving ahead.   EASL HCV Can Be Cured with Only Oral Therapy: Quadruple Therapy With BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 Weeks Results in 100% SVR12 in HCV Genotype 1 Null Responders: "HCV infection can be cured without interferon & ribavirin: 2 orals BMS790052+BMS650032" - (04/02/11)   EASL: Investigational Compound PEG-Interferon Lambda Achieved Higher Response Rates with Fewer Flu-Like and Musculoskeletal Symptoms and Cytopenias Than PEG-Interferon Alfa in Phase IIb Study of 526 Treatment-Naive Hepatitis C Patients - BMS press release - (04/03/11)   The 2nd major story here is the development of potent nucleotides by the little biotech Pharmasset which appear to have a very high barrier to resistence, so far no resistance seen & this is a key to the success of these drugs. They reported 3 key studies here on PSI-938 & PSI-7977 in combination in genotype 1 patients without peg/rbv where all the patients essentially achieved undetectable in relatively short-term followup, thy reported a nucleotide in combination with peg/rbv which also displayed essentially 100% undetectability in patients in early followup, and they reported the same for genotype 2/3 patients. So taking these 2 developments together, the cure data & the potency of these nucleotides, the meaning is that perhaps we can cure HCV with nucleotide therapy in short term oral combination regimens. Recently, BMS & Pharmasset announced a joint study that will combine the BMSNS5A with a Pharmasset nucleotide, 2 potent drugs expected to perform well together. Events are unfolding in an accelerated way now in HCV drug development coming out of this meeting.   EASL: ONCE DAILY DUAL-NUCLEOTIDE COMBINATION OF PSI-938 AND PSI-7977 PROVIDES 94% HCV RNA < LOD AT DAY 14: FIRST PURINE/PYRIMIDINE CLINICAL COMBINATION DATA (THE NUCLEAR STUDY) - (03/31/11)   EASL: PSI-7977 QD Plus PEG/RBV In HCV GT1: 98% Rapid Virologic Response, Complete Early Virologic Response: The PROTON Study - (03/31/11)   EASL: PROTON Study: PSI-7977 QD with PEG/RBV: 12-week Safety, RVR, cEVR, & SVR12 in Treatment-naïve Patients with HCV GT2 or GT3 - (04/01/11)   EASL: Pharmasset Initiates Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes - (03/31/11)   Of note BMS reported the first SVR12 results in a dose-ranging study of its NS5A inhibitor BMS-790052 where patients received the drug +peg/rbv vs just peg/rbv and the results are impressive with as much as 92% (11/12) receiving BMS-790052 + peg/rbv achieving SVR12 vs 42% (5/12) receiving syandard of care, only peg/rbv).   EASL: First Report of SVR12 for a NS5A Replication Complex Inhibitor, BMS-790052, in Combination With PegIFNα-2a and RBV: Phase IIA Trial in Treatment-Naive HCV Genotype 1 Subjects - (03/31/11)   Roche reported SVR data on their nuke R7128+peg/rbv. Vertex and Merck reported numerous studies on telaprevir & boceprevir regarding IL28B and other data on how the drug will be used in support of the phase 3 studies reported at AASLD in November, the FDA hearing is scheduled for April 2011 & the drugs are expected to be approved. And Pharmasset announced the start of a cutting edge study called ATOMIC which will look at various treatment scenarios. Of particular note because this seemed to go below the radar probably because of all the headline grabbing new developments, is the first-time data reported on low-dose ritonavir boosted danoprevir, the Roche PI. Those of you who have worked in HIV know that boosting a HIV PI with low-dose ritonvir provides much better efficacy compared to unboosted PIS, and although HCV is different in some ways I feel strongly that boosted HCV PIs may provide additional benefits & the data so far supports this. The danoprevir/r results went below the radar but in fact they reported at an oral session in preliminaty data after 12 weeks in null-reponders 88% (14/16) of genotype 1B patients achieved undetectable and 50% (4/8) of genotype 1A. Roche was the first to report combination therapy with 2 oral drugs with the INFORM study but their development program was delayed because of an ALT elevation observation seen with their PI but boosting it with ritonavir lowered the cmax & appears to have resolved that issue & now Roche is moving along quickly with development.   EASL: Activity of danoprevir plus low-dose ritonavir in combination with peginterferon alfa-2a (40KD) plus ribavirin in previous null responders - (04/01/11)   EASL: First SVR data with the nucleoside analogue polymerase inhibitor mericitabine (RG7128) combined with peginterferon/ribavirin in treatment-naive HCV G1/4 patients: interim analysis from the JUMP-C trial - (04/03/11)   Of particular note was the phase 2B oral presentation Novartis' investigational oral agent alisporivir (DEBO25) + peg/rbv in genotype 1 naives with a 76% SVR rate compared to 55% for the peg./rbv arm. A phase 3 study in gentotype 1 naives is underway. Alisporivir is the first in a new class of drugs called cyclophilin inhibitors. Unlike other compounds in development that target the hepatitis C virus directly, alispirovir, targets host proteins that the hepatitis C virus uses for replication. This therapy has particular appeal because not only does resistance appear hard to develop one does not expect any cross-resistance to other classes of HCV drugs so if it were available today & a patient tried it & failed they could go out & take a protease without having to worry about resistance. A study in nonresponders is planned as I spoke with company officials. A Phase IIb trial looking at the potential of the agent in HCV patients with genotypes 2 and 3 is underway. The host proteins are needed for replication in all types of HCV infection so there is potential for the agent to have broad activity; there are six variations of HCV.   EASL: Once daily alisporivir (DEB025) plus Peg-IFN-alfa-2A/ ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment-naïve patients - The ESSENTIAL study - (03/31/11)   EASL: Once daily alisporivir (DEB025) plus Peg-IFN-alfa-2A/ ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment-naïve patients - The ESSENTIAL study - (03/31/11)   Tibotec had a few presentations on their once daily TMC435 protease but as they have already entered Phase 3 having shown an impressive 84% SVRs in naives in phase 2 & are on a fast track to get to the market their presentations here included IL28B data and a couple of other posters, the ASPIRE Studywith preliminary data in nonresponders which is posted on the NATAP.org website and a poster of 5 patients treated with TMC435 monotherapy & retreated with TMC435 & peg/rbv showing they were at least in short-term followup able to reach undetectable.   EASL: The ASPIRE Trial: TMC435 in treatment-experienced patients with genotype 1 HCV infection who have failed previous PegIFN/RBV treatment: Week 24 interim analysis - (04/01/11)   Medivir Announces Positive Phase 2b 48-week (SVR24) Interim Results of TMC435 in Treatment-Naive Patients Chronically Infected With Genotype-1 Hepatitis C Virus - (02/22/11)   Tibotec Starts Global Phase 3 Clinical Trials Studying TMC435 in Adults With Chronic Genotype 1 HCV - (02/22/11)   Medivir Kicks Off Phase 1a Trial of the Hepatitis C Polymerase Inhibitor TMC649128 - (02/17/11)   Boerhinger Ingelheim reported phase 2 data on their protease inhibitor BI201335 plus peg/rbv in naives & treatment-experienced and announced publicly they are starting phase 3. They have a NNRTI as well.   EASL: SILEN-C1: sustained virological response (SVR) and safety of BI 201335 combined with peginterferon alfa 2a and ribavirin (PegIFN/RBV) in treatment-naïve patients with chronic genotype-1 HCV infection - (04/01/11)   EASL: SILEN-C2: sustained virological response (SVR) and safety of BI 201335 combined with peginterferon alfa 2a and ribavirin (PegIFN/RBV) in chronic HCV genotype-1 patients with nonresponse to PegIFN/RBV - (04/01/11)   Presidio had a poster on their NS%A development program here and issued this announcement about the clinical efficacy of their lead candidate PPI-461 in patients in an ongoing study:   EASL: Presidio Pharmaceuticals, Inc. Announces Positive Results in a Phase 1b Clinical Trial of PPI-461, a Novel, Potent Broadly-Active Hepatitis C Virus (HCV) Inhibitor - (03/30/11)   Drug development for HCV is moving up to the next level. At the meeting many companies reported important new study results. Second generation protease inhibitors are moving along but still in earlier development stages as they look like they will provide a higher barrier to resistance and have perhaps activity against some of the mutations the early generation PIs are associated with. There are several more NS5A inhibitors in development by several companies in the wake of the potent first in class by BMS. Abbott reported here clinical data in patients on their potent looking 2nd generation protease inhibitor (ABT-450) that will be boosted by low-dose ritonavir which like in HIV boosted protease inhibitors appears to give this drug added potency & resistance benefits so this PI may be able be very useful. Abbott has NNRTIs and has reported on them previously but reported here on preclinical data on their own NS5A so now Abbott has 3 classes of oral HCV drugs. Intermune reported on a 2nd generation protease that Roche is developing that appears to be active against the key protease mutation 155, and Intermune also reported for the first time on their own NS5A inhibitor. Gilead reported a breathtaking 24 presentations here, this was their coming out party, as they reported followup clinical data on their QUAD, their protease+NNRTI+peg/rbv with patients all undetectable in the followup. Gilead also revealed the many new drugs they are developing in multiple classes including additional protease inhibitor, their own nucleotide, in the wake of Pharmasset's very successful nucleotides, their own NS5A inhibitor, so Gilead now has several drugs in several different drug classes. And Gilead reported on a TLR7 inhibitor which appears to be active against HBV & HCV, so this immune-based type of therapy may bring a new dimension to HBV therapy. GSK has now entered the field, they reported here on their 2 new drugs, a NS5B polymerase inhibitor GSK248585 and GSK2336805, a NS5A inhibitor.   As mentioned above it appears that patients with genotype 1a and we now know CT & TT patients do not do as well. So a patient can test to see if they are CC, CT or TT and also if they are genotype 1A or 1B. Being 1A is anindication that response to therapy may not be as good, as we have now seen in several studies with lower SVR rates observed in 1As, and also we see that CT & TT patients don't do as well as CC patients in terms of SVR rates. So these appear to be considerations in treatment decision making.   As I have been saying for a while now I expect we will be able in theory to cure all patients with HCV except for those who may be too sick. We are now moving to the next level of drug development where 1 oral HCV drug+peg/rbv is not enough, we need mutltiple oral HCV drugs in a regimen with or without peg/rbv. Some studies plan to look at 2 orals+RBV without pegIFN and some studies will obviously look at multiple oral drugs without peg/rbv. The future of HCV therapy, what we need to move to now, is multiple oral HCV drugs, 2 -4 in regimens.   The issue of drug resistance has evolved to another level. The majority opinion that appears to have emerged at this meeting of EASL and many leading academic & industry researchers and industry virologists said publicly & privately at this meeting that resistance will not be a problem, it will disappear after 1.5 to 2 years, as evidenced in the study reported here by Vertex on telaprevir, and I reported the slides report on the NATAP website, so you can re-treat with the very same protease inhibitor after having failed it with resistance mutations emerging, they said you will be able to get at least a coulple of logs, some level of good antiviral activity from the drug, maybe not full activity so you can re-use it in combination with other classes of oral drugs. To support that Tibotec reported here, which I believe was the same 5 patients previously reported, they retreated 5 patients who had received TMC435 monotherapy with TMC435+peg/rbv and in the short-term they achieved undetectable viral load. There is a minority opinion here including me and other virologists & researchers who feel strongly we do not know yet if this is true, and this is the case. The majority opinion is only an opinion we do not know what will happen in the future. The worst case scenario is virologically failing patients remain on failing therapy and accumulate mutations & compensatory mutations which do not disappear or they disappear by a insensitive test and reappear after re-using a protease, which is what happens in HIV, which renders the PI in HIV not useful. The telaprevir-Vertex resistance study I mention above used resistance testing that could only measure down to 20% of mutations so resistance of less than 20% could not be seen, they did not evaluate with other more sensitive testing. The Tibotec example also can be undercut because the peg/rbv could have been doing all the work. The only way to know for sure if you can re-use a protease 2 years later after resistance had disappeared by standard testing is to do a clinical study in patients who actually experienced viral failure and mutations emerged and wait & retreat them. This type of study is not easy to design & implement but without such a study you cannot answer this question and to say you know patients can be re-treated and the protease can in fact cause a log reduction by itself is just an opinion, and frankly I think not very scientific.   Another issue being discussed in the wake on much data reported here on how IL28B affects treatment outcomes with peg/rbv, and triple therapy with an oral HCV protease+peg/rbv is what is the real usefulness of IL28B testing & how it will be used by clinicians & treaters and of note payers in the USA & most crucially in europe where payers are likely to be more stingy in support of boceprevir & telaprevir use with peg/rbv. There was at this EASL to me surprisingly quite a lot of talk about using a lead-in of peg/rbv to block use of boceprevir or telaprevir, in the sense that if a patient had a good peg/rbv response at week 4 they could continue peg/rbv and NOT add boceprevir or telaprevir. I do not think that scenario is in the best interest of patient outcomes & do not think this will be implemented in the USA. In the USA I think payers will appreciate the cost-effectiveness of using the best treatment and using an oral PI plus peg/rbv provides the best opportunity for patients to achieve SVR and to shorten duration, remember that in genotype 1 48 weeks remains the duration standard of care and adding the protease increases the number of patients achieving SVR and can shorten duration of therapy to 24 weeks, which obviously is a major benefit.   At EASL there was a panel discussion on global HCV, participating on the panel were Jake Liang from the US NIH and John Ward from the US CDC and a someone from WHO. I went to the mic and asked what the prospects are for funding, money, from the US federal government and they did not provide any information suggesting money will be provided. The HHS HCV Strategy plan is expected to be publicly unveiled in May but there was no indication from this panel or from any source I know that actual money will be allocated to HCV. There are no large-scales HCV testing & screening programs from the fed, the states or from cities. There is no discussion that I know of that addresses large scale care in HCV, as in HIV there is the Ryan White Care Act. There is a difference between HIV & HCV, granted, but some HCV spending & programs would be appropriate. I have been working in policy on HCV since 1999 statewide, city & federal and there has never been any federal funding for HCV of any significant magnitude and in general states have not done very much although more recently thanks to HCV activists in NY recent NY State Budgets have included a few million dollars for HCV. I estimate as many as 8 million people in the USA have HCV, which is much higher than the 3-5-4 million from the CDC & 5 million from Brian Edlin, in large part because of potentially high rates of HCV-infection of immigrants to the USA, who are prevalent in high numbers in major urban areas. Perhaps due to this last point there might be as many as 750,000 in NYC with HCV. Immigrant communities include Russians, various Asian communities, Africans, immigrants from various Indian peninsula countries and of course China.   The key oral presentations have already been reported by NATAP to the listserve in real-time from the conference & are mostly already posted on the NATAP.org website. All of these additional new drugs & studies I discussed above will be reported on the NATAP website & to the listserve very soon.   Jules Levin http://www.natap.org   Eurpopean Association for the Study of the Liver March 30th - April 3rd 2011 Berlin, Germany