Rapid report: state of HCV policy, treatment, access
Jules Levin, NATAP
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 non-responders achieved SVR24 cure using only the two oral BMS HCV drugs (the protease inhibitor BMS-650032 and the NS5A inhibitor BMS-790052). 
This was proof of concept that we can cure at least some patients without PEG-IFN and ribavirin.
We know 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-1a comprised more of the failures.
Patients with viral failure quickly added PEG-IFN plus ribavirin and all responded with undetectable HCV viral load. This was reported in November 2010 at American Association for the Study of Liver Diseases conference (AASLD) and is equally important. BMS also reported that using the QUAD therapy (BMS-650032, BMS-790052 plus PEG-IFN and ribavirin) 9/10 patients achieved SVR24 cure and the outlying patient had <LLOQ at week 24 post treatment undetectable on retesting 35 days later.
BMS also 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 programme is moving ahead. 
The second major story at EASL was the development of potent nucleotides by the small biotech company Pharmasset that appear to have a high barrier to resistance. So far no resistance has been seen and this is a key to the success of these drugs. Pharmasset reported three studies on PSI-938 and PSI-7977 in combination without PEG-IFN and ribavirin in patients with genotype-1. More than 90% patients essentially achieved undetectable over relatively short-term follow up. 
They also reported a nucleotide in combination with PEG-IFN and ribavirin that also displayed essentially 100% undetectability in patients in early follow up, and they reported similar results for people with genotype 2 and 3. [4, 5]
Taking these two developments together, the cure data and the potency of these nucleotides, we can perhaps cure HCV with nucleotide therapy using 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.
BMS also reported the first SVR12 results in a dose-ranging study of its NS5A inhibitor BMS-790052 plus PEG-INF plus ribavirin vs PEG-INF plus ribavirin. SVR12 were 92% (11/12) receiving BMS-790052 vs 42% (5/12) receiving standard of care. 
Roche reported SVR data on their ritonavir-boosted HCV protease inhibitor danoprevir (RG7227) and on their nucleoside analogue polymerase inhibitor mericitabine (RG7128), both used in combination with PEG-IFN plus ribavirin. [7, 8]
Of particular note, this is the first-time data reported on low-dose ritonavir boosting danoprevir. In with HIV protease inhibitors, ritonavir-boosting provides better efficacy compared to unboosted PIs, and although HCV is different boosted HCV PIs may provide additional benefits.
The danoprevir/r results were under-reported due to many other headline studies but preliminary data after 12 weeks in null-responders reported undetectable viral load in 88% (14/16) of genotype-1b patients and 50% (4/8) of genotype 1a. Roche was the first company to report combination therapy with two oral drugs with the INFORM study but their development programme was delayed because of an ALT elevation observation seen with their PI. Ritonavir-boosting lowers the Cmax and appears to have resolved that issue development is continuing.
Numerous studies were reported by Vertex on telaprevir and by Merck on 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 and both drugs are expected to be approved.
Pharmasset announced the start of a cutting edge study called Atomic which will look at various treatment schedules. 
Novartis presented SVR rates in a phase 2b study of a non-immunosuppressive cyclosporine-A derivative called alisporivir (DEBO25) used with PEG-IFN plus ribavirin in genotype-1 treatment-naive patients of 76% rate compared to 55% for the PEG-IFN plus ribavirin. 
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 but cross-resistance to other classes of HCV drugs is unlikely. This increases options for non-responders who could use other experimental compounds. A phase 3 study in gentotype 1 naives is underway and study in non-responders is also planned. A Phase 2b trial looking at the potential of the agent in HCV patients with genotypes 2 and 3 is also 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 in all six variations of HCV.
Tibotec had a few presentations on their once daily TMC435 protease inhibitor but as they have already entered Phase 3 having shown an impressive 84% SVRs in treatment-naive patients in phase 2 and are on a fast track to get to the market. These included IL28B data and a couple of other posters including the ASPIRE Study with preliminary data in nonresponders and a poster of five patients treated with TMC435 monotherapy & retreated with TMC435 plus PEG-IFN and ribavirin showing they were at least in short-term followup able to reach undetectable. [11, 12, 13, 14]
Boerhinger Ingelheim reported phase 2 data on their protease inhibitor BI201335 plus PEG-IRN plus ribavirin in naives & treatment-experienced and announced publicly they are starting phase 3. 
Presidio had a poster on their NS5A development programme and issued an announcement about the clinical efficacy of their lead candidate PPI-461 in patients in an ongoing study. 
Drug development for hepatitis C is moving up to the next level.
At the meeting many companies reported important new study results. Second generation protease inhibitors are progressing but are still in earlier development stages. They will hopefully provide a higher barrier to resistance and have perhaps activity against some of the mutations the early generation PIs are associated with.
New NS5A inhibitors are in development by several companies in the wake of the potent first in class by BMS. Abbott reported clinical data in patients on their potent looking second-generation protease inhibitor (ABT-450) that will be boosted by low-dose ritonavir. Abbott also has NNRTIs and has reported on them previously but reported here on preclinical data on their own NS5A. So Abbott now has three classes of oral HCV drugs.
Intermune reported on a second-generation protease in development with Roche 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 24 presentations at the meeting. This was their coming out party, as they reported follow-up clinical data on their four-drug combination of protease, NNRTI, PEG-IFN plus ribavirin, with all patients becoming undetectable in the follow up. Gilead also revealed the many new drugs they are developing in multiple classes including additional protease inhibitor, their own nucleotide and NS5A inhibitor. So Gilead now has several drugs in several different drug classes. And Gilead also reported on a TLR7 inhibitor that appears to be active against both hepatitis B and C, so this immune-based type of therapy may bring a new dimension to HBV therapy.
GSK has also entered the field. They reported here on two new drugs, a NS5B polymerase inhibitor GSK248585 and GSK2336805, a NS5A inhibitor.
Patients with genotype 1a and IL28 CT and TT 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. Genotype 1a is an indication that response to therapy may not be as good, with lower SVR rates observed in several studies. Also CT & TT patients dont do as well as CC patients in terms of SVR rates, so these appear to be important considerations in treatment decision-making.
The expectation is that we will be able in theory to cure HCV in all patients except for those who may be too sick. We are now moving to the next level of drug development where one oral HCV drug plus PEG-IFN and ribavirin is not enough. We need multiple oral HCV drugs in a regimen with or without PEG-IFN and ribavirin. The range of studies is currently looking at a broad range of approaches.
Drug resistance has also evolved to another level. The majority opinion emerging at EASL amongst leading academic and industry researchers, publicly and privately, is that resistance will not be a problem. Resistance is hoped to disappear after 1.5 to 2 years, as evidenced in the study reported here by Vertex on telaprevir. This would enable people to re-treat with the same protease inhibitor in combination with other classes of oral drugs, after having failed it with resistance mutations. To support this hope Tibotec reported retreating five patients who had received TMC435 monotherapy with TMC435 plus PEG-IFN and ribavirin and in the short-term they achieved undetectable viral load.
There is however a significant minority opinion who feel strongly that we do not yet know yet if this is true. Here it is important to stress that the majority view 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 and compensatory mutations that do not disappear or they disappear by a insensitive test and reappear after re-using a protease, as in HIV.
The telaprevir-Vertex resistance study above used resistance testing that had a population sensitivity cut-off of 20%, so resistance of less than 20% could not be seen. The Tibotec example also can be undercut because the PEG-IFN plus ribavirin could have been doing all the work. This can only be demonstrated in clinical studies of recycling compounds in people with treatment failure. This type of study is not easy to design and implement.
Another issue being discussed in the wake on much data reported here on how IL28B affects treatment outcomes. Surprisingly, there was a lot of talk about using a lead-in of PEG-IFN and ribavirin to block use of boceprevir or telaprevir in Europe, in the sense that if a patient had a good PEG-IFN and ribavirin response at week 4, they could continue on this and not add boceprevir or telaprevir. This scenario is not in the best interest of patient outcomes as treatment would still be 48 rather than 24 weeks.
At panel discussion on global HCV included Jake Liang from the US NIH and John Ward from the US CDC who did not provide any information suggesting US federal government money will be provided. The HHS HCV Strategy plan is expected to be publicly unveiled in May. There are no federal, state or city large-scale HCV testing & screening programmes. There are no discussions that address large-scale care in HCV, similar to the Ryan White Care Act for HIV.
This year EASL as significant in terms of a change in direction for the management of HCV as the World AIDS Conference in Vancouver 1996 was for the management of HIV. 2011 is the year that heralds triple combination therapy for difficult to manage genotype 1 HCV infection. At a preliminary FDA hearing at the end of April 2011, both first-generation NS3/4 protease inhibitors that have completed phase 3 studies (boceprevir from Merck and telaprevir from Vertex/Jannsen-Cilag) received unanimous support from the FDA expert panel and will shortly receive formal FDA approval for treatment in combination with PEG-IFN and ribavirin for genotype 1 HCV infection.
There are, however, a number of unanswered questions for these two drugs. These included whether it will be possible to use a shorter duration of treatment for all patients or will some groups need to use response-guided lengths of therapy? How will clinicians manage the complexities of response-guided therapy? Will virology laboratories manage to turn around HCV viral load results in time? How will we mange potential side effects in clinical practice (anaemia for boceprevir, rash for telaprevir)?
In addition to these, the questions surrounding the emergence of resistance mutations and their significance for future treatment options remain unanswered. Although data from both boceprevir and telaprevir studies suggest that the majority of mutations disappear by 2-3 years post therapy, the potential re-emergence and cross-resistance with the use of second- and third-generation PIs thereby reducing the efficacy of future PI-containing treatment options remains a concern for some.
Whilst we grapple with these issues and learn how to use the first-generation NS3/4 inhibitors, a plethora of other DAAsPIs, NS5b polymerase inhibitors (both nucleosides and non-nucleosides) and a few NS5a inhibitorsare getting ready to go into phase 3 studies. The next question that whether PEG-IFN and ribavirin can still be considered as standard-of-care therapy for genotype 1 HCV infection?
For HIV doctors treating co-infected patients, although there is some preliminary data with telaprevir in triple combination (CROI 2011), data with boceprevir is yet to be presented. Over the next months, whilst we wait further data and formal approval of the first two anti-HCV protease inhibitors, the key issue to consider is who should we treat now with PEG-IFN and ribavirin and who should wait for triple therapy?
Unless stated otherwise reports and links are to natap.org. Many of these reports include a selection of presentation slides.
- Lok A et al. HCV cured without peginterferon/ribavirin with two oral HCV drugs.
- 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. (03 April 2011).
- Lawitz E et al. 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).
- Nelson DR et al. PSI-7977 QD plus PEG/RBV in HCV GT1: 98% rapid virologic response, complete early virologic response: the PROTON study.
- Larezari J et al. PROTON study: PSI-7977 QD with PEG/RBV: 12-week safety, RVR, cEVR, & SVR12 in treatment-na patients with HCV GT2 or GT3.
- Pol S et al. First report of SVR12 for a NS5A replication complex inhibitor, BMS-790052, in combination with pegIFNa-2a and RBV: phase IIA trial in treatment-naive HCV genotype 1 subjects.
- Rouzier R et al. Activity of danoprevir plus low-dose ritonavir in combination with peginterferon alfa-2a (40KD) plus ribavirin in previous null responders.
- Pokros P et al. 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.
- Pharmasset initiates phase 2b ATOMIC trial of PSI-7977 for multiple HCV genotypes. Pharmasset press release. (30 March 2011).
- Flisiak R et al. Once daily alisporivir (DEB025) plus Peg-IFN-alfa-2A/ ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment-na patients – The ESSENTIAL study.
- Zeuzem S et al. The ASPIRE Trial: TMC435 in treatment-experienced patients with genotype 1 HCV infection who have failed previous PegIFN/RBV treatment: Week 24 interim analysis.
- Medivir announces positive phase 2b 48-week (SVR24) interim results of TMC435 in treatment-naive patients chronically infected with genotype-1 hepatitis C virus. Medvir press release. (22 February 2011).
- Tibotec starts global phase 3 clinical trials studying TMC435 in adults with chronic genotype 1 HCV. Tibotec press release. (18 February 2011).
- Medivir kiicks off phase 1a trial of the hepatitis C polymerase inhibitor TMC649128. Medvir press release. (16 February 2011).
- Sulkowski M et al. SILEN-C1: sustained virological response (SVR) and safety of BI 201335 combined with peginterferon alfa 2a and ribavirin (PegIFN/RBV) in treatment-na patients with chronic genotype-1 HCV infection.
- 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. Presido press release.