"Using a new palette of treatment options for HCV

"Using a new palette of treatment options to paint the portrait of cure for patients infected with hepatitis C on our clinical canvas."

EASL 2009 Copenhagen April 23-26 2009

Robert Gish MD

CPMC- Department of transplantation and Division of Hepatology and Complex GI, California Pacific Medical Center, San Francisco, CA

INTRODUCTION: Current treatment of hepatitis C is both exciting and fraught with frustrations. The current cure rate, after a course of pegylated interferon therapy, is between 40 and 90% and is dependent on many factors, including hepatitis C virus (HCV) genotype, treatment tolerance, the use of full doses of pegylated interferon and optimal doses of ribavirin, as well as completion of treatment with full adherence and compliance with the recommended treatment instructions as per treatment guidelines. Key factors in predicting who will have further on-treatment response and who will ultimately obtain a sustained viral response (SVR) include baseline viral load, and the level of fibrosis prior to therapy, as well as on-treatment viral response at 4 weeks. Currently, we comfortably use the phrase “SVR” synonymously with a cure in most patients, recognizing that there are a few manuscripts in the literature where this question of "cure" is being further investigated. Importantly, most clinicians, practitioners and researchers believe that most patients with this RNA virus, which does not integrate into the host genome, is capable of being cleared from all compartments of infection within the human body.

EASL 2009: The recent meeting in Copenhagen was blessed with clear skies, favorable weather, and blooming trees and flowers as well as a panoply of new therapeutic options that were either entering the pre-clinical stage or phase I, II or III trials for hepatitis C. The purpose of this review is to place the general groups of new treatment options into perspective and discuss specific new therapies as well as to place these emerging treatments into a structure where we can map out how to manage your patients over the next 3-5 years. We also, hopefully, can communicate to our colleagues and patients that there is substantial hope for increasing cure rates, providing a shorter duration of therapy, or both with only a modest (if any) increase in toxicity, side effects or complexity of care. We are currently hearing the song “Should I stay or should I go” with the revised lyrics “Should I stay on course and plan on immediate therapy or should I delay treatment and wait for future treatment options that may evolve in the next 2-5 years?”. Clearly, for some patients, treatment will eventually progress toward both interferon- and ribavirin-free therapy. I do believe, however, as do most clinical investigators, that interferon will be here for the short and intermediate term, although we may be able to bring about incremental dose reductions in interferon and ribavirin as powerful new targeted therapies enter our armamentarium. Each day in the clinic, we are having dialogue with both our patients and our colleagues regarding whether we should "warehouse the patient” pending emergence of these new treatment options, or should instead treat in the near term and then assess treatment responses at 4 weeks (or less) in order to determine whether to terminate therapy or to continue. This rapid virological response (RVR) rule allows us to accurately select many patients who can obtain a substantial chance at SVR. Bringing this treatment rule into a new perspective was a paper by Holland that measured virus at 48 hours to predict RVR. Motivated patients with advanced disease (stage 3-6 by Ishak fibrosis score) and no evidence of liver decompensation clearly form a subset of patients who will be more interested in initiating therapy immediately with the current standard of care. When offered very early stopping rules, patients often gain even further motivation based on their understanding that they will not be faced with 24 or 48 weeks of therapy that may end up being futile. This early response rule provides an immediate motivation to start therapy for many patients. Conversely, we have been offering slow responders to therapy the option to continue therapy for as long as 72 weeks in order to increase cure rates, based on multiple past publications. An important paper by Buti, et. al., at this meeting demonstrated that prolonged therapy to 72 weeks did not result in an increased SVR rate and brought into question whether we should be continuing therapy for 72 weeks, even in patients who have mid to late on-treatment response. Also, from the EPIC 3 study, presented by Bruix et al, we gained further confirmation (complementing the HALT- C study) that maintenance therapy has minimal or no role in treating patients in general who are non-responders.

NEW SMALL MOLECULES:
As was highlighted at this meeting by NATAP, there are over 25 STAT-C medications in clinical development. The two small molecules in the STAT-C group that are likely to reach clinical practice by 2011 are telaprevir (Vertex) and boceprevir (Schering-Plough). The next group of protease inhibitors includes the compound R7227 (also known as ITMN-191) which Roche is developing with InterMune. Further adding to the Roche armamentarium is the nucleoside polymerase inhibitor R7128 which is being developed with Pharmasset. In the late breaker session at EASL, Gane et al presented results of the phase I study INFORM-1, showing that the combination of these two oral medications (the protease R7227 with the polymerase nucleoside R7128) resulted in significant HCV viral load reduction. This was an important proof-of-concept study, showing at least short-term efficacy and safety with an exclusively oral combination.
[Gane EJ, Roberts SK, Stedman C, et al. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009. Late-breaker Abstract 1046.]

If other compounds, such as PSI 7851, Pharmasset?s second generation nucleotide polymerase inhibitor, could be brought forth early and quickly, as well, we will have even more options by 2014 or sooner. Additional protease compounds such as Merck?s MK-7009, Boehringer Ingelheim?s BI 201355, and Schering-Plough?s SCH 900518 all showed substantial possibilities of therapeutic benefit in either animal models or early phase I studies. Abbott and Enanta are moving towards a model of once-a-day therapy, as is the current standard for HIV treatment, with their protease inhibitors EA-058 and EA-063. Tibotec?s TMC435 is in early study in patients and is also once-daily.

Additional polymerase NRTI/NNRTI inhibitors are in development by a number of companies, including Pfizer, Idenix, Anadys, Vertex/ViroChem, ViroPharma/Wyeth, Boehringer Ingelheim, Merck, GeneLabs/GSK, and Gilead, using either every 12 or every 24 hour dosing, with what appears in early development to be more favorable side effects profiles with less resistance and predictors of non-overlapping resistance profiles.

Advances in immunomodulation include a series of new compounds that are being looked at that enhance one or more components of the human immune response that targets HCV infection. These new compounds have the potential for similar or improved side effect profiles and less frequent dosing. These molecules include pegylated lambda interferon, a controlled release interferon (Locteron), and an interferon variant, albinterferon alfa-2b (Albuferon), a genetic fusion polypeptide of albumin and interferon alfa-2b. Albuferon has completed large phase III studies, known as ACHIEVE 1 and ACHIEVE 2/3, in which albinterferon alfa-2b given every two weeks was compared to weekly peginterferon alfa-2a, both in combination with ribavirin. The data reported at EASL showed non-inferiority and similar adverse events with the two drugs, and submission for approval by the FDA is expected in the near term. Biolex Therapeutics? Locteron, a controlled-release interferon alpha 2b, has completed its phase 2a PLUS trial in which it was compared to PEG-Intron. Locteron was given on a once-every-two week dosing schedule compared to the once weekly schedule for PEG-Intron, with both drugs accompanied by ribavirin. The initial trial results reported at EASL showed comparable viral load suppression. Flu-like symptoms were reported to be less frequent and milder in patients receiving Locteron. ZymoGenetics reported results on its phase 1a trial with PEG-interferon lambda. Neither fever, fatigue, insomnia, irritability, injection site pain, nor significant hematologic changes, including neutropenia, were observed at any dose level tested. Reversible liver enzyme and bilirubin increases were noted at higher doses. There is ongoing research with other medications with immunomodulating effects, including nitazoxanide, IV silibinin (a silymarin derivative) and cyclophilin inhibitors, such as Debio 025, NIM811 and SCY-635. With further product improvement and teasing out key clinical information, these products may also enter into partnerships with STAT-C molecules and decrease or eliminate the need for interferon/ribavirin-based therapies. Importantly, if we can obtain profound suppression with minimal resistance with 2 oral STAT-C medications, these newer immunomodulatory medications may be able to arrive on the "scene" of the infected hepatocyte while also attacking in extrahepatic locations of replication or sanctuaries, thus performing a "mop-up" of viral infection and allowing high SVR rates. Hopefully, these compounds will ultimately allow us to clear virus in a great majority of patients, with a much lower impact on quality of life that will allow for high rates of full employment and maintenance of normal activities of daily living. Ribavirin and oral ribavirin analogues that allow increased exposure in the hepatocyte compartment would allow lower systemic blood levels and lower rates of anemia. Taribavirin is such a molecule and data at EASL demonstrated the potential role this medication may have in sparing patients anemia and possibly allowing for a beneficial partnership with STAT-C molecules. This may be particularly important for STAT-C molecules that demonstrated significant bone marrow suppression with anemia such as boceprevir.

Additional classes of medications include the Progenics? entry inhibitor PRO206 and Bristol-Myers Squibb?s BMS-790052, a first-in-class NS5A inhibitor. Such medications are going to potentially provide further enhancement of our arsenal of weapons to fight hepatitis C. Studies using various combinations of direct nucleoside polymerase inhibitors, non “nuke” polymerase inhibitors and other small molecules targeted at the HCV protease protein, both NS3 and NS3-4A, may lead to further exciting advances for managing our hepatitis C patients, hopefully, by 2015.

NATAP: EASL 44th Annual Meeting (European Association for the Study of the Liver)

April 22-26, 2009
Copenhagen, Denmark

REGULATORY ENVIRONMENT:

Within our new millennium of drug development, in the U.S. and worldwide, dialogue with regulatory authorities emphasizes an almost zero tolerance for risks with an emphasis on the highest possible safety level while still espousing the need for an accelerated approach to medication development. The potential for conflict between these two goals has led to a substantial level of drug development, including combination therapy, moving off shore. With 2 oral medications appearing to dominate the new concept of drug development for HCV, it is disappointing that all of these studies are being performed outside the U.S. The INFORM-1 study was an example of this new development and was probably the most exciting abstract presented at EASL in the clinical domain. As mentioned above, this study, in process in New Zealand, showed very high on-treatment response rates at two weeks using a protease and polymerase inhibitor as a pair without any interferon or ribavirin exposure.
The natural history of hepatitis C is a rainbow disease state that includes many individuals who never develop advanced disease in their lifetimes and thus, are never at risk of developing cirrhosis or cancer or of needing a liver transplant. There is a subset of these HCV-infected patients who are symptomatic based on the presence of circulating hepatitis C immune complexes or other inflammatory reactions. These HCV-related effects are difficult to quantify and documenting the association level between hepatitis C and somatic symptoms has been difficult and elusive. Thus, the impression that HCV treatment is non-urgent inhibits the energy at a regulatory level to support accelerated drug discovery, research and regulatory approval. Unfortunately, 40,000 people die of endstage liver disease each year in the US, with HCV being a major contributor to this mortality rate. Nearly 7,000 patients undergo costly liver transplants in the U.S. each year, with more than half of the adults receiving these transplants requiring them as the result of chronic hepatitis C infection. The current and predicted costs of HCV infection have been well documented in the medical literature. Rates of hepatitis C-induced cirrhosis and liver cancer are accelerating as the disease matures, and these patients are much more difficult to treat. The challenge in managing these patients includes a lower SVR rate, enhanced symptoms and enhanced toxicity. This is a very important group that should be at the forefront of activities and activism to signal the regulatory authorities that we are spending huge amounts of money on managing liver failure, liver transplants and liver cancer each year, much of which might be avoided with early and effective HCV treatment. In the near term, the cycle needs to be broken. Other special groups include African-Americans, who appear to have a lower response rate to interferon-based therapies, and hepatitis C/HIV coinfected individuals and other immunosuppressed individuals who also have a lower response rate to interferon/ribavirin therapy, with higher toxicity. Importantly, after liver transplant, more than half of patients have cirrhosis in 10 years. This is double the rate of cirrhosis in a non-transplant population and decreases the time period to develop cirrhosis by 50-80% because of the immunosuppressed setting and probable interactions with the allograft and host immune system. This is an urgent medical problem that should support accelerated drug development in the US to parallel other efforts worldwide.

A discussion about the U.S. hepatitis C burden also took place during the EASL meeting and looked at individuals who are infected and undiagnosed, diagnosed and untreated, actively being treated, and defined as treatment failures. Although many publications estimate the current infection rate in the U.S. as 5,000,000, this publication started with a much more conservative estimate of 2.7 million infected and then derived their model that identified that nearly 600,000 individuals have failed pegylated interferon/ribavirin treatment in the US patient population. This study by Jang and his colleagues at Johnson & Johnson highlighted that the reduction of infections by the introduction of STAT-C molecules would markedly decrease the incidence of new cases of chronic hepatitis C infection, as well as decrease the prevalence of current HCV disease, thus markedly decreasing the development of advanced liver disease incidence over time and ultimately culminating in a marked decrease in mortality. This data provides an even greater motivation for developing and rapidly bringing to market new therapies for hepatitis C.

The treatment boneyard

A variety of compounds including NM283, which was stopped due to GI toxicity and R1626, which was stopped due to bone marrow suppression, highlight the hazards of drug development. VX796 treatment was stopped due to the documented risk of hepatotoxicity, as was a Gilead polymerase compound that led to renal problems, identifying that there may be a variety of “class effects” for drug toxicity that may include bone marrow toxicity, renal toxicity, as well as GI problems that may present as pancreatitis, A variety of both new and known side effects are being identified in phase I and II studies with the new HCV compounds. These toxicities are concerns that will add additional complexities to managing our HCV patients over time. Hopefully, with appropriate clinical and pre-clinical homework, the graveyard for hepatitis C small molecules and other classes of compounds will remain relatively small, and the majority of medications will be able to reach our clinical practice within the next decade.

Back to the Future

Painting an exceptionally bright picture was easy for the field of HCV treatment as we place the many colors of treatment on our art easel. We hope to move from the current “still life” to an active 3 D movie where we can continue our “Battle for the Terra of HCV infections” I think that with all of these compounds in development, it behooves us to enhance the education of all of our colleagues who are managing hepatitis C in the liver disease space, because as we add new compounds, hepatitis C management will become ever more complex due to demands that arise from patient's concerns, from colleagues? fear of treatment toxicity and from the current safety-focused regulatory environment at the US FDA. An active educational process about new options in HCV treatment will enable us to retain the large number of hepatitis C “treaters” worldwide, including a large number of infectious disease experts and gastroenterologists. Conversely, focusing patient treatment in specialty liver centers has been proposed by a number of experts in the U.S. and worldwide. Challenges to such a specialty setting would be long travel times for many patients since they would have to be taken care of in a “face-to-face” clinic setting that might be a long distance from their homes. Whether there is actually a need for treatment of patients only by specialized individuals with extensive experience in managing hepatitis C and knowledge of the smorgasbord of new compounds remains to be proven. One major advantage of managing liver disease in such a specialty liver center would be to provide financial support by regulatory authorities and insurance companies as well as governmental insurance-run plans to pay for patients to be managed by video conferencing. In addition, an extensive amount of care could take place via email and telephone, with infrequent face-to-face visits. These clinic visits could be reserved for special adverse events and for patients requiring a special clinic setting. This new and innovative system would allow the distribution of liver disease expertise over broad regional areas while saving time, fuel and energy in this new green era where each of us is trying to enhance medical care but minimize our carbon footprint.

Robert Gish, M.D.

Medical Director

Liver Transplant Program

Robert Gish, M.D.

Medical Director

Liver Transplant Program