The 4th International Workshop on Clinical Pharmacology of Hepatitis Therapy

Meeting Report - The 4th International Workshop on Clinical Pharmacology of Hepatitis Therapy



Boston, MA June 27, 2009

Jennifer J. Kiser, Pharm.D.
Assistant Professor
University of Colorado Denver

The 4th International Workshop on the Clinical Pharmacology of Hepatitis Therapy was held June 26 and 27, 2009 in Boston, MA. There was record attendance at this year's meeting and twice the number of abstracts submitted. This meeting will continue to grow as new drugs become available for the treatment of hepatitis.

This year's meeting followed the 4th International Workshop on Hepatitis C, Resistance and New Compounds. There are many shared interests between those attending these workshops, thus four lectures were presented in a joint session on the first day of the meeting. A brief summary of these joint lectures is provided, but this report will primarily focus on lectures and selected original research presented during the second day of the Workshop.

· The pharmaceutical industry is divided on whether to use animal models to guide drug selection and dosing decisions in the development of drugs to treat viral hepatitis. David Standring (Idenix) described his experiences and some of the strengths and limitations of performing studies of investigational agents in chimpanzees.

· Bambang Adiwijaya (Vertex) discussed the ways in which viral inhibition, replicative fitness, viral dynamics, and pharmacokinetics contribute to the likelihood of achieving a sustained virologic response (SVR) on telaprevir or boceprevir plus peginterferon and ribavirin.

· Advances in molecular diagnostics have greatly enhanced our ability to detect acquired viral variants in persons with HIV (Simen JID 2009;199:693). Dwight Dubois (Cenetron Diagnostics and Cenetron Central Laboratories) discussed the application of this technology, known as "ultradeep" or "next generation" sequencing, to the field of Hepatitis C Virus (HCV).

· Stuart Ray (Johns Hopkins University) described the implications of Hepatitis B and C viral diversity on treatment.

Invited Lectures

· Kimberly Struble (FDA Division of Antiviral Products) provided guidance on "bridging the data gap" from drug discovery to FDA-approval, with specific emphasis on the progression from the first human trial to Phase III trials, studies of combinations of drugs, and studies in special patient populations (e.g., post-transplant, decompensated cirrhosis, those coinfected with HIV, and pediatrics). Dr. Struble stressed that although early trials in treatment naïve patients are preferred, that a broad population of patients should be studied, including those with compensated cirrhosis. She said there were multiple trial designs that could be considered for Phase II and III trials, but that adequate SVR data (SVR12 or SVR24) was needed from Phase II trials before beginning Phase III. Studies to investigate combinations of investigational HCV agents are encouraged, particularly for populations with the greatest need (previous null responders, those for whom the standard of care is contraindicated, or those unable to tolerate the standard of care). While data is required on the individual agents, combination animal studies are no longer required. Though the FDA does not require drug-drug interaction data prior to use of investigational drugs in combination unless an interaction is "expected" based on the pharmacology of the agents, I would argue that not all interactions can be predicted and it seems the most conservative and responsible course of action would be to perform an interaction study in healthy volunteers prior to studying the combination in patients and risking an unexpected interaction and its potential consequences (e.g., toxicity or virologic failure and the development of resistance)

· Bill Poland (Pharsight) discussed the role of population pharmacokinetic modeling to determine the impact of adherence to new HCV agents on the likelihood of achieving SVR. Dr. Poland's modeling suggests that many of the investigational HCV compounds appear sensitive to lapses in adherence and that compounds with more "forgiving" pharmacokinetics (e.g., long half lives and less frequent dosing) are desirable.

· Kathleen Schwarz (Johns Hopkins University) discussed the state-of-affairs of treating Hepatitis B and C in children. For Hepatitis B, there are few treatment options for children less than 12 years (only interferon and lamivudine are approved), entecavir is being studied for children ≥ 2 years. In addition to increasing our treatment options, Dr. Schwarz felt to move the field of pediatric Hepatitis B treatment forward, better predictors of response (other than e seroconversion) are needed, that long-term monitoring for durability of response and the incidence of hepatic flares is necessary, and that studies in immunotolerant children should be considered. In terms of HCV, combination peginterferon and ribavirin achieve better rates of SVR than treatment with peginterferon alone. The predictors of SVR in children are similar to those in adults. Children have less anemia from ribavirin than adults, but teratogenecity is a concern since many pediatric patients with HCV are women of childbearing potential. To move the field of pediatric HCV forward, more effective treatments are desired and research is needed to select the best candidates for treatment.

· By 2015, the majority of patients with HCV treated in clinics in the Western world will have advanced liver disease. Dr. Massimo Pinzani (University of Florence) discussed pharmacology considerations for the treatment of patients with bridging fibrosis and/or cirrhosis and various invasive and non-invasive methods to monitor for disease progression and regression in these patients. The goals of treatment depend on the degree of liver damage and go beyond viral eradication (e.g., fibrosis regression, preventing cirrhosis, reduce portal pressure, etc.). Our current standard of care for HCV has significant limitations in this population, but there is no information on the pharmacokinetics of investigational agents in those with advanced fibrosis/cirrhosis and these studies are needed, as are studies in patients with renal impairment. Drug-drug interaction studies with the investigational agents will also be extremely important for patients with advanced disease on multiple other medications.

Selected Original Research Presentations

· Ribavirin Dosing in Patients with Renal Dysfunction: Ribavirin is contraindicated in patients with CrCl < 50 mL/min and this limits treatment options for HCV-infected persons with renal dysfunction. Peter Morcos and colleagues from Roche determined ribavirin pharmacokinetics and safety and tolerability in HCV-infected persons with renal impairment. Subjects with moderate (n=17), severe (n=14), and end stage renal disease (ESRD) on hemodialysis (n=18) were enrolled, as were 13 subjects with normal renal function (CrCl > 80 mL/min) to serve as controls. Despite using much lower doses than those FDA-approved for patients with normal renal function (600 mg and 400 mg daily for those with moderate and severe renal impairment, respectively), 65-79% of subjects developed anemia. Those with ESRD on hemodialysis tolerated the ribavirin dose of 200mg once daily (30% developed anemia, similar to rates in those with normal renal function), but the efficacy of this dose was not assessed.

· Treatment Durations with Telaprevir or Boceprevir in Combination with Peginterferon and Ribavirin: Bambang Adiwijaya and colleagues at Vertex developed a model of the evolutionary dynamics of viral variants in subjects chronically infected with HCV and used the model to predict outcomes of various treatment durations of telaprevir or boceprevir in combination with peginterferon and ribavirin. The model suggested four weeks of combination therapy was insufficient, but that 12 weeks of telaprevir plus peginterferon and ribavirin appeared sufficient to eliminate wild-type and variants with low levels of resistance and longer durations did not appear to offer significantly improved rates of SVR. The model suggested that 48-weeks of combination treatment with boceprevir was superior to 24 weeks.

· R7227 Interactions: R7227 (an investigational HCV protease inhibitor [PI]) increased midazolam (MDZ) and the alphahydroxy-midazolam (1'-OH MDZ) metabolite AUC by 27 and 41%, respectively, and the metabolic ratio of 1'OH-MDZ:MDZ was 1.11. MDZ half-life was not noticeably affected. In a separate study, R7227 (at a dose of 50mg) AUC and Cmax were increased 6.28-fold and 4.22-fold, respectively and half-life increased 2-fold in combination with ketoconazole. The most frequent side effects were headache and dyspepsia. These studies support that R7227 is a substrate for, and a weak inhibitor of CYP3A and an inhibitor of the drug transporter p-glycoprotein (P-gp). R7227 is therefore susceptible to drug interactions with CYP3A modulators, and may increase levels of other P-gp substrates. Many HIV PIs and NNRTIs are CYP3A and P-gp substrates, inducers, and/or inhibitors. Thus, the interactions observed with R7227 highlight the importance of studying this and other investigational HCV drugs in combination with HIV medications. The dosing of the HCV and/or HIV drugs may need to be altered in combination or a significant interaction could unfortunately preclude the use of some of these medications in combination. (from Jules: in plain words based on this data, there appear to be potential drug interactions between HIV PIs and NNRTIs and HCV protease inhibitors that could in some instances require adjustments in dosing or difficulty in combining HIV & HCV regimens.)

· Ritonavir-Boosting of Acylsulfonamide PIs: At this workshop in 2006, Dale Kempf showed that ritonavir could be used to boost the ketoamide HCV PIs telaprevir and boceprevir in rats. EA383 and EA702 concentrations in rats, dogs, and monkeys were significantly increased by single doses of 5-15 mg/kg of ritonavir. Ritonavir boosting increased liver concentrations and prolonged the liver half life but did not appreciably affect the liver:plasma ratio.

· HCV PI with Novel Mechanism of Action: AVL-181 has unique chemistry compared to other HCV PI under development. AVL-181 covalently binds to a specific amino acid (C159) on the HCV protease enzyme, which silences the protein. C159 is conserved in all HCV genotypes and even drug resistant strains. Because the compound silences NS3 protease activity even when the drug is very low or undetectable in plasma, it seems the functional half-life is dependent on protein turnover rather than on continuous exposure to the drug. While the mechanism of action of this compound is intriguing, the drug has not been studied yet in humans. Phase I studies are planned for early 2010.

· PI/Polymerase Combination Study: The combination of R7227 (PI) and R7128 (cytidine nucleoside analog) was evaluated in a Phase I trial of 45 treatment-naïve patients with HCV genotype 1. R7227 was dosed at 100 or 200mg three times daily and R7128 was dosed at 500 or 1000mg twice daily. There was no apparent plasma interaction between the drugs. The drug appeared well tolerated, 11% had an increase in glucose, but these were not fasted measures. There were no treatment-related serious adverse effects, dose modifications, or discontinuations. A 4-5 log drop in HCV RNA was observed after 13 days of the combination of R7227 and R7128. Studies are ongoing investigating this combination with twice daily dosing strategies of R7227 in more treatment-experienced patients. It will be imperative to see if the use of these two drugs alone provides a sustained effect, or as in the case of HIV, if additional agents with different mechanisms of action against the virus are needed to prevent the development of resistance.

· Caspase Inhibitor for NASH: GS9450 is a caspase 8 and 9 inhibitor under development for nonalcoholic steatohepatitis (NASH). In vitro experiments suggested the drug had pH-dependent stability, but GS9450 did not interact with esomeprazole (a proton-pump inhibitor) in healthy volunteers. Since patients with NASH can also have type II diabetes mellitus, a drug-drug interaction study was also performed in healthy volunteers with the anti-diabetic agent glyburide. Following a single dose of glyburide, GS9450 increased glyburide Cmax an average of 23% (range 16-31%), but AUC was unchanged. The mechanism and clinical significance of this interaction are unknown. Glyburide is a substrate for the human organic anion transporting polypeptide 1B1 (OATP1B1) transporter and metabolized primarily by CYP2C9, with CYP3A4 playing a minor role. Studies to better characterize the pharmacology of GS9450 are ongoing, and may elucidate a potential mechanism for the observed interaction.

In closing, this Workshop allows individuals from industry, academia, and the FDA to discuss topics and present research related to the clinical pharmacology of hepatitis therapy. A comprehensive understanding of the clinical pharmacology of antiviral drugs has revolutionized the treatment of HIV, and will likely do the same for the treatment of viral hepatitis.

From Jules Levin:

Accelerated HCV Drug Access Needed for Patients At Greatest Risk & Coinfected: recognition they are at risk for death soon

I was at the HCV Resistance meeting preceding the PK meeting and stayed for Kim Struble's talk at the PK meeting. I made comments at the microphone related to HCV drug development and access for HCV/HIV coinfected patients and patients with advanced HCV disease: HCV/HIV coinfected patients are a unique group for which parallel drug development should be considered and discussed. As well, early access for coinfected and advanced disease also should be considered and discussed by the companies and the FDA. The FDA is treating HCV drug development differently than they previously treated HIV drug development in the early days, the 1990s. Because HIV was a disease from which people were quickly dying they needed quick access to drugs and so early drug access programs were implemented, thus Expanded Access. This was at least in part due to activist pressure. It appears the FDA subscribes to the thinking that HCV is different, that HCV disease is not as serious a threat for imminent death, and it generally is not: after 20-30 years with HCV only 20% get cirrhosis or serious disease. As well, there is no activist pressure today in HCV. BUT, not all patients have the same disease pathogenesis, some patients progress more quickly: in particular HIV accelerates HCV disease, coinfected patients can seriously progress within 5-10 years; HCV is the leading cause of death and hospitalization in HIV and many patients can't tolerate peg/RBV and don't respond well to it. Two studies with paired biopsies have reported in HCV/HIV coinfected patients that HCV disease progressed 2 stages over 3 years in a significant percent of coinfected patients. So, what is needed is access as quickly as possible to at least 2 oral HCV drugs in combination with peg/RBV for coinfected patients who cannot wait because their disease is progressed and they are in serious danger of decompensated cirrhosis and death. For patients with advanced monoinfection disease they too are in danger of decompensation and death. So what is needed is a full open discussion between the FDA and stakeholders, the companies, to consider if there is a reasonable way to address these needs. I spoke with the FDA about this at the meeting in Boston, as well as discussing it at the microphone in front of many researchers from numerous companies developing HCV drugs. At this meeting were officials from Vertex, Abbott, Tibotec, Merck, Boerhinger Ingelheim, Pharmasset, Roche and others. My comments received some brief discussion, but I discussed the issue face-to-face with the FDA and certain attendees as well. What emerged is an idea to hold a public meeting on this subject. I am suggesting consideration of parallel drug development for coinfection with the goal that coinfected patients would get access to a combination regimen as quickly as possible with safety in mind that contains at least 2 oral HCV drugs plus peg/RBV because I don't think 1 oral plus peg/RBV is adequate for coinfected patients in general; and for moninfected patients in great need for access to therapy soon or they are at great risk. Above in the report mention is made regarding Dr Struble saying in her talk that the FDA encourages study in special patient populations like coinfected and cirrhotics and in patients with the greatest need, so I think these comments were made to address my concerns expressed directly to the FDA several days before this meeting. Nonetheless, these comments and my discussion with the FDA show the FDA supports an effort to further discuss the needs I mention above for parallel development for coinfection and early access for patients in the greatest need. These patients are at risk for death or decompensation, as much at risk as HIV+ patients were in the early 90s that gave impetus to early access and accelerated HIV drug development. However, we want to consider safety and the risk for HCV drug resistance a part of this discussion so we can balance the risks and benefits. Another consideration is the resources needed by the companies to address these concerns. Added staff, oversight, and finances are required, as well, the potential risk for safety issues emerging that can endanger drug development and the investment are important and reasonable considerations and barriers, so all this ought to be considered.