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The Hepatitis C Treatment Pipeline

September 2011

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Novel Interferons

If DAA combination therapy doesn't pan out for everyone, new types and formulations of interferon will come in handy. These may be more convenient, or more tolerable. For example, peg lambda interferon was more effective at 12 weeks than peginterferon alfa 2a, as well as more tolerable. Flulike symptoms, anemia, neutropenia and thrombocytopenia were significantly lower among people who got peg lambda than peginterferon alfa, although the incidence of depression was similar. Transient elevations in direct bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were reported in the highest-dose peg lambda arm, but resolved when the dose was lowered or discontinued.9

Generic peginterferon could make HCV treatment accessible to millions of people who need it. There is at least one generic peginterferon (y-shaped peginterferon alfa 2a) in development, which hopefully will make HCV treatment accessible to the millions who need it and are unable to afford Merck's Peg Intron or Roche's Pegasys. In any case, patents in the United States and Europe will be expiring in 2016 (PegIntron) and 2017 (Pegasys).


Table 9. Novel Interferons in Development
Agent/SponsorPhase and PopulationComments
BMS 914143 (Peg Lambda interferon)
Bristol Myers Squibb
Phase II; HCV genotypes 1, 2, 3, and 4, treatment-naiveOnce weekly subcutaneous, fixed-dose injection; with ribavirin

With ribavirin and BMS 790052 (NS5a inhibitor) and/or BMS 650032 (protease inhibitor) for 16-48 weeks
Locteron Interferon alfa 2b, Controlled Release Formula (CR2B)
OctoPlus; Biolex Therapeutics
Phase IIb in HCV genotype 1, treatment-naive has been completed; Phase III has not been announced as of May 2011Biweekly subcutaneous injection; with ribavirin Lower incidence of depression and flulike symptoms reported in lower-dose Locteron arms, but more severe adverse events than peginterferon alfa 2b
Y-shaped peg interferon alfa 2a
Biogeneric Pharma and Xiamen Amoytop Biotech Co
Phase I/III, no HCV genotype specified, treatment-naiveGeneric product; subcutaneous, fixed-dose injection, once weekly versus once every ten days, versus biweekly, with ribavirin


Immunomodulators

Exploration of additional ways to stimulate the immune response against HCV continues, with a variety of different approaches, including monoclonal antibodies, therapeutic vaccines, and TLR-7 agonists.


Table 10. Immunomodulators in Development
Agent/SponsorPhase and PopulationComments
CHRON-vac C
ChronTech Pharma AB and Inovio
Phase II, HCV genotype 1, treatment- naiveTherapeutic vaccine; unique delivery system. Administered once per month, for two months, followed by peginterferon and ribavirin
GI5005
Globe Immune
Phase II, HCV genotype 1, treatment- naive and partial responders (null responders excluded)Therapeutic vaccine, administered subcutaneously; multiple dosing schedule. Studied as both lead-in to peginterferon and ribavirin and as salvage therapy Expanded to include 40 people with the IL28B TT genotype
GS9260
Gilead Sciences
Phase I; healthy volunteersTLR-7 agonist; oral drug


For HIV/HCV Coinfected People

HCV treatment trials for HIV/HCV-coinfected people are underway, after years of pressure from activists, clinicians, and regulatory agencies. The first two trials, of boceprevir and telaprevir, were slow to enroll because coinfected people did not want to wind up receiving pegylated interferon and ribavirin with placebo (in the control arm). Regulatory guidance has changed since the first boceprevir and telaprevir trials. Regulators have now stipulated that a control arm is not necessary, as SVR with standard of care has been well-documented, and is suboptimal. A single-arm, 300-person study is sufficient for gaining an indication in coinfection.

Unfortunately, drug-drug interactions have limited the options for antiretroviral therapy coadministration with HCV protease inhibitors to date. Hopefully, dual and multiple DAA studies, with and without ribavirin and with and without peginterferon, will be launched as soon as there are data from HCV monoinfection trials and drug-drug interaction studies to support them.


Table 11. Trials in HIV/HCV-Coinfected People
Agent/SponsorPhase and PopulationComments
BI 201335 (HCV protease inhibitor)
Boehringer Ingelheim
Phase III; HIV-1 /HCV genotype 1, treatment-naive and relapsers
N=316
With PEG-IFN/RBV comparing 12 weeks of triple therapy followed by 36 weeks of PEG-IFN/RBV versus 24 weeks of triple therapy followed by 24 weeks of PEG-IFN/RBV

First large, phase III study of a direct-acting antiviral to include coinfected treatment-naive and treatment-experienced persons

Not open as of 24 August 2011
Boceprevir (HCV protease inhibitor)
Merck
Treatment-experienced trial co-sponsored by French National Agency for Research on AIDS and Viral Hepatitis Rennes University Hospital Schering Plough
Phase II; HIV-1/HCV genotype 1, treatment-naive
N=99

Phase II; HIV-1/HCV genotype 1, treatment-experienced
N=80
With PEG-IFN/RBV; placebo-controlled study; fully enrolled (opened in 2009)

With PEG-IFN/RBV; opened in April 2011 (France only)
Nitazoxanide (antimicrobial)
Romark Laboratories (sponsored by National Institutes of Health)
Phase I/II; HIV-1/HCV genotype 1, treatment-experienced
N=75
With PEG-IFN/RBV; opened in 2010
Telaprevir (HCV protease inhibitor)
Vertex/Tibotec
(Treatment-experienced trial co-sponsored by French National Agency for Research on AIDS and Viral Hepatitis)
Phase II; HIV-1/HCV genotype 1, treatment-naive
N=68

Phase II: HIV-1/HCV genotype 1, treatment-experienced (null responders with cirrhosis excluded)
N=80
With PEG-IFN/RBV; placebo-controlled study; fully enrolled (opened in 2009)

With PEG-IFN/RBV; opened in April 2011 (France only)


And More ...

Other approaches to HCV treatment are being studied: Santaris Pharma's injectable microRNA inhibitor, SPC3649 is entering phase II; it is being studied in treatment-naive people with HCV genotype 1.

Silymarin, the active ingredient in milk thistle, is being studied in acute viral hepatitis, as monotherapy and with peginterferon and ribavirin in treatment-experienced people.


Conclusion: Getting Ducks in a Row

Investments in research and drug development have paid off for hepatitis C. We need a parallel investment in health care, to fully realize the benefits of therapeutic advances. HCV drug development is moving forward rapidly, but the capacity and resources to treat people with HCV have stalled. Millions of people are without access to HCV treatment; high drug prices and the global fiscal crisis make attainment of universal access a challenge. Access to drugs is not all that is required. HCV care and treatment must be offered with linkage to mental health care, case management services, peer support, addiction treatment, and harm reduction services.

Unfortunately, boceprevir and telaprevir were approved in the absence of treatment guidelines (aside from their prescribing information). Clinicians need information about how best to use these new drugs. Otherwise, therapeutic chaos may ensue, leading to treatment failure and drug resistance.

Our biggest challenge is not curing hepatitis C, it is getting health care systems ready for the people who will be using them, as we prepare people to deal with these fragmented systems. Hepatitis C is prevalent among poor, marginalized people. Many of them struggle with addiction, psychiatric disorders and medical comorbidities as well as socioeconomic challenges such as homelessness, unemployment, poverty and incarceration. Multidisciplinary HCV care and treatment, including peer support and education programs, is effective, and these delivery systems need to be expanded. Developing and marketing new drugs will not cure people; good health care will.

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This article was provided by Treatment Action Group and HIV i-Base. It is a part of the publication 2011 Pipeline Report.
 
See Also
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More on Hepatitis C Drugs in Development

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