Hepatitis B drugs in development

1 July 2010. Related: Pipeline report, Hepatitis coinfection.

Lei Chou

Introduction

After a burst of hepatitis B virus (HBV) drug discovery and development over the last decade, the year 2010 saw the development pipeline dry up. While several currently available drugs are highly effective at controlling viral replication and keeping the disease in check, only about one-third of people are able to reach a key treatment goal: sustained viral control while safely off treatment. Life-long suppressive therapy with antiviral drugs appears to be the HBV treatment model for the near future for most people with chronic hepatitis B.

Although antiviral drugs can control HBV, drug resistance may develop over time, leaving people with no treatment options. This is of particular concern as resistance can develop faster for people coinfected with HIV and HBV. Long-term toxicity is likely to be an issue. These concerns will not be resolved until there is a robust drug pipeline. Advances in basic science are needed to better understand HBV pathogenesis, identify new drug targets, and to stop HBV’s destructive track.

While overall cancer rates are on the decline nationally, liver cancer is bucking this trend, driven primarily by chronic viral hepatitis. A recent Centers for Disease Control and Prevention (CDC) publication reported that liver cancer is on the rise: between 2001 and 2006, the incidence of liver cancer increased at an annual rate of 3.5 percent, representing over 45,000 reported cases in the same period. Asians, Pacific Islanders, and African Americans have the highest rates of increase (CDC 2010).

HBV treatment can prevent the development of life-threatening complications, such as cirrhosis and liver cancer. But in the U.S., an estimated 5.3 million people with chronic viral hepatitis (hepatitis B and C) are over 50% percent of the undiagnosed. The challenge is to screen, diagnose, monitor, and treat people in a timely matter, before they develop serious complications. HBV treatment may prevent these complications, not treat them. Sadly, U.S. federal investment in research, testing, surveillance, and publicly funded treatment programs is grossly inadequate at present.

According to the National Viral Hepatitis Roundtable (NVHR), the proposed 2011 annual budget for CDC’s Division of Viral Hepatitis is only $21 million, just two percent of the overall budget for the National Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Disease, and Tuberculosis Prevention (NCHHSTP). Shockingly, this is less than the Division’s budget of $25 million from ten years ago (NVHR 2010).

Key provisions in the new healthcare reform law passed in March could help this dire situation. The insurance industry’s discriminatory practice of withholding coverage from people with pre-existing conditions will be banned by 2014. This means that people with chronic HBV can finally gain access to what will hopefully be affordable healthcare. However, implementation of the new legislation is expected to be an uphill battle, and will take a few years.

A recently released Institute of Medicine report (Colvin 2010) highlighted the lack of provider awareness about HBV contributes to the problem. Doctors often do not identify at risk people for screening, nor do they consult current guidelines on how and when to treat chronic HBV. According to one survey, 44 percent of primary care providers did not know HBV can be controlled with treatment.

Hopefully, the gradual expansion of access to health care will drive demand for new and better HBV treatment, and provide more financial incentives for the drug industry to invest in discovery and development of new compounds. In the meantime, there are no investigational new drugs in late stage development in the U.S. for HBV. Instead, the glimmer of hope—for what it’s worth—is coming from a handful of immune-based therapies, although these are all in early stage development.

Table 1. HBV Experimental Agents in the Pipeline

Oral antivirals

Access to new brand-name drugs in Asia is limited by their prohibitive cost, an option only available in higher-income countries. The need for new drugs with better potency and higher resistance barriers are particularly pressing in the region, since lamivudine monotherapy has been the primary treatment for many years due to the availability of low-cost generics, and the drug’s weak resistance profile has contributed to wide-spread lamivudine resistance in people with chronic HBV. Although hepatitis B is endemic in Asia, there are only two oral antivirals in late stage development in China and South Korea.

Clevudine

Despite Pharmasset’s halting U.S. development of clevudine due to post-market reports of severe myopathy (muscle weakness) last year, the South Korean drug maker Bukwang is forging ahead with development and marketing plans for clevudine in Asia. Studies in South Korea and a phase III trial in China are underway. Bukwang’s Asian partner, Eisai Pharmaceuticals, has launched clevudine (brand name: Revovir) in the Philippines, with pending licensing plans for India, Indonesia, Malaysia, and Thailand. It will be up to doctors and regulatory authorities in these countries to keep a close eye on reports of myopathy, since the condition can develop after eight months of clevudine use, and people must stop taking it to avoid potentially fatal consequences. In a rapid communication published in Hepatology (Seok 2009), the main symptom of clevudine induced myopathy was slowly progressive muscular weakness in the limbs over several months. The condition can take up to four months to resolve after clevudine is stopped.

LB80380

LG Life Sciences published data from its safety and efficacy study of the new nucleotide analog LB80380 in Hepatology (Yuen 2010). The small study done in treatment-experienced Chinese volunteers with lamivudine-resistant chronic HBV showed potency comparable to entecavir and tenofovir, the two leading antivirals on the market. No significant drug-related toxicities were seen in this 12-week dose-finding study. A phase II study in treatment-naive volunteers is enrolling in South Korea and Hong Kong.

Tenofovir is the first-line treatment for lamivudine-resistant HBV in the U.S. and Western Europe. Resistance to tenofovir has not yet been characterized three years after the drug’s approval to treat HBV, but second-line drugs for people who become resistant to tenofovir may be needed in the future. Although LB80380 may be useful as a second-line drug for people with lamivudine resistance, an in vitro study revealed that LB80380 has only partial efficacy against adefovir and potential tenofovir resistant HBV strains. Development plans for the United States and Europe are unclear.

Emtricitabine/Tenofovir

This Gilead workhorse HIV combination pill is being studied in several ongoing HBV trials in different patient populations. Truvada is being studied in HIV/HBV coinfected people with a detectable HBV viral load despite current treatment, both in combination with pegylated interferon, and in a head-to-head comparison with entecavir. Trials are also underway in people with decompensated liver cirrhosis and liver transplant recipients.

Lagociclovir Valactate (MIV-210)

The Swedish drug maker Medivir has out-licensed MIV-210 to South Korean Daewoong Pharmaceutical to advance its development in Asia this year. This drug was initially developed for HIV and failed. Now it’s enjoying a second chance as an HBV treatment. MIV-210 has shown in vivo activity against lamivudine-resistant HBV strains in an animal model study done nearly ten years ago. Daewoong plans to launch a phase II study in South Korea.

Simvastatin

The University of Oklahoma and the U.S. Veteran’s Administration are conducting a phase I proof-of-concept study looking at the cholesterol lowering agent simvastatin, after in vitro data showed anti-HBV activity and synergistic activity when combined with approved HBV drugs (Bader 2010). The small three-arm study will compare simvastatin alone vs. simvastatin with either tenofovir or entecavir. Since the drug is available as a generic, it will radically change the current HBV market if proven effective on its own.

Bay 41-4109

Bayer’s Bay 41-4109 is a heteroaryldihydropyrimidine (HAP) that inhibits HBV assembly by interrupting viral capsid formation. The drug has recently resurfaced in an investor report from the German company AiCuris, a Bayer spin-off drug discovery company. Clinical development plans are unclear. Since it is the only experimental candidate that targets a different part of the viral life cycle than drugs currently on the market, the compound—if it is ever developed—could be used to treat drug-resistant HBV.

Immune-based therapies

CYT107

A new entrant from the immune-based front is French company Cytheris’ recombinant human Interleukin-7 (CYT107). This immunomodulator is also being studied for HIV and hepatitis C. The CONVERT study will compare CYT107 with the HBV preventive vaccine GenHevac B versus CYT107 alone in HBeAg negative patients on stable tenofovir or entecavir treatment. This phase I/IIa study is enrolling volunteers in France and Italy. The hope is that the agent will stimulate the immune system and restore immune response to HBV so that people do not have to stay on life-long antiviral therapy.

Several other immunomodulators and therapeutic vaccine candidates are currently in early phase development; however no study data have been published in the past year. For detailed descriptions of these agents, please see TAG’s 2009 Pipeline Report.

• Interferon gamma 1b (Actimmune)—A phase II study of this chemically manufactured form of human interferon gamma has not yet opened for enrollment.
• Thymosin alpha1 (Zadaxin)—A phase IV trial of this synthetic version of a substance produced naturally by the thymus is still active in South Korea.
• HBV naked DNA vaccine pCMVS2.S HBV—A phase I/II study is still ongoing with completion expected in late 2010.
• Mixed plasmid DNA (HB-110) vaccine—A phase I study combining the vaccine with adefovir is still enrolling patients in Korea.
• Hepatitis B vaccine (synthesized peptide PA-44)—A phase I study in China is still ongoing.
• HBV DNA plasmid pdpSC18 vaccine—A phase I study has been completed but no data are published as yet.
• DV-601—A phase I study is open and enrolling patients using this therapeutic vaccine being developed by Dynavax in Europe.

Preventive vaccine

Heplisav

Dynavax successfully resuscitated this preventive vaccine after a series of setbacks. After the U.S. Food and Drug Administration (FDA) placed a clinical hold on the development of Haplisav in 2008 due to a case of vasculitis (inflammation of the blood vessels), a potentially deadly autoimmune condition also known as Wegener’s granulomatosis, Merck pulled out as a development partner. Dynavax was able to convince the FDA to release the hold by redesigning its development to target the vaccine for subsets of people with immune deficiencies that render currently approved HBV vaccine ineffective, altering the risk-versus-benefit equation to favor development. The company has since launched two large-scale phase III studies, one in people with end-stage renal disease, and the other in people over the age of 40. While this vaccine could be helpful to some HIV-positive people who do not achieve protective immunity with currently approved vaccines, no study in HIV-positive people is being planned. The vaccine will require only two shots within one-month, compared to the current standard of three shots in six months. It has demonstrated non-inferiority with GSK’s Engerix-B vaccine, and data from the two phase III studies are expected in mid-2011.

Hepatitis B Clinical Research Network

The anticipated opening of the Hepatitis B Clinical Research Network’s first trials at the end of 2009 did not materialize. Reportedly, the delay is due to complex contract negotiations with drug and diagnostic companies regarding provision of drugs and funding. This delay is disappointing, as several of the Network’s planned trials will address many research questions critical to our understanding of chronic HBV disease progression, as well as optimal treatment strategies with currently available drugs. TAG hopes the negotiations will be completed quickly so as not to impact the duration of these studies, since the network is nearing the start of the third year in the seven-year grant from the U.S. National Institutes of Health (NIH) without enrolling a single patient.

References

Bader T, Korba B. Simvastatin potentiates the anti-hepatitis B virus activity of FDA-approved nucleoside analogue inhibitors in vitro. Antiviral Res. 2010 Jun;86(3):241-5.

CDC. Hepatocellular Carcinoma—United States, 2001–2006. MMWR: Morbidity and Mortality Weekly Report 2010;59:17

Colvin HM, Mitchell AE (eds). Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Institute of Medicine. 2010.

NVHR. National Viral Hepatitis Roundtable Warns “Systemic Underfunding” of Federal Viral Hepatitis Programs Puts Five Million Americans at Risk. Press release. March 16, 2010

Seok JI, Lee DK, Lee CH, et al. Long-Term Therapy with Clevudine for Chronic Hepatitis B Can Be Associated with Myopathy Characterized by Depletion of Mitochondrial DNA. Hepatology. 2009 Jun;49(6):2080-6.

Yuen MF, Han KH, Um SH, et al. Antiviral Activity and Safety of LB80380 in Hepatitis B e Antigen–Positive Chronic Hepatitis B Patients with Lamivudine-Resistant Disease. Hepatology. 2010 Mar;51(3):767-76