HBV: Drugs in Current Clinical Development

Christine M. Kukka
HBV Project Manager;

In late 2006, there were two types of drugs available to treat hepatitis B: interferons, which boost the immune system to fight the hepatitis B infection, and antiviral medications, which deliberately interfere with the virus’s DNA so it can’t reproduce efficiently. Below are the drugs that are currently approved by the U.S. Food and Drug Administration (FDA) to treat hepatitis B, and the up-and-coming drugs that may someday be used to eradicate a hepatitis B virus (HBV) infection.

Interferons

Interferon has an “immunomodulator effect,” which means that it tweaks the immune system to produce lymphocytes (specialized immune cells) that either attack the virus’ antigens directly by creating antibodies, or they attack the HBV-infected liver cells.

• B lymphoctyes (B cells) are the immune cells responsible for the production of antibodies. They zero in on individual antigens, such as the HBV’s surface, core or “e” antigens, by producing antigen-specific antibodies to combat and vanquish each antigen.

• Cytotoxic T cells (T cells) are specialized cells that recognize and kill HBV-infected liver cells and cancerous liver cells.

Interferons do something else that is very helpful. They enhance the “expression” or presence of certain antigens on the surface of HBV-infected liver cells. When these antigens are expressed,” the T cells can find them more easily and zero in and destroy the infected cells. This process is called enhanced cell surface expression of Class 1 Major Histocompatibility, or MHC.

Researchers are working to develop a variety of immune stimulants and enzymes that will trigger T cell, B cell and other immune cell production so these “soldier” cells will find and vanquish the HBV infection.

FDA-Approved Interferons

Today, there are two FDA-approved interferons to treat hepatitis B. One is called conventional interferon or interferon alpha 2b, that the FDA has approved for the treatment of hepatitis B in adults and children. This interferon requires three injections each week and, unfortunately, has had limited treatment success.

Only about 30 percent of those treated are able to clear their bodies of HBV DNA (the genetic material that signals the presence of the virus in the blood), and only 33 percent were reported to clear the “e” antigen. About 12 percent of those treated with conventional interferon achieved normal liver enzymes (ALTs) and cleared HBV DNA and “e” antigen.

The second interferon is called pegylated interferon. It has been, used with great success against hepatitis C and it requires only one injection each week. This interferon has a time-release formula so it remains present in the liver at a constant level to achieve a consistent “immune boosting” level.

Pegylated interferon is also believed to more efficiently distribute itself throughout the liver, the main site of HBV infection, than conventional interferon. According to a study by Roche, the company that developed the pegylated interferon called Pegasys, pegylated interferon was twice as successful as conventional interferon in treating hepatitis B.

Roche researchers reported that Pegasys, given for six months at the same 180 microgram dose used in the treatment of hepatitis C, showed an “e” antigen (HbeAg) loss, HBV DNA below 500,000 copies/ml, and normalization of ALT in 28 percent of those treated, compared to 12 percent treated with conventional interferon.

One of Roche’s studies specifically examined the effectiveness of Pegasys in patients with difficult-to-treat hepatitis B, which includes patients with the “e” antigen, high HBV DNA (high levels of virus replicating in the patient’s liver), and low ALT levels—all of which indicate that the person’s immune system is not noticing the virus nor attacking infected liver cells.

As of late 2006, only conventional interferon had been approved for treatment of children with HBV.

Immune Stimulators (Similar to Interferons) Under Development

Immune enhancers or stimulators are similar to interferon, but they specifically help T cells find and fight tumors and viruses.

HE2000 (Immunitin), developed by Hollis-Eden Pharmaceuticals, is similar to interferon in that it spurs the immune system. This substance, however, stimulates key immune fighting cells necessary to fight infections in people with hepatitis B and HIV. This drug is currently in Phase II clinical trials for hepatitis B in Singapore.

Zadaxin is thymosin alpha 1, a thymic hormone that enhances the maturation of T-cells. The drug’s developer, SciClone Pharmaceuticals, reported that when this drug was combined with conventional interferon, it produced a 71 percent long-term sustained response rate in patients with difficult-to-treat hepatitis B after one year of treatment. This sustained response rate compares favorably to only 20 percent of patients using interferon alpha in combination with lamivudine, and 10 percent of patients using interferon alpha alone. After administration, thymosin alpha 1 circulates at 50 to 100 times its normal level in the body. Zadaxin has been approved for sale in more than 30 countries. This drug is currently in Phase II clinical trials.

Quick Reference Chart

Antiviral Medications or Nucleoside Analogs

Nucleoside analogs (also called nucleoside reverse transcriptase inhibitors, or NRTIs) and non-nucleoside antivirals prevent the hepatitis B virus from replicating. These drugs interfere with the HBV’s DNA and the viral proteins that orchestrate its reproduction. Most antiviral medications are pills that are taken daily.

When an antiviral enters a hepatitis B virus, it is able to inhibit certain cellular functions that are necessary for DNA production or viral replication. As a result, the virus is unable to replicate in liver cells.

These antivirals are valuable because they lower the rate of HBV replicating in the liver. Generally, when viral load drops, liver damage declines because there are fewer viruses invading liver cells, and ALT levels also normalize. Researchers hope that one day a combination of immune enhancers and antiviral medications will be developed that can produce a strong immune response and lower viral load, resulting in the eradication of an HBV infection.

FDA-Approved Antiviral Medications

There are four FDA-approved antiviral medications available to HBV-infected patients: lamivudine, approved for adults in 1998 and for children in 2000, adefovir, approved for adults in 2002 and currently in clinical trials for children, entecavir, approved for adults in 2005, and telbivudine, approved in October 2006 for adults.

Lamivudine (brand name Epivir HBV): Administered as a daily pill or oral solution, lamivudine generally produces normal ALT levels and undetectable HBV DNA in about 65 percent of the adults who take it.

While lamivudine is safe and rarely causes side effects, it is not a permanent or complete cure. It keeps the virus in check for only as long as it is taken. When treatment stops, HBV DNA and ALT levels usually rebound.

Lamivudine has one serious drawback. Some hepatitis B viruses with certain mutations are able to continue to  reproduce despite lamivudine’s antiviral punch. Over time, these lamivudine-resistant HBVs increase in number until viral load and ALT levels start to climb once again. After four years of lamivudine treatment, more than 60 percent of patients develop lamivudine-resistant HBV.

Adefovir (brand name Hepsera): Adefovir appears to have all of lamivudine’s antiviral clout, but it does not cause rapid viral resistance. Today, doctors frequently switch patients to adefovir who have developed viral resistance to lamivudine.

Adefovir also appears effective against hepatitis B viruses with certain mutations that are able to replicate without secreting HBeAg. The immune system has a hard time identifying and zeroing in on this type of hepatitis B virus. When an HBV infection exists and lab tests can’t find the “e” antigen, despite high viral loads and elevated ALT, it is called HBeAg-negative hepatitis.

Entecavir (ETV- brand name Baraclude) is a potent inhibitor of HBV replication. In clinical trials, this antiviral has shown the ability to reduce viral CCC DNA levels, which are believed to promote development of liver cancer. In studies that compared entecavir with lamivudine, entecavir was more effective in reducing HBV DNA levels, even when ALT levels were only slightly elevated. Early studies also suggest that entecavir-treated patients had a more sustained response to the drug, even after treatment ended, including those with HBeAg-negative hepatitis B. There have been some reports of viral resistance to entecavir, but nearly all occurred in patients who had already developed lamivudine-resistant viruses.

Telbivudine (brand name Tyzeka), approved by FDA in October 2006, is a nucleoside analog that has shown similar success in suppressing viral load and improvement of liver inflammation as lamivudine. One 52-week study that compared telbivudine to adefovir in 135 patients with HBeAg-positive hepatitis B and elevated ALT found it produced more significant declines in HBV DNA than adefovir. The daily dose is 600 mg/day. The most common side effects were elevated CPK (creatinine phosphokinase), an enzyme that is present in muscle tissue and is a marker for breakdown of muscle tissue, upper respiratory tract infection, fatigue, headache, abdominal pain and cough.

Antivirals in Development

There are several experimental antiviral medications currently in Phase III or late-stage clinical trials.

Emtricitabine (FTC, Emtriva), already approved by FDA for treatment of HIV, has been found to be effective in lowering HBV DNA. Gilead Sciences reported treatment with emtricitabine reduced liver fibrosis in 62 percent of patients who received the drug, compared to 25 percent of patients who received a placebo, and substantially lowered HBV DNA in 56 percent. However, researchers have found some instances of viral resistance to emtricitabine.

Clevudine (L-FMAU) has demonstrated potent antiviral activity and the ability to produce a sustained response, even months after treatment has ended. In one study, 71 percent of patients who took clevudine maintained normal ALT levels six months after treatment ended, which is longer than with other antivirals. Clevudine, produced by Gilead, appeared to be well-tolerated, and no HBVs have developed resistance to clevudine to date.

BAM-205, developed by Novelos, also interferes with proteins involved in viral reproduction. BAM-205 was approved for use in Russia in 2001. Preclinical studies support BAM-205’s anti-viral effects in more than 250 Russian hepatitis B patients studied. Viral load was reduced and ALT levels also declined. According to Novelos, more than 700 Russian hepatitis patients have been treated successfully with BAM-205. Commercialization of BAM-205 is underway in Russia, and plans are underway to develop and sell BAM-205 in China. In the United States, BAM-205 is in Phase II/III clinical trials.

Tenofovir (Viread): Several studies have found that the antiviral tenofovir, developed by Gilead Sciences, is effective against both HIV and HBV. One study showed that treatment with tenofovir resulted in 0.6-log decrease in HIV level and a five-log decrease from baseline for HBV level. Similarly, another coinfection study showed a four-log decrease in HBV DNA level by week 24 and an increase in CD4 cells. However, there have been reports of renal toxicity and hypophosphatemia associated with tenofovir therapy. Clinical trials exploring the safety and effectiveness of tenofovir to treat people coinfected with HIV and hepatitis B are continuing.

Ampligen: Currently in Phase II trials for treatment of hepatitis B with Hemispherx Biopharma, Ampligen is a nucleic acid drug that mimics DNA and RNA, and which inhibits production of certain enzymes that HIV and hepatitis B viruses need for viral reproduction. Ampligen can also control the growth of certain human tumor cells. Administered intravenously twice a week, it is also being studied for possible applications in renal carcinoma and malignant melanoma. To date, it has caused no dangerous side effects.

For more information about hepatitis B, contact the following organizations:

Hepatitis B Foundation
1-215-489-4900, www.hepb.org

Hepatitis B Support List
www.hblist.org

Hepatitis Foundation International
1-800-891-0707, www.hepfi.org

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