Other Drugs

Introduction

There are trials of new drugs being carried out by various pharmaceutical companies, hospitals and medical research teams and you may wish to consider joining one of these. Most of these studies are double blind. I.e. you will not know if you are taking the new drug or a placebo. Some studies also combine interferonwith the new drug.

In considering to take an experimental drug you must make a decision regarding the possible gains (A cure) and the possible risks (unknown side effects) and should discuss things very thoroughly with your medical advisor.

Some of the drugs currently under study are shown below, I have also included details of drugs that have been found ineffective or unsuitable for reference purposes.

Acylovir

This drug which has an antiviral activity against the herpes simple virus was found ineffective against Hepatitis B.

Adenene Arabinoside (ara-AMP)

This drug has been shown to be a potent inhibitor of Hepatitis B virus DNA polymerase. Suppression of HBV DNA has been demonstrated and clearance ofHBeAg was achieved in 33% of patients in a controlled study. Usually 8 weeks of treatment is required to effect loss of HBeAg and HBV DNA, unfortunately this drug showed serious neurotoxicity in many patients and was therefore deemed unsuitable as a therapeutic agent.

However a recent study (Hepatology April 1996) has shown that Adenine arabinoside monophosphate coupled to lactosaminated human albumin (L-HAS-ara-AMP) administered over a four week period exerted the antiviral activity of ara-AMP without producing neurotoxic effects. Unfortunately L-HAS-ara-AMP must be administered by intravenous infusion and this has prompted investigation of new ara-AMP conjugates which my be injected via the intramuscular route.

Adefovir Dipivoxil (GS 890)

FOSTER CITY, Calif., Sept 16 (Reuter) – Gilead Sciences Inc said Monday its GS 840 drug produced “significant and sustained antiviral activity” in a clinical test of 20 patients with chronic Hepatitis B virus, 65 percent of whom also tested positive for the human immunodeficiency virus, the virus that causes AIDS.Gilead said that during four weeks of treatment, GS 840 resulted in a statistically significant mean decline in HBV DNA levels of 97 percent from baseline numbers, compared with an increase of seven percent in the placebo group. All treated patients experienced a greater-than-90 percent decrease in HBV DNA versus none of patients on placebo.

Levels of HBV DNA returned to baseline between one and six weeks after the 28 days of GS 840 dosing. This underscored the antiviral effect of drug treatment, the company said.

During the first eight weeks, one marker of hepatitis infection (Hbe antigen) became transiently undetectable in one patient. GS 840 was well tolerated with only mild to moderate reactions, including moderate nausea in two patients, Gilead said.

GS 840 is an oral drug from a class of antiviral compounds known as nucleotides that seek to prevent viral replication, Gilead said. The drug is also being tested in combination with other drugs to treat HIV.

The company said that in its study, the mean time since Hepatitis B diagnosis was four years and 25 percent of the patients had failed Hepatitis B virus treatment with interferon-alpha.

Antibody Therapy

In a Phase I/II trial of Protean Design Labs Human Anti-Hepatitis B Antibody in 12 patients with chronic Hepatitis B, levels of key markers for Hepatitis B disease such as Hepatitis B surface antigen, Hepatitis B DNA, and enzymes released into the blood by damaged liver cells declined at least temporarily during the treatment period by at least 50% in half or more of the patients who had elevated levels before treatment. Patients were treated for about 5 weeks. In addition, Boehringer Mannheim has conducted a Phase I study in 33 healthy volunteers, and determined that the antibody has a half life of approximately 20 days and was well-tolerated. While the Phase I and Phase I/II trial results are encouraging, the results of early clinical trials may not be predictive of results in larger later-stage trials for various reasons, including differences in patient populations, study size, and trial design, and there can be no assurance that the Phase II clinical trial will demonstrate safety or efficacy.

The Phase II/III trial is expected to begin in early 1997.

Colchicine

Colchine was not shown to improve survival rates in patients with chronic Hepatitis B. However a more recent study showed that colchicine may be of benefit for those with cirrhosis.

ddI

Initial Trials indicate that is ineffective against HBV.

Famciclovir

SmithKline Beecham is evaluating its antiherpes agent Famvir (famciclovir) in the treatment of hepatitis and has recently presented Phase II clinical data for the treatment of chronic Hepatitis B infection, according to Datamonitor. The report notes that significant antiviral effect was observed in interferon unresponsive and refractory patients. These results may have an enormous impact in the treatment of chronic hepatitis patients, if Famvir’s potential use in long-term therapy is proven.

In a recent double blind study (Nov 1996) involving 333 patients Famciclovir treatment resulted in a dose-dependent suppression of Hepatitis B virus replication. A reduction of serum Hepatitis B DNA levels was evident in all famciclovir treatment groups within one week and was maintained throughout the 16 week treatment period. In addition famciclovir reduced patients’ levels of ALTand the normalisation of liver enzymes was sustained eight months after the 16 week treatment period in fifty percent of patients who took 500mg of famciclovir 500 three times a day. Loss of the “e” antigen was also observed and was significantly higher than that found in the placebo group.

Further clinical trials are taking place to determine famciclovir effectiveness as a therapy for Hepatitis B.

Fialuridine

This drugs was found to have severe and lethal toxicity.

Foscarnet (trisodium phosphonoformate)

This is an inhibitor of DNA polymerase which has been shown to have activity against Hepatitis B in vitro. When administered by continuous intravenous infusion it can cause renal dysfunction and results obtained do not suggest an important role for this agent.

Gancilovir.

Given intravenously this drug inhibits HBV DNA but replication continues once treatment is stopped.

Granulocyte Macrophage colony-stimulating factor

A small pilot study of this therapy demonstrated an antiviral effect, as documented by a fall in serum HBV DNA, and may have promise particularly in patients with leukopenia, who would otherwise benefit from interferon therapy

Interferon Beta

Trials are in progress. One study on patients that failed to respond to interferon alpha showed after a 16-24 week treatment with 9 – 15m million units of interferon beta three times a week showed (after 6 months follow up) a sustained clearance of HBV DNA and loss of HBeAg in 30% of cases and seroconversion with the appearance of HBeAb in 19.4% of cases.

Interferon Gamma

Studies suggest that the antiviral activity of interferon gamma is half that ofinterferon alpha.

Interlukin-2

Some transient inhibition of HBV DNA Polymerase has been observed and it could prove useful as it increases lymphocyte counts and CD4 cells.

Interleukin-12

Studies have indicated that interlukin-12 may be beneficial in modulating the antibody and cellular response to Hepatitis B and improve clearance of Hepatitis B.

Isoprinosine

This compound has antiviral and immunoregulatory activity and was reported to induce a serocoversion of HBeAg positive patients in a small trial (Par et al. 1989)

Lamivudine or 3TC

This drug is a potent inhibitor of the Hepatitis B virus by inhibition of DNAsynthesis. Studies to date show it can decrease HBV DNA but in most cases HBV DNA reappeared once treatment was stopped although sustained suppression of HBV DNA and the disappearance of HBeAg has been observed.

Lamivudine has a fairly quick-acting therapeutic effect in many patients and longer therapy is expected to produce more lasting results. The drug is well-tolerated and may be safe for long-term or even indefinite use. To date, over 1,000 patients have received lamivudine for Hepatitis B indications. Glaxo Wellcome is currently conducting 12 trials in 22 countries using lamivudine alone and in combination with alpha-interferon, suggesting that the company believes the drug has considerable potential for Hepatitis B. Most of these are Phase III studies testing the drug for one year using the 100 mg/day dosage. Lamivudine is taken orally, has negligible side effects and is expected to be rather affordable for long-term therapy, possibly under $1,000/year. In contrast, conventional alpha-interferon treatment requires injections three times/week for months, has significant side effects, a course of treatment costs up to 5-times more and has only about a 25%-30% cure rate. Lamivudine eventually may show sufficient long-term efficacy to be used on its own or in combination with interferon or other drugs in development.

Extract From:HIV Drug Works Against Hepatitis B

By Denise Mann. Medical Tribune.January 11, 1996.
Already used to treat HIV, the nucleoside analogue lamivudine also appears to suppress the Hepatitis B virus in the DNA of patients with the chronic form of the disease, Harvard researchers report.

In the study of 32 chronic Hepatitis B patients, traces of the virus disappeared in the DNA of all patients who took 100-mg or 300-mg doses daily of lamivudine (Epivir, 3TC, Glaxo Wellcome) for 12 weeks, according to Jules L. Dienstag, M.D, of the Gastroenterology Unit and Liver-Biliary-Pancreas Center at the Massachusetts General Hospital and the department of medicine at Harvard Medical School in Boston.

Dr. Dienstag and colleagues noted that while Hepatitis B virus (HBV) DNA reappeared in most patients after completion of therapy, six patients (19%), including five who had been unresponsive to interferon, had sustained suppression of HBV DNA, along with a normalization of transaminase elevations.

Moreover, Hepatitis B e antigen disappeared in four of these six patients (12%), he said.

But a longer course of the drug could suppress the virus indefinitely and prevent subsequent liver disease, said Raymond Koff, M.D., chairman of medicine at MetroWest Hospital in Framingham, Mass. The findings are “an exciting new observation, and in a small number of people, we can start thinking about the notion of a cure,” Dr. Koff said. In the double-blind trial, the patients were assigned to either a 25-mg, 100-mg or 300-mg oral dose of lamivudine daily for 12 weeks. Levels of the Hepatitis B virus in genetic material became undetectable (≤ 1.5 pg/ml) in 70% of the chronic Hepatitis B patients who took 25-mg doses of lamivudine, and 100 % of those taking the higher doses, Dr. Dienstag reported in The New England Journal of Medicine (1995;333: 1657-1661).

“It may be premature to get extraordinarily excited,” Dr. Koff said. “But if longer term follow-up studies are done, we may really be talking about a cure.”

Though lamivudine was well-tolerated, all participants in the trial experienced an increase in alanine aminotransferase. In the study, alanine aminotransferase levels at least doubled in five patients given the 25-mg dose and eight patients given the 100- or 300-mg dose. “Although this substance does have a toxic effect on the liver, in most cases it is usually a mild [effect],” said Alfred Prince, M.D., director of virology at the New York Blood Center in New York City.

Lamivudine, also known as 3TC and part of a new class of drugs called nucleoside analogues, seems to be more effective in treating chronic Hepatitis B than interferon, which only works in about 40% of Hepatitis B patients. “It looks as if nucleoside analogues work in people who fail to respond to interferon,” Dr. Koff said, because 17 study participants had no response to earlier therapy. Larger multicenter trials involving 12-month courses of treatment with lamivudine are now underway, the study authors noted. A trial involving the treatment combination of interferon and lamivudine may yield interesting results as well, Dr. Koff said.

Levamizole

This was claimed to inhibit HBV replication in up to 60% of patients (Fattovich et al, 1986) but the results were not proved to be reproducible. Combined trials of levamizole with interferon revealed a higher response rate in those treated with interferon alone(38%) than those treated with the combination (10%) (Fattovich et al, 1992)

N-Acetyl-Cysteine (NAC)

ANTI-HEPATITIS-B VIRUS ACTIVITY OF N-ACETYL-L-CYSTEINE (NAC) – NEW ASPECTS OF A WELL-ESTABLISHED DRUGN-acetyl-L-cysteine (NAC) is commonly administered as an antidote against acetaminophen (paracetamol) intoxication and is the preferred agent in the treatment of pulmonary diseases. It is furthermore commonly considered that it restrains human immunodeficiency virus (HIV) replication by scavenging reactive oxygen intermediates (ROI) and thus suppressing activation of nuclear factor kappa B (NF kappa B). We Show here that NAC is in addition able to inhibit Hepatitis B virus (HBV) replication, but by a mechanism independent of the intracellular level of reactive oxygen intermediates. Treatment of HBV-producing cell lines with NAC resulted in an at least 50-fold reduction of viral DNA in the tissue culture supernatant within 48 h. This decrease of viral DNA and thus of virions in the tissue culture supernatant is caused by a disturbance of the virus assembly, rather than by a reduction of viral transcripts. Our data strongly suggest a potential use of this well-established, non-toxic drug for the treatment of HBV infection. Since NAC, in contrast to interferon, exerts its anti-HBV activity at a post transcriptional level, a combination of NAC with the established interferon therapy could also be considered.

Please see the section on complimentary medicine for more information on NAC.

PC1323

KIRKLAND, Wash., Dec 15 (Reuters) – ProCyte Corp said it presented findings showing the company’s PC1323 compound inhibits the Hepatitis B virus by preventing release of the virus from infected cells.

PC1323 is an isomer, or restructured compound, of ProCyte’s BCDS-copper compound, which the company is studying for its antiviral effects. “We are continuing to find that this family of proprietary compounds appears to inhibit specific viruses related to the outer core, or envelope, of the virus, said ProCyte principal scientist Andrew Branca, in a statement.

Polyadencyclic polyuridylic acid.

In a small trial this compound normalised elevated ALT levels and induced loss ofHBeAg in 11 out of 19 patients and loss of HBV DNA in 12 out of 19 patients. (Hahm et al, 1994)

Reticulose

In a small study this did not have a significant benefit for patients infected with Hepatitis B.

T cell vaccine

Still in the pilot study phase is the use of a vaccine which takes advantage of a T cell epitope for CTL in subjects with HLA-A2.1. It is hoped that this vaccine will induce sufficient immune recognition to initiate viral eradication by cell-mediated mechanisms and immune clearance, without inducing massive hepatocellular necrosis. It is possible that this vaccine may convert the carrier in the inactive `immune tolerant’ phase of their Hepatitis B to an active phase which seems to be a prelude to viral eradication.

Theradigm-HBV

Cytel Corporation, announced some preliminary results from a phase II trial, of 27 patients, of their therapeutic vaccine, Theradigm-HBV.

It appears that Theradigm-HBV stimulated an immune response in patients chronically infected with Hepatitis B. These flares were dose dependent and noflares had been observed prior to the first injection or in those recieving a 50mg dose. Out of 10 patients in the 500 microgram dose group, 2 flares were observed (20%) while 5 of the 12 patients (42%) in the 5000 microgram dose group exhibited flares in their ALT. This observation is potentially significant because the majority of patients who ultimately clear chronic HBV infection as a result of interferon therapy produce a flare in their ALT prior to viral clearance. Another indication of a potential clinical effect is normalization of ALT. Normalization was achieved in 3 of 12 subjects (25%) in the 5000 microgram dose group, and in none of the patients in the 50 and 500 microgram dose groups.

A dose dependent drop in HBV DNA was also observed, despite the high viral burden of the patients in the study group. A drop in the level of HBV DNA at 2 or more time points during the study was defined as a potentially useful clinical effect. None of the 5 patients at the 50 microgram dose level had a 50% or greater drop in DNA, while 2 of 10 (20%) at the

500 microgram dose level and 3 of the 12 (25%) at the 5000 microgram dose level had decreases in HBV DNA greater than 50%. In addition, one patient in the 5000 microgram dose group showed total clearance of HBV DNA and HBeAg.

Thymosin Alpha (Zadaxin)

This drug, produced by SciClone pharmaceuticals has been licensed for the treatment of Hepatitis B in the Philippines, the republic of China and Singapore , SciClone has also filed new drug applications for permission to market Zadaxin in Hong Kong, India, Indonesia, Malaysia, Mexico and Cyprus.

Thymosin is an immune stimulator known to enhance suppresser T cell activity and synthesis of IgG. Given by subcutaneous injection tymosin has been shown to induce clearance of HBV DNA and loss of HBeAg, rates as high as 54% have been reported and rates as high as 76% when used in conjunction with interferon.

The drug is reported to have few side effects and the results from phase III trials are now starting to appear and show promise for Thymosin Alpha as a therapy for Hepatitis B.

Title: A RANDOMIZED CONTROLLED TRIAL OF THYMOSIN-ALPHA-1 VERSUSINTERFERON-ALFA TREATMENT IN PATIENTS WITH HEPATITIS B E-ANTIGEN ANTIBODY-POSITIVE AND HEPATITIS B VIRUS DNA-POSITIVE CHRONIC HEPATITIS B
Abstract: It has recently been shown that thymosin-alpha 1 (T.alpha 1), a synthetic polypeptide of thymic origin, is able to promote disease remission and inhibition of Hepatitis B virus (HBV) replication in patients affected by Hepatitis B e antigen (HBeAg)-positive chronic active hepatitis. We evaluated the efficacy and safety of T-alpha(1) treatment in patients with Hepatitis B e antibody (anti-HBe) and HBV -DNA-positive chronic hepatitis. Thirty three patients were randomly assigned to receive either T-alpha(1), 900 mu g/m(2) body surface area twice weekly (17 patients) or 5 MU of interferon alfa (IFN-alpha) three times weekly (16 patients) for 6 months. At baseline, both groups were comparable concerning age, sex, liver histology, and alanine transaminase (ALT) levels. At the end of treatment, complete response (defined as ALT normalisation and HBV-DNA loss) occurred in 5 of 17 (29.4%) in the T-alpha(1) group and in 7 of 16 (43.8%) in the IFN-alpha group (P = not significant). After a follow -up period of 6 months, a complete response was observed in 7 of 17 (41.2%) in the T-alpha(1) group and in 4 of 16 (25%) in the IFN-alpha group (P = n.s.). Compared with the results observed in a group of 15 patients never treated with IFN-alpha and followed for 12 months, the rate of complete response was significantly higher in the IFN-alpha group at the end of therapy (1 of 15 vs. 7 of 16, respectively; P < .05) and in the T-alpha(1) group at the end of follow-up (1 of 15 vs. 7 of 17, respectively; P < .05). Unlike IFN-alpha T-alpha(1) was well tolerated by all patients. The only side effect, reported by some, was local discomfort at injection sites. The results of this trial suggest that T-alpha>(1) is able to reduce HBV replication in patients affected by anti-HBe positive chronic hepatitis, Furthermore, compared with IFN-alpha, T-alpha(1) is better tolerated and seems to induce a gradual and more sustained ALT normalisation and HBV-DNA loss. In conclusion, T-alpha(1) appears to be a safe and effective alternative treatment for anti-HBe-positive chronic hepatitis. The benefit of this agent in producing long-term inhibition of HBV replication must be confirmed by future trials.

Author: ANDREONE P, POLICLIN S ORSOLA, VIA MASSARENTI 9, I-40138 BOLOGNA, ITALY

Source: HEPATOLOGY 1996 OCT;24(4):774-777

Thymopentin

Results indicate that this agent is ineffective.

Vaccine Therapy

Research has indicated that vaccines may have a use in the treatment of chronic Hepatitis B. See Theradigm-HBV

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