Clinical Trials in the United States.

Treatments for Hepatitis and Liver Disease: What Does The Future Hold

Compiled by Trudy Schreiner

Time seems to crawl when you are waiting for something BIG to happen, like the holidays, your birthday (well, maybe not a birthday), or a new treatment for hepatitis C (HCV). Sometimes it may seem that time is at a standstill. But, rest assured time is also of great importance to researchers who are working to find answers to the viral puzzle called "hepatitis." Did you know that there are a number of new liver disease treatments currently in various stages of clinical trials?

"What are my treatment options?" is probably one of the most frequently asked questions, with, "When will there be new treatments available?" following closely. For several years now, combination therapy, interferon and ribavirin, has been the standard treatment protocol for hepatitis C. But, the side effects, which can include fatigue, muscle aches, headaches, nausea, weight loss, irritability or depression, may be difficult for some patients.

So, what are the options? For now, patients have few choices. It’s monotherapy, interferon alone; the combo treatment; or wait in hopes that something new will soon be available. If you are mildly chronic, with no evidence of fibrosis or cirrhosis, then waiting might be the best option, especially if you are genotype 1, which has proven the most resistant to current therapy.

However, if you have signs of scarring, your physician may recommend that you consider treatment now to try to stop or at least slow down the progression of liver damage. And, for the immediate future, interferon-based treatments will continue to be the standard of treatment.

What are Interferons?
Interferons, first discovered in 1957, are produced naturally by human cells in response to viruses, tumors and foreign substances that can cause the production of antibodies. They "are members of the family of glycoproteins, classified as cytokines, which contribute to the body’s natural defenses against foreign substances," according to the "Frequently Asked Questions" site found at the Interferon Sciences Inc. Website. Interferons have been found to have an antiviral effect or to interfere with a virus’ ability to replicate itself in the body.

Researchers have identified four major classes of human interferons: alpha, beta, gamma, and omega, but only alpha and beta have proved the most useful in medical applications. Alpha interferons have become one of the most important classes of therapeutic products in the world.

New Treatments in the Immediate Future
It is projected that within the next year, a newer form of interferon called pegylated will become available to the public. The pegylated interferons, or long-acting interferons, are alpha interferons that are modified by polyethylene glycol (PEG) so that they can be given once a week and provide a sustained level of interferon within the patient. The pegylated formulations may avoid the peaks and troughs of interferon levels and interferon side effects that occur when it is given three times a week.

Current leaders in the race to bring pegylated interferon to market are Hoffman La Roche and Schering Plough Corporation. Both companies have recently applied to the U.S. Food and Drug Administration (FDA) for marketing approval of their versions of pegylated interferons called PEGASYS (Hoffman La Roche) and PEG-INTRON (Schering Plough Corp.). The new versions of interferons may be especially beneficial to those who have relapsed following monotherapy or combination therapy.
Clinical trials are on-going to study the effects of combining pegylated interferon with ribavirin, an antiviral compound that appears to enhance the effect of interferon in treating hepatitis.

What Therapies are Currently in Clinical Trials?
There are several promising new therapies in various stages of clinical trials. Hoffman La Roche and Maxim Pharmaceuticals are collaborating on a combination of Roche’s pegylated interferon, PEGASYS, and Maxim’s lead drug called Maxamine (histamine dihydrochloride). "Roche clearly represents a great development partner for Maxim due to the success they have had with the clinical development of PEGASYS, and the fact that they share our commitment to advancing the treatment of hepatitis C and cancer," says Larry G. Stambaugh, Maxim’s chairman and chief executive officer.

Research suggests that a universal mechanism in the human body suppresses the capacity of the immune system to detect and destroy virally infected cells in patients with chronic infectious diseases. Maxamine is designed to reverse this immune suppression, thereby enhancing the effectiveness of immunotherapy, a class of therapies that employs the body’s immune system to fight these diseases. Maxamine protects critical immune cells and is administered in combination with stimulators of these same immune cells (cytokines such as interferon-alpha).

SciClone Pharmaceuticals product, ZADAXIN, a synthetic preparation of thymosin alpha 1, a naturally occurring peptide that enhances the ability of the body’s immune system to fight and destroy infected cells, has been approved for sale in 20 countries, including Mexico, Italy, the Philippines, China, Argentina and Peru. The drug, principally used for the treatment of hepatitis B (HBV) and hepatitis C, is presently in phase 2 clinical studies in the U.S. in combination with lamivudine for the treatment of HBV. SciClone plans to start a pivotal phase 3 ZADAXIN hepatitis C trial in the U.S.

Researchers believe that ZADAXIN works by boosting the ability of the body’s immune system to produce T cells, the body’s most potent defense against infectious diseases. SciClone reports that ZADAXIN has a unique therapeutic effect in the treatment of HBV. Patients continue to improve long after treatment has ceased.

In the treatment of HCV, SciClone reports "ZADAXIN has been most successful when used in combination with interferon." Clinical trials indicate that the combination of ZADAXIN and interferon produces "a better, longer-term response than interferon alone, with a positive response seen in 41.9 percent of the patients treated compared with only 16.6 percent among patients treated with interferon alone."
Both Maxim and SciClone report that Maxamine and ZADAXIN, respectively, have been found to be safe with no serious drug-related side effects.

Ribozyme Pharmaceuticals, Inc (RPI) is partnering with Eli Lilly and Company in the development of the anti-hepatitis C ribozyme, LY 466700. Ribozymes are the product of Nobel Prize-winning science and are synthetically engineered to act as "molecular scissors" capable of cleaving target RNA in a highly specific manner. "The unique mechanism of action of this compound offers the possibility for a significant step forward in the treatment of chronic hepatitis C," says Dr. Willis Maddrey, professor of Internal Medicine at Southwestern Medical Center at Dallas.

Clinical development of the compound is continuing, and last May the company reported that in single dose safety trials the drug appeared to be well tolerated in normal volunteers. "We are pleased to be progressing with Lilly to the next study of our hepatitis C treatment," says Ralph E. Christoffersen, Ph.D., president and CEO of Ribozyme Pharmaceuticals. "Thus far, as in other ribozyme clinical trials to date, we have been gratified by the tolerability of the drug."

Administration of LY 466700 to chronic HCV patients is underway in a clinical trial designed to study safety and tolerability and to assess the effect of the compound on HCV viral RNA levels following a 28-day dose-response regimen. The drug is administered daily by subcutaneous injection. Ribozymes are naturally occurring pieces of RNA that act as enzymes and perform numerous functions.

Viragen, Inc. reported in August that it expects to start enrollment of an additional 100 patients by year-end which will mark the beginning of the final stage of its Phase II European clinical trials for HCV with its lead natural interferon alpha drug, Omniferon. Viragen also reports that it will file an Investigational New Drug application (IND) with the FDA by year-end, marking the company’s intention to advance toward regulatory approval in the U.S.

Dr. Peter Cooper, a Viragen Europe Ltd director, says that the trials are being conducted according to both European and FDA criteria. "Therefore, the data from our European trials should be acceptable to the FDA," Cooper says, "and opportunities do exist for expedited FDA review."

The company states the trials will target HCV patient populations representing the following unmet clinical needs, the main requisite for FDA expedited review: 1) Patients who have failed to respond to previous standard treatment; 2) Patients who cannot tolerate the current standard treatment; 3) Patients for whom the current standard combination therapy is absolutely or relatively contra-indicated. The Phase II clinical trial is designed to present clinical data which not only shows that Viragen’s natural human Omniferon fills these unmet needs, but that it may be equivalent or superior to current synthetic interferons. Omniferon is currently in Phase II clinical trials in Europe for HCV.

HBV International Study of Zeffix
In an international study, results showed that the vast majority (86 percent) of patients who lost hepatitis B virus e antigen (HBeAG), a marker of active HBV replication, while taking Zeffix (lamivudine), showed no evidence of disease recurrence almost two years after completing their treatment.

The study, led by Professor Eugene Schiff, University of Miami, tracked 43 patients who had previously lost HBeAG after an average of one year of Zeffix treatment (100 mg once daily) and had then stopped therapy, according to the study protocol. The patients were entered into this study within 12 months of stopping treatment and were followed for an average of nearly two years (21 months).

The interim results presented in May indicate that 86 percent of patients still remain HBeAG-free, with the majority (65 percent) of these patients also showing normal levels of the liver enzyme alanine aminotransferase (ALT) at their last assessment.

An additional result of this study was that 21 percent of the patients who lost HBeAG, has also achieved HBsAG seroconversion. HBsAG seroconversion is widely considered to be an indicator of a probable cure of chronic hepatitis B.

"We are really excited about these results, as the vast majority of our patients who lost HBeAG and then stopped Zeffix treatment, remain in remission. This could completely change current thinking on the length of Zeffix treatment needed for many patients," says Professor Schiff. "The most remarkable finding from our study was that 21 percent of patients have also achieved HBsAG seroconversion. For the vast majority of patients, this is the best indicator that their hepatitis B has been cured." Zeffix is currently available in more than 25 countries including the U.S. (as Epivir-HBV); Canada (as Heptovir); and, China (as Heptodin).

New Anti-rejection Drug for Liver Transplant
Hoffman-La Roche Inc announced in August that it has received marketing clearance from the FDA for expanded use of CellCept (mycophenolate mofetil, or MMF) for the prevention of organ rejection in patients undergoing liver transplantation. CellCept, previously approved for use in kidney and heart transplantation, is used with cyclosporine and corticosteroids.
The FDA based its decision on a double-blind, randomized 565 patient multicenter study to examine the effect of CellCept on acute rejection and survival in liver transplant patients comparing the use of MMF against azathioprine (AZA) in combination with cyclosporine and corticosteroids.

The study, led by Dr. Russ Wiesner, Mayo Clinic, Rochester, Minn., showed CellCept to be superior to AZA in preventing acute rejection six months post-transplant (statistically significant at the <0.05 level).
"The study is affirmation, from a controlled multicenter study, of what numerous single-center studies have previously found," says Dr. Robert Gordon, medical director, Transplantation, Roche Laboratories. "It confirms that CellCept is a very effective anti-rejection tool in kidney, heart and now liver transplants."

THYMITAQ for treatment of Liver Cancer in Fast Track Status
Zarix, Inc announced in August that the FDA has indicated that the design of the pivotal Phase III trial for THYMITAQ (nolatrexed dihydrochloride) for the treatment of unresectable hepatocellular carcinoma is acceptable. The multi-center clinical study will be conducted as a global program with clinical study sites in the U.S., Canada, Europe and South Africa. Zarix anticipates that patient enrollment in the trial will begin in early fourth quarter 2000.

THYMITAQ, a thymidylate synthase inhibitor, is a novel oncology compound that is being developed to treat several different cancers, with an initial emphasis in hepatocellular carcinoma (liver cancer).
"It is our goal to submit a targeted NDA [New Drug Application] package to the FDA so that this potentially life-saving anti-cancer drug can be available for patients as quickly as possible," says Elizabeth Corsi, president of Zarix.

The company expects completion of patient enrollment for the hepatocellular cancer trial in 18 months, with completion of the trial in 24 months and release of the anticipated data results from this trial six months later.

Conclusion
With so many new treatments on the horizon, hepatitis patients have much to look forward to with some therapies, such as pegylated interferons, coming available in the immediate future. But there is still much work to be done before a cure will be found. At the present, the most patients can hope for is a more tolerable treatment that will slow the progression of liver damage. And, for some that will be a welcome relief, in the nick of time.

http://www.hepatitismag.com/stories/Dec/Treatments_for_Hepatitis.htm