Articles on Latest Trials

Patients in a small pilot study have shown positive results using a combination of three medications for hepatitis C (HCV) as a therapy for previous treatment non-responders.¹

It's one in a series of small studies that have been unveiled in the past several years as doctors try to find an effective therapy for patients who don't respond to standard interferon/ribavirin therapy for hepatitis C.

'Improved Response Rates'
The study, sponsored by SciClone Pharmaceuticals, tested the efficacy of Zadaxin (thymosin alpha 1) in combination with pegylated interferon alfa and ribavirin in a group of 23 patients.

"This is the first triple therapy study to evaluate Zadaxin in combination with pegylated interferon alfa and ribavirin," said Eduardo Martins, M.D., Ph.D., vice president of Medical Affairs at SciClone. "These positive 12-week data support our previous data showing Zadaxin used in combination with standard therapies has improved response rates for non-responders."

The researchers found that nearly two-thirds of the patients achieved an early virologic response (EVR), defined as having a positive effect on viral levels as soon as 12 weeks after the start of therapy. Doctors in this study tested patients for evidence of HCV RNA—genetic material in the bloodstream that indicates the virus is present—as a benchmark to determine whether a patient had achieved an EVR.

A patient's EVR is considered necessary to achieve a sustained response, defined as having undetectable levels of the virus 6 months after therapy ends.² But evidence shows a patient who may achieve an early response may or may not achieve a sustained one. Therefore, an early response may not accurately predict treatment outcome, particularly for a patient who hasn't responded previously to hepatitis treatment.

But it is known that if you don't achieve an EVR, it's highly likely you won't achieve an SVR either.

No Treatment for Non-Responders
Currently, there is no one treatment standard for hepatitis patients who don't respond to therapy. According to guidelines from the National Institutes of Health,³some patients who fail to achieve a sustained virologic response (SVR) the first time may benefit from re-treatment with pegylated interferon or ribavirin.

But this depends on the previous type of response, the previous therapy and the difference in potency of the new treatment, the severity of the patient's liver disease, and other factors. Doctors, therefore, must make decisions about re-treating a non-responder on a case-by-case basis.

Sometimes, nonresponders find their viral levels have declined substantially during treatment, but never achieve either an EVR or SVR. Still others may find the condition of their liver improves with treatment, even though they never achieved a sustained response.³

More Trial Plans
Based on positive initial findings, doctors in the Zadaxin study plan to recruit a total of 50 patients with HCV who've failed to respond previously to treatment. None of the patients in this study have shown a response to prior interferon/ribavirin combination therapy.

Of the 23 patients who completed the interim phase of the study, the researchers reported that 61 percent achieved an EVR (a minimum of a 2log10 reduction in HCV RNA), and about half tested negative for evidence of HCV RNA.

Of about 20 patients in the study who had the genotype 1 strain of the virus, which is generally regarded as the most difficult to treat, about 60 percent reported an EVR, and 10 of them tested negative for HCV RNA, the study investigators noted.

During the course of this study, patients will receive 12 months of triple therapy (Zadaxin 1.6 mg two times per week, peginterferon alfa-2a 180 mcg per week, and ribavirin 1000 mg per day), and will be observed for 6 months after completing therapy to measure their sustained response.

The researchers hope to not only reduce viral load, but normalize liver enzymes, which would indicate improved liver function.

"We intend to analyze subsequent data from this study, as well as consider future additional triple therapy studies," Martins explained.

Phase 3 Clinical Trials Ongoing
"However, our primary clinical focus continues to be our two U.S. phase 3 clinical trials targeting Zadaxin in combination with pegylated interferon alfa to be the first FDA approved therapy to specifically address the needs of non-responders," he said.

In each of those phase 3 studies, doctors are testing the safety and effectiveness of Zadaxin combined with pegylated interferon and ribavirin, as well. In one study, patients with HCV but no cirrhosis are being enrolled. Hepatitis C patients with mild cirrhosis will be recruited for the second phase 3 study.

About 1000 patients are expected to be enrolled in the first trial, which is anticipated to conclude in late 2005.

Trials Elsewhere
Other pharmaceutical companies are also in the process of developing drugs to help non-responding patients. Infergen, manufactured by InterMune, is known as consensus interferon. The medication is currently being tested in an ongoing trial, the initial results of which have been positive, investigators at three medical institutions and at InterMune report.

In the open label study, more than half of the 12 patients enrolled who had previously failed to respond to therapy showed a greater than 100-fold drop in viral load after 24 weeks. There's no word on when that study might conclude.

1. 54th Annual Meeting of the American Association for the Study of Liver Diseases. 2003 Oct 24-28. Boston, MA.
2. National Center for HIV, STD, and TB Prevention. Centers for Disease Control and Prevention.
3. National Institutes of Health. Consensus Development Conference Statement. Management of Hepatitis C: 2002. 2002 Jun 10-12.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.

H.I.V. Lessons Used in Hepatitis C Treatment

By ANDREW POLLACK

rugs that interfere with H.I.V. have had a major effect in reducing death and disability from AIDS. Now drug companies are beginning to test the first similar drugs for the hepatitis C virus, which can cause fatal liver disease and has infected far more people than H.I.V.

"If they work, they could have the same impact on H.C.V. that the H.I.V. drugs do," said Dr. Frank Chisari, a professor of virology at the Scripps Research Institute in San Diego.

Hepatitis C is now treated by the combination of alpha interferon, an immune system protein, and a pill called ribavirin. The newest versions of the combination can virtually eliminate the virus in about half of the patients.

But that leaves the other half at the mercy of the virus. Moreover, the treatment has severe side effects that include anemia, birth defects, flulike symptoms, depression and even an urge to commit suicide.

"There's a huge need for better drugs, less toxic drugs," said Dr. Michael G. Katze, a professor of microbiology at the University of Washington.

Neither interferon nor ribavirin was specifically designed to attack hepatitis C. Each appears to give a general boost to the immune system to help it attack the virus, though scientists do not fully understand how they work.

But the new hepatitis C drugs entering clinical trials are designed to interfere with enzymes that the hepatitis C virus needs to replicate, like protease and polymerase. Similarly, the AIDS drugs interfere with two enzymes used by H.I.V. to replicate, protease and reverse transcriptase. Some of the AIDS drugs can also be used for hepatitis B but not for hepatitis C, which operates differently.

It will take years to know if the new drugs will work. But scientists are encouraged by a proof of principle reported by Boehringer Ingelheim, a German drug company, at the American Association for the Study of Liver Diseases conference in Boston in November. The company said its experimental protease inhibitor reduced viral levels by a range of a hundredfold to more than a thousandfold in a small number of patients who took the drug for only two days.

"Sort of a hush went over the audience," Dr. Charles M. Rice, director of the Center for the Study of Hepatitis C at Rockefeller University in Manhattan, recalled.

Others are now entering the race. ViroPharma, a biotech company in Exton, Pa., announced in January that it had begun a clinical trial of a polymerase inhibitor in partnership with the Wyeth drug company. So did Idenix Pharmaceuticals, a biotech company based in Cambridge, Mass. Japan Tobacco reports having a polymerase inhibitor in Phase 2, the middle stage of clinical trials.

Vertex Pharmaceuticals, also of Cambridge, has said it will start a trial later this year of a hepatitis C protease inhibitor and Rigel Pharmaceuticals of South San Francisco, Calif., plans to start a polymerase inhibitor trial this year. Isis Pharmaceuticals of Carlsbad, Calif., is in Phase 2 trials with a drug that tries to interfere with a different part of hepatitis C.

Hepatitis C has infected about four million Americans and 170 million people worldwide, about four times as many as H.I.V.

Hepatitis C is spread mostly by needles or blood transfusions, rarely sexually. The rate of new infections in this country has dropped sharply to about 25,000 a year since a test to screen donated blood for the virus was approved in 1990. But there are still many people infected before the test was used that have yet to develop symptoms. The Centers for Disease Control and Prevention estimates that the number of deaths from hepatitis C, now 8,000 to 10,000 annually in the United States, could triple by 2010.

But while there are now well over a dozen drugs that directly interfere with H.I.V. enzymes, there are none that work that way for hepatitis C.

Scientists say one reason for the discrepancy is that the hepatitis C virus was identified in 1988, four years after H.I.V. Still, numerous drugs for AIDS were approved within 15 years of its discovery. In contrast, 15 years after the hepatitis C discoveries, the first drugs are only entering clinical trials.

Another reason, some scientists say, is that there has been much more federal financing for H.I.V., which has been considered more of a crisis than hepatitis C and has patients who have fought hard for money for research and treatments. Also, many people with the hepatitis C virus never get sick or do so only 10 or 20 years later.

Yet another factor, some say, is that the Chiron Corporation, the biotech company in Emeryville, Calif., that first identified the hepatitis C virus, has demanded too much money for licenses to its patents, discouraging companies from entering the field.

"Chiron has been a little bit like a dog with a bone," said Dr. Donald G. Payan, executive vice president and chief scientific officer of Rigel. "I think they really slowed the field down. A lot of people just didn't want to get into it."

Gilead Sciences, which has developed successful antiviral drugs for H.I.V. and hepatitis B, dropped work on hepatitis C after being sued by Chiron. Vertex, which says it does not violate the patents, is in the midst of a lawsuit.

Robert P. Blackburn, chief patent counsel for Chiron, said the company's patents were available for drug discovery to all comers for a modest upfront fee and royalties if a drug made it to market. He said Chiron took a significant risk in embarking on research to discover the virus and deserved to share in the proceeds from drugs developed by others.

"Clearly companies like Vertex would not be working on an H.C.V. drug today but for our inventions," Mr. Blackburn said.

Still, most scientists agree, the biggest obstacle to the development of drugs for hepatitis C has been the inability to grow the virus in the test tube, a fact that makes it hard to study the virus or to test potential drugs. In addition, there are no animals that get hepatitis C except chimpanzees, which are expensive to use in testing.

Scientists have started to circumvent those problems. In 1999, Dr. Ralf Bartenschlager, then at the University of Mainz and now at Heidelberg University in Germany, developed an artificial viral system known as a replicon. Dr. Rice of Rockefeller University, who was then at Washington University in St. Louis, improved on it.

The replicon consists of some of the RNA from hepatitis C, including that for the protease and polymerase enzymes. This RNA is put into liver tumor cells that can be grown in culture.

The replicon does not produce complete new viruses. But it does reproduce itself using the protease and polymerase enzymes. So drug companies can use the replicon to test if their protease or polymerase inhibitors seem to interfere with replication of the replicon.

"That's definitely a breakthrough that every group has used," said Dr. Marc Collett, vice president for discovery research at ViroPharma.

As with H.I.V., hepatitis C virus mutates rapidly and is likely to develop resistance to drugs, so combinations of drugs will probably be needed. "No one really knows what it's going to take for the antiviral effect to outrun the resistance effect," said Dr. Nathaniel Brown, vice president for hepatitis clinical research at Idenix Pharmaceuticals.

But, he and others said, hepatitis C may be easier to treat in some ways than AIDS. That is because H.I.V. turns its RNA into DNA, which is incorporated into the chromosomes of cells it infects, making it hard to totally eliminate the virus. But hepatitis C virus does not do that, and the experience with interferon has shown that if the virus can be eliminated, patients can be cured.

Dr. Amy Weiner, director of hepatitis C research at Chiron, is optimistic. "It does appear with the data we have to date that it is possible to cure people with H.C.V., which has never been shown with H.I.V.," she said.

IIntercell starts European Phase II trials of therapeutic hepatitis C vaccine
European multi-centre study to assess safety, efficacy and dosage

Vienna, Austria, November 25, 2002 – Intercell AG today announced the start of a Phase II clinical study of its therapeutic hepatitis C vaccine. The European multi-centre, dose-escalation study will be conducted on hepatitis C virus (HCV)-positive patients who exhibit no response to interferon-ribavirin combination therapy (the primary treatment on the market). Around 15-30% of patients do not respond to the interferon-ribavirin combination therapy, which can have severe side-effects, and for these patients there is currently no alternative treatment. The trial will assess the safety, efficacy, and the most viable dosage of the vaccine. Intercell is one of a few companies worldwide with an HCV-vaccine in this stage of development.

“Following earlier successful studies it is very exciting to see our novel vaccine moving into a new phase of development and becoming a highly promising product for the future treatment of chronic hepatitis C,” said Intercell’s CEO Alexander von Gabain.

Internationally recognised experts at 5 different renowned institutes in Europe will administer the treatment, which consists of six injections over five months. The vaccine combines a pool of five peptides, which make up various components of the hepatitis C virus, and poly-L-arginine which is known to stimulate the immune system. Once the vaccine is administered, the stimulated immune system learns to recognise and destroy the five HCV peptides. If the patient now becomes infected with HCV, or is already infected with HCV, the immune system will have retained the ability to destroy the HCV peptides and will remove the HCV infection. The five peptides were identified through studies of rare people who have natural immunity to HCV. Intercell’s vaccine enables patients to mimic the immune systems of people with natural immunity.

Intercell’s clinical director Jürgen Frisch said: “If the study, which is scheduled for completion towards the end of 2003, is successful we plan to go ahead immediately with further development of the vaccine to enable international regulatory filing of the product to start in 2007.”

Intercell AG: Intercell is an international biotechnology company located in Vienna, Austria, with a staff of 94 drawn from 18 different countries. The company is developing a new generation of therapeutic and prophylactic vaccines against infectious diseases including hepatitis and tuberculosis, and against certain types of cancer. Intercell has a number of technology platforms which it is using to develop so-called “smart vaccines”. These consist only of the essential components — antigens and “immunizers”(adjuvants) — required to bolster the body’s natural immune defences.

For additional information please contact: Guido Unterberger Corporate Communications

INNOGENETICS GETS POSITIVE HEPATITIS TRIAL RESULTS

BRUSSELS (Reuters) Jul 03 - Innogenetics said on Thursday the latest
test results on its hepatitis C vaccine showed that it not only halted
but also reversed related liver disease, sending its stock more than 10
percent higher.

The Belgian biotechnology firm said additional results from mid-stage,
or Phase II, clinical trials supported previous findings on the
vaccine's effectiveness.

"These results...strengthen the evidence that the E1 therapeutic vaccine
may not only halt, but actively induce regression of HCV-related liver
disease," read a statement.

The stock initially climbed 10.8 percent before falling back to 12.52
euros, up 6.10 percent on the day. Volume totalled 23,583 shares,
slightly more than the average daily volume. The share has nearly
doubled in price since April.

ING analyst Maud Watelet said the news reinforced the impression that
the firm was making progress on developing a therapeutic vaccine with
huge market potential, given the millions of people infected by the
disease. "It has a positive effect," she said.

The trials involve 35 patients in Belgian hospitals.The therapeutic
vaccine, which uses the E1 protein, is designed to treat people already
infected by the disease.Based in Ghent, Innogenetics is investing about
half its research and development budget into developing a series of
treatments for hepatitis C, the therapeutic vaccine being the most
important one, said spokesman Jean-Christophe Donck.

The firm, which works with major drug companies like Bayer and Roche to
develop medical test kits and therapeutic vaccines, hopes to market it
by 2008, he said

Alexander(Andy) Aitken.
National Chair
canadian hepatitisCnetwork (CHCN)
Toll Free: 1-866-895-0690
Fax: (416) 969-7420
151 Bloor Street West
Suite 600
Toronto, Ontario. M5S 1S4

March 11, 2003

H.I.V. Lessons Used in Hepatitis C Treatment