Coming Attractions

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Coming Attractions

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Experimental treatments for hepatitis B and C are moving through the approval process

by Tutt

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Treatment decisions have never been easy for people with hepatitis B or C. Many hepatitis C patients, for example, must decide whether to endure 48 weeks of pegylated interferon/ribavirin treatment for, at best, a 50 percent chance of being cured. Patients without severe liver damage may opt to wait, hoping that a more effective treatment will become available before the virus causes irreparable liver damage. Others still, who tried treatment but did not clear the virus, have little choice but to wait and hope.

“I’m dying for another treatment,” says Gavriela de Boer, of Corrales, N.M., a small community between Albuquerque and Santa Fe. De Boer, 59, had seemingly beaten the hepatitis C virus with 72 weeks of treatment. There was no sign of hepatitis C in her bloodstream. But the virus returned and, rather than go through the side effects again, which were harsh for her, she and her doctor have decided to wait for other drugs to become available.“I’m closely monitored to make sure my enzymes and viral load don’t go crazy,” says de Boer, who contracted a rare strain of hepatitis C – genotype 4 – through a blood transfusion in Africa in the late 1960s. “I take good care of myself. I haven’t had a drop of alcohol since I was diagnosed 15 years ago,” she says. As president of the New Mexico Hepatitis C Alliance, a nonprofit advocacy/awareness organization, she keeps abreast of the current hepatitis C research in hopes that one of the drugs being developed will someday rid her of the virus. The good news for patients like de Boer is that there are many experimental hepatitis C drugs in various phases of development. What remains to be seen is how effective they will be and how soon they will be on the market.

Hepatitis C researchOne of the hepatitis C drug candidates that is furthest along in clinical trials is the protease inhibitor telaprevir, formerly known as VX-950, which is being developed by Vertex Pharmaceuticals.

Protease inhibitors are part of a broader category of drugs called STAT-C (specifically targeted antiviral therapy for hepatitis C), says Alam, M.D., executive vice president of medicines development and chief medical officer at Vertex. “These are drugs that target very specifically a component of the virus – most importantly, a component of the virus that it needs to make additional copies of itself ... to continue to infect someone,” says Dr. Alam, who has been involved in antiviral research for more than 15 years.Any given particle of the hepatitis C virus is in the body for only a few hours, Dr. Alam explains, and the virus must continually reproduce itself in order to maintain an infection. “It’s an active virus in the sense that the virus is dying off, but before it dies off, it makes additional copies of itself to continue,” he says. “The idea behind the STAT-C agents is that if you can target the parts of the virus’ machinery that are involved in making additional copies of itself, then, in principle, you can shut off the infection.

“The two parts of the virus’ reproductive machinery that are best understood by researchers are protease and polymerase,” continues Dr. Alam. “When the (hepatitis C) virus gets inside a liver cell, it already has the machinery that it needs to make additional copies of itself, but it comes as a package that needs to be cut into the individual components before it can make the copies.” He uses a model airplane as an illustration: The pieces of the model are fused together on a plastic sheet and have to be broken apart before they can be assembled into an airplane. “And the job of cutting the individual pieces – that job lies with the protease,” he says. “When you have all the individual components, one of those components that it uses to make individual copies of itself is the polymerase.”

Like protease inhibitors, polymerase inhibitors are STAT-C drugs that interfere with the reproductive machinery of the virus. Several polymerase inhibitors are in early clinical trials, including Roche’s R1626, ViroPharma/Wyeth’s HCV-796, XLT Biopharmaceuticals’ XTL-2125 and Idenix’s NM283 (valopicitabine). , M.D., vice president for global medical affairs at Idenix, says that the different types of STAT-C drugs yield different results. “Clearly, from the results we’ve seen so far from companies that are developing protease inhibitors versus polymerase inhibitors, the polymerase inhibitors provide you with a modest but durable response and offer low resistance over time, and protease inhibitors typically offer you a potent response – but there is certainly more concern in terms of resistance,” says Dr. , who has worked in HIV, hepatitis B and hepatitis C drug development for 15 years.

Although STAT-C drugs are currently being tested as monotherapy or in combination with pegylated interferon/ribavirin, Dr. says that the future of hepatitis C treatment is likely to involve combinations of polymerase inhibitors like valopicitabine and protease inhibitors such as Vertex’s telaprevir or Schering’s SCH 503034. “We’re very excited about the future of combination therapy,” she says. “Talking about where these drugs act, they both would inhibit viral replication, but ... they target different points in the virus life cycle.”

Dr. says that there are no specific plans for Idenix to start a combination trial with valopicitabine and a protease inhibitor; however, the FDA indicated in October that such a study might be allowed even before both drugs have completed phase III trials. “Up until now, I think people have been skeptical as to whether the FDA would permit that. But I think they’ve given us at least a signal that they are willing to consider combination registration trials if each individual agent has existing phase IIb data.” The safety and efficacy data gathered in phase II studies would enable the FDA to assess the risks and benefits of such a study, she says.

“It’s a very similar arena to what we saw in HIV a decade ago,” Dr. says. “Certainly, the main goals of therapy for all antiviral agents are similar: You want to get the best potent viral suppression that you can, and you want to avoid or minimize viral resistance in the long term. The combination of a polymerase inhibitor and a protease inhibitor is most likely to offer that to patients.”

Dr. Alam says that he also expects the FDA to allow combination studies involving two STAT-C developmental drugs when the drugs have adequate safety data. “We are very much actively considering starting one or more studies of telaprevir with a polymerase inhibitor,” he says, adding that such a study could begin “within the next year or two.” He adds, “All of us in the field, both on the industry side and the clinician side, would say that this is where the field would have to move to get the best outcome from an efficacy standpoint as well as – if we can remove the interferon – from a side effect standpoint.”

Dr. agrees. “We feel it’s probably pertinent to start looking at combinations of these drugs so that we can aim for better SVR (sustained viral response) outcome,” she says. “We’re pretty excited that combination therapy seems to be the trend for the future.”

Other experimental drugs currently being tested --include Migenix’s Celgosivir and VGX Pharmaceuticals VGX-410C, which inhibit hepatitis C viral proteins, and Achillion’s ACH-0137171, which inhibits replicase, a polymerase enzyme. Suvus, an antiviral drug developed by Bioenvision, is being tested in hepatitis C genotype 4 patients in Egypt.Numerous trials of longer-lasting interferons are ongoing, including a phase III trial of Human Genome Sciences’ Albuferon. Viramidine, a form of ribavirin developed by Valeant to reduce the anemia side effect, failed to meet the efficacy endpoint of its phase III trial last year. The drug is now being evaluated in a phase IIb study to determine its efficacy at higher, weight-based doses. Dr. Alam says the improved interferons and improved ribavirin are, for the most part, “designed to improve side effects, not necessarily to improve the percentage of patients who get to an SVR.”

Hepatitis B researchHaving multiple treatment options can be a mixed blessing. As hepatitis B patients know, having multiple FDA-approved treatments does not necessarily guarantee a cure. Six drugs currently are approved by the FDA for the treatment of hepatitis B: interferon-alpha (Intron A), pegylated interferon (Pegasys), lamivudine (Epivir), adefovir dipivoxil (Hepsera), entecavir (Baraclude) and telbivudine (Tyzeka). Of these, lamivudine, adefovir, entecavir and telbivudine are polymerase inhibitors.

Block, Ph.D., a professor at Drexel University College of Medicine, serves as president of the Hepatitis B Foundation and its research institute, the Institute for Hepatitis and Virus Research. Dr. Block says that there is a “huge importance” in having a variety of hepatitis B polymerase inhibitors because one drug might be effective on a strain of the virus that is resistant to another drug.“They’re very important in the management of the disease. Will they result in lasting milestones – strong clinical benefits beyond drug usage – or do you have to take these drugs forever? That remains to be seen. Certainly the early indications are that they’re doing a lot of good, but for many people – maybe half the population of people who take these drugs – there’s not a clear long-term benefit. That’s why we at the foundation are so committed to finding alternatives.”

The Hepatitis B Foundation is located in Doylestown, Pa., a suburb of Philadelphia, and is one of the nation’s leading research organizations. “We have more than 55 or 60 scientists working on hepatitis B, C and liver disease,” says Dr. Block. “We at the Hepatitis B Foundation are searching for molecules – and have leads – that inhibit hepatitis B virion formation and secretion. And we’re working toward molecules that inhibit CCC DNA formation.”

Covalently closed circular (CCC) DNA, he explains, is “considered the root of all evil for hepatitis B. It’s the chromosome of the virus that lodges itself in the middle of the nucleus of a cell, and no drug can get rid of it. It just sits there.” When treatment is stopped, Dr. Block says, if any CCC DNA exists in a patient’s cells, the hepatitis B virus re-emerges.

“It’s kind of like you keep your foot on the barn door with the polymerase inhibitors, and nothing can get out. Then you take your foot away. Eventually it re-emerges.” Dr. Block says that previous research done at the Hepatitis B Foundation’s research facilities led to the discovery of glucosidase inhibitors, which are currently being studied as treatments for both hepatitis B and C. Celgosivir (MX-3253), a glucosidase inhibitor being developed by Migenix, has been shown to complement interferon’s anti-hepatitis C activity in phase II trials. “It inhibits viral protein folding and dooms the virus proteins and particles in the infected cell to degradation,” Dr. Block says, adding that glucosidase inhibitors are in early trials for hepatitis B as well.

XTL Biopharmaceuticals is testing monoclonal antibodies to fight both hepatitis B and C. According to Dr. Block, monoclonal antibodies are proteins that bind to the virus’ outer envelope, which is also called the S envelope. “People with chronic HBV do not make antibodies against HBV envelope S and are thus defenseless,” Dr. Block says. “People who are successfully vaccinated make these antibodies and are thus protected.” The possible risks of this type of drug, Dr. Block continues, include the emergence of mutant strains of the virus and the possibility of toxicity.

HepaVaxx B is a therapeutic vaccine being developed by Virexx in Canada. “Their compound is a chimeric molecule of hepatitis B proteins and a molecule that directs the protein to immune dendritic cells,” Dr. Block says. A chimeric molecule contains genetic material from two different species.

Several new polymerase inhibitors may soon be available for hepatitis B treatment. Gilead’s emtricitabine (Emtriva) and tenofovir (Viread), which are both approved for HIV treatment, are being tested in phase III trials in hepatitis B patients. Also in phase III testing is Pharmasset’s clevudine, which Dr. Block calls “the most immediate thing in the pipeline” for hepatitis B. Among the polymerase inhibitors in phase II trials for hepatitis B are Idenix’s valtorcitabine and Anadys’ ANA 380.

The FDA approval processClinical trials are designated as phase I, phase II or phase III trials depending on the drug’s stage of development and on the purpose of the trial. In general, phase I trials evaluate the safety of the drug in humans, then phase II trials determine the dosing for phase III, which is a larger study (usually more than 1,000 patients) to determine safety and efficacy. The FDA and/or the regulatory agencies of other countries are involved in every step of the clinical trial process.

Hallinan, who holds a Ph.D. in pharmacology from the National University of Ireland, is the vice president of regulatory affairs for Idenix. He has been with the company throughout the testing and approval process for telbivudine, which was approved for hepatitis B by the FDA in October. The approval process began, he says, with the investigational new drug (IND) application, which must be approved by the FDA before a drug can be used in clinical trials in the United States.

“There’s a whole battery of those animal studies and those test tube studies that the FDA mandates that you conduct before you start your clinical trial,” Dr. Hallinan says. “You send the FDA all of your preclinical (data) and all of your lab manufacturing information, as well as your planned protocol. The purpose of the IND is to get approval to do a clinical trial. The supporting information has to justify the safety and the duration of that clinical trial.”

Idenix was under no obligation to file its IND application at that time because the phase I studies were done in Hong Kong and Singapore. “That was primarily because this was hepatitis B, and the bulk of the patients are in Asian countries,” Dr. Hallinan says, but adds that the company prefers to have the FDA involved early in its drug development process. “It has always been our corporate philosophy to do all of our drug development under a U.S. IND.” The alternative would have been to wait and file the IND prior to beginning phase II or phase III trials in the U.S.Normally, the first phase I trial of a drug is done in healthy volunteers – in this case meaning volunteers without hepatitis B – to determine the drug’s safety. However, Dr. Hallinan says that because telbivudine had been through extensive animal trials with an excellent safety profile, the first human trial of the drug was a four-week safety and efficacy trial in patients with hepatitis B.

“Then, when you move into phase II, you are trying to refine and hone in on your dose,” Dr. Hallinan says. Phase II trials are done in patients who actually have the virus, and the trial has a longer duration than a phase I trial. The phase II studies of telbivudine compared 400 mg and 600 mg doses of the drug, as well as a combination of telbivudine and lamivudine.

While phase I and phase II studies are taking place, animal studies might be ongoing to determine the effects of long-term use. Dr. Hallinan says that when phase II trials are completed, the drug company and the FDA have a meeting. “The primary purpose of your end-of-phase-II meeting is to get the FDA to buy in on your phase III plan,” he says. “This plan includes the endpoints of the proposed trial, patient inclusion and exclusion criteria, treatment duration and dosage, etc. The FDA will then suggest changes to parts of the plan.”

In the case of telbivudine, Dr. Hallinan says that the meeting was part of an ongoing dialogue between the drug company and the FDA. “We got a lot of positive feedback from the FDA, and we were able to incorporate that into a revised phase III protocol that we then resubmitted back to the FDA before we started the phase III trial.”

The GLOBE trial, as the phase III telbivudine trial was called, enrolled more than 1,300 patients at 40 sites in 20 countries. According to Dr. Hallinan, it was the largest phase III hepatitis B clinical trial performed to date. With sites in North America, Europe and Asia, he says, it was “truly a global program.”

Submitting the clinical trial applications and going through the review process for 20 countries was “a tremendous undertaking,” Dr. Hallinan says. Meetings similar to the end-of-phase-II meeting with the FDA were held with regulatory agencies from these nations, and the company had to develop a protocol that was acceptable to all of them. “Before you can do any clinical trial in any country, you have to submit the protocols and the appropriate backup information via a clinical trial application,” he explains. “Each country has its own regulatory review and ethical committee review process ranging anywhere from one month to – Italy took 12 months, but that’s well known, for Italy to take their time in approving protocols.”

The GLOBE study was done with an active control group – that is, patients not receiving telbivudine received lamivudine (an FDA-approved anti-HBV drug) rather than a placebo. Dr. Hallinan says the study began in late 2002. “It took a long time to enroll so many patients.”

At the end of the phase III trial, another crucial meeting between the pharmaceutical company and the FDA takes place: the pre-NDA (new drug application) meeting. “Typically you have the meeting six to nine months before you plan to submit the marketing application – the NDA,” Dr. Hallinan says. At this meeting, the FDA reviews the existing data from the trials, including virology data such as resistance profiles. Also, the format and content of the NDA is discussed.

Dr. Hallinan says that the NDA for telbivudine was submitted in the relatively new electronic format called electronic common technical document (ECTD). “It facilitated enormously the FDA’s review of our application.” The ECTD contains in one disk information that would fill 50 bound volumes, according to Dr. Hallinan. “The old days of having a big truck back up to your loading ramp at the back of the building and filling it with 60 to 100 boxes of paper are long gone now.”

Idenix delivered the NDA to the FDA on Dec. 30, 2005 and received approval in October. While this was going on, similar marketing applications were going through the approval process in other countries. Dr. Hallinan describes the six-and-a-half year interval between the IND application in May 2000 to FDA approval as “a remarkably short period of time.” He says that the process takes seven to 11 years for most drugs. In part, he credits this to the drug’s “remarkable” safety profile.In addition to the major meetings, Dr. Hallinan says that conference calls between the drug company and the FDA take place throughout the development process.

Clinical trialsThe drug development process begins long before the first clinical trials. Dr. Alam says Vertex began researching protease inhibitors in the late1990s, and the first animal studies of telaprevir were done in 2002. Then three phase I trials were done to confirm the drug’s safety and to determine how long the drug would remain in the body. The first two trials tested telaprevir in healthy volunteers; in the third trial, hepatitis C patients received telaprevir plus pegylated interferon. Dr. Alam explains that this was considered a phase Ib study instead of a phase II study because the duration of the trial was not long enough to be considered treatment. However, researchers did check patients’ viral loads to confirm antiviral activity.

“What we saw was a substantial reduction in HCV RNA levels in the blood with two weeks of giving the drug,” Dr. Alam says, adding that the viral load reduction was greater than he had ever seen in an investigational drug. “What that led us to is a concept of combination therapy where telaprevir is suppressing most of the virus, while pegylated interferon essentially mops up the virus that telaprevir can’t take care of by itself.”

Vertex filed for and received fast track designation when it submitted the IND application for telaprevir. This was done before the first phase II trial because the phase I trials had been done in Europe. Dr. Alam says that the fast track designation allows the drug company to work more closely with the FDA to “better and more expeditiously” develop drugs that could be important medical advances.

In the phase II study, 12 patients received telaprevir plus pegylated interferon plus ribavirin for 28 days. All 12 patients achieved undetectable virus levels. These results provided the rationale for a larger phase II study, which is in progress, of several different treatment combinations of telaprevir with pegylated interferon and/or ribavirin. Data from the phase II trials will be available over the next year.

Dr. Alam says that he and other researchers expect the side effects of telaprevir to be minimal because the drug targets protease, which is not found in human cells. “As far as we know, there are no analogous components (to protease) in the human proteins,” he says. “You’re not working by affecting some component of the human body.”

Many drugs, however, are found to be unsafe during clinical trials. In February, Gilead Sciences and Achillion Pharmaceuticals announced that they were halting development on a drug called GS 9132, also known as ACH-806. A phase Ib trial showed that the drug, which inhibits a viral protein that binds to the hepatitis C virus protease, caused elevations of serum creatinine (a marker of kidney function) in the study subjects. Although such setbacks are disappointing, medical researchers know that they are to be expected.

In the trenchesA clinical trial may take place at multiple testing sites. These are the front lines of drug development, where laboratory research meets clinical treatment – and each site has a principal investigator, a doctor who makes sure that the predetermined protocol is followed while helping the patients themselves with treatment decisions. Dieterich, M.D., chief medical officer of Mount Sinai Medical Center in New York City and an associate professor at New York University School of Medicine, is the principal investigator of the current phase II trial of valopicitabine (NM283) plus pegylated interferon at the Mt. Sinai site.

The study began with five treatment arms, but it was reduced to two arms after patients receiving higher doses of the polymerase inhibitor experienced gastrointestinal side effects. Dr. Dieterich says that some patients have completed the trial and others are finishing treatment now, so the SVR data should be available within six months.

So far, Dr. Dieterich is enthusiastic about the results. He says that he expects the phase III trial of valopicitabine to be launched this year. “I think it will be one of the building blocks for hepatitis C combination therapy in the future, with or without interferon,” he says. “This is one of the first two active antiviral drugs that are being tested. One drug will be approved first and the next one will add something to it, and the next one will add something else. It’s an exciting time in hepatitis C research. It’s like HIV was 15 years ago.”

It is indeed an exciting time in hepatitis research – so exciting that it’s difficult to keep up with all the new drugs being tested.

http://www.liverhealthtoday.org/viewarticle.cfm?aid=161