New Drugs For Hepatitis C: Part 1 & 2 – Boceprevir And Telaprevir Provide Higher Cure Rates

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New Drugs For Hepatitis C: Part 1 – Boceprevir And Telaprevir Provide Higher Cure Rates

This article is first in a two-part series that will discuss the benefits and drawbacks of two drugs, boceprevir and telaprevir, which are being developed for hepatitis C. Part 1 discusses the efficacy of the two drugs in clinical trials. Part 2 will discuss the complications and side effects for each drug.

A United States Food and Drug Administration advisory committee unanimously recommended this week that two new hepatitis C drugs, boceprevir and telaprevir, be approved. If the FDA follows the committee’s recommendations, people with hepatitis C – including those who are co-infected with HIV – will have promising new treatment choices. However, these new treatment options also have new side effects and potentially complicated dosing regimens.

If the Food and Drug Administration (FDA) follows the advice of the committee and approves the drugs, the drugs could be available to patients as soon as late May. Although the FDA is not required to follow the recommendations of its advisory committees, it usually does.

For many patients, including those who have already been treated with these drugs in clinical trials, the benefits of the drugs outweigh their risks.

Ann Mann Hester, a participant in a telaprevir Phase 3 clinical trial, received several prior treatments for hepatitis C, none of which were successful. Although she experienced side effects while taking telaprevir, she said the treatment was worth it.

“This saved my life. I was living to die. Now I’m living until I die, which is a whole new concept for me,†said Hester.

Nonetheless, many advocates and patients raised concerns about the side effects and dosing schedules, and whether they would affect patients’ ability to successfully take the drugs.

“A three-times-a-day drug every eight hours, with food, with fat, while you’re having diarrhea, nausea, and vomiting – I’m concerned about adherence,†said Lorren Sandt, Executive Director of the Caring Ambassadors Hepatitis C Program.

Boceprevir And Telaprevir Offer Better Cure Rates Than Standard Hepatitis C Treatment

Boceprevir (also known by its proposed brand name, Victrelis) and telaprevir are both hepatitis C virus (HCV) protease inhibitors, which work by inhibiting HCV replication in the body. Both drugs are meant to supplement the current standard for hepatitis C treatment, a combination of the drugs ribavirin (Rebetol, Copegus) and Pegasys (pegylated interferon alfa-2a) or PegIntron (pegylated interferon alfa-2b).

The cure rate of current hepatitis C treatment is around 50 percent. Both boceprevir and telaprevir, when added to the current standard treatment, offer the prospect of better cure rates.

Phase 3 clinical trials showed that boceprevir raised cure rates in both treatment-naïve and treatment-experienced HCV patients to around 66 percent. Cure rates for telaprevir were around 70 to 80 percent for treatment-naïve participants and 65 percent for treatment-experienced patients.

Patients who had participated in clinical trials for the drugs were enthusiastic about the results.

“I had been under four different treatments before and had failed every one by week 12. I had given up hope. I couldn’t be happier,†said Levin, who participated in a telaprevir clinical trial and spoke at the meeting on Thursday. Levin said he had advanced hepatitis C with cirrhosis when he enrolled in the study.

Although the rates for telaprevir appear higher than those for boceprevir, it is not clear whether telaprevir is actually more effective.

Patients who received the standard treatment of just ribavirin plus Pegasys in the telaprevir trials had a higher cure rate than patients in the boceprevir trials who received just ribavirin plus PegIntron. As a result, it is possible that the differences in cure rates between the trials are actually due to Pegasys versus PegIntron, or other differences between the studies. Some studies have found that Pegasys is more effective than PegIntron.

Trials in which telaprevir and boceprevir are compared directly will be necessary before determining whether one drug is more effective than the other.

For people who are co-infected with HCV and HIV, the new drugs may also offer better cure rates. Typically, standard HCV treatment is less effective in people who are also infected with HIV (see related AIDS Beacon news).

While clinical trials in HCV-HIV co-infected patients are ongoing, results so far are promising. Preliminary results from a Phase 2 clinical trial have shown that after four weeks, 70 percent of participants who received telaprevir plus ribavirin and Pegasys had undetectable levels of HCV, compared to 5 percent of participants who received only ribavirin and Pegasys (see related AIDS Beacon news).

In addition, 68 percent of participants who completed 12 weeks of treatment with telaprevir had undetectable HCV levels (note that not all participants had reached 12 weeks of treatment yet when these results were reported). In clinical trials with people who had HCV only, 80 to 90 percent of participants who had undetectable HCV levels at weeks four and 12 were cured after completing treatment.

Merck, which is developing boceprevir, does not yet have information on the efficacy of the drug in patients who are co-infected with HIV and HCV, although a clinical trial is ongoing.

New Drugs For Hepatitis C: Part 2 – Boceprevir And Telaprevir Dosing Regimens And Side Effects

This article is second in a two-part series that will discuss the benefits and drawbacks of two drugs, boceprevir and telaprevir, which are being developed for hepatitis C. Part 1 discussed the efficacy of the two drugs in clinical trials. Part 2 discusses the complications and side effects for each drug.

An advisory committee to the U.S. Food and Drug Administration recommended this week that two new drugs for hepatitis C, boceprevir (made by Merck) and telaprevir (made by Vertex Pharmaceuticals) be approved. Although both boceprevir and telaprevir promise a better chance of a cure, neither drug is particularly easy to take.

Both have fairly complicated proposed dosing regimens in which the length of treatment depends on how well a patient responds to the drugs. In addition, as with all drugs, both boceprevir and telaprevir can cause unpleasant or even dangerous side effects.

Complicated Dosing Schedules

The complexity of Merck’s proposed dosing schedule for boceprevir (also known by its proposed brand name, Victrelis) was a topic of conversation at the advisory committee meeting on Wednesday.

Dr. Lawrence Friedman, one of the advisory committee members, said that clinicians would need “the wisdom of Talmudic scholars†to decipher boceprevir’s prescribing information. The Talmud is the notoriously complex book of ancient Jewish law.

Both Merck and Vertex have proposed that most patients undergo response-guided therapy. Under this model, the length of treatment varies depending on how well a patient responds to the drugs.

For boceprevir, treatment-naïve patients would receive four weeks of standard treatment (ribavirin plus Pegasys or PegIntron), then 24 weeks of standard treatment plus boceprevir (for a 28 week total treatment length). However, if patients still had detectable hepatitis C virus (HCV) levels after eight weeks of boceprevir, treatment would be extended with an additional 20 weeks of standard treatment after finishing boceprevir (for a total treatment length of 48 weeks).

Patients who have been treated previously for hepatitis C would receive four weeks of standard treatment, then 32 weeks of standard treatment plus boceprevir (for a 36 week total treatment length). If patients still had detectable HCV levels after eight weeks of boceprevir, treatment would be extended with an additional 12 weeks of standard treatment after finishing boceprevir (for a total treatment length of 48 weeks).

If HCV is still detectable after 24 weeks or 12 weeks of treatment for treatment-naïve and treatment-experienced patients, respectively, Merck recommends discontinuing treatment with all three drugs.

The dosing regimen for telaprevir is simpler but still complex. Patients take telaprevir, ribavirin, and Pegasys or PegIntron for 12 weeks. If patients have undetectable HCV levels after four and 12 weeks of treatment, they continue to take ribavirin plus Pegasys/PegIntron for an additional 12 weeks (for a total treatment length of 24 weeks). If they have detectable HCV levels at four or 12 weeks, they take ribavirin plus Pegasys/PegIntron for an additional 36 weeks (48 weeks of treatment total).

For both drugs, the FDA may recommend that certain subsets of patients – such as treatment-experienced patients who have had only partial or minimal response to standard treatment in the past – undergo treatment for the maximum 48 weeks.

Both drugs are taken three times daily (every seven to nine hours) and should be taken with food. Vertex noted during the meeting Thursday that it is working on a twice-daily dose of telaprevir.

Patients and patient advocates were both concerned by the proposed dosing schedules and whether their complexity would discourage physicians from prescribing the drugs.

“It’ll be very imperative for the labels of these products, and the medical provider education materials, to be carefully constructed to make prescribing of these drugs an option for a wide group of providers and their patients, and not just a handful of specialists,†said Martha Saly, Director of the National Viral Hepatitis Roundtable, at the meeting on Thursday.

Side Effects May Include Anemia And Rash

Both of the new drugs also have potentially serious side effects. Patients in clinical trials for both drugs commonly experienced fatigue and nausea.

In addition, both drugs were associated with more frequent and severe anemia (low blood iron levels), which was a concern for the advisory committee.

Standard hepatitis C treatment, particularly with ribavirin, is already associated with anemia. Anemia can result in symptoms such as weakness or fatigue; in severe cases it can lead to heart problems and may necessitate blood transfusions.

In the boceprevir trials, around 50 percent of participants experienced anemia, compared to 30 percent of participants who did not receive the drug. In the telaprevir trials, rates were 36 percent and 15 percent for participants who did or did not receive the drug, respectively.

However, participants in the boceprevir trial were allowed to treat their anemia with erythropoietin (EPO), a drug that stimulates production of red blood cells, or lower their dose of ribavirin. As a result, it is uncertain how often boceprevir causes anemia or how severe it is. EPO is not approved by the FDA for treatment of anemia in hepatitis C patients, although some doctors prescribe it anyway.

Participants in the telaprevir trial were not allowed to receive EPO. Around 3 percent of participants taking telaprevir discontinued the drug due to anemia, versus less than 1 percent of participants taking only ribavirin plus Pegasys.

In addition to anemia, a majority of participants taking telaprevir (56 percent) reported getting a rash; around 20 percent experienced discomfort (such as itchiness or inflammation) in the anus or rectum. For most participants these symptoms were mild or moderate and did not lead to discontinuation of the drug.

However, a small number of participants experienced life-threatening rashes while taking telaprevir. In particular, three patients had suspected cases of s Syndrome, a potentially fatal condition in which the top layer of skin begins to die due to a severe immune system reaction.

Usually s Syndrome is extremely rare, affecting an estimated 300 people per year in the U.S. Several committee members were highly concerned that three cases appeared during the telaprevir clinical trials, which included around 2,200 participants.

Some patients expressed concern about the “telaprevir rash†during the meeting on Thursday, and whether patients and clinicians would know how to deal with it.

“What happens if a patient, who knows nothing about rash, gets a rash on a weekend? What are they going to do? They might get nervous. They might stop telaprevir without knowing that they might have waited until Monday to go see their doctor,†said Jules Levin from the National AIDS Treatment Advocacy Project.

Spangenberg, a nurse and participant in one of the telaprevir trials, agreed that careful doctor and patient education would be needed. “I would really like to encourage development of more precise identifying and treatment protocols,†said Spangenberg.

As part of its bid for approval, Vertex has agreed to provide patient and physician educational material on the rash, including when telaprevir should be discontinued.

Spangenberg stated that she did not feel that the side effects of telaprevir, including the rash, were significant enough that people should not take the drug.

“I experienced every single one of the side effects that were mentioned here today,†she said. “I heartily endorse this drug approval. I think it’s just too beneficial to snag up on something like that.â€

http://www.aidsbeacon.com/news/2011/04/29/new-drugs-for-hepatitis-c-part-1-boceprevir-and-telaprevir-provide-higher-cure-rates/

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