Tuesday, August 16, 2011

Incivek/Victrelis; New approvals may change treatment for hepatitis C

Hepatitis C Resource Center
Posted August 16, 2011

New approvals may change treatment for hepatitis C

The recent approvals of the new medications for hepatitis C are expected to revolutionize treatment.

Boasting sustained viral response rates of up to 75% in treatment-naive patients, telaprevir (Incivek, Vertex Pharmaceuticals) and boceprevir (Victrelis, Merck) are being heralded within the infectious disease community, but many clinicians are urging judicious use.
The FDA approved telaprevir in May, based on results of trials that looked at the use of telaprevir 750 mg assigned three times daily for 12 weeks combined with peginterferon and ribavirin. This medication increased sustained virological response rates by 20% to 40% across a broad range of disease and demographic characteristics.

The FDA also approved boceprevir in May for the treatment of chronic hepatitis C virus genotype-1 infection combined with peginterferon alfa and ribavirin in adult patients. That approval was based on data from the HCV-Respond 2 trial and the SPRINT-2 trial, which suggested that the addition of boceprevir to peginterferon-ribavirin treatment resulted in significantly higher rates of sustained virologic response in patients previously treated and patients with previously untreated HCV genotype-1 vs. pegylated interferon and ribavirin alone.
To further explore what these approvals mean, the editors at Infectious Disease News interviewed experts on these medications and their implications for treatment. It is our hope that, because there are currently no head-to-head comparison trials of these medications, this story can provide a snapshot of some of the differences between the medications.

IDN: What do the approvals of boceprevir and telaprevir mean in terms of current practice for patients on standard therapies?

Rajesh T. Gandhi, MD, associate professor of medicine at Massachusetts General Hospital: Approval of these two agents means that most patients with genotype HCV infection can now be treated with the three-drug combination therapy of a protease inhibitor plus peginterferon plus ribavirin. In addition, a substantial fraction of patients can be successfully treated with 6 months of triple therapy rather than 1 year. This is a major advance that promises to revolutionize HCV treatment.

Paul J. Pockros, MD, director of clinical research, Scripps Translational Science Institute and head of the division of gastroenterology/hepatology, Scripps Clinic, in La Jolla, Calif: We are on the verge of a new era in HCV management, but there will be challenges in terms of implementation, as is the case when all new medications are brought to market. Practice requirements will likely increase as patient visits increase. Laboratory tests will be needed before these medications are prescribed for some patients, including genotype subtyping for G1 and IL28B polymorphism testing for selected patients. Physicians will need to pay careful attention to the subtype of G1 virus because the data show that both telaprevir and boceprevir are less effective in G1a than G1b, mostly due to a higher rate of viral breakthrough. Also, viral load testing will be needed frequently during the first 24 weeks of therapy to comply with response-guided therapy guidelines and early futility rules established for the two drugs.

Debra Birnkrant, MD, director of the FDA’s antiviral products division: Chronic hepatitis C is both a global and domestic problem, with 170 million estimated to be infected worldwide and approximately 3 million infected in the United States, according to FDA data. Of the 5.6 million veterans in veterans’ health care in 2008, 2.6 million had a diagnosis of chronic hepatitis C. Although the incidence of infection in the United States is decreasing, chronic hepatitis C-related complications are increasing such as psorosis and hepatocellular carcinoma. With the aging of the infected population, more liver-related complications are expected in the next 10 to 20 years without the use of potent antiviral therapies.

IDN: What are the biggest differences reported to date between boceprevir and telaprevir? What has been reported in terms of adverse events?

Gandhi: A 4-week lead-in period of peginterferon plus ribavirin is given with boceprevir but not with telaprevir. In terms of adverse events, in phase 2 and phase 3 clinical trials, 49% of patients in the boceprevir groups had hemoglobin values less than 10 g/dL, compared with 28% of those in the control groups, according to findings published in The New England Journal of Medicine. Use of erythropoiesis-stimulating agents to treat anemia was more frequent in the boceprevir groups (43%) than in the control groups (24%). However, discontinuation of treatment was only about 1%. Decreased neutrophil and platelet counts were more common in the boceprevir groups, as was dysgeusia (35%-44% in boceprevir groups vs. 11%-16% in control groups).
The main adverse effects of telaprevir that have been associated with the medication include rash, anemia, nausea and other gastrointestinal symptoms, and anorectal discomfort. In clinical trials, rash developed in 56% of patients who received T+PR, compared with 34% who received PR alone. Patients with mild to moderate rashes may continue therapy with careful monitoring. Telaprevir should be stopped if a rash progresses and becomes severe, or if systemic symptoms develop.

Pockros: Frequent physical examinations and laboratory testing for anemia, rash, decreased hemoglobin and other adverse events will be needed with both of the medications.

Birnkrant: Rash and pruritus were identified in phase 2 trials of telaprevir and a monitoring and management plan was instituted for the phase 3 trials. There was also a dermatology expert panel that reviewed cases retrospectively. Clinically and histologically, the rash seen with telaprevir is comparable to that seen with pegylated interferon and ribavirin. It is described as an exematous maculopapular and papular lichenoid rash. The rash did not appear to be a drug-induced hypersensitivity type of rash. Less than 1% of subjects experienced a suspected severe rash such as Stevens-Johnson and not all occurred during telaprevir dosing period. The mechanism of rash was investigated, but remains unknown, and there were no deaths related to rash.

I’ll now turn to anemia. The most problematic adverse effect of ribavirin therapy is reversible hemolytic anemia. Telaprevir adds to the frequency and severity of this toxicity. Anemia was seen in non-clinical studies, so we knew we had to monitor for it in the clinical trials. It’s highlighted in the warnings and precaution section of the label with recommendations of how to deal with anemia such as measuring hemoglobin baseline and every 4 weeks, utilizing ribavirin dose reduction to manage anemia, and it’s important to note that Incivek should not be dose-reduced, and if discontinued, then should not be restarted.

Regarding anorectal disorders, approximately 20% of patients receiving telaprevir had an anorectal disorder compared to 5% on control. The most commonly reported disorders in this category were hemorrhoids, anorectal discomfort, and anal pruritus. The time to onset is approximately10 days. Less than 1% were serious. Most were managed with topical agents. Again for this adverse event, the mechanism is unknown and, in some, mostly remains bothersome and rarely treatment limiting.

Adverse reactions seen in greater than or equal to more than 5% higher frequency in telaprevir subjects compared with control were as follows: rash, fatigue, pruritis, nausea, anemia, diarrhea, vomiting, hemorrhoids, anorectal discomfort…or interference with taste.

Jeffrey Murray, MD, deputy director of the FDA’s antiviral products division: Besides pregnancy warnings relating to the use of boceprevir in combination with peginterferon and ribavirin, the major warnings pertaining to Victrelis are hematologic adverse events. Boceprevir can exacerbate anemia and neutropenia already seen with peginterferon and ribavirin, and in fact, the number of transfusions and dosage reductions of ribavirin were higher when Victrelis was added to a PR regimen compared to a PR regimen alone. In addition to anemia and neutropenia, other clinical adverse reactions are fatigue, nausea, headache and an unpleasant taste of the drug.

IDN: What are the potential drug interactions with both of these medications?

Gandhi: Boceprevir is a strong inhibitor of CYP3A4/5 and should not be administered with drugs that are highly affected by this pathway, such as alfuzosin, carbamezepine, rifampin, simvastatin, phenytoin and oral midazolam. Telaprevir inhibits CYP3A and should not be administered with drugs that are highly affected by this pathway, including alfuzosin, rifampin, HMG-CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin) and oral midazolam.

IDN: What about patients with comorbidities? Can they take these medications?

Gandhi: We need to know more about certain populations. For example, these drugs are not yet approved for patients with HIV coinfection, and trials of these agents in patients with HIV are ongoing. We also don’t know how liver transplant patients with graft HCV reinfection should be treated and how to treat patients with decompensated cirrhosis, in whom peginterferon therapy is contraindicated.

Pockros: Drug developers face a conundrum in terms of testing new classes of medications in patients with comorbidities. The possibilities with the four major classes of drugs currently being developed include a PI/NPI, PI/NS5a, PI/NNPI, NPI/NNPI, NPI/NS5a and a purine NPI plus pyrimadine NPI together. Several issues need to be considered with each of these combinations: dosing convenience; safety; adverse event profiles; resistance; and others. It will be a long process.

IDN: Do you expect that we will see resistance with these medications?

Gandhi: Yes, there will definitely be resistance to these agents in patients who do not achieve virologic suppression. Such resistance has already been seen in clinical trials and reaffirms the importance of adherence and close virologic monitoring.

IDN: As the recommended treatment regimens are fairly complex, do you anticipate opportunities for misdosing?

Pockros: There is a lot of potential for misuse of these new drugs for multiple reasons, not the least of which is the fact that both medications are approved for three [times a day] dosing, which means a considerable pill burden. Poor adverse event management, lack of understanding of these medications’ use in treatment-experienced populations, and lack of monitoring for resistance are all likely to complicate management, so physicians must remain vigilant for all as they are prescribed. – by Colleen Zacharyczuk

For more information:
Bacon BR. N Engl J Med. 2011;364:1207-1217.
Poordad F. N Engl J Med. 2011;364:1195-1206.

Disclosures: Dr. Gandhi is an associate professor of medicine at Massachusetts General Hospital. He reported no relevant financial disclosures. Dr. Pockros is director of clinical research, Scripps Translational Science Institute and head of the division of gastroenterology/hepatology, Scripps Clinic, in La Jolla, Calif. He reports being a consultant and serving on advisory boards for: Genentech, Vertex, Merck, Gilead, BMS, Abbott, Phenomix, Tibotec, Pharmasset, Pfizer, Conatus, 3RT, Novartis, J&J, Achillion and Regulus Therapeutics; and has grants/contracts with: Genentech, Vertex, Gilead, BMS, Abbott, Quest, Conatus, Tibotec, Pfizer, GlobeImmune, Debio, Novartis, Mochida, ZymoGenetics and HGS. Dr. Murray is deputy director of the FDA’s antiviral products division. He reported no relevant financial disclosures. Dr. Birnkrant is director of the FDA’s antiviral products division. She reported no relevant financial disclosures.

Follow InfectiousDiseaseNews.com on Twitter.

No comments:

Post a Comment