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61th Annual Meeting of the American Association for the Study of Liver Diseases
Boston, MA, Hynes Convention Center
October 30-November 3, 2010
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Vertex's telaprevir and Merck's boceprevir: Compliance issues due to toxicity raise resistance concerns, physicians say
  2010-10-28 Pharmawire
-- Emergence of resistance mutant strain seen as possibility
-- Resistance profile may drive use of next generation agents
The association of Vertex's (NASDAQ: VRTX) telaprevir and Merck's (NYSE: MRK) boceprevir with rash and anemia, respectively, is likely to worsen compliance issues for HCV patients, possibly leading to the emergence of resistant forms of the disease, physicians said.
Telaprevir and boceprevir are first generation protease inhibitors for the treatment of HCV that have demonstrated improvement in sustained virologic response (SVR) rates over the standard of care (SOC). Both companies will present final Phase III study results at the upcoming American Association for the Study of Liver Diseases (AASLD) meeting and finish their NDA submissions by year end, according to respective company reports.
The addition of a protease inhibitor to SOC will superimpose protease toxicities onto the already well-established side effect profile of interferon and ribavarin, said Dr Raymond Chung, director of hepatology and chief of gastroenterology at Massachusetts General Hospital. "It's not going to be an easy regimen, no matter what [protease inhibitor] we choose," he said.
Compliance, which is already an issue for patients on SOC, "could become worse," said Dr Andrew Muir, director of gastroenterology and the hepatology research program at Duke University. "These [telaprevir and boceprevir] need to be taken three times a day and on a different schedule than interferon and ribavirin, and require a lot of organization [on the part of the patient]," he said.
This sentiment was echoed by Dr Melissa Palmer, director of hepatology at New York University's Hepatology Associates, who said, "One of the things we have to stress to physicians and patients is that adherence is going to be even more difficult with a third agent, with more side effects, even if the dosing window may be shorter." The dosing window may be 24 weeks for patients who are eligible for response guided therapy if they demonstrate rapid virologic response, rather than the normal course of 48 weeks, per clinical trial protocol.
"Both the time frame and the intensity of the side effect profile lead to discontinuations and dose reductions, and even prevents some patients from ever starting therapy," Muir said.
Dr Silvia Degli Esposti, director of the Center for Women's Gastroenterology Services at Women and Infants Hospital of Rhode Island, added that she does not intend to use protease inhibitors in patients who have issues with compliance. Rash, which is a concern for patients using telaprevir, and anemia, a problem with boceprevir, present unique concerns for tolerability, said Degli Esposti.
She added that her patients have difficulty tolerating either side effect profile. Although anemia may require treatment with an erythropoietin stimulating agent (ESA), many of her patients have a harder time tolerating the rash than the anemia, she said.
Additionally, the need to use ESAs in boceprevir patients who present with anemia makes treatment more "complicated and expensive," said Dr Nancy Reau, a member of the AASLD Professional Practice Committee and associate professor of medicine at the University of Chicago.
ESAs "have a bad name right now" due to issues surrounding their safety and use, said Chung. Not all hepatologists have experience using them, as "we're not in the business of dealing with anemias as a manner of our practice, but as a side effect of a different medicine we're using," he said. Some physicians have not become comfortable using ESAs, and the FDA's black box warning on their use also discourages some physicians from prescribing them. Additionally, third party payers may direct more barriers to the use of boceprevir on the grounds of cost, he noted. The need for ESAs will likely introduce additional hurdles for the adoption of boceprevir, said Chung.
Poor compliance with protease inhibitors presents additional concerns regarding resistance,
said Degli Esposti, who explained that if a patient does not complete a full treatment regimen, viral resistance may emerge. This concern was also noted by Dr Paul Gaglio, medical director of the Liver Transplant Center at Montefiore Medical Center and professor of clinical medicine at Albert Einstein College of Medicine, who said, "I'm going to guarantee there are patients who miss their middle dose [of protease inhibitor], and end up exhibiting viral resistance."
Gaglio also expressed concern that telaprevir and boceprevir appear to have similar resistance profiles. As a result, one protease may be unable to cover the resistance mutant strains which appear, such that there are mutant strains incapable of being addressed by available therapies, he said. If such a scenario manifests, "the use of second generation agents will be driven by the resistance mutants generated by first generation agents," he said. Gaglio also noted that the mutant strains appear to be less fit than the wild type virus, and added that he hopes that if therapy is discontinued in a patient who presents with resistance mutant strains, that the wild type will remerge, and thus resistance will be less of an issue. Conversely, these mutants can be "archived, and reappear on future therapy with second generation agents," he said.
by Christine Livoti