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Vertex’s lead drug telaprevir, for the treatment of Hepatitis C (HCV) will have to be monitored for the emergence of drug resistance, physicians told Pharmawire, due to the drug’s potency.
When asked whether drug resistance will be an issue with telaprevir, and a class effect of protease inhibitors, Dr John Alam, Vertex’s chief medical officer, said finding ways of minimizing resistance will be true for every company developing a polymerase and protease inhibitor.
Vertex remains focused on identifying a dose and duration of telaprevir-based treatment that will minimize the likelihood of drug resistance. ”We did see resistance very early, when the drug was given by itself, in lower doses,” he said.
Dr Eduardo Martins, Vice President of Clinical Development at Dynavax Technologies, a company that develops products to prevent infectious diseases, believed that Vertex “took a big risk that others didn’t,” as the potency seen with Vertex’s drug was “quite remarkable.”
Martins added that one of the concerns is the potential of inducing a super drug resistant virus, as it is so potent. However, the data so far suggests the majority of patients who received telaprevir have a sustained viral response, he said.
Alam explained that 7% of patients reported viral breakthrough in the US-based PROVE-1 trial, versus 2% in the European study. ”Most of [the resistance] happens very early in treatment, within first 2-3 weeks. In order to prevent further resistance, the patients are taken off treatment. About 5% of patients will get screened out very early on, so the impact of resistance will be minimized,” he explained.
Romark Laboratories, a private Florida-based biotech, may emerge as a potential ”wild card” in the HCV developmental landscape, with a drug that does not seem to show the same levels of drug resistance as it is in an entirely different class.
”Drug resistance is very important,” said Marc Ayers, CEO of Romark Laboratories. Romark’s drug candidate Alinia (nitazoxanide), does not induce drug resistance in the same way as these new protease and polymerase inhibitors.
Dr Ned Snyder, chief of Clinical Gastroenterology and Hepatology at University of Texas Medical Branch, added that Alinia is a completely different drug and a ”little bit of a wild card.” However the drug is currently marketed and sports a safe side-effect profile. In Genotype 4 patients, the drug reported an impressive 79% SVR rate in interferon-naive patients.
With direct acting antivirals, such as protease inhibitors, SVR rates are reported very high earlier on in the course of treatment, but the rate drops off as the treatment progresses, due to side-effects and drug resistance and viral breakthrough between week-4 and week-12, Ayers explained.
Another potential concern is the rash that is reported in certain patients undergoing telaprevir treatment, which has been reported in previous trials. This may affect patient compliance, physicians have noted.
Amy Martin-Holohan, an HIV specialist pharmacist at Medco, explained that with certain HIV drugs, patients who missed “only a few doses” became resistant to the virus. Patients are required to take at least 95% of the scheduled doses at the scheduled time to prevent drug resistance. She highlighted Merck’s recently approved integrase inhibitor Isentress, as an example. With HIV, the prevalence of drug resistance is between 6%-16%, she added.
”Vertex just announced their Phase III and they’re looking to try the triple combination of the addition [of telaprevir] just for a short period of time,” said Claire Steers, a spokesperson for Switzerland-based Roche.
In partnership with InterMune, Roche is currently developing a Phase Ib protease inhibitor ITMN-191 (R7227). The drug is currently undergoing multiple-ascending-dose studies for the consideration as potential monotherapy. Roche is also developing polymerase inhibitor candidates.
Steers agreed that drug resistance may be an issue with protease inhibitors. ”Polymerase inhibitors are attractive compounds as they have a much lower incidence of resistance than protease inhibitors,” she added.
Reimbursement and pricing will also have to be taken into consideration, as many patients on Hepatitis C treatment have to take an additional EPO product to treat anemia that is encountered due to the side-effect of ribavirin.
However, the main issue remains whether or not Vertex can sustain the current SVR rates previously reported in Phase II trials.
Dr Roger Pomerantz, president of Tibotec Research and Development, who previously chaired the FDA panel for anti-virals, said the main goal is the decrease the treatment time patients are on interferon and ribavirin. He said that there is “no ulterior motive” than to drive down the treatment timeframe, and the shorter treatment duration was not because of the potential issue of drug resistance.
“We’re very excited about telaprevir. It’s not clear that one drug will be the answer. There may be combination drugs,” said Pomerantz. Tibotec is also currently partnered with Vertex on the development of telaprevir.
Jarrod Dalton, a biostatistician with the Cleveland Clinic Foundation said that there will be comparative ”statistical noise” between Phase II and Phase III trials as the drug will be tested in a larger and more diverse patient population.
When asked whether the transition to Phase III trials may lead the 61-67% SVR rates seen in Vertex’s Phase II trials to drop even lower in Phase III trials, Dalton said Phase II trials generally have more exclusion criteria than Phase III trials, which results in less patient-to-patient variability in the measured outcome.
Idenix Pharmaceuticals’ Director of Biostatistics, Bruce Belanger, explained that Phase II trials allow companies to learn which patients will do well on therapy. In Phase III trials, companies want to have a wider scope as possible to have applicability in the real world setting, which will add extra variation.
”The goal of Phase II trials is to demonstrate potential efficacy of a drug in a select group of patients, or patients where the investigator believes there to be the highest potential for efficacy,” Dalton added.
Patient enrollment for Phase III trials is expected in March 2008.
Vertex has a current market cap of USD 2.68bn.
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