Pharmawire reported back in 2008, that the next-generation protease inhibitors would likely see ritonavir boosting:
now, it's finally begun. well, it was first the SGP '518 compound.
11-Sep-08 16:10 Next generation HCV protease inhibitors could theoretically benefit from ritonavir boosting, despite first generation failures - analysis
Story Next generation hepatitis C (HCV) protease inhibitors could still theoretically benefit from ritonavir boosting, despite past failures with first generation inhibitors, physicians said.
The current standard of care for the treatment of HCV is combination therapy with pegylated interferon-alfa, which is an injectable, and ribavirin. If left untreated, HCV can cause serious liver disease, including liver failure.
Vertex and Schering explored drug-drug interactions between ritonavir and their respective compounds telaprevir and boceprevir in earlier clinical studies. Vertex worked with experts in the HCV community in 2006 and 2007, and the conclusion from those studies was that ritonavir does not boost telaprevir, according to a company spokesperson.
Yet some physicians and an investigator still said that HCV protease inhibitors could theoretically benefit through pharmacokinetic enhancement by ritonavir, similar to what is currently done in the treatment of HIV. Ritonavir, trade name Norvir (Abbott Laboratories), is an antiretroviral drug from the protease inhibitor class used to boost HIV drugs.
Previous studies by Abbott showed that there was a benefit to ritonavir boosting with both boceprevir and teleprevirin in mouse studies. These studies suggested that ritonavir boosting may significantly increase levels of these two protease inhibitors, and promote better dosing regimens. Abbott declined to comment for this article.
A leading investigator on numerous ongoing HCV trials in the US said that although first-generation protease inhibitors by Vertex and Schering did not benefit from ritonavir boosting, a next-generation protease inhibitor eventually will be boosted. "When you boost, it means you have a longer half-life and a more robust effect. I'm telling you, we’re going to see it," he said.
Second-generation protease inhibitors which act on a different pathway or metabolize differently may benefit from ritonavir boosting, the physicians said. Ritonavir boosting of protease inhibitors currently happens in HIV treatment, but can lead to liver toxicity at high doses, the leading investigator said.
One researcher working at a company developing an HCV compound agreed that ritonavir boosting is possible. Evidence from the Abbott study suggested it may be possible, he said, but there may be complications due to drug-drug interactions, as well as difficulties with HIV co-infected patients.
Depending on the individual compound and how it is eventually metabolized, a spokesperson for Schering said ritonavir boosting could improve dosing regimens for newer, second generation agents in development. "In theory, it could work. But I don’t know if anyone has reported anything on this issue."
Dr Christopher O'Brien, chief of clinical hepatology at the Divisions of Liver and GI Transplantation at the University of Miami, School of Medicine, said that Vertex and Schering's protease inhibitors did not benefit from ritonavir boosting as these compounds inhibit CYP450 in humans.
Ritonavir undergoes cytochrome P450-mediated biotransformation in human liver microsomes to three major metabolites, explained O'Brien.
Dr Andrew Talal, associate professor of medicine at Weill Medical College, said the main safety issue concerning potential interactions between antiretroviral therapy and HCV drugs is the efficacy of ritonavir boosting, and whether they are tolerable in patients, who may already be receiving an additional HIV protease inhibitor in addition to HCV therapy.
The physicians also predicted that future treatment would evolve into an all oral regimen of direct antivirals, but there is a potential for drug resistance with teleprevir, and protease inhibitor monotherapy will produce a lot of resistant mutations, the investigator said.
Dr Eugene Schiff, professor of medicine and director of the Center for Liver Disease at the University of Miami, said boceprevir and teleprevir are both robust drugs. "What is lagging, is the development of polymerase inhibitors that are safe and effective. Many of the polymerase inhibitors have had side effect issues," said Schiff.
Idenix is one company developing a polymerase inhibitor, despite the failure last year of its valopicitabine compound, which was found to cause liver toxicity. The company has since reformulated its compound to prevent liver toxicity in current trials. "What you want is a drug that you can give once a day rather than three times a day," said Schiff.
There are currently 300,000 people with HCV who have been treated, and approximately 700,000 who have been diagnosed and not treated, said Schiff. "As HCV treatment gets closer to combinations of small molecules, with a low side-effect profile, more people will get treated because of the attractiveness of a higher cure rate," he said.
Schiff said that, despite the current debate regarding the possibility of a non-interferon based regimen, future treatment would be a combination therapy utilizing a potent protease inhibitor paired with a less robust polymerase inhibitor, which effects another part of the virus to reduce the chances of "escape resistant" mutations.
Merck tried combination therapy using a polymerase and protease inhibitor to treat an infected chimpanzee with HCV. It was ultimately cured without using interferon or ribavirin.
Although combination therapy with a protease and polymerase inhibitor is possible, it may encounter challenges from the FDA, said O'Brien.
The FDA is against prolonged treatment with small molecule agents alone, as there is evidence to suggest the emergence of resistance within one or two weeks when interferon is eliminated from therapy, said O'Brien. "Some companies have both a polymerase and protease inhibitor in development, but they are reluctant to combine them," he added.
Patients likely have three potential resistant mutations present before treatment, said Schiff, and when they are treated with one protease inhibitor, their viral levels drop significantly, which allows resistant mutations to take over and replicate at a much higher level, leading to drug resistance.
The FDA has advised that both ribavirin and interferon should be given with protease inhibitors to clear out resistant mutations. "That's why you don’t use Vertex’s protease inhibitor alone," said Schiff.
Telaprevir is a robust drug, but can cause a minority of patients to develop a rash, Schiff said. "But when it develops, it’s pretty significant. And the longer you’re on it, the greater the likelihood," said Schiff. The four week lead in group seems to show a higher SVR, or cure rate. "They’re getting four weeks of the peg-intron and ribavirin first, to prime the immune system before adding the protease inhibitor," Schiff said.
Many patients are currently reluctant to receive HCV treatment due to the current requirement for interferon therapy, and the mild to moderate flu-like symptoms, such as fever, muscle and joint aches, and chills, according to Schiff. In the US, only 150,000 people are currently receiving HCV treatment out of the 4 million sufferers, estimated the Schering spokesperson. But once the treatment paradigm shifts into all oral therapy, it really should increase and open up the market.
Vertex has a current market cap of USD 3.72bn.
by Kimberly Ha and Elizabeth Krutoholow
Source Pharmawire
Drug Norvir
R1626
boceprevir
telaprevir
Originator Abbott Laboratories
Originator Roche Holding Ltd
Originator Schering Plough Corporation
Originator Vertex Pharmaceuticals Incorporated
OTHER Abbott Laboratories
OTHER Roche Holding Ltd
OTHER Schering Plough Corporation
OTHER Vertex Pharmaceuticals Incorporated
Intel. Type Product Development
Other
Countries USA
Intel. Grade Strong evidence
Intel. ID 696600
Market Data 
Markets 
AI
