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Physician community does double-take on Vertex’s BID telaprevir version
Vertex's telaprevir will have to show at least a 5% SVR improvement for use in 48-week over 24-week therapy; relapse rate/efficacy challenge twice-daily dose
* cost-effectiveness of increased treatment to 48-weeks questioned
* excitement over twice-daily dosing potential, but efficacy and relapse rate could hinder success
Vertex's lead hepatitis C drug, telaprevir, has to show at least a five per cent SVR increase at 48-weeks of therapy over 24-weeks to be cost-effective, key opinion leaders said.
Sustained viral response (SVR) is defined as an undetectable serum HCV-RNA at week 72, and is the primary endpoint in hepatitis C (HCV) trials.
Dr Arthur J. McCullough, president of the American Association for the Study of Liver Diseases, told Pharmawire that if these new protease inhibitors can show an additional five per cent SVR improvement over their current improvement with additional six-month treatment, out to 48-weeks, then physicians will have to weigh the cost-effectiveness of the six and 12-month difference. Still, for that extra couple thousand dollars he questioned whether a slight improvement in SVR rate was really worth it.
What also will be important is the NNT, or number-to-treat, which is essentially how many patients will have to be treated before that improvement in SVR rate is seen. If the improvement is five per cent SVR with an additional six months of treatment, in order to see that difference, physicians will have to treat at least a certain number of patients. "It will be a qualitative decision,” said McCollough.” But probably a five per cent SVR improvement will be significant"
Dr Eric J. Lawitz, an investigator for a number of HCV drugs in development, and medical director and principal investigator for Alamo Medical Research, said SVR is more important than the duration of therapy. Putting patients past the six-month treatment timeframe for telaprevir will be more expensive, and if the improvement is less than five per cent SVR, along with meager results, physicians will have to ask themselves if it is worth it. "If it's a one per cent % SVR improvement, will it be worthwhile?" he questioned.
However, Dr Hashem El-Serag, an investigator for Vertex and chief of the gastroenterology and hepatology at Baylor College of Medicine, said he did not believe that SVR is the most important factor, as some patients who are treatment-failures will be unlikely to continue with additional six-months of treatment, for a marginal improvement in SVR. "At each duration, there will be a balance of cost and side-effects,” he said.” We're making those decisions on a daily basis."
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A spokesperson for Vertex said the company's Phase III program is designed to optimize SVR rates and provide the opportunity for many patients to shorten therapy duration as well.
Dr Jean-Michel Pawlotsky, chief of the virology unit in department of bacteriology and virology at the Henri Mondor University Hospital in France, said a "respectable" increase in SVR would have to be seen to justify to patients and payers why telaprevir's use would be extended past the 24-week duration.
Dr Eugene Schiff, professor of medicine and director of the center for liver disease at the University of Miami, said the problem with telaprevir is that based on viral kinetics, and the rate of viral replication in HCV, use of protease inhibitors may knock out some mutations, and cause resistant mutations to flourish.
Regarding telaprevir's potential to be dosed twice-daily (BID) as opposed to every eight hours (TID), physicians cautioned on potential drug resistance with twice-daily dosing, if patients miss a dose.
Dr Mitchell Shiffman, who is affiliated with Vertex, and chief of hepatology at Virginia Commonwealth University School of Medicine, said regarding compliance, BID dosing will be easier than TID. "In the end, they are all relatively effective." El-Serag added that speculation on which dose is better for patients remains premature, but admitted that the relapse rates were higher for the BID dosing versus TID.
Pawlotsky said the problems so far with the twice-daily dosing is the potential for increased rate of relapse. But a potential criticism of the trial is the number of patients on this trial was small, he added.
Dr Paul Kwo, lead investigator for a competing protease inhibitor, Schering's boceprevir, said he hopes telaprevir twice-daily dosing will work, but this is the first generation of protease inhibitors. The field is going to evolve towards drugs that will be dosed once-daily, he added. Patients will sacrifice some inconvinience for efficacy, even if they need to take this drug every eight hours.
If patients are on the twice-daily dose and miss a dose, then the amount of drug in their system will be less compared to if the drug was dosed TID. There was also concern regarding the efficacy of the BID dose versus TID dose, some physicians said.
Jean-Pierre Sommadossi, CEO of Idenix Pharmaceuticals, who have three different classes of HCV antivirals in the pipeline, said there is not much difference between once and twice-daily dosing - but a huge difference between BID and TID. He added that TID dosing is not an option in order to be competitive in this crowded field.
Some industry experts said the efficacy of the first generation protease inhibitors - telaprevir and boceprevir - will be the same. The battle will come down to tolerability and convenience, they added. "We will get comparable SVR rates for these new drugs, which will have different toxicity and dosing profiles," said Shiffman. He added that the first direct antiviral that can make it with once-daily dosing will be preferred. "Vertex is going for 24-weeks, but not everyone is a rapid responder."
Vertex has a current market cap of USD 4.04bn.
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