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A big week for treatment of Hepatitis C Virus: 2 new drugs get FDA panel OK - miraculous breakthrough for patients with HCV.....
  April 29th, 2011 10:35 am ET
Elisabeth Morris
Boston Health News Examiner
"This is going to be a real game changer for our hepatitis C practices, " said Dr. Barbara McGovern, Tufts University School of Medicine. "I can't wait to get back and talk to my patients about it." panelist described as a "stunning success........Even hard-to-treat patients like African Americans responded extremely well......Treatment can be individualized but both doctors and patients need to be educated and clear about when and how this drug is to be taken......Close attention was paid to the drug's side effects.......they agreed more studies are needed, including in more black patients and in patients over age 65 years.
'Once the two drugs are approved, several panelists noted that it would no longer be considered ethical to conduct treatment studies using pegylated interferon and ribavirin as the control group. And panelists agreed that triple therapy would become the new standard of care, once the protease inhibitors are approved.'
'The manufacturer, Vertex Pharmaceuticals has devised a plan to help clinicians and patients identify and manage rashes and is planning or conducting studies in different populations, including black patients, patients with cirrhosis, patients coinfected with HIV and HCV, post-transplant patients, and children and adolescents aged 3-17 years. The company is also planning to study a twice-daily dosing regimen.'
There is an enormous amount of excitement in the medical community and in patients with Hepatitis C virus infections. An estimated 170 million people have chronic hepatitis C virus (HCV) infection, and in many of those people liver cirrhosis and eventual liver transplantation is the only option. Current treatment for patients is injection of interferon alfa and oral ribaviron for up to 12 months, and only 40-50% of treated patients respond positively to the treatment. In the other 50-60% of patients who do not respond, the only path is retreatment with the same course of drugs, and chance of success the second time around is minimal. Both Merck and Vertex have been developing oral HCV inhibitors Both companies have tested these drugs in combination with interferon and ribaviron, and have demonstrated a tremendous increase in treatment success with this triple course of therapy. Both companies were asked to present their data to a FDA panel of experts this week in preparation for a decision by the FDA for drug approval expected next month.
On Wednesday, Merck presented the data for boceprevir, their oral inhibitor of the NS3/4A HCV protease, a viral enzyme required for replication of the HCV virus. It is dosed 3 times a day, and was tested in HCV patients who had never been treated before in combination with interferon and ribaviron. 63-66% if patients were 'cured' defined as achieving 'sustained viral response' (SVR) which means there was no detectable virus in the blood 6 months after treatment ended. This is compared to 38% of patients who achieved SVR after treatment with interferon and ribaviron alone. The more difficult patients are those who respond after initial treatment with interferon/ribaviron, then relapse, and most challenging are patients who never respond at all to therapy. Retreatment of relapsers with the triple drug resulted in 75% SVR compared to only 29% SVR in patients retreated with only interferon/ribaviron the second time around. Although Merck presented data in 'non-responders', careful analysis of the patient population revealed that these patients were actually relapsing or partial responders. Boceprevir was never tested in patients who did not respond to interferon/ribaviron, which is a serious drawback compared to its competitor drug telaprevir, and there was discussion whether these patients should be allowed to be treated. The panel advised that these patients could be treated with the drug. The panel also discussed the potential poor compliance by patients required to take 3 pills a day. Merck had no data in patients treated less frequently.
So, why would the FDA want to hear these results in front of a panel of experts? Because there are definitely important side effects which need to be weighed along side the positive results. Addition of boceprevir to the treatment regime essentially doubles the incidence of clinically important anemia (40% of treated patients develop anemia that required treatment with recombinant erythropoietin, a drug to increase red blood cell production). The panel discussed the anemia side effect and determined that it could be managed effectively as long as the patients were monitored for anemia during treatment. Another important finding is that addition of boceprevir can induce mutation of the virus so that it becomes resistant to the drug. Merck (and Vertex) have both predicted that this resistance may occur and have looked carefully at the changes in the virus after treatment. They have found that some mutation and resistance does occur in a very small percentage of patients, but after treatment is withdrawn, some experiments suggest the resistance goes away, although actual clinical evidence has not been presented. It is unlikely that the companies will actually perform a clinical study to test this in patients. Several other companies are developing HCV therapies that act differently, so the small numbers of cases of viral resistance combined with the option to use other drugs in the future made this a less vital worry. On Wednesday, the FDA panel discussed the positive clinical results as well as the side effects at length and voted unanimously (18 to 0) to recommend approval of boceprevir to the FDA.
We in Boston have been closely following the Vertex story, as telaprevir, their treatment for Hepatitis C Virus, is the first drug to potentially hit the market from this biotech company based in Cambridge, MA which was founded more than 20 years ago (a long wait for a first approval for sure!) Telaprevir is a small molecule pill, also taken orally 3 times a day, which inhibits exactly the same enzyme as Merck's boceprevir. It is also given in combination with the standard therapies of interferon and ribaviron. The results from Vertex's phase III trials have shown even more impressive results than Merck's boceprevir.
In the phase III study of patients who had never been treated for HCV, addition of telaprevir resulted in a cure, or SVR, of 72-79% of patients compared to 44% for patients treated with interferon/ribaviron alone. In patients who had previously been treated and cured, then relapsed, the telaprevir regimen led to cure rates of 64-66% compared to 17% for patients treated with interferon/ribaviron alone (from Jules: Treatment-Experienced, all received 48 weeks therapy: this study looked prospectively at null responders - prior partial responders: 61% SVR; 85% for relapsers; 32% for null responders). Addition of telaprevir was able to cure between 29-33% of patients who did not respond at all to initial treatment (null responders) of interferon/ribaviron compared to a 5% cure rate for these patients when re-treated with with the same 2 drugs. This is remarkable news for non-responding patients who previously had no options except retreatment, and only a tiny chance of a successful cure. The side effects of telaprevir were primarily skin rashes in about 56% of patients and a less common chance of anemia. Vertex said the rashes disappeared when telaprevir was stopped. The main safety concern discussed by the panel was severe rashes in a small number of patients, including three suspected cases of Stevens-Johnson Syndrome, a life-threatening outbreak of blisters. No deaths occurred as a result of the rash and treatment of rash typically included corticosteroids and anti-histamines. The skin rash problem was much less concerning in the phase III studies after this side effect was understood from earlier studies and clinicians were looking to treat more aggressively to prevent severe rash. Panelists urged Vertex to warn about the potential for rash and tell doctors and patients how to spot a serious rash and when to stop treatment if needed. Vertex also presented some data indicating efficacy of the drug in patients treated for only 48 weeks total with only 12 weeks of telaprevir, and also some data indicating efficacy could be demonstrated with twice daily dosing instead of three times a day. More studies will continue to explore these treatment options.
At 3pm yesterday, the FDA panel of experts voted 18-0 to recommend approval of telaprevir for patients with HCV. These recommendations will be taken seriously by the FDA, which is expected to approve both of these drugs by the end of May. What a miraculous breakthrough for patients with HCV. Although analysts predict telaprevir has an edge in the market with a predicted $1 billion in sales in 2012, according to The, boceprevir (which will be marketed as Victrelis)will be a welcome alternative for patients who do not tolerate telaprevir.
FDA Advisory Committee Unanimously Recommends Approval of Telaprevir for People with Hepatitis C - Vertex press release - (04/29/11)
Boehringer Ingelheim starts patient recruitment in HCV drug trial Phase 3 Protease Inhibitor BI201335 - (04/29/11)
FDA Panel Votes 18-0 Recommending Boceprevir Approval for Treatment of HCV in Genotype 1 Patients - Merck press release - (04/29/11)
HCV Standard of Care Controversy: report from FDA Hearing; what can new era of HCV antivirals offer by Ira Jacobson; Key Treatment Outcomes for Boceprevir & Telaprevir, Essentially Doubling SVR Rates - (04/29/11)
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