Pharmacology Watch

Two New Drugs Approved for Treatment of Hepatitis C

In this issue: Two new drugs for treatment of hepatitis C; NSAIDs and myocardial infarction risk; AIM-HIGH clinical trial stopped; and FDA actions.

Two new drugs for hepatitis C

The FDA has approved two new drugs for the treatment of hepatitis C — the first new drugs to be approved in years. The approvals came within days of each other, pitting the two drugs (and their companies' marketing departments) against each other in this multibillion dollar market. Both drugs are protease inhibitors and both have similar indications. First to be approved was Merck's boceprevir (Victrelis), which is indicated for adults with hepatitis C who still have some liver function and who either have not been treated previously with drug therapy or who have failed drug therapy. Boceprevir is approved for use in combination with peginterferon alpha and ribavirin. The approval was based on two phase 3 clinical trials of 1500 adults in which two-thirds of patients in the boceprevir, interferon, and ribavirin treatment group experienced a significantly increased sustained virologic response at 24 weeks compared to 38% with interferon and ribavirin alone. Boceprevir is taken orally three times a day with food. The second drug approved was Vertex Pharmaceutical's telaprevir (Incivek), which also was approved for patients with hepatitis C who either have not received interferon-based drug therapy or who have not responded adequately to prior therapies. Telaprevir is also approved for use with peginterferon alpha and ribavirin. Approval was based on three phase 3 clinical trials of over 2000 adults. In previously untreated patients, 79% of patients in the telaprevir group experienced a sustained viral response compared to 46% for standard treatment. Most patients experienced virologic response at 24 weeks suggesting that treatment times may be reduced from 48 weeks to 24 weeks. Telaprevir is also taken orally three times a day with food. Both drugs are approved to treat genotype-1, the most common form of hepatitis C and the most difficult to treat. The drugs have similar side effects, which include anemia and serious rashes. Several other drug manufacturers have similar drugs in the pipeline with approval expected within the next year or two. It is estimated that about 170 million people worldwide and 3.2 million Americans are infected with chronic hepatitis C, which is the most common cause of progressive liver disease leading to liver transplant. Telaprevir is expected to cost nearly $50,000 per treatment course, while bocepavir is expected to cost between $26,000 to $48,000 per treatment course depending on the duration.

NSAID use in patients with prior MI

A new study points out the risk of nonsteroidal anti-inflammatory drug (NSAID) use in patients who have had a myocardial infarction (MI) — suggesting that even brief use increases the risk for death and recurrent MI. Researchers from Denmark reviewed the records of nearly 84,000 patients who were admitted with first time MI and their subsequent NSAID use. The risk of death and recurrent MI was correlated to the duration of NSAID treatment. From 1997-2006, 42.3% of patients received NSAIDs. There were more than 35,000 deaths or recurrent MIs in the cohort of whom 43% had filled a prescription for an NSAID. Use of an NSAID was significantly associated with an increased risk of death or recurrent MI at the beginning of treatment (hazard ratio [HR] 1.45; 95% confidence interval [CI], 1.29 to 1.62) and persisted throughout the NSAID treatment course (HR 1.55; 95% CI, 1.46 to 1.64 after 90 days), returning to baseline soon after stopping the drug. The risk of death or recurrent MI varied with different drugs and was somewhat higher with increased COX-2 selectivity. Diclofenac was associated with the highest risk (HR 3.26; 95% CI, 2.57 to 3.86). Duration of therapy was also reviewed with diclofenac causing an increased risk from the beginning of treatment and persisting throughout the treatment course. Ibuprofen showed an increased risk when used for more than one week, whereas celecoxib showed an increased risk after 14-30 days of treatment. Naproxen was not associated with a statistically significant increased risk of death or MI for the entire treatment duration. The authors conclude that short-term treatment with most NSAIDs is associated with increased cardiovascular risk. This suggests that there is no apparent safe therapeutic window for NSAIDs in patients with prior MI and "challenge the current recommendations of low-dose and short-term use of NSAIDs as being safe" (Circulation 2011;123:2226-2235). One interesting aspect of this study was the use of rofecoxib (Vioxx) prior to its withdrawal in 2004. While rofecoxib was found to increase cardiovascular risk (the reason for its withdrawal from the market), it appeared to be no more dangerous than other commonly used NSAIDs and was apparently safer than diclofenac.

NHLBI stops AIM-HIGH trial

Niacin may not be effective in preventing cardiovascular disease. The National Heart Lung and Blood Institute (NHLBI) has prematurely stopped the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health (AIM-HIGH) clinical trial 18 months earlier than planned. Analysis of the data found that adding high-dose, extended-release niacin to statin treatment in people with heart and vascular disease did not reduce the risk of cardiovascular events. AIM-HIGH participants had well-controlled low-density lipoprotein levels on a statin, however they were at risk of cardiovascular disease due to previous history of cardiovascular disease and a combination of low high-density lipoprotein (HDL) cholesterol and high triglycerides. During the nearly 3 years of the study, patients who took high-dose, extended-release niacin with a statin had increased HDL cholesterol and lower triglyceride levels compared to those who took a statin alone; however, the combination was not effective at reducing fatal or nonfatal heart attacks, strokes, hospitalizations for acute coronary syndrome, or revascularization procedures. There also was a "small and unexplained increase in ischemic stroke rates in the high-dose, extended-release niacin group" that contributed to the decision to halt the trial. Termination of the AIM-HIGH trial was announced by press release from the NHLBI on May 26.

FDA actions

The FDA has approved linagliptin for the treatment of type 2 diabetes in adults. The drug is an inhibitor of DPP-4, an enzyme that degrades incretin hormones (GLP-1 and GIP). It is approved for use as a stand-alone therapy or in combination with other drugs for type 2 diabetes including metformin. The approval was based on eight double-blind, placebo-controlled trials of nearly 4000 patients that showed improved blood glucose control compared to placebo. Linagliptin is marketed by Boehringer Ingelheim Pharmaceuticals as Tradjenta.

The FDA has approved rilpivirine, a new non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of adults with HIV-1 infections who are treatment naïve. Rilpivirine is to be used as part of a highly active antiretroviral therapy (HAART). The approval was based on two phase 3 trials of nearly 1400 adults with HIV who were observed for 48 weeks, and an additional 96-week trial in which the drug was compared to efavirenz as part of multidrug combinations. Rilpivirine was found to be comparable to efavirenz with regard to percentage of patients with undetectable HIV viral load. Patients who failed rilpivirine are more likely to develop drug resistance than patients who failed efavirenz. Rilpivirine is marketed by Tibotec Therapeutics as Edurant.

Rosiglitazone (Avandia) remains on the U.S. market, but its days may be numbered. In a new step to restrict use of the drug, the FDA has updated the Risk Evaluation and Mitigation Strategy to include a restricted access in distribution plan. Physicians and patients must enroll in the distribution program in order to receive the drug. Rosiglitazone will no longer be available in commercial pharmacies after mid-November and will only be available by mail order through certified pharmacies. Use of the drug is limited to patients who are currently on rosiglitazone and whose diabetes is not controlled by other treatments and who are unwilling to change to pioglitazone (Actos).

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5404. E-mail: