Tuesday, April 23, 2013

EASL- Bristol-Myers oral hepatitis C regimen daclatasvir/asunaprevir/BMS-791325

Study: Bristol-Myers oral hepatitis C regimen looks competitive
April 23, 2013 6:04 am by
(Reuters) - A combination of three experimental Bristol-Myers Squibb hepatitis C drugs appeared to be highly effective, according to data from a mid-stage clinical trial, keeping the company in the race for developing an all-oral treatment regimen for the serious liver disease.

The combination therapy, which involves three direct acting antiviral drugs that each attack different targets needed for replication of the hepatitis virus, achieved cure rates as high as 94 percent when given for either 12 weeks or 24 weeks, according to results of the small study.

Current treatment regimens for the disease still include the older, difficult-to-tolerate drugs interferon and ribavirin and are typically taken for either 24 weeks or 48 weeks. When used with newer drugs, they have cure rates as high as about 80 percent.

Several companies are developing hepatitis C regimens that do not include interferon - which is given intravenously and often causes miserable flu-like symptoms - while also pursuing much shorter treatment durations.

Gilead Sciences Inc and Abbvie Inc are widely seen as ahead of the pack with treatments that could reach the market as soon as next year. But those will likely, at least initially, include ribavirin, which many patients also have difficulty tolerating.

Data from the Bristol-Myers combination, to be presented this week at the European Association for the Study of the Liver (EASL) meeting in Amsterdam, does not include ribavirin, potentially giving the company a competitive advantage. Bristol-Myers said it expects to begin Phase III testing of its combination by late 2013, so it is still playing catch-up.

"The speed of drug development is moving quicker than any of us would have thought and the potency of these regimens with high (cures) is very good for the field and for patients," Dr. Eric Lawitz, one of the investigators who worked on the trial, said in a telephone interview from Amsterdam.

The multi-pronged study included 66 patients with the most common and difficult to treat genotype 1 form of the disease who had not previously been treated. It tested a combination of daclatasvir, from a promising new class of drugs called NS5A inhibitors, a protease inhibitor called asunaprevir, and either 75 milligrams or 150 milligrams of BMS-791325 ('325), a non-nucleoside polymerase inhibitor. The combinations were tested for either 24 weeks or 12 weeks of treatment.

With the lower dose of '325, the sustained virologic response 12 weeks after completing treatment (SVR 12) was 94 percent, and that was essentially maintained through 24 weeks. Patients in whom the virus is undetectable 24 weeks after completing treatment (SVR 24) are considered to be cured.
If data was excluded from the few patients who either missed a planned doctor visit and could not be tested or withdrew consent to participate, then all 28 patients in the lower dose arms of the trial were cured, Bristol-Myers said.

"It looks overall very promising," said Lawitz, medical director of the Texas Liver Institute in San Antonio. "Anytime we can hit 90 percent SVR, we're very interested."
There was less available data ready in time for the EASL meeting from patients who got the 150 mgs of '325, but that dose appeared to be a bit less promising than the lower dose.

The SVR 12 rate for those who received 12 weeks of treatment was 89 percent. But there was one patient who had viral breakthrough, in which the virus comes back during treatment after initially responding, and one patient who relapsed after completing treatment. There was also one viral breakthrough reported in the 24-week treatment group.

There were no patient discontinuations due to intolerance to the drugs or adverse events and no serious elevations in liver enzymes reported, the company said.

Two serious adverse events were reported. One patient suffered from kidney stones, which was deemed unrelated to the Bristol-Myers drugs by researchers, and one case of cerebral vasoconstriction (a narrowing of blood vessels in the brain) in a patient taking interferon and ribavirin following viral breakthrough.

The most commonly reported side effects were headache, diarrhea, muscle weakness and nausea, the company said.

"There hasn't been any safety signal that has been concerning from what's been reported to date," said Lawitz, adding that much larger studies with more diverse patient populations, such as those with cirrhosis, must be conducted to confirm the findings.
An estimated 170 million people worldwide are infected with hepatitis C. If untreated it can lead to cirrhosis, liver cancer or the need for a liver transplant.
(Reporting by Bill Berkrot; Editing by Tim Dobbyn)

By Peter Loftus

An experimental drug cocktail from Bristol-Myers Squibb Co. (BMY) cleared the hepatitis C virus in most patients in a mid-stage clinical trial--results that could keep the company in the race to develop the next generation of treatments for the liver disease. The company had to shift gears after a major setback last year, when another hepatitis C drug in development was linked to serious safety concerns. Bristol scrapped development of that drug, dubbed a "nuke" because it was known as a nucleotide polymerase inhibitor. Now, Bristol is moving ahead with a combination of three drugs that use different mechanisms to combat the hepatitis C virus: daclatasvir, asunaprevir and BMS-791325. Based on positive results in mid-stage studies so far, Bristol expects to begin late-stage, or phase 3, clinical testing of the triple combination in late 2013 or early 2014, which could support filing for regulatory approval if results remain positive.

Douglas J. Manion, a Bristol-Myers senior vice president of development of virology drugs, said the company remains in the hunt for the next generation of hepatitis C drugs, despite dropping its "nuke" from development. "We think we're highly competitive," said Dr. Manion. Bristol's triple therapy is all oral, stripping out two elements of the current standard treatment for hepatitis C: the injected interferon and orally administered ribavirin, both of which have side effects that can be difficult for patients to tolerate. Bristol is jockeying with Gilead Sciences Inc. (GILD) and AbbVie (ABBV) to develop an all-oral treatment that would at least eliminate interferon from the mix.

The hope is that the new treatments will be easier to tolerate, shorter in duration and potentially more effective than the current standard of care. Analysts say a multi-billion-dollar market opportunity awaits the next generation of hepatitis C drugs. Bristol tested its three drugs in a mid-stage, or phase 2, study in patients with the most common form of hepatitis C, known as genotype 1. Patients were given the combination for either 12 or 24 weeks. Some were given lower doses of BMS-791325 while others were given higher doses. Bristol previously presented partial results from the study, showing that 94% of patients receiving the lower dose of BMS-791325 had sustained virologic response four weeks after the completion of 12- and 24-week treatment regimens. Sustained virologic response, or SVR, is a marker that liver specialists say closely correlates to a cure. For those receiving the higher dose of BMS-791325, some 94% achieved SVR4 after a 24-week treatment regimen, while 89% achieved SVR4 after a 12-week regimen, according to data set to be presented this week at the annual meeting of the European Association for the Study of the Liver in Amsterdam.

Two serious adverse events were reported in the study: a kidney stone that was determined to be unrelated to treatment, and a cerebral condition associated with interferon and ribavirin treatment that were given to a study patient who experienced a viral breakthrough, or a return of viral levels following treatment. Most adverse events were mild to moderate, Bristol said, with headache and diarrhea among the most common.

Write to Peter Loftus at peter.loftus@dowjones.com  Subscribe to WSJ: http://online.wsj.com?mod=djnwires


  1. this article states that the interferon is administered intervanously....this is not true!!

  2. Interferon is injected subcutaneously (under the skin)