BMS-790052/ NEW Bristol compound potent against HCV/Fewer Side Effects

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BMS-790052/ NEW Bristol compound potent against HCV/Fewer Side Effects

Reuters) - An experimental Bristol-Myers Squibb compound called BMS-790052 is proving to be the most potent yet at treating hepatitis C, an infection poorly treated with existing drugs, company researchers said on Wednesday.HealthAn early, phase I safety study of the compound found it was highly effective at blocking the protein NS5A, a new target that might provide one more weapon against a virus that can quickly develop resistance."A lot like HIV, it is anticipated that a combination of at least three drugs will be required to prevent the emergence of resistance," said Bristol-Myers Squibb's Meanwell, who worked on the study published in the journal Nature."We are targeting a different protein. This will provide a unique resistance profile," Meanwell said in a telephone interview.Hepatitis damages the liver, causing chronic liver

problems, liver cancer, cirrhosis and death.It is the leading cause of liver disease worldwide, affecting an estimated 3.2 million people in the United States alone and 170 million worldwide.Typical treatment involves 52 weeks of interferon plus the antiviral drug ribavirin. The combination works in only about half of all patients, and some develop such taxing side effects that they have to stop.The Bristol-Myers compound works differently than a new class of drugs called protease inhibitors being developed by Merck's Schering-Plough division and Vertex Pharmaceuticals Inc .SUPPRESSING VIRAL LOADMeanwell said BMS-790052 helps inhibit the hepatitis C virus from replicating.Infected patients who got a single 100 milligram dose of the compound saw their viral load -- a measurement of the virus in their blood -- drop more than 99.9 percent.Early

results of a phase II study presented last week at the European Association for the Study of the Liver in Vienna were also promising. Seven out of eight patients who got the highest dose of the drug had undetectable levels of the virus. The eighth patient had stopped taking the drug for a while."It's got potency and effectiveness in a single dose that is unmatched by anything else," Meanwell said.He said the findings are very early, but the hope is that the compound could be used in a cocktail of drugs to keep the virus from developing resistance long enough for patients to clear the disease."The data we've seen so far is extremely encouraging," he said.New treatments for hepatitis C infection have drawn much attention on Wall Street.Vertex Pharmaceuticals' experimental hepatitis C treatment telaprevir, which is expected to have phase III results in the second and third quarters of this year, is projected to have

peak U.S. sales of $3.9 billion in 2013, if it wins U.S. approval as expected in the first half of 2011.Merck & Co, which is developing a rival drug in the same class called boceprevir, will present phase III results later this year

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http://www.reuters.com/article/idUSTRE63K5QB20100421

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In Early Test, New Hepatitis C Drug Shows PromiseMedication offers hope for treatment with fewer side effects, experts sayBy Randy DotingaHealthDay Reporter

WEDNESDAY, April 21 (HealthDay News) -- Researchers are reporting that a drug is showing promise in early testing as a possible new treatment for hepatitis C, a stubborn and potentially deadly liver ailment.

/It's too early to tell if the drug actually works, and it will be years before it's ready to seek federal approval to be prescribed to patients. Still, the drug -- or others like it in development -- could add to the power of new drugs in the pipeline that are poised to cure many more people with hepatitis C, said Dr. Eugene R. Schiff, director of the University of Miami's Center for Liver Diseases.

..The greater possibility of a cure and fewer side effects, in turn, will lead more people who think they have hepatitis C to "come out of the woodwork," said Schiff, who's familiar with the study findings. "They'll want to know if they're positive."An estimated 4 million people in the United States have hepatitis C, but only about 1 million are thought to have been diagnosed. The disease, transmitted through infected blood, can lead to liver cancer, scarring of the liver, known as cirrhosis, and death.

..Existing treatments can cure about half of the cases. As Schiff explained, people's genetic makeup has a lot to do with whether they respond to the treatment. Those with Asian heritage do better, whereas those with an African background do worse, he said.And there's another potential problem with existing treatments. The side effects, particularly of the treatment component known as interferon, can be "pretty hard to deal with," said A. Meanwell, a co-author of the study and a researcher with the Bristol-Myers Squibb pharmaceutical company.

,The study, published online April 21 in Nature, examines an experimental drug designed to combat the hepatitis C virus. It appears to work by interfering with a protective coating around a part of the virus that's key to its ability to reproduce, Meanwell said.In a phase 1 trial, the first of three types of studies that new drugs must go through, researchers gave doses of the drug to a small number of people.The level of the virus in their bodies dropped significantly for several days. The main side effect was headache, Meanwell said.At this point, it's not clear how much the drug might cost or how it would work with existing drugs. However, Meanwell said, it could become part of a combination treatment of several drugs.

,Schiff, the University of Miami doctor, said other companies are pursuing similar drugs.For now, much of the attention in the world of liver disease is on two drugs -- telaprevir and boceprevir -- that Schiff expects will become available within the next year and a half.Combination treatments using these drugs will become the standard treatment for many people, he said, and boost cure rates into the range of 70 to 80 percent. The drugs now under development, like the one in the new study, could be added to the regimen, he said.

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From Nature JournalChemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effectMin Gao1, E. Nettles2, Makonen Belema3, Lawrence B. Snyder3, Van N. Nguyen3, A. Fridell1, H. Serrano-Wu3, R. Langley4, Jin-Hua Sun1, R. O’Boyle II1, A. Lemm1, Chunfu Wang1, Jay O. Knipe5, Caly Chien2, J. Colonno1, Dennis M. Grasela2, A. Meanwell3 & Lawrence G. Hamann3Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USADepartment of Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USADepartment of Discovery Chemistry,Department of Computer-Aided Drug Design,Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research

and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USACorrespondence to: A. Meanwell3 Correspondence and requests for materials should be addressed to N.A.M. (Email: .Meanwell@...).Top of pageAbstractThe worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people1. Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus2, 3. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B4. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC50) towards

replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log10 reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.To read this story in full you will need to login or

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