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Abbott HCV Protease & Polymerase Drug Development Program
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from Jules Levin: Abbott has an ambitious oral HCV drug development program. They are working on a series of HCV protease inhibitors and 2 NNRTI polymerase inhibitors were recently reported as well. At the recent HCV Resistance Workshop in June in Boston Daniel Cohen from Abbott presented for the first time publicly dose-ranging 2-day monotherapy data in genotype 1 treatment naives (the first link immediately below). The maximal viral load reduction at the highest dose used was -1.50 to -2.2 log and they said they are planning combination studies. At the same meeting in Boston they presented a -4.5 log reduction in viral load in vitro for ES-383, a protease inhibitor developed along with Enanta. At EASL they presented in vitro data on EA-058 and EA-063, and said these 2 are potentially once daily. They said all 3 are very potent and presented in vitro data, in the report below, that these 2 protease inhibitors were more potent than several others already in clinical studies in patients. In February 2009 Abbott and Enanta announced, see press release below the start of a study in healthy volunteers with ABT-450.
An important consideration is the potential drug interactions between oral HCV drugs and HIV ART drugs. At the meeting in Boston, Roche reported data that suggests their HCV protease inhibitor may interact with HIV protease inhibitors. See attached report from Pharmacology Workshop at same Boston Workshop. These data suggest that if both HIV & HCV treatment regimens are administered at the same time there could be potential for the need to make adjustments. This also suggests that when possible HCV therapy should perhaps precede HIV therapy when possible or perhaps HAART should be interrupted during HCV therapy, which does not sound like a good alternative. At this time however there has not been much public discussion yet about these questions.
Another important consideration is regarding therapy for HCV/HIV coinfected and prior null responders. Obviously these patients will not respond well to peginterferon/RBV and African-American coinfected have the worst response. The best chance for SVR and to avoid HCV drug resistance for these patient populations is 2 oral drugs plus peg/RBV until if perhaps peg/RBV could be eliminated which we won't know for a few years at least. At this time Roche has been the only company to conduct a study in patients of 2 oral HCV drugs. They reported the results of the INFORM Study at EASL, and the potency and safety was good. So at the Boston meeting I made several requests publicly at the microphone and to the FDA that we should discuss this concern with stakeholders to see if we can improve the situation. I suggested parallel development in these hard-to-treat patient populations and some type of early access program with 2 orals in a regimen. My comments are at the bottom of the report linked to below from the Pharmcology Workshop in Boston.
A look at clinicaltrials.gov says an ABT-450 study is recruiting and several early studies of ABT-33 & ABT-072 in genotype 1 patients have been completed.
New HCV Drugs, Special Population (Coinfectio) Access: 4th International Workshop on Hepatitis C, Resistance and New Compounds 25-26 June 2009, Boston, MA U - (06/30/09)
Meeting Report - The 4th International Workshop on Clinical Pharmacology of Hepatitis Therapy - written by Jennifer J. Kiser, Pharm.D - (07/12/09) "Accelerated HCV Drug Access Needed for Patients At Greatest Risk & Coinfected: recognition they are at risk for death soon"
EASL Studies, April 2009
Abbott/Enanta - Potent HCV Protease Inhibitors with the Potential for Once-daily Dosing and Broad Genotype Coverage - (05/05/09)
Preclinical Characterization of ABT-072: A Novel Non-Nucleoside HCV Polymerase Inhibitor - (05/05/09)
"ABT-333 is a novel non-nucleoside HCV polymerase inhibitor with potent activity against genotype 1a and 1b HCV replicons. It is currently being evaluated for safety, pharmacokinetics and antiviral efficacy in chronically-infected HCV patients. Nucleoside and non-nucleoside HCV polymerase inhibitors are typically differentiated by their respective binding sites and mechanisms of inhibition". As well, NNRTIs can bind at different sites so there is potential that 2 NNRTIs could be combined in one regimen. "ABT-072 is a potent non-nucleoside genotype-1-selective HCV polymerase inhibitor with 5-9 fold greater potency than ABT-333 in the presence of 40% plasma."
Preclinical Potency, Pharmacokinetic and ADME Characterization of ABT-333, A Novel Non-Nucleoside HCV Polymerase Inhibitor - (05/05/09)
Pharmacokinetics and Tolerability of the HCV Polymerase Inhibitor ABT-333 Following Single Ascending Doses in Healthy Adult Volunteers - (05/05/09)
Pharmacokinetics, Safety and Tolerability of the HCV Polymerase Inhibitor ABT-333 Following Multiple Ascending Doses and Effect of Co-Administration of Ketoconazole in Healthy Subjects - (05/05/09)
Characterization of Resistance Mutations Selected In Vitro by Non-Nucleoside HCV Polymerase Inhibitors ABT-333 and ABT-072 - (05/05/09)
Press Release
Abbott and Enanta Initiate Phase 1 Clinical Trial on ABT-450 HCV Protease Inhibitor
February 18, 2009
Abbott Park, Illinois, and Watertown, Massachusetts Ñ Abbott and Enanta Pharmaceuticals announced today the advancement of their Hepatitis C (HCV) collaboration with a first-in-human study evaluating ABT-450, an oral protease inhibitor for the treatment of chronic HCV. The objectives of the trial include assessment of safety, tolerability and pharmacokinetics. ABT-450 was discovered as part of a worldwide alliance between Abbott and Enanta to discover, develop and commercialize protease inhibitors for the treatment of HCV.
"Hepatitis C is a serious global health concern, with 170 million people currently infected by six different HCV genotypes," said John M. Leonard, M.D., senior vice president, Global Pharmaceutical Research and Development, Abbott. "As a global leader in the development of antiviral therapies and diagnostics, Abbott is bringing its decades of antiviral experience, particularly with protease inhibitors, to this collaboration and to the fight against HCV."
"ABT-450 demonstrated favorable potency in vitro across various HCV genotypes and highly resistant strains," said Jay R. Luly, Ph.D., president and CEO of Enanta Pharmaceuticals. "We look forward to working with Abbott to advance ABT-450, and to our building a pipeline of HCV protease inhibitors that addresses this widespread disease."
Phase 1 Study Design
The Phase 1, double-blind, placebo-controlled study for ABT-450 announced today is a single, ascending oral dose trial in healthy volunteers.
About the Hepatitis C Virus
Hepatitis C is a liver disease affecting more than 170 million people worldwide. The virus is spread through direct contact with the blood of an infected person. Hepatitis C increases a person's risk of developing chronic liver disease, cirrhosis, liver cancer and death.
Liver disease associated with HCV infection is growing rapidly, and current therapies only provide sustained benefit in about half of patients with the genotype 1 form of the virus. Specifically targeted antiviral therapies for HCV, such as NS3/4a protease inhibitors, may have the potential to increase the proportion of patients in whom the virus can be eradicated.
About Enanta
Enanta Pharmaceuticals is a research and development company that uses its novel chemistry approach and drug discovery capabilities to create best-in-class small molecule drugs in the anti-infective field. Enanta is developing novel protease, polymerase and cyclophilin-based inhibitors targeted against the Hepatitis C virus (HCV). Additionally, the company has created a new class of macrolide antibiotics, called Bicyclolides, which overcomes bacterial resistance. Antibacterial focus areas include superbugs, respiratory tract infections and intravenous and oral treatments for hospital and community MRSA. Enanta is a privately held company headquartered in Watertown, Massachusetts. Enanta's news releases and other information are available on the company's web site at www.enanta.com.
About Abbott
Abbott is working to advance the treatment of Hepatitis C (HCV) through a multifaceted discovery and development program that leverages the company's deep experience in antiviral medicines. Compounds in various states of development include protease inhibitors (ABT-450) and polymerase inhibitors (ABT-333 and ABT-072). In addition to developing HCV therapies, Abbott also offers laboratory tests for patient diagnosis, blood screening tests for hospitals and blood banks, and molecular diagnostic tests to measure HCV viral load and resistance.
Abbott is a global, broad-based health care company devoted to the discovery, development, manufacture and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs approximately 69,000 people and markets its products in more than 130 countries.
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