Abbott HCV NNRTI polymerase inhibitor ABT-333

New HCV Drugs, Special Population (Coinfectio) Access: 4th International Workshop on Hepatitis C, Resistance and New Compounds 25-26 June 2009, Boston, MA U



Reported by Jules Levin
June 25-26 2009, Boston, Mass

I am in Boston at the 4th Intl Workshop on Hepatitis C - Resistance & New Compounds June 25-26 2009 followed on saturday by the HCV Clinical Pharmacology one-day meeting, by the Charles Boucher group. Saturday is the HCV Clinical Pharmacology Meeting at the same venue and a report by NATAP is forthcoming.

Friday June 26

D Cohen from Abbott just presented data for the first time publicly on the Abbott HCV NNRTI polymerase inhibitor ABT-333 on 2 day monotherapy at increasing doses in naives in genotype 1 in patients at the HCV meeting in Boston now. Doses ranged from 100 mg once and twice daily and also 600 mg once & twice daily. 2/3 of patients has genotype 1a. They reported no treatment related adverse events. With the 600 mg bid maximal mean change was -1.52 logs, 2 patients achieved -2.09 to -2.21 log reduction. One patient had -1.27 and another -0.75 log after 2 days. The study was not intended to characterize maximal viral load response and this will be assessed in further combination studies. Safety was good, one patient developed elevated ALT after stopping therapy and phase 2a study is ongoing. Abbott also is developing HCV protease inhibitors.

At the HCV meeting in Boston ongoing today there was a talk by someone from the FDA when I took the opportunity to speak about the need for early access for 2 oral HCV drugs in combination with pegIFN and RBV for patients who are coinfected due to the risk for accelerated disease and for patients with advanced HCV disease. Both of these patient populations likely have genotype 1 or are nonresponders and need early access to a regimen with a better chance for achieving SVR. This would be for patients who cannot wait, who make a decision with their doctor that they cannot risk deferring therapy. This would be for patients who are at greater risk for decompensation and death. One HCV protease inhibitor plus peg/RBV may not be adequate therapy and put the patient at risk but 2 orals plus peg/RBV provides a much better chance for success.

Thursday June 25

The first presentation today was by a research group at the Cleveland Clinic that RNase L is a host target for anti-HCV drug development.

The 2nd talk is about a new HCV drug AVL-181. "Using a new paradigm in the design of inhibitors of hepatitis C virus protease, we have designed a novel compound with the ability to rapidly and completely silence HCv protease through covalent bonding of the protein. AVL-181 is a potent inhibitor of wild-type and drug resistant HCV protease mutations with pharmacokinetic and pharmacodynamic properties to enable once daily dosing. M Hagel from Avila Therapeutics said this drug in vitro is twice as potent as telaprevir. AVL-181 is the first experimental agent in a new paradigm for the treatment of HCV that has the potential to overcome the clinical liabilities of current investigational HCV-P inhibitors. AVL-181 has a rapid onset of inhibition (< 1 hr) in a direct in vitro assay of HCV-P activity against wild-type and drug-resistant mutations and this activity is prolonged for greater than 24 hours after compound removal, a property not observed with current HCV protease inhibitors." I think they said it could be active across genotypes. AVL-181 inhibitis some HCV protease mutaions such as the R155K mutation associated with other protease inhibitors currently in studies in patients. The drug is a potent inhibitor of wild-type HCV-P in biochemical (IC50=0.4nM) and replicon cellular (EC50=4.6nM) in vitro assays. The drug works in a unique way and suggests efficacy against HCV protease inhibitors. The resistance profile of the drug is being studied and they said it would be presented at AASLD.

The 3rd talk this morning is by G Wang from Enanta who is developing HCV protease inhibitors along with Abbott. They have a series of compounds but EA-383 appears to be a lead compound. EA-383 appears potent in vitro and is active against all genotypes but a little better against genotype 1. The drug has a "very" high exposure in the liver and a high liver-plasma concentration and a 600 times higher concentration in the liver than in the plasma, even 24 hours after dosing had a high liver level. He said it is potent against HCV resistant mutants which will be presented next by Krishnan from Abbott.

Preethi Krishnan from Abbott is now presenting on this series of protease inhibitors. These are different types of HCV protease inhibitors than others in development. EA-383 has a higher genetic barrier than other compounds to resistance to the usual mutations. In vitro ES-383 showed about a 4.5 log viral log reduction. In vitro they showed data that EA-383 was more potent than ITMN-191 in genotype 1. It appears more potent in vitro against geno 1A. the data presented reported EA-383 was active against some HCV protease mutations but not other mutations. So I asked the presenter about that - if a patient fails a protease inhibitor with several protease mutations EA-383 did not appear to be able to suppress such a virus. In response Krishnan said if they could reach high blood levels with this drug perhaps they could suppress resistant viruses, and if a patient fails with only the mutation against which EA-383 is active then EA-383 could be potently active. Then Dale Kempf spoke and I think he suggested the 155 and 168, the usual HCV PI mutations could be problematic.