ABT-378: Abbott "Second Generation" Protease Inhibitor

The first public data on ABT-378, a new protease inhibitor designed to be effective even against HIV which had become resistant to the approved protease inhibitors, was presented in several talks and posters at the 4th Conference on Retroviruses and Opportunistic Infections. These results were based on tests in the laboratory and in several animal species; ABT-378 has not yet been tested in humans.

ABT-378 was designed to take advantage of the fact that HIV resistance to ritonavir (Norvir(R), Abbott's approved protease inhibitor) and to indinavir (Crixivan(R), from Merck) usually starts with a mutation at position 82 in the HIV gene which encodes for the protease enzyme (the target of protease inhibitor drugs). ABT-378 does not use this position when it binds to its target on the protease enzyme. As a result, ABT-378 is active against viruses which have become resistant to ritonavir or indinavir.

It is possible to create HIV which is partly resistant to ABT-378, by exposing the virus to low concentrations of the drug. But so far, the resistant virus created in this way has remained fully sensitive to saquinavir (Invirase(TM)). And in animal tests, even the trough level of ABT-378 (the lowest level in the blood between doses) is more than enough to be effective against this partly resistant virus -- meaning that the drug may be able to suppress even this resistant HIV.

ABT-378 by itself is eliminated from the bloodstream fairly rapidly, so if the drug were used alone it would have to be taken often during the day. But a small amount of ritonavir (probably a fraction of the usual dose) delays the body's destruction of ABT-378 enough that the drugs are expected to be dosed only twice a day, or even only once a day.

ABT-378 is about ten times as active as ritonavir against "wild type" HIV (viruses from patients who have not developed drug resistance), and about as active against ritonavir-resistant viruses as ritonavir is against non-resistant ones.

Abbott plans to begin human trials later this year.

Comment

No one knows if a drug will work until human testing has been done. But whatever the fate of ABT-378, the message from its development is that drug resistance is not something beyond human control, but can be minimized by careful design of a new drug's chemical structure -- and by maintaining high concentrations of the drug in the blood at all times.