February 25, 2002
Despite the success of HAART in decreasing mortality in HIV infection, current antiretroviral regimens are not enough for patients who may have developed some level of resistance or who are not able to tolerate these drugs due to their toxicities. In the face of lacking other treatment modalities such as vaccine or immune-modulators, other targets to attack HIV are going to be needed soon.
There are currently 16 different anti-HIV drugs on the market but all of them only inhibit two sites in the HIV life cycle (the reverse transcriptase and protease enzymes). Different companies are currently investigating other potential sites for action.
Shionogi, in collaboration with GlaxoSmithKline, is developing an interesting compound, currently named S-1360, with a novel mechanism of action. It can potentially become the first in the new class of anti-HIV drugs called "integrase inhibitors." The integrase enzyme is essential for HIV to integrate its proviral DNA into the host cell chromosome. S-1360 is a low molecular weight molecule, for oral use, that inhibits the integrase enzyme in HIV-1.
Dr. Yoshinaga, who works with the Shionogi Company, described the in vitro activity of this new compound. He first presented the EC50 and EC90 of several similar compounds, and explained why S-1360 was selected based on its better inhibition of HIV-1. He then compared the EC50 of S-1360 (63.0) against ddI (763) and 3TC (53.6), indicating that the activity of S-1360 is similar to the one seen with 3TC, but more potent than ddI.
In vitro resistance analysis showed that there is absolutely no cross-resistance with HIV-1 mutant harboring TAM's, or other NNRTIs and PIs mutations. On the other hand, the investigators were able to isolate S-1360 resistant mutants in vitro. The amino acid substitutions responsible for the drug resistance were in close proximity to the integrase active site. The role of the mutation in codon 66 and others mutations conferring S-1360 resistance were confirmed by the induction of those mutations, or site-directed mutagenesis.
Dr. Yoshinaga also described some in vitro synergy observed when S-1360 was used in combination with AZT, 3TC, nevirapine and nelfinavir. Studies in animal models (rats and dogs) have been conducted with doses ranging from 100-300 mg/Kg/day. Results in those studies showed that this compound appears to be well tolerated and with good animal PK profile. These results in animal studies support the ongoing phase I-II studies that are currently underway in humans. It is good to know that this new compound appears to have good oral bioavailability and PK profile. This PK profile hopefully will allow for a BID dosing. Studies in humans to determine dose, safety and efficacy are planned.
It is much too early to speculate what is going to happen with this new compound, but the result of these studies with S-1360 are very welcome in the HIV arena. It is obvious that we are going to need, in the near future, a different class of anti-HIV drug with a completely different resistance profile. Although another class of drugs for HIV inhibition (fusion inhibitors, T-20, T-1249) is at a more advanced stage of development, they are inundated with multiple unknowns, including the difficulty in the route of administration, the development of resistance and variable efficacy.
Although the information presented by Dr. Yoshinaga in this session appears both interesting and encouraging, we must be careful not to get our expectations too high. Most drugs at this stage of development unfortunately never make it to a higher stage of clinical investigation, and, if they do, it takes many years to reach full development. Nevertheless, it is nice to see that the search for new compounds to fight HIV is still vigorous and that our pipeline for new antiretroviral drugs remains very active.
In fact, in this same session other investigators presented data on other compounds, also in very early stages of development, and even information on another new class of drug! Dr. Colonno, from Bristol-Myers Squibb Pharmaceutical presented new information on the mechanism of action, virology and resistance of a novel inhibitor of HIV entry. Dr. Paul Sax will summarize that presentation next in this conference coverage.
We will continue to follow the progression of the development of these new drugs. In the mean time, considering the odds that both compounds will make it to full development, we wish both Shionogi and Bristol-Myers Squibb good luck in their endeavors!