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HIV Entry Inhibitor: BMS-806
Reported by Jules Levin
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At the 9th Retrovirus Conference in February 2002, Rich Colonno from Bristol Myers Squibb made a big splash and news by presenting for the first time publicly their program to develop attachment inhibitors, a type of entry inhibitor. This talk and others on integrase inhibitors created quite a stir and hope and optimism for new future treatment options for HIV. Bristol Myers Squibb (BMS) researchers reported at the recent ICAAC meeting (Sept 2002, San Diego) further preclinical research on their attachment inhibitor drug development program (abstract H-181). BMS-806 is a novel small molecule HIV-1 attachment inhibitor expected to be administered orally, and 806 is just a prototype for several potential drugs it is researching. BMS-806 has shown potency against laboratory and clinical strains of HIV. It has shown to be active against virus resistant to other classes of ART drugs. So far in vitro and in vivo studies have shown no safety concerns. At the Resistance workshop (Summer 2002), BMS reported that in preliminary studies 806 was not cross-resistant with other entry inhibitors tested, since BMS-806 works at a different point in the 3-step process of HIV entry into the CD4 cell. BMS-806 prevents attachment, one of 3 steps in the entry process. There are 3 steps: attachment, coreceptor binding, and fusion. T-20 is a fusion inhibitor, BMS-806 is an attachment inhibitor, and the Schering Plough drugs (SCH-C and SCH-D) are co-receptor inhibitors that inhibit binding to CCR5. Attachment occurs first, then the virus binds to the co-receptor, and then HIV fusion into the CD4 cell occurs. Perhaps all 3 types of entry inhibitors will ultimately be combined together in one regimen and/or with integrase inhibitors. T-20 is in the last phase of studies and FDA approval is expected by April 2003. SCH-C and SCH-D are in early human studies.
Review of BMS-806 at Resistance Wksp (Summer 2002)
www.natap.org/2002/HIVDrugRes/day7.htm
The development of new classes of drugs is crucial to future treatment of HIV. With resistance developing to the current classes of drugs, we need therapies that are not cross-resistant to current drugs. As well, patients need drugs that have less side effects and complications and are more tolerable. Strong and continued commitment to developing these new classes of drugs is the underpinning to this effort. It is important for us to have hope and faith regarding the development of new classes of drugs and to support this commitment.
The study authors addressed several apparently key points with this study. First, in this study the inhibitory mechanism was investigated and the authors reported confirmatory evidence that this novel class of HIV entry inhibitors selectively blocks HIV-1 access into cells by binding to viral gp120and inhibiting the gp120/CD4 interaction. gp120 is a protein on the surface of HIV that binds to CD4. Second, there is concern that drug-resistant viruses with mutations in the gp-120 region bound by the drug could emerge which may prevent effective binding, but BMS researchers say that 806 appears to bind to a conserved region of the virus based on the location of resistance mutations that emerge. The keys to overcoming any resistance liability will likely be potency and high blood exposure levels. The current reported work provides a better understanding of how this drug works, and that 806 binds to gp120. They reported confirmatory evidence of where BMS-806 binds, deep within the cavity of gp120, and they found the development of mutations to 806.
Bear in mind these are preliminary test tube studies. Clinical studies in humans are necessary to establish antiviral effectiveness and safety. Bristol Myers Squibb reports aggressively pursuing this potential treatment approach. BMS-806 is a prototype for several similar drugs in this class that BMS is researching, and clinical studies in humans are ongoing. Stay tuned to this interesting story.
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