February 7, 2001
In a State-of-the-Art Lecture, Gregory Reyes from Schering-Plough discussed his company's ongoing effort to develop a CCR5 antagonist for treatment of HIV. His talk was preceded by a cautionary note from David Ho, who reminded the audience that since Dr. Reyes represented private industry, the talk possibly would not cover the field with complete "balance." Nonetheless, Ho felt that given the quality and the importance of the work, Schering-Plough deserved to have this prominent voice.
Reyes started by reviewing the main reason why CCR5 antagonists represent such an attractive target site for antiviral drug development: lucky individuals who are homozygous for the "naturally" occurring mutation delta 32 are virtually immune to infection with HIV and furthermore have no apparent immune defect. Furthermore, patients who have acquired HIV and have only one mutant copy of the CCR5 gene have a slower rate of HIV disease progression. Thus blockage of CCR5 pharmacologically could potentially have no adverse effects yet provide a new way of inhibiting viral replication, namely through interference with this co-receptor's interaction with the virus.
The goal of Schering-Plough's program is to develop a broad-spectrum, orally-bioavailable compound which blocks CCR5. The compound furthest along in development is SCH-C, which is highly specific for this receptor and does not block the other well-described chemokine receptor, CXCR4. Since non-replicating virus will not be affected by co-receptor blockade, it is likely that any CCR5 inhibitor will be used in combination with existing antiretroviral agents.
Reyes described several in-vitro studies demonstrating that SCH-C does indeed have antiviral effect, with the interesting property of retaining inhibitory action even 25 hours after the drug had been washed away from the infected cells. In addition, the drug showed antiviral activity when given to an animal model (SCID-hu mice) of HIV infection. Finally, when the agent was given in escalating doses to HIV-negative volunteers, the drug was subjectively well tolerated, although at the highest dose (600 mg) a prolongation in the QT interval was seen.
Several questions remain before this (and other) CCR5 receptors can be made available for HIV treatment: Will acquired inhibition (as opposed to inherited mutations) in CCR5 function cause immunodeficiency? What is the pathway by which HIV resistance to CCR5 develops? Is there a role for simultaneous blockage of another chemokine receptor, such as CXCR4? Will the QT prolongation seen in this phase I study be an unanticipated class effect or something limited to this particular compound? Although answers to these questions are not yet known, there is reason for optimism -- Schering has already developed an additional drug (SCH-D) that is 10 times more potent than SCH-C, and at least three other compounds (AMD 3100, PRO140, TAK779) are under investigation by other companies as well.
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