New AIDS study suppresses T cells to stop viral growth
Experimental but safe’ trial under way
Suppress T cells to battle HIV? This sounds like a counterproductive way to fight a virus that kills people by destroying their T cells.
But this theory has knocked around AIDS research circles for several years, and is about to be tested in earnest by Biocryst Pharmaceuticals in Birmingham, AL, and scientists at the neighboring University of Alabama at Birmingham (UAB).
"Experimental but safe" is how Biocryst CEO Charles Bugg describes the clinical trial of his lead drug, BCX-34, which began in mid-May.
This immunosuppressive agent is being dispatched against HIV in a sleight of hand aimed at depriving the AIDS virus of the activated CD4 T cells it infects and uses to replicate, without contributing to the decline of the patient’s immune system.
"It’s a radically different approach," Bugg observes, but "the drug is highly reversible. When it’s withdrawn, T cell counts return [to pre-treatment levels]."
The theory behind what appears to be a contradictory treatment is research showing HIV spreads as fast as the immune system activates T cells to combat it, particularly in the early stages of the viral invasion.
The faster HIV replicates, the quicker it mutates and becomes resistant to antiviral drugs, such as reverse transcriptase and protease inhibitors that are thrown at the virus in combinations to try to counteract its evasive maneuvers.
"The pathogenesis of AIDS is clearly driven by the replication cycle of the virus infecting cells, producing more virus and infecting new cells," says HIV researcher George Shaw, professor of medicine at UAB and deputy director of UAB’s Center for AIDS Research. "The virus requires activated T cells."
The theory then becomes: Slow T cell activation to slow the spread of HIV.
Very few drugs have been used to try to suppress T cells to treat the disease, Shaw observes. Immunosuppressives, such as cyclosporines and corticosteroids, have been tested, but are too toxic. Shaw was the one who urged Biocryst to try its drug.
BCX-34 already is in two Phase III studies for cutaneous T cell lymphoma, which involves abnormal proliferation of T cells, and for psoriasis, an autoimmune disease in which T cells attack skin tissue.
In earlier clinical trials for both diseases, the drug proved safe and demonstrated an ability to suppress T cells.
Shaw is excited about BCX-34 for two major reasons. If it works, the drug may be able to force HIV’s demise by suppressing T cell activation, the vehicle that sustains it. Although HIV can infect resting CD4 cells, research has shown the virus degrades in several hours if the cells do not divide.
But Shaw says the other reason for his enthusiasm is even if the drug only slows the rate of HIV replication, BCX-34 would significantly reduce the speed with which the virus becomes resistant to antiviral agents.
"If BCX-34 only has a modest effect on viral load that is, if for example it decreases viral load by threefold, which is what AZT does then BCX-34 may be expected to extend by three-fold the time it takes HIV to become resistant to an antiviral agent," Shaw says.
Shaw and David Ho, director of New York University’s Aaron Diamond AIDS Research Center, were among the first scientists to recognize that HIV’s spread was directly proportional to the proliferation of CD4 T cells. Their findings led to use of combinations of antiviral drugs to attack HIV, rather than trying to stimulate production of more T cells to fight the virus.
But Shaw notes the reverse transcriptase and protease inhibitors do not kill the virus completely, and eventually HIV will develop resistance, no matter how potent the antiviral cocktail.
Shaw is conducting the BCX-34 study with Michael Saag at UAB, a clinical investigator who played a pivotal role in development of several antiviral AIDS drugs.
It was Shaw’s enthusiasm, Bugg says, that pushed his company to seek FDA approval to conduct the AIDS trial. Biocryst’s scientific advisory board also was excited, but was cautious when Shaw first approached the company two years ago with the idea.
Why risk potentially damaging publicity from failure of BCX-34 in a long-shot AIDS study when the drug was marching successfully to market for other debilitating diseases?
The scientific advisory board wanted to make sure BCX-34’s safety profile was established, Bugg says. Since then, clinical studies of BCX-34 demonstrated it does not produce the kind of toxicity associated with other immunosuppressive agents.
In addition, BCX-34’s suppression of T cells is reversed within two weeks of withdrawing the drug.
However, to ensure the safety of AIDS patients participating in the trial, the FDA and Biocryst agreed on strict guidelines for judging when the drug’s T cell suppression might begin to cause more harm than good.
"If CD4 T cell counts go down more than 25%, that’s the signal the drug is having too much of an effect," says J. Claude Bennett, MD, Biocryst’s president. "That’s a tough endpoint because T cell counts vary a lot in patients."
Endpoints for the study will be safety, evaluation of T cell suppression, and the resulting effect on the amount of HIV in the bloodstream.
The studies will involve four groups of seven patients, five receiving BCX-34 and two receiving a placebo. All patients will continue to take their antiviral drugs, probably a combination of AZT and 3TC.
Each group will start at a progressively higher BCX-34 dose level. Patients will receive treatments for two weeks, take two weeks off, and then increase the dose for another two weeks of treatment. A final two-week period of observation will follow.
The groups, starting with the one receiving the lowest BCX-34 doses, will be treated consecutively, with each group completing its two-month regimen before the next group begins so T cell suppression can be closely monitored at every dose level.
Bennett came to Biocryst last year from his post as president of UAB. He said BCX-34’s T cell suppression mechanism makes it an attractive candidate for the AIDS study.
Therapy homes in on dividing T cells only
The drug is a small molecule inhibitor of purine nucleoside phosphorylase, an enzyme believed to be involved in T cell replication. BCX-34 does not suppress the immune system’s antibody-producing B cells and does not kill T cells. The drug leaves resting T cells alone, interfering only with those that are dividing. Studies have shown the drug also appears to target the fastest-dividing T cells.
T cells generally do not proliferate rapidly. However, recent research has suggested HIV initially targets a subset of T cells, and once infected, those cells divide more rapidly than normal. That means BCX-34 may specifically suppress proliferation of T cells infected with HIV.
"If it works," Bugg says, "BCX-34 will be a whole new arrow in the quiver for attacking HIV."
Adds Shaw, "We know something is going to happen. We know BCX-34 is safe and we know it suppresses T cells."
The study is placebo-controlled and blinded, but investigators expect to examine results as each group completes the treatment protocol. Preliminary data could be available in the next several months, Biocryst officials say.