The exhilaration and the frustration of drug development were both apparent at a meeting between the community and the pharmaceutical company Schering-Plough in Chicago Aug. 28. The main subject was a compound that the company is developing as AIDS drugs, the entry inhibitors known as Schering -C ( Sch-C ) .
Entry inhibitors block HIV at one of three different steps the virus must take to bind to and enter a cell. The first drug in that class, T-20, is likely to be approved by the FDA within the next few months. However, because it must be injected twice a day, T-20 is likely to be used by only the most desperate patients who have few other options.
The Schering drug is a pill that would be taken once or twice a day and may prove to be a major advance in therapy. But that process of taking a promising compound and developing it into a useful drug is likely to take a few more years.
Mark Laughlin, Schering's lead researcher in this area, reviewed the process of inhibition of HIV entry into cells and data on Sch-C, much of which had been presented at scientific meetings such as the AIDS conference in Barcelona.
The surface of a human cell is very complicated, with about 150 different types of protein receptors and coreceptors ( and thousands or tens of thousands of copies of each type ) on its surface. Most receptors have specialized roles important to the health and function of the cell. Proteins that bind to these receptors set off a string of specific chemical actions inside the cell.
CCR5 is the coreceptor that most HIV binds to in order to enter the cell. The theory is that if you can block this receptor with a drug compound, you can prevent HIV from entering the cell to continue its deadly cycle of replication and infection.
CCR5 does not seem to be crucial for any other cellular function. We know this because some people have a rare genetic variation and have very few or even no CCR5 receptors. People who inherit the trait from one parent progress very slowly with HIV disease, while people who inherit it from both parents are virtually impervious to becoming infected in the first place. So most researchers believe that this receptor can be blocked safely.
That may not be the case with blocking CXCR4, the second coreceptor that HIV can use to enter cells. Animals that are genetically manipulated to have no CXCR4 receptors show severe developmental disability and die.
The CCR5 receptor is "a donut with a hole in the middle," said Laughlin. He believes that Sch-C binds inside that hole, which perhaps explains the stability of the binding. Compound can be washed off of cell cultures and 24 hours later it still seems to prevent HIV from infecting the cells.
One major stumbling point in the development of Sch-C has been heartbeat irregularities seen in dogs but not in other animals. It also was seen in some of the first humans given the drug. The people didn't notice any problems themselves but they were hooked up to telemetry equipment that continuously monitored their heart.
The effect is called a QT prolongation. The QT interval is the time that it takes for potassium in heart cells to return to depolarization, or electric neutrality, so that an electrical charge can polarize them again and the cells contract in unison. The unified firing of these cells provides a strong heartbeat that effectively pumps blood. When cells are out of sync, the result is a heart that twitches and does not effectively pump blood. It is a serious condition that can quickly result in death. Sch-C seems to prolong this interval by a small amount of time in some people. There are no good baseline studies as to how frequently these prolongations occur and self-correct naturally in a normal or a HIV-positive population.
Laughlin said 40-50 already approved drugs cause QT prolongation, including the antibiotics erythromycin, many of the quinolones, and many antipsychotic drugs.
Martin Delaney, with Project Inform in San Francisco, expressed limited concern with the QT effect. He reminded the meeting participants of the community's extensive experience with "poppers," which have a similar effect on heart function.
The participants had a lively discussion about the design of phase II clinical trials to determine the proper dosing of Sch-C. It became clear that neither the community nor the company were of a single mind. All parties recognized the difficulty of designing a trial or trials in the current environment where a new drug must be evaluated against a standard of care regimen rather than placebo.
A very sick population that has run through most treatment options is not a good trial pool because many of those patients have virus that has switched to using the CXCR4 coreceptor, and they would not be expected to respond well to the drug. Negative trail results from this population might preclude development of the drug in a more promising population.
In a therapy-naive population, a standard of care regimen will result in undetectable viral load in 80+% of patients at 24 weeks, while a significant portion of detectable viral load will be attributed to initial infection with drug-resistant virus and/or inadequate adherence to the prescribed regimen. That makes it difficult to tease out the impact of Sch-C or any other drug.
