Gov. Gretchen Whitmer addressed the State of Michigan after a plan to kidnap her and other Michigan government officials was thwarted by state and federal law enforcement agencies. She started by saying thank you to law enforcement and FBI agents who participated in stopping this [...]
By Bob Roehr
Doctors and patients looking for the next new drug to fight HIV found no immediate prospects at the 11th retroviral conference, all of the leading candidates are several years away from approval. But the pipeline continues to be a robust one with candidates that attack the virus in completely different ways, as well as refinements on current strategies.
Entry inhibitors are the hot new approach that aims to block one of the several steps that HIV takes to enter the cell to wreck its havoc. The first step is when a gp120 molecule on the surface of the virus latches on to a CD4 receptor that studs the surface of the cell; the molecule then changes its shape so that another portion of the virus can grab on to a coreceptor (in most cases the CCR5 receptor but in more advanced disease the CXCR4 receptor); finally the membrane of the virus fuses with the cell and pumps its RNA into the cell to take it over.
Last year brought approval of T-20 or Fuzeon, the first in this new class of drugs, but it is expensive and requires daily injections. Some of the other candidates in development are small molecules that can be taken as a pill once or twice a day.
Bristol-Myers Squibb is working on BMS-488083 a compound that binds to the virus’ gp120 molecule to prevent it from grabbing the CD4 receptor. Two years ago the company presented data on a similar compound, but this one has a longer half-life and sticks around longer in the body.
In a proof of concept trial, the drug was given alone for seven days to a dozen relatively healthy patients with HIV who had not yet started therapy. Company researcher George Hanna said the viral load of the group receiving the larger dose dropped an average of 0.96 logs (a range of 0.24 to 2.05 logs) and their CD4 count increased by an average of 106. The drug was well tolerated, with no serious adverse events.
“The main advantage is that it works on a clear and distinct target” that no other drug currently uses, so there should be preexisting problems with resistance, said Hanna. The company is preparing more advanced studies.
Schering D gloms on to the cell’s CCR5 coreceptor and blocks the virus from using it for the second step of the entry process. Some Northern Europeans with a specific genetic mutation have few or none of these receptors on the surface of their cells, so the theory is that no harm will come from blocking it with a chemical agent. That appears to be the case, at least so far.
The Schering-Plough Corporation had developed a similar earlier compound that looked good in the lab but ran into problems when they tried it in humans. This follow-on compound appears to be much more bioavailable.
The trial enrolled a dozen patients at each of three dose levels for a 14-day trial. Schering researcher Mark Laughlin said the patients had to have been off therapy for at least eight weeks and have a CD4 count greater than 200.
Those who received the lowest dose, 10 mg of Schering D twice a day, showed a mean reduction in viral load of 1.08 logs, while those on the highest dose of 50 mg twice a day saw a reduction in viral load of 1.62 logs. Altogether some 275 patients have taken Schering D, with no serious adverse events.
Laughlin said it is important to monitor the patient’s viral swam because the compound has no effect on virus that uses the CXCR4 receptor. That variation of the virus generally does not emerge until very late in disease, when the CD4 count falls well below 100. He said, “This drug will never be used as a monotherapy,” but only as part of a cocktail with other classes of drugs.
GlaxoSmithKline also is developing a CCR5 inhibitor, GW873140. They presented data from an earlier stage of research evaluating how the body handles the compound in non-HIV infected individuals.
Pfizer tried out its candidate CCR5 inhibitor in a patient infected with a dual-tropic virus, a mix of virus that used either the CCR5 or the CXCR4 coreceptor to enter a cell. The drug suppressed the dominant CCR5 virus but the other variant remained, and the CCR5 virus regained dominance when the drug was stopped.
Reverset is a traditional nucleoside reverse transcriptase inhibitor (NRTI) that has shown activity against virus that has become resistant to AZT, 3tc, and other nukes. Northwestern University researchers Robert L. Murphy said the drug has an intracellular half-life of 17 hours and in the lab showed no evidence of mitochondrial toxicity that is associated with some of the other NRTIs, particularly d4t or stavudine.
The study enrolled 30 patients who had not been on therapy and who had a viral load greater than 5,000 copies. They were given varying doses of the drug once a day for ten days. Those on the 100 mg a day dose showed a mean drop in viral load of 1.8 logs, with a range of 1.2 to 2.3 logs reduction. There were no serious adverse events. The biotech company Incyte is enrolling patients in a proof of concept trial.
Tibotec is developing a protease inhibitor, TMC114, that has shown good action in cell cultures against virus that has developed resistance to many of the already approved protease inhibitors. Preliminary testing in humans has shown similar positive results, though the trials have only been for a very short period of time, so it is impossible to tell if resistance will develop.
It also is developing TMC125, a non-nucleoside reverse transcriptase inhibitor (NNRTI) that shows a different pattern of resistance mutations than other approved drugs in that class. The drug has entered phase III clinical trials and meaningful data should be presented at the conference next year.
So, overall, the pipeline of new drug candidates continues to remain quite robust and promising, though the odds are that some will drop by the wayside as problems arise during the development process. What is less clear is how those that are approved might be priced. The tendency has been for prices to escalate with each new drug or class of drug.