Two new classes of HIV medications expected to be approved by FDA sometime this year; successful trials generate enthusiasm at conference

Dr. Howard Mayer led the team that developed maraviroc. (Photo by Bob Roehr)

Two new classes of drugs to treat HIV are likely to be approved later this year by the FDA, a move that many consider to be a milestone second only to the introduction of powerful combination drug therapies more than a decade ago.

The mounting evidence of the success of the new therapies created an exuberant atmosphere at the 14th retroviral conference hel Feb. 25-28 in Los Angeles.

The new classes of drugs are CCR5 inhibitors, such as Pfizer's maraviroc, and integrase inhibitors, such as Merck's raltegravir.


Maraviroc

One of the new drugs expected to be approved is maraviroc, a CCR5 inhibitor that blocks specific types of HIV from entering a cell. It acts at the same point in the virus' life cycle as Fuzeon (T-20), but with a somewhat different mechanism of action. And unlike Fuzeon, which must be injected twice a day, maraviroc is a pill, though it, too, must be taken twice a day.

The first pair of trials involved patients with very advanced disease who had failed drugs in all three of the approved classes of antiretrovirals, and had a viral load greater than 5000.

They also had to be tested to see if they have the R5-tropic version of HIV, which uses the CCR5 coreceptor to enter the cell. About half of all patients who were screened had R5 virus, the remainder had virus strains that either used the CXCR4 receptor (X4-tropic) or were a mix of the two viruses (dual-tropic).

Physicians in the trial used resistance data to create an individualized optimized background therapy and then the patients were randomized to receive placebo or maraviroc once or twice a day.

At the end of 24 weeks, more than half of the patients on maraviroc had a viral load that was below 400 copies, compared with less than a third of those who received only the optimized background therapy plus the placebo. Their CD4 cell counts increased by more than 100, twice as much as the increase of those in the placebo arm of the study.

Howard Mayer, M.D., who led the team at Pfizer that developed maraviroc, said, "Patients receiving maraviroc were twice as likely, in both studies independently, to achieve an undetectable HIV-1 RNA compared with the best available regimen."

And, he said, the side effects were at least as manageable as the placebo group.

Daniel Kuritzkes, M.D., director of AIDS Research at Brigham and Women's Hospital in Boston, called the results "important news for people who need salvage therapy regimens."

"Even though we have new protease drugs like tipranavir and darunavir, there are already large numbers of patients who have virus that is partly resistant to those PIs," said Kuritzkes, who did not participate in the trials. "Many people don't want to be on an injectable, so T-20 is not an option for them."

Rob Camp with the community-based Treatment Action Group, applauded Pfizer for toning down the hype, particularly with regard to safety data.

"Instead of concluding, "'So it is safe,' they very responsibly pointed out the short term of therapy so far, and promised to "'continue reviewing the data to identify the frequency and severity of infections.'"

Camp says that caution likely grew out of Pfizer recently having to stop a cholesterol trial because of higher rates of death.

The longterm effect of blocking the CCR5 receptor is not known, and that is likely to be the central topic of ongoing monitoring when an FDA advisory committee meets on April 24 to review approval of maraviroc. But those questions are not likely to hold up approval, which should come in June.


Raltegravir

Integrase inhibitors are the other major new class of drugs. They prevent HIV from inserting itself into the DNA of the cell to crank out more copies of the virus.

Raltegravir (MK-0518), by Merck, is the farthest along. Again, the patients in the twin ongoing trials were heavily treatment experienced, having developed resistance to all three approved classes of drugs. An OBT was put together and patients were randomized to either placebo or raltegravir twice a day.

David Cooper, M.D., with the Australia National HIV Center, presented a 24-week interim analysis showing that 43 percent of the trial participants suppressed their viral load below 400 on the OBT plus placebo arm, compared to 79 percent on raltegravir.

Side effects were about the same in both groups.

Part of the reason why the OBT performed so well is that the study allowed use of unapproved drugs as part of the regimen. The one used in this instance was darunavir, which was then available through expanded access and has since been approved. Roughly 20 percent of patients in the slightly earlier study incorporated darunavir into their regimen and that rose to about 50 percent in the second study that started a bit later.

The principle weakness of raltegravir and possibly to the entire class of integrase inhibitors is that resistance can develop fairly easily, Cooper said.

"My understanding is that there is no cross resistance" with any of the approved classes of drugs, he said, but he cautioned against reading any clinical relevance into these findings because of the relatively small number of patients and short duration of use of the drug.

Merck is preparing to submit raltegravir to the FDA for approval, which may come by the end of 2007.

Gilead Sciences presented data on its integrase inhibitor, elvitegravir, which is in an earlier stage of development. It looks to be about as effective in terms of suppressing the virus and has a similar profile of side effects.
Unfortunately, the same resistance mutations seem to develop with both drugs in the class.


Response

John Mellors, M.D., vice chair of the conference, was rhapsodic about the new classes of drugs.

"When HAART initially came out, the response [of viral load below 400 copies] was in the 60 to 80 percent range" among treatment-naive patients, he said.

Mellors added that to see the same results with these new drugs in patients who are highly treatment-experienced "is really a remarkable development."

New York City physician Roy Gulick said he is most intrigued by the possibility of using the two new classes of drugs in combination.

"Pharmacokinetically, it looks o.k., but it hasn't been done yet," he said. 

Kuritzkes was a bit more restrained, saying, "What clinicians need to be doing with their experienced patients is assessing the patient's clinical status carefully and not leap to introduce any one of the new drugs until they are convinced they can put together a fully active regimen."

That may mean using an expanded access program, or holding off until the drug becomes available, he said, adding, "You really need to use these drugs in combination, whenever possible."




This article appeared in the Dallas Voice print edition March 09, 2007