by Bob Roehr
WASHINGTON, DC – An FDA advisory committee unanimously recommended approval of raltegravir (Isentress(TM)) as part of combination therapy for treatment-experienced patients with HIV, at a meeting on Sept. 5. The pharmaceutical company Merck expects that final approval will come by mid-October.
Raltegravir is the first in a new class of drugs called integrase inhibitors, which works by permanently interrupting the final step of HIV integration into host cell DNA.
Chicago AIDS activist Matt Sharp provided the emotional high point of the meeting. The twenty-year veteran, person with AIDS (PWA) has burned through many drugs as essentially sequential monotherapy, and was the second patient enrolled in the raltegravir expanded access program (EAP).
"I added Prezista and Truvada to raltegravir in the EAP. I achieved an undetectable viral load in less than two weeks and have experienced almost a doubling of CD4 cells, maintained now for almost a year. It appears my immune system is gaining ground as my T-cells are higher than they have been in 16 years…and recalcitrant cutaneous warts have started to literally dry up and fall off."
Sharp praised Merck for having listened to and worked with the community in allowing use of other experimental drugs to construct a salvage regimen in clinical trials. And he made a plea to the company to keep the pricing reasonable.
The initial pair of trials were conducted in patients who had experienced failure of at least one drug in each of the three classes of anti-HIV drugs that were available when the trial began. Background therapy was optimized and patients were randomized to receive either raltegravir or placebo.
Close to 80 percent of patients on raltegravir were able to suppress their HIV viral load below 400 copies, nearly double the rate of those who only had their background therapy optimized.
That high rate of undetectable viral load is commonly seen among patients who start an initial combination therapy, but seldom is seen among the heavily treatment experienced patients who were enrolled in these trials.
The trials also reinforced the need for two or more active drugs in a regimen to prevent the virus from mutating resistance to those drugs.
Robin Isaacs, MD, Merck's executive director for clinical research for HIV, said, "In patients who had limited or no activity in their optimized background therapy, the placebo group is responding very poorly," with only 10 percent suppressing viremia below the level of detection; "Whereas the raltegravir group has a response of 57 percent."
Early data from the trials had shown an imbalance in the rates of malignancies in the raltegravir compared to the placebo arms of the trials. But it turned out to be a statistical fluke that disappeared with two more months of data. The imbalance was not a higher than expected rate of cancers among patients on raltegravir, but rather a lower than expected rate among those on placebo.
raltegravir has an uncommonly large "therapeutic window" – it works equally well at low or high doses – and low toxicity. The body also processes it differently than other HIV drugs, which greatly reduces the possibility of drug to drug interactions. However, there are some interactions with non-HIV drugs.
Merck selected a dose of 400 mg. twice a day because that maintains adequate levels of the drug in the bloodstream regardless of the possible interactions. It simplifies therapy rather than having to worry about dose adjustments due to interactions.
