In the news ... 2006 archive

End of the Road for DFC (Reverset)

July 20, 2006

Pharmaceutical company Incyte has stopped development of its lead experimental anti-HIV drug DFC (formerly called Reverset). The decision was due to increased concerns over toxicity seen in phase II trials of the drug.

DFC was one of a class of anti-HIV drugs called nucleoside analogs, or NRTIs. Other drugs in this class include Retrovir (zidovudine, AZT), Viread (tenofovir) and Videx EC (didanosine, ddI). Earlier research suggested DFC would be effective for people with resistance to other, older drugs in this class. DFC languished in development for some time. The decision to halt development was due to severe (or Grade 4) hyperliposemia, a marker of damage to the pancreas.

While the loss of another potential anti-HIV drug is always disappointing, there is some good news in this story. The problems that became evident with DFC were similar to those seen with older nucleoside drugs, especially the d-drugs: Videx, Zerit (stavudine, d4T) and HIVID (zalcitabine, ddC). When those drugs were being developed there weren’t many effective anti-HIV drugs available, so the risk of such side effects was considered acceptable. With well over 20 products on the market today, the bar for approval is somewhat higher than it once was. Toxicity and side effects that were once grudgingly tolerated are now clearly unacceptable.

Incyte has another anti-HIV drug, called NCB9471, which is entering the first phase of human trials in July 2006. This drug belongs to a new class of anti-HIV drugs called CCR5 inhibitors. Other experimental drugs in this class include maraviroc, being developed by Pfizer, as well as Schering’s vicriviroc.

The failure of DFC raises the broader question of whether it may soon be time to retire many, if not all, of the old drugs of this class. The use of two NRTIs has long been considered the “backbone” of three-drug combination therapy for HIV, but this was largely an accident of the history of HIV drug development rather than a deliberate choice. If other, better drugs had been available to combine with protease inhibitors and NNRTIs, the side effects and limited activity of the older NRTIs might have led researchers to make other choices. Now that many better drugs are becoming available, this old rule of “two nukes and a protease inhibitor” may need to be revisited. Watch for an article about “retiring the nukes” in the next issue of PI Perspective.