Did Animal Research Delay Protease Inhibitors?

Peter Tatchell recently repeated his absurd claim that animal research delayed the development of protease inhibitors in an article posted on the Stop Huntingdon Animal Cruelty site. According to Tatchell,

Merck made the false, unscientific assumption that animal experiments provide an accurate model of how anti-HIV drugs interact with humans. The result? Research on a promising protease inhibitor was halted by Merck in 1989 and clinical trials of a new protease drug (crixivan) did not start until 1993. This disastrous setback in protease research is one of the greatest scandals of the AIDS epidemic, possibly contributing to the premature deaths of up to 50,000 people worldwide.

. . .

Merck admits that animal studies were not used in the primary research that led to the invention of protease inhibitors as a treatment for HIV. An animal-free breakthrough, the inhibitor drugs were designed on computers and safety-tested using human cell cultures and biochemical assays. It was only when Merck decided to further test the new drugs on laboratory animals that they ran into trouble, with the dogs and rats dying of liver failure. Protease inhibitors do not, of course, have these same fatal consequences for people. On the contrary, they are lifesavers.

Researchers at Merck had scored a coup in 1989 when Nature published their three-dimensional structure of HIV’s protease. Modifying compounds in the lab, Merck developed a compound — L-689,502 — which had good activity in laboratory tests. When they tested it in dogs in March 1990, however, the dogs all suffered from severe liver toxicity. Merck then abandoned the compound and moved on to other similar compounds, finally settling on indinavir (marketed as Crixivan), which went into clinical trial in 1993 and was approved for sale by the U.S. FDA in 1996.

Tatchell makes an absurd claim when he suggests that, “Protease inhibitors do not, of course, have these same fatal consequences for people. On the contrary, they are lifesavers.”

Tatchell is correct — the protease inhibitors that were eventually approved don’t cause fatal liver problems in human beings. Indinavir was remarkable precisely because it had both high efficacy in laboratory tests and caused very little toxicity in animal tests.

Second, it is likely that L-689,502 would have been highly toxic in human beings. Contrary to Tatchell’s claim, most of the FDA approved protease inhibitors cause liver toxicity to one degree or another in some patients and those taking protease inhibitors are advised to have their liver function monitored. The only reason that “protease inhibitors do not” have fatal liver consequences in human beings is due to such monitoring. Merck would have been highly irresponsible to have gone forward with development of a protease inhibitor that had such obvious liver toxicity side effects in animal models.

Source:

Protease inhibitors: a tale of two companies. (Merck and Abbott Laboratories) Jon Cohen. Science, June 28, 1996 v272 n5270 p1888(2).

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