In the antiviral drug war on AIDS, Boehringer IngelheimPharmaceuticals Inc. has asked the FDA for approval of anothercombatant, different from nucleoside analogs and protease inhibitorsalready on the market or under review.
Boehringer Ingelheim Pharmaceuticals, of Ridgefield Conn.,submitted a new drug application (NDA) for Viramune, whosegeneric name is nevirapine, a non-nucleoside reverse transcriptaseinhibitor. The company is a U.S. subsidiary of Boehringer IngelheimGmbH, of Ingelheim, Germany.
Nucleoside analogues also inhibit reverse transcriptase, an enzymenecessary for replication of HIV, but they work with a mechanism ofaction different from non-nucleoside compounds.
And while both nucleoside and non-nucleoside drugs attack HIVreplication in the beginning of the process, inhibitors of protease,another viral replication enzyme, strike near the end of the cycle.
Five nucleoside analogues are on the market for HIV, includingLondon-based Glaxo Wellcome plc's AZT, which was the first AIDSdrug approved in 1987.
Hoffmann-La Roche Inc., of Nutley, N.J., won FDA approval of thefirst protease inhibitor, Invirase, in December 1995. Hoffmann-LaRoche is a U.S. subsidiary of Roche Holdings Ltd., of Basel,Switzerland.
Two other pharmaceutical firms have protease inhibitors underreview by the FDA.
Boehringer Ingelheim is the first company to seek clearance of a non-nucleoside compound. Merck & Co., of Whitehouse Station, N.J.,dropped development of its non-nucleoside drug in 1991 because itstests showed AIDS patients quickly developed resistance to theantiviral.
Maureen Myers, Ingelheim's clinical program director for virology,said all drugs result in resistance. If the treatment is working,however, the virus doesn't get a chance to resist, she observed.
In the past year, numerous studies have demonstrated a combinationof drugs is more effective against AIDS than any one drug alone.
Myers said clinical studies submitted to support Ingelheim's NDAshow a therapy of Viramune and nucleoside analogues was moreeffective in fighting AIDS than either one nucleoside compound or acombination of two.
In one study, Viramune was used with AZT and ddI, which is madeby Bristol-Myers Squibb Co., of New York. Myers said patientsreceived the triple combination or a placebo with AZT and ddI. After48 weeks, the Viramune treatment group experienced statisticallysignificant improvement in the standard surrogate markers _increase in CD4 counts and decrease in viral load _ compared withthe placebo group.
Another study tested Viramune in combination with AZT. In thattrial, patients on the combination therapy showed significantimprovement in CD4 counts after six months, but only transientimprovement in viral load.
Myers said clinical studies are continuing with Viramune incombination with other nucleoside analogues.
The difference between non-nucleoside compounds and nucleosideanalogues, she said, is the way they interfere with reversetranscriptase, which helps copy DNA from the RNA template forreplication of the virus.
As the enzyme pieces together nucleic acids, the nucleoside analog,which is a synthetic look-alike for nucleic acids, gets hooked in lineinterrupting the process.
Non-nucleoside compounds, Myers said, do not look like nucleicacids. The drug attaches directly to the reverse transcriptase enzyme,changing its shape and prohibiting it from functioning. n
-- Charles Craig
(c) 1997 American Health Consultants. All rights reserved.