AIDSWEEKLY Plus; Monday, July 27 & August 3, 1998
Daniel J. DeNoon, Senior Editor

DuPont Pharma and Bristol-Myers Squibb made giant leaps in their effort to wrest market share from Glaxo, the overwhelming market leader.

Efavirenz (trade name Sustiva) is the word on everyone's tongue at the 12th World AIDS Conference, held June 28-July 3, 1998, in Geneva, Switzerland. The novel DuPont antiretroviral - a potent non- nucleoside reverse-transcriptase analog (NNRTI) - proved much more powerful than anyone expected for a drug of this class.

Excitement over the drug comes from clinical trial results showing that the drug works at least as well as any of the highly proclaimed protease inhibitors as part of combination therapy with zidovudine (AZT) and lamivudine (3TC). If these results hold up over the long term, efavirenz combinations could well become the first-line treatment of choice for many physicians.

A major new development at this AIDS conference was the realization that all of the currently available protease inhibitors induce serious lipodystrophies in a sizeable minority of patients. These toxicities can lead to a variety of disfiguring body changes and sometimes diabetes. While the drugs' benefits clearly outweigh this side effect, the buzzwords of this conference have been "protease- sparing regimens."

And protease-sparing regimens is just what Bristol-Myers already has.

The firm now heralds its stavudine (d4T, trade name Zerit) as the "thymidine analog of choice." Glaxo's AZT, recently overtaken by d4T in sales, is a thymidine analog.

Moreover, Bristol's didanosine (ddI, trade name Videx) has achieved new life as a potent partner to d4T. New studies confirm that the d4T/ddI combination is highly potent, in many cases achieving the kinds of viral load reduction seen with protease inhibitors. A new, enteric-coated version of ddI is entering trials, as is a test of twice-daily dosing.

Even better news for Bristol-Myers is that relatively low doses of hydroxyurea - already an approved cancer chemotherapy - make ddI and the ddI/d4T combination much more potent.

Of course, protease inhibitors have not gone away. Merck is tagging along on the efavirenz bubble: a clinical trial of Merck's indinavir (trade name, Crixivan) in combination with efavirenz shows potent and sustained anti-HIV action.

All the fuss about protease-sparing regimens has thrown cold water on the AIDS conference strategies of Abbott and Roche.

Abbott scientists are not alone in believing that anti-HIV therapy should "hit early and hit hard," which was the buzz-phrase of last winter's Retrovirus conference. Taken to its logical conclusion, this theory suggests that simultaneous use of two protease inhibitors are better than one. Thus Abbott has highlighted research showing that its ritonavir (Norvir) enhances other protease inhibitors and achieves a very strong and sustained antiviral effect as part of a two- protease-inhibitor regimen.

Meanwhile, Roche is very proud of the fact that its soft-gel version of saquinavir, trade name Fortovase, gave significantly better CD4 increases than indinavir in a head-to-head showdown (all patients also received AZT and 3TC).

Meanwhile, Agouron's protease inhibitor, nelfinavir, continues to do well in clinical trials. During the conference the firm strengthened its base of HIV drugs in the pipeline by purchasing another promising protease inhibitor and an NNRTI.

And look out for Triangle Pharmaceuticals, which has several strong candidates in early clinical trials:

* An NNRTI called MKC-442. This nucleoside functioning as NNRTI is known as a HEPT derivative and shows synergy with other anti-HIV drugs.

* FTC, an oxathiolane nucleoside analog four to 10 times more potent than 3TC in vivo.

* DMP-450, the first of a new class of protease inhibitors based on cyclic urea.

* DAPD, a nucleoside reverse-transcriptase inhibitor (NRTI) with potent in vitro anti-HIV and anti-hepatitis B virus (HBV) activity.

* L-FMAU, a pyrimidine nucleoside analog with anti-HBV activity.

Another firm making a strong showing was Gilead, which has shown that its NRTI bis-POM PMEA, now called adepovir dipivoxil (trade name Preveon) is very good in three-drug combinations. The drug may offer real hope of salvage treatment in patients who have failed currently- available drugs.

And last but certainly not least is Glaxo, which threatens to win back all the market share it may lose. The firm is ready to launch two impressive new anti-HIV drugs: abacavir (formerly 1592U89), a very powerful NRTI; and amprenavir (formerly 141W94), a protease inhibitor that everyone hopes can be used in patients who fail currently approved drugs. And the convenient Combivir pairs the firm's two leading AIDS drugs, AZT and 3TC, in a convenient single pill.

AZT, of course, is proven to reduce maternal HIV transmission. Look for Glaxo to strike deals with UNICEF and some developing nations for reduced-price sales.

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