Trial results of the experimental HIV drug 3TC, in combination withAZT, showed that the duo worked significantly better than AZTalone. The results were so impressive that the companies who own3TC plan to file for regulatory approval next year.
Two Phase II/III European studies were revealed Sunday at the 2ndInternational Congress on Drug Therapy in HIV Infection inGlasgow, Scotland. They showed that 3TC, invented by BioChemPharma Inc. and licensed to Glaxo Holdings plc, and BurroughsWellcome Co.'s AZT used in combination had a statisticallysignificant effect on three surrogate markers used to measure HIV:increases in CD4 cell counts and decreases in levels of virus in theblood cells and in the blood plasma/serum.
"The results are stunning," Sam Isaly, a partner and analyst withMehta and Isaly, told BioWorld. "There's been nothing like it in myexperience in surrogate markers for HIV infection," he said, addingthat a trial assessing clinical endpoints, such as survival and time tofull-blown AIDS, still is needed.
A week earlier, data were presented showing a different formulationof the nucleoside analogue 3TC, or lamivudine, was effective inreducing hepatitis B virus to nearly undetectable levels in a Phase IIU.S. study. "This is a billion dollar chemical," Isaly said. (See BioWorldToday, Nov. 15, 1994, p. 1.)
Still to come are results from two North American Phase II/III trial,which will be reported on in January in Washington. Those trials arecomparing AZT (zidovudine) and 3TC to 3TC alone, to AZT aloneand to the combination of AZT and Roche Holding Ltd.'s ddC.
Ramona Jones, supervisor of media relations for Glaxo Inc., said thecompany would wait until the North American results are in beforesubmitting for marketing approval of the combination therapy. Glaxosaid it intends to file for approval in the U.S. and Europe in the firsthalf of 1995. She said combination trials assessing clinical endpointsare expected to begin early next year.
Glaxo Halts Negotiations With Wellcome
In a related development, also announced Sunday, Glaxo said it hasdiscontinued negotiations that would have given Wellcomemarketing rights for 3TC.
"As you would expect, when you have new information on acompound, negotiations would be modified accordingly," Jones said."It was an option [in the form of letter of intent signed in March].We were unable to reach agreement."
Neither Jones nor Kathy Bartlett, Burroughs Wellcome's director ofcommunications, would offer specifics on why the talks broke down.Regardless, BioChem Pharma retains the royalty structure it agreedto in 1990 with Glaxo. BioChem Pharma will get double-digitroyalties and an overall return of 13 to 15 percent, Francesco Bellini,president and CEO of Laval, Quebec-based BioChem Pharma, said.Glaxo has worldwide rights to the drug for both hepatitis B and HIV,excluding North America, where it will be manufactured by a jointventure of the two companies. The joint venture will sell the productin Canada and Glaxo will sell it in the U.S.
Isaly said Glaxo's retention of rights to 3TC says something abouthow convincing the trial results were. But he said he wouldn't besurprised if Wellcome and Glaxo came to terms on some sort ofmarketing agreement more favorable to Glaxo.
The Phase II/III studies involved 352 patients. One of the studies,involving 129 HIV-positive patients, was reported on by ChristineKatlama from the Hospital Pitie Salpetiere in Paris.
Katlama said the levels of virus in the blood were reduced 99 percentat week 24 for those in combination therapy, with a sustainedreduction of 99 percent below baseline at 48 weeks. Those takingAZT alone had viral levels reduced by 70 percent at week four,which returned to within 11 percent of baseline by week 24. Thosestarting on AZT alone who switched to combination therapy at week24 had a reduction of 98 percent at week 48.
"We did not expect such things," Bellini said. "We never anticipatedviral load would be down 99 percent over 48 weeks. At this pointAZT and 3TC are a winning combination."
Those admitted to the study had CD4 cell counts between 100 and400 and had fewer than four weeks of prior therapy with AZT.
Katlama said those taking combination therapy had a maximumaverage increase of 85 CD4 cells, which occurred at week eight. Theincrease was sustained at 80 cells above baseline at week 24. Atweek 48, the average increase was more than 49 cells. In contrast,those taking AZT alone had a maximum average increase of 34 (atweek four), but had an average decrease of seven cells belowbaseline by week 24. Those on AZT alone who switched tocombination therapy at week 24 showed an average increase of 40cells above baseline at week 48.
The third marker area measured levels of the virus in blood/plasmaserum, which were reduced by 92 percent below baseline at weektwo in the combination therapy group, and sustained at 86 and 91percent at weeks 24 and 48, respectively. Levels in the AZT-alonegroup were reduced by 76 percent at week two, but returned to 36percent by week 24. Those switching to combination therapy at week24 had a 92 percent decrease in virus levels from baseline at week48.
Similar results were seen in a German study involving 223 HIV-positive patients.
The exact effect the combination therapy has on the disease isuncertain. Bellini said most of the speculation after the results werepresented focused in two areas: One theory said patients resistant toAZT who takes 3TC can become resensitized to AZT, so they willrespond to that drug again. The other, which Bellini espouses, says3TC cripples the virus, keeping it from replicating, and then AZT isable to keep the virus under control.
Regardless, those involved in the area agree that combinationtherapy is the wave of the future.
Tim Wilson, an analyst with Hambrecht & Quist Inc., said thecombined data package suggests about a "10-fold increase ineffectiveness of the combination over AZT, which remains the goldstandard in AIDS today. Taken together, these results stronglysuggest to us that the 3TC/AZT combination ought to be approved[in the U.S. and Europe].
Isaly said it will be interesting to see results in January of 3TC as amonotherapy, on whether it does better than AZT alone. "It looksnow that AZT is the standard and 3TC is the add-on," he said. "Thiswill be the combination of choice."
BioChem Pharma (NASDAQ:BCHXF) stock was up $1.13 Monday,closing at $12.75. Glaxo Holdings (NYSE:GLX) closed at $19.38,up 38 cents. n
-- Jim Shrine
(c) 1997 American Health Consultants. All rights reserved.