By Lisa Seachrist
WASHINGTON * The development of new drugs can sometimes be stymied by the fact that current therapies work so well. That is precisely what NABI discovered when comparing its passive immunotherapy to AZT therapy.
The National Institutes of Health (NIH) stopped a clinical trial testing how well NABI's HIV drug, HIV-IG, prevented the vertical transmission of HIV from mother to child because so few infants in the trial became infected it would be impossible to show that HIV-IG was any better than AZT.
"In a sense this is good news, because it confirms the Public Health Services' recommendations that all women be tested for HIV and be offered treatment with AZT," said Lynne Mofenson, assistant branch chief of clinical research for the Pediatric, Adolescent and Maternal AIDS Branch of the National Institute of Child Health and Human Development.
In another sense, aborting this trial early is bad news because researchers now are unable to determine whether HIV-IG is effective. David Gury, chairman, CEO and president of NABI, told BioWorld Today, "One of the frustrations that exist in this circumstance is that the trial has not allowed us to determine what effect passive immunization has on vertical transmission of HIV."
The Boca Raton, Fla., company's stock (NASDAQ:NABI) fell 17 percent from $7.81 to $6.50 on the news.
The Pediatric AIDS Clinical Trials Group (ACTG), a consortium of leading medical research centers, undertook the trial ACTG Protocol 185 to test the benefit of adding HIV-IG therapy to the current AZT regimen used to prevent vertical HIV transmission.
That regimen essentially involves mothers starting oral AZT after the first trimester, getting intravenous AZT during labor and giving the baby AZT for six weeks after birth. The clinical test of this regimen, Pediatric ACTG Protocol 076, showed that AZT reduced the transmission of the virus from 23 percent to 7.6 percent of all births to HIV-infected women with CD4 counts above 400 and no HIV symptoms, who hadn't taken AZT.
The most recent trial enrolled much sicker women. All of the women were on AZT and all had CD4 counts below 500. Twenty-three percent had CD4 counts below 200. All of the women were treated with the standard regimen, but half of the women also received infusions of HIV-IG during labor.
HIV-IG is naturally produced polyclonal antibodies against HIV that are collected from HIV-infected donors with high antibody titers. The antibodies are rendered noninfective and administered to the mother and infant in the hopes that the antibodies will block HIV infection.
Because the women were sicker, Pediatric ACTG 185 was designed with the assumption that there would be an infection rate between 11 percent and 15 percent, Mofenson said. Using those numbers, the trial would need to enroll 800 women to see a 50 percent reduction in transmission as a result of HIV-IG therapy.
However, when the trial's Data and Safety Monitoring Board reviewed the infection rates of the 445 women enrolled, 394 of whom had given birth to 402 infants, they found an overall transmission rate of 4.8 percent. Such a low rate caused the group to suggest stopping the trial because it would have to be expanded to 2,500 women in order to show that HIV-IG had any effect whatsoever. That process could take as long as 10 years.
"These results extend the efficacy of AZT into much sicker women," Mofenson said. "And the infection rate is similar to what we are seeing around the country: in North Carolina and New York the vertical infection rate has dropped to 5 percent."
Nevertheless, the results also mean that HIV-IG cannot be tested in the U.S. because AZT therapy is available. However, Mofenson noted that it is still important to determine if passive immunity could prevent maternal transmission of HIV because AZT therapy is prohibitively expensive in developing countries and AZT exposure in utero may have as-yet-unknown effects.
"In developing countries like Uganda, treating mothers with the 076 protocol would break the medical system," Mofenson said. "Passive immunity would be a much more feasible way to prevent transmission."
Gury said he was pleased that Mofenson was interested in pursuing passive immunity and said NABI would work with the NIH on any foreign trials that they attempted. He also noted that HIV-IG is not dead in the water.
"We are working with NIH on the Pediatric ACTG Protocol 273 testing HIV-IG in children between the ages of 2 and 14 who have not responded well to AZT therapy," he said. "This unfortunate result isn't the end of the drug by any means." *