By Lisa Seachrist
The Immune Response Corp.¿s attempt to prove its immune-based therapy, Remune, effective for the treatment of HIV fell victim to the success of ¿triple-drug therapy¿ that has drastically reduced the rate at which HIV-infected patients see their disease progress.
The Carlsbad, Calif.-based company and partner Agouron Pharmaceuticals Inc. announced that an independent data safety monitoring board (DSMB) determined that the trial should be stopped following an interim analysis. The 2500-patient, placebo-controlled study tracked the ability of Remune to slow disease progression by tracking the clinical endpoints of a diagnosis of AIDS or death.
The DSMB found that there was no difference in those endpoints between the placebo-treated patients and the Remune-treated patients and that a substantial difference between the two groups was unlikely to develop by completing the study.
The news sent Immune Response¿s stock (NAS DAQ:IMNR) sharply lower as it fell 36 percent to close at $7.562 a share, down $4.25.
Despite the seeming failure of this pivotal trial, Immune Response and La Jolla, Calif.-based Agouron consider the trial a success because a subset of patients whose blood was intensively monitored for the presence of HIV showed that Remune significantly reduced the amount of circulating virus as compared to placebo-treated patients.
¿I look at this as a major step forward for Remune,¿ said Dennis Carlo, president and CEO of Immune Response. ¿We now know where to aim and all we have to do is hit the target again.¿
Remune is an inactivated form of HIV lacking its envelope that is combined with a mineral oil-based adjuvant. The drug, which is injected every three months, is designed to stimulate a patient¿s own immune defenses to keep the virus in check. In 1996, when Immune Response began its Phase III study of Remune, the rate of disease progression for HIV-infected patients was 6 percent.
However, in the intervening period, that progression rate has dropped to below 1 percent thanks to the advent of highly active antiretroviral therapy (HAART), including HIV protease inhibitors. HAART has meant a significant decrease in suffering for AIDS patients, but has left the research community with a bit of a dilemma.
Surrogate Endpoints Replace Clinical Endpoints
¿I don¿t think it¿s possible for anyone to do a clinical endpoints study in HIV these days,¿ Carlo said. ¿It would take such large numbers of patients for such a long period of time to get the data.¿
Instead, many companies have moved to studying the surrogate endpoint of showing a reduction in viral load in the bloodstream as a means of demonstrating efficacy. Immune Response, in fact, chose 250 patients on a random basis at the beginning of the study to receive monitoring of their viral load as well as a measure of their cell-mediated immunity.
¿Low viral load and a cell-mediated immune response have been shown key to slowing the progression of this disease,¿ Carlo said. ¿We had statistically significant reductions in viral load for Remune-treated patients in this group of 250, and we showed that we could re-establish cell-mediated immune responses with these patients.¿
The results for those 250 patients confirm the results of a smaller Phase II study that examined Remune¿s effect on the immunologic markers. However, all of the products that have been approved using the surrogate endpoint have been small-molecule drugs that have been approved through the FDA¿s Center for Drug Evaluation and Research.
The FDA¿s Center for Biologics Evaluation and Research (CBER) ¿ and Remune as a vaccine is a biologic ¿ has up to this point not accepted reduction in viral load as a surrogate endpoint. However, just last month, Agouron convinced CBER to accept a viral load study for Remune as an indication of efficacy.
Companies Intent On Getting Product Approved
¿When we signed the agreement for Remune, we did so knowing that there would be a low number of clinical endpoints in this trial,¿ said Barry Quart, vice president of regulatory affairs for Agouron. ¿We had an alternative regulatory strategy to get Biologics to change their minds to accept viral load as an endpoint. That has now been agreed to, and both Agouron and Warner-Lambert are committed to getting this product approved.¿
In January, Warner-Lambert Co. purchased Agouron for $2.1 billion, just six months after Immune Response and Agouron signed a $77 million pact to develop Remune. Agouron and Warner-Lambert, of Morris Plains, N.J., finalized their merger Monday. (See BioWorld Today, Jan. 27, 1999, p. 1; and June 12, 1998, p. 1.)
Carlo said the two companies were going to analyze the data and combine it with international studies testing Remune¿s ability to reduce viral load. He also noted that the company would talk with the FDA following that analysis to ascertain what studies, if any, needed to be conducted to win an approval for Remune.
¿There are too many variables to determine when we could expect a filing,¿ Carlo said. ¿But there is a precedent for using surrogate endpoints.¿ n