<But I find it a weird quirk of fate that the testing of Remune, a therapy which is supposed to keep people from dying of AIDS, is halted because not enough people are dying of AIDS. Something circular in that discussion, but I can't point it out right away. >
What it indicates is that the clinical endpoints used to judge the effectiveness of Remune are outdated and need to be revised. Agouron and IRC have succeeded in changing the endpoints for Remune to viral load instead of clinical endpoints, no small accomplishment.
Immune Response Corporation (IRC) did not have a choice about which endpoints to use. These clinical endpoints, that is, death or progression to AIDS or the development of opportunistic infections, were the only endpoints acceptable by the Biologics division at the time the study began in 1996, and until very recently.
Therapeutic vaccines like Remune are considered Biologics, and are regulated by the Center for BIOLOGICS Evaluation and Research or CBER.
Antivirals drugs like protease inhibitors are drugs and are evaluated by the Center for DRUG Evaluation and Research or CDER; a separate division with different standards.
Viral load was only approved as an endpoint for CDER in the latter part of 1997, after much discussion and many requests.
It is unfortunate that viral load was not approved as an endpoint or surrogate marker for immunologic therapy then as well, but it is not too surprising, since the emphasis in 1996 and 1997 was on trying to eradicate HIV with antiretroviral therapy. Now that it has been shown that some HIV persists in a latent state in different reservoirs, and that HAART does not completely rebuild the immune system, attention has turned to ways to eliminate the reservoirs and/or reconstitute the immune system.
During the conference call with analysts on May 20th, Dr. Barry Quart said that Agouron and the IRC had been working diligently with the Biologics division for the last nine months, to try to get them to accept viral load surrogate markers as an acceptable basis for submitting an application.
About a month ago, the Biologics division agreed to allow viral load endpoints as surrogate markers.
Below is some information and notes from the analyst conference call that Immune Response Corporation and Agouron held for analysts on May 17th. It is old information now but some of it has not been posted on SI and there still appear to be misconceptions about why Remune Study 806 was halted by the Data Safety Monitoring Board (DSMB.)
It was NOT because Remune was a failure or ineffective.
Very few patients develop clinical endpoints when they are on HAART and most patients were on HAART.
The first protease inhibitors were approved the year the study and they became part of HAART.
The progression rate to AIDS was around 6 percent before HAART; now it is less than 1%.
Agouron and IRC were told by the DSMB that in this day and age of HAART it will be very difficult to conduct a study using clinical endpoints as the numbers in a study required to reach significance would be enormous and the time required would be to long.
While Agouron hoped that the clinical end point study would be positive, they certainly knew from the beginning that was unlikely as the low number of clinical end points seen in the HIV population in general would make it very difficult to get a positive outcome. Thus Agouron wanted to have an alternative regulatory strategy; or different markers or endpoints that could be used to apply for approval, independent of clinical end points.
More importantly, IRC/Agouron did find statistically significant decreases in viral load and increases in lymphocyte proliferation in a separate evaluation of 250 patients. This group of 250 patients was completely randomly selected from the different sites at the beginning of the trial in 1996 and has had intensive surrogate marker analysis done, and much more frequent viral load sampling that the rest of the subset. They have 48 week and 96 week data for this group.
Agouron/WLA and IRC feel that the data is highly significant and it will be presented at some scientific meeting. Dr. Carlos was asked if the magnitude of the differences found in Study 806 using viral load compares favorably with the difference seen in trials of other drugs using viral load surrogate markers endpoints and he answered affirmatively. Warner Lambert has committed more funds for extra viral load studies (~$27 million more) and they remain committed to working as hard as possible to get Remune registered. Barry Quart said that Agouron/Warner-Lambert will be responsible for the conduct of the viral load studies.
Agouron/WLA intend to analyze the viral load data from the remaining 2250 patients of Study 806 which will take several months. Agouron/WLA/IRC are hoping to submit the viral load data from the 250 patient cohort; the viral load data from the 2250 patients, and the data from the Spanish trial to the FDA as part of an NDA. They don't know if the Biologics group of the FDA will accept an NDA on this basis, but it will certainly be discussed.
There is a Spanish trial ongoing with 300 patients, randomized and blinded, which is looking at viral load as well. An analysis a few months ago was encouraging. They will have another analysis by the final quarter of this year and if that is positive they will be using that to apply for approval in Europe.
Thailand is conducting their own study, independent of IRC. In Thailand, the clinical endpoints are CD4 counts, weight gain, and viral load. One cannot compare the data from Thailand to 806 because antiretroviral therapy is not available in Thailand. However after an interim look in Thailand on March 13th 1999, they were told by the DSMB that they had a high chance for approval. They will be applying to the Minister of Health in the next 60 to 90 days for accelerated approval in Thailand.
Agouron/WLA are now proceeding to work on two additional phase III trials, using viral load as an end point, in the event that the FDA does not accept the above studies,. Dr. Quart said they anticipate at least one study will have naive patients; comparing standard HAART including Viracept plus or minus Remune. Remune is given in an injection once every three months.
Many patients in Study 806 have been on Remune for three years and have very low viral loads. AGOURON and IRC have discussed a trial that takes these patients off HAART to see if there is a viral rebound. Normally when patients stop taking triple drug therapy, the viral load rebounds. They will see if patients treated with Remune have less rebound or slower rebound.
If other trials are required, it would take about six months to enroll, plus 48 weeks of study, and time to analyze the data. That would mean it would be sometime in the early to middle part of 2001.
I wonder if Remune will receive fast track designation or if it will be applied for. Accelerated approval decisions in the CDER division are based on significant differences in viral load data based on 16 to 24 week data. |
