Elise Wang & Paine Weber are having a conference call this afternoon:
An update from ICAAC, with Dr. Calvin Cohen, Research Director of Community Research Initiative of New England.
Rick: re Remune data:
Valentine's presentation at Geneva is still available at the Webcast using a Real Player, which can be downloaded - free. . Valentine discusses the 20 week data- and there are numbers there - charts, tables, statistics. It looked pretty impressive to me and was statistically significant at high levels.
"Effects of HAART compared to immunogen HAART plus an inactivated HIV on lymphocyte proliferative responses to HIV antigens" Fred Valentine
Richard: There is another lecture there that should interest you and may answer some questions you have, as to whether this anti-HIV proliferative response is what causes non progression in LTNP.
Mark Connors, from the National Institute of Health:
"In Vivo Resistance to Resistance of HIV Challenge Virus Mediated by CD8 T-cells & associated with a proliferative response to P24."
"Although strong cellular and humoral HIV directed responses have been demonstrated there remains no direct evidence that such responses are the reason for non progression or the cause of restriction of challenge virus replication
Both lectures are available at the Geneva AIDS World Conference site: aids98.ch
Double click on Video webcast - on the left; then select - Review Friday July 3rd Then select whichever lecture you want.
The weekly prescription data continues to look strong and Viracept's market share has probably increased even more over the 32% or 33% from last week. Even though weekly data is not always a reliable indicator of trends, it wouldn't be too surprising to see it keep increasing, due to Agouron's favorable profile re: BID efficacy, tolerability; favorable cross resistance profile; lowest incident of side effects; least reported lipodystrophy; and the only protease inhibitor that reacts favorably with Sustiva etc etc. Also:
-the unavailability of Ritonavir capsules, and their replacement with the foul tasting liquid Ritonavir
-the withdrawal of Crixivan BID regimens due to ineffectiveness and increased side effects.
-the FDA approval of Sustiva mainly due to its effectiveness in combination with Viracept*
-the realization (finally) that Crixivan and Ritonavir are difficult protease inhibitors to tolerate and have significant adverse events.
I got the impression from all the Dupont press releases that the FDA would not have approved Sustiva just on the basis of Dupont's Study 005 and 006*. The FDA unexpectedly required that the results of ACTG Clinical Trial 364 be unblinded at 24 weeks. There had been an interim report at 16 weeks and the next one was not supposed to be until 48 weeks. This study of Sustiva in combination with Viracept in treatment experienced patients was used to support FDA approval of Sustiva and the results will become part of the package insert.
Similarly, the results of pediatric study PACTG382 ""The study directly contributed to accelerated Food and Drug Administration approval earlier this month of efavirenz as a treatment option for HIV-infected children."
The study used Sustiva once a day in combination with Viracept and one or two nukes. The statement from the National Institute of Health said:
<<Study Shows Efavirenz Promising in Treating Pediatric HIV Infection; Leads to Approval of New Drug for Treating HIV-Infected Children>>
The FDA may have required more data than Dupont supplied, like that available in ACTG364 and 382, which are blinded, randomized clinical trials. Dupont studies 005 and 006 were open label trials. It certainly looks to me, at least, that Sustiva was approved by the FDA partly or largely, on the basis of the results of Sustiva in combination with Viracept, than for its use as a "protease sparing regimen."
This is just my opinion, but I also wonder if the FDA asked Dupont to stop promoting their drugs, because there was so much hype about Sustiva at Geneva and so little at ICAAC. According to a news story before ICAAC and FDA approval, Dupont was planning the same hype for ICAAC:
"DuPont will try to keep the momentum going at ICAAC, where researchers will present a number of studies of the drug, including its use in combination with Merck's Crixivan and with Agouron's Viracept. More long-term data will also be available.> “Dupont Plans to Grab AIDS Doctors Attention at Medical Meeting.” techstocks.com
Dupont's press releases upon FDA approval were muted.
In ACTG 364, 80% of patients on Nelfinavir+Sustiva+plus one or two nukes were <400 at 24 weeks, which was better than treatment arms with either Sustiva or Viracept alone with nukes. These were patients heavily pretreated with nukes, from two different previous clinical trials, where some nukes were used as monotherapy (monotherapy is great for causing resistance to develop.)
Included in the release from the Department of Health and Human Services was a statement that Sustiva labeling recommends that health care providers monitor patients' liver enzymes, especially in those infected with hepatitis B or C viruses and cholesterol levels because clinical studies could not distinguish whether this drug contributed to elevated levels or not. Several AIDS drugs have been associated with increased cholesterol and liver enzyme levels." fda.gov
So it is possible that Sustiva causes elevated cholesterol levels, like PI's and elevated liver enzyme levels like Nevaripine, another NNRTI or Ritonavir.
Time will tell what the side effects of Sustiva are.
Sustiva is certainly not as tolerable as it was made out to be at Geneva, not with Dupont reporting that more than 50% of patients had CNS symptoms and 27% of patients on Sustiva had rashes and there was a 20% dropout rate in Study 006. Well, 20% is better than Crixivan's 30% or 40% dropout rate, but 20% is high. Viracept has a low dropout rate.-about 4%.
The FDA now requires data to be reported using "Intent to treat" and not "On Treatment analysis. On treatment analysis does not include data from patients who have withdrawn from the study due to side effects, treatment failure, lack of compliance, etc.
It was only Dupont's "On Treatment" analysis at Geneva in 005 and 006 that impressed everyone, that gave those 95% "eye-poppping" figures. By intent to treat, they were more like 35%-50%.
However at ICAAC, Dupont again used "On treatment " analysis to present data for Sustiva..
Dupont's press releases acknowledge that the high dropout rate seen in patients on Crixivan may bias results in favor of Sustiva. In other words, the higher dropout rate of Crixivan itself could have caused the supposed superiority of the Sustiva arm. "this dropout rate (Crixivan) accounted for a substantial fraction of the difference between the treatment regimens." The open label design of the study makes it difficult to assess the relative efficacy of the treatment arms."
sustiva.com So this data is non-conclusive, which is probably why the FDA required additional studies.
Since Geneva, Merck has withdrawn studies of Crixivan BID and Crixivan BID with Sustiva. Crixivan is not the Gold Standard of Treatment, as Dupont made it out to be. Dupont compared Sustiva's performance to Crixivan, a drug that is "easy to beat" because of all its side effects and tolerability problems. And because Dupont "beat" Crixivan, they felt justified charging almost the same as for protease inhibitors. A Dow Jones Newswire on 9/18 quoted Stephen LeBlanc, a participant in the first Sustiva Trials, who has been using the drug for two years with a protease inhibitor, as saying that the expectations for Sustiva were overblown. Activists are protesting Dupont's pricing of Sustiva. They don't think it is justified, as the costs are much less than that of PI's and they feel that Sustiva should be priced as other NNRTI's in the same class which are $2000 a year less.
Merck presented data showing better "preliminary" results for Crixivan BID vs TID, in small studies at Chicago in February and 32 week data at Geneva. Then Crixivan BID was withdrawn, and Merck said that the data from more patients at 24 weeks showed the opposite, that BID was worse than TID, and there were more side effects in the BID vs TID. If anyone had looked at the numbers in the studies, in February and June, they would have waited, as many did, for more data.
There is a good article about Merck trying to make Crixivan BID in the June Issue of POZ: Bull Market Message 4650255
People should think twice , unless they are desperate and have no choices left, before switching to a new unproven combination. There isn't any long term data for Sustiva yet, nor data on how patients do who switch from a protease inhibitor to Sustiva. The FDA grants accelerated or conditional approval on the basis of six months of viral load data and 48 weeks for complete approval. In all of the treatment arms where Sustiva was used with two nukes, changes were made at 16 weeks, and no one knows how many patients had their regimens changed. Dupont does not specify.
"Companies often make claims that turn out to be incorrect or exaggerated, on the basis of small preliminary studies." I would think that there are lessons to be learned from Merck withdrawing BID Crixivan. Many patients were put on Crixivan BID, on the basis of very preliminary results that did not hold up. The data on Sustiva as a protease sparing regimen is still preliminary, and not longitudinal, and some caution wouldn't hurt, imo. And I'm not saying this because I am long Agouron. I've looked at the numbers in 005 and 006, the "Intent to Treat" and not the "On Treatment analysis. |
