Finn, on the rebound effect I note that your 2nd citation suggesting this problem was published in MAY 2002 as conference coverage of the 2002 AAN Conference. Yet the Phase 2 trial was NOT published in a peer-reviewed journal until JANUARY 2003. The NJEM paper on the Phase 2 trial is at:
http://content.nejm.org/cgi/content/fu ... code=nejm
(sorry, I don't know how the link thing works).
Here is an excerpt from the paper at the above link.
Study Design and Randomization
Patients were randomly assigned to one of three treatments — 3 mg of natalizumab per kilogram of body weight, 6 mg of natalizumab per kilogram, or placebo — with use of a computer-generated block randomization schedule. Randomization was performed centrally by PPD Development. Patients received an intravenous infusion every 28 days for 6 months and were then monitored for an additional 6 months for adverse effects. Neither the study personnel nor the patients were aware of the blinded treatment assignments.
When the values obtained at month 9 and month 12 were combined, the number of new enhancing lesions and scans showing activity were similar in all three groups (Table 2). After treatment, there was no significant difference among the three groups either in the total number of relapses or in those objectively confirmed (Table 3).
In other words, NO rebound effect was noted. Speculation by some after the P1 trials suggested possible rebound was one of the purposes of the P2 trial. I wonder why no one has suggested rebound affect after the P2 trial was published in January 2003. If you have some more recent data on a possible 'rebound effect', or comments thereon, I'd certainly like to see it. TIA.
So I don't know where Dr. Freedman comes up with his comments:
A similar loss of relapse benefit was noted, but with a slightly higher relapse rate seen in the higher-dose group.
This agent presumably works by stemming the flow of lymphocyte traffic across the blood brain barrier. Given alone, it would appear that the cells capable of causing disease simply pile up and enter the brain upon drug cessation. This raises concern over a possible "rebound" effect when the drug is stopped, and speaks for the need to use a concurrent immunomodulatory agent, such as an IFN, to act upon potential disease-causing cells in the periphery.
but it appears that Dr. Freedman is merely speculating on the basis of data that are not statistically significant ('slightly higher relapse rate'). And no others have echoed this speculation, even after the paper was published. Hmmm. But what do I know? Let the reader decide.
And just a further note, from an interview with Dr. Freedman
Disclosure: Mark S. Freedman, MD, has disclosed that he has received grants for educational activities and clinical research from Serono. He has served as an advisor for Serono, Berlex/Schering, Biogen Idec, and Teva.
This disclosure information does NOT invalidate his concerns published in May, 2002, nor suggest any impropriety. It is simply worth noting and being aware of.
As for the FDA request for 1 yr filing, I must be reading something differently than you, as here is the excerpt from the article you reference from page 3:
“It wasn’t a sure thing that [Antegren] would affect relapses to a similar degree that it affected lesions,” he says. “When we saw the results we got very excited. Then we went down to the FDA, and they broke their prior
Phase III trial precedent of requiring two years of data, allowing us to file with one year of data—that was an exciting moment.”
So does this indicate that Biogen initiated the filing process? Not IMHO. The trials had pre-approved one-year endpoints, and the companies were obliged to report this to the FDA in the normal course of the trial. Are you suggesting that in this reporting, the companies asked to file on 1yr data? Maybe they did, but where does the article you posted say that? Does the phrase 'allowing us' indicate that Biogen Idec initiated the process? Open to interpretation.
But substantially more details of the pre-NDA process are outlined in several statements at Investment Conferences where Dr. Lars Eckman, Elan's President of R&D, said the FDA encouraged Biogen Idec and Elan to file. Here is one quote from Dr. Eckman, speaking at the Lehman Brothers 3 March 2004 Global Healthcare conference
"So, why is the Agency excited about Antegren? Well, there were two reasons. When we presented the Phase II data two years ago, we presented two things or three things. One was that the galinieum enhanced lesions, the new lesions, were reduced by 90%. We did prove that we could reduce the number of relapses with 50% to 60 % in the two categories. And we had excellent safety data. Safety data that did not reveal any difference between placebo and control in any aspect. At the time the Agency said: “If you can provide exceptional data,” and by that they said “in this space” then they would consider a one-year filing.
Since then, we have delivered 2, 200 patients in two trials, one is a monotherapy trial, the Affirm trial. The other one is a combination [trial] with Avonex, [the Sentinel trial]. It’s Avenex vs. Antegren plus Avenex in partial failures. This data has now been presented to the Agency. The Agency came back to me or to us as a team and said, “We want to meet you. We want to have a pre-NDA meeting.” We had the meeting. It was a very constructive meeting and they encouraged us to file. "
There are other references to the FDA guiding the process, but they say basically the same thing: the FDA encouraged the filing. I'll let the readers decide whether to believe Dr. Eckman, but I'd ask why would he make such a statement in a public forum if it were not true? Wouldn't he think the FDA might be a bit upset about him 'putting words in the FDA's mouth' if they were untrue?