Harryz
Upon returning to my office, I can now access the full text of the NEJM Correspondence that you started this thread with. Don't ask me why - from a Singapore hotel room Internet connection, I could not, but from my office internet, I can access it. Strange.
I note that I was in error - the Correspondence that Harryz referred to was about the Phase 1 study, a very small study in (I think) 1999. The Jan 03 Authors (who reported on the P2 study) response is given below, and I believe puts the Correspondence into perspective.
As I think all would agree, we need the full P3 results, particluarly the EDSS results, to fully evaluate Tysabri. Again, I SPECULATE that the EDSS results will be very good, and that is the reason the FDA approved Tysabri (they looked at the data that were available - not ALL of the P3 data since the trials were incomplete - but enough to convince them that Tysabri was beneficial). Lets hope my speculation is correct.
________________________________________
From the April 2003 NEJM Corresondence regarding Natalizumab (Tysabri):
Natalizumab for Relapsing Multiple Sclerosis
To the Editor: As participants in the original exploratory study,1 we did not find that treatment with anti–4 integrin antibody was of clinical benefit. Miller and colleagues ( Jan. 2 issue)2 report that monthly natalizumab infusions in patients with multiple sclerosis significantly reduced relapse rates and enhancing lesions on magnetic resonance imaging (MRI), but this effect was not carried forward in the six months after treatment. The treatment had no effect on the disability score (on the Kurtzke Expanded Disability Status Scale). There was no evidence that long-term natalizumab infusions modify the course of multiple sclerosis.
Epidemiologic studies have shown a biologic dissociation between relapses and progressive disability once a score of 4 to 4.5 on the Expanded Disability Status Scale is reached.3 It may be argued that all patients with multiple sclerosis should start receiving natalizumab at the time of their first clinical presentation; however, the effects of pregnancy in multiple sclerosis clearly indicate that the progression of disability is independent of clinical relapses.4 Longitudinal MRI studies show that perivenous inflammatory changes are associated with local alterations in the blood–brain barrier and are not obligatory events in the evolution of the plaques in multiple sclerosis.5
The results of immunotherapy trials in multiple sclerosis suggest that although such treatments may reduce relapse rates, they do not modify progressive loss of function. In a three-year follow-up of a trial of treatment for acute optic neuritis, a benefit of antiinflammatory treatment was not evident.6 We are not convinced that the effects of natalizumab on relapsing multiple sclerosis are any exception.
Abhijit Chaudhuri, D.M., M.D.
Peter O. Behan, D.Sc.
University of Glasgow
Glasgow G51 4TF, United Kingdom
ac54p@udcf.gla.ac.uk
References
1.Tubridy N, Behan PO, Capildeo R, et al. The effect of anti-alpha4-integrin antibody on brain lesion activity in MS. Neurology 1999;53:466-472.[Abstract/Full Text]
2. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15-23.[Abstract/Full Text]
3. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438.[Abstract/Full Text]
4. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T, Pregnancy in Multiple Sclerosis Group. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998;339:285-291.[Abstract/Full Text]
5. Narayana PA, Doyle TJ, Lai D, Wolinsky JS. Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 1998;43:56-71.[ISI][Medline]
6. Beck RW. The optic neuritis treatment trial: three-year follow-up results. Arch Ophthalmol 1995;113:136-137.[CrossRef][ISI][Medline]
--------------------------------------------------------------------------------
The authors reply: Chaudhuri and Behan refer to an early exploratory study of natalizumab in multiple sclerosis. This was a study of 72 patients, of whom 37 were randomly assigned to receive two doses of natalizumab, one month apart (and 35 to receive placebo).1 There was a significant decrease in the number of new gadolinium-enhanced lesions on MRI during the 12 weeks after the first dose of natalizumab, as compared with placebo. Given the small size of the study and the limited duration of treatment, however, it is not surprising that no clinical benefit was observed. The positive MRI result did, however, provide us with a reason to undertake our six-month study. Although this study was powered only to investigate the effect of treatment on MRI activity, it showed a significant treatment-associated reduction in relapses. It is not surprising that there was no significant change in disability in either the treated groups or the placebo group over a six-month period.
The mechanisms by which irreversible disability develops in multiple sclerosis are not well understood. Chaudhuri and Behan cite evidence supporting the independence of the progression of disability and relapses,2,3 but these events are not completely unrelated. Incomplete recovery from relapses is one mechanism of permanent disability. The effect of natalizumab on long-term progression of disability can be addressed only by larger, longer-term, phase 3 studies. Two such studies designed to investigate this issue are currently under way.
In our article, we omitted acknowledgment of J. O'Riordan and J. Parratt (Ninewells Hospital, Dundee, United Kingdom), who were investigators in the trial, and Dr. Martin Sanders, who provided helpful comments on the manuscript.
David H. Miller, M.D.
Institute of Neurology
London WC1N 3BG, United Kingdom
d.miller@ion.ucl.ac.uk
Paul W. O'Connor, M.D.
University of Toronto
Toronto, ON M5B 1W8, Canada
Editor's note: Dr. Miller reports having received grant support from Elan, Schering, and Biogen; honorariums for giving expert advice to Biogen, Wyeth, Bristol-Myers Squibb, and Schering; and lecture fees from Serono. Dr. O'Connor reports having received grant support from Elan, Biogen, Athena Neurosciences, Aventis, Berlex, Serono, Teva Neurosciences, Angiotech, and Amgen.
References
1. Tubridy N, Behan PO, Capildeo R, et al. The effect of anti-alpha4-integrin antibody on brain lesion activity in MS. Neurology 1999;53:466-472.[Abstract/Full Text]
2. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T, Pregnancy in Multiple Sclerosis Group. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998;339:285-291.[Abstract/Full Text]
3. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438.[Abstract/Full Text]
Related Article
by Miller, D. H.
Find Similar Articles
PubMed Citation
This article has been cited by other articles:
Mittelbrunn, M., Molina, A., Escribese, M. M., Yanez-Mo, M., Escudero, E., Ursa, A., Tejedor, R., Mampaso, F., Sanchez-Madrid, F. (2004). VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses. Proc. Natl. Acad. Sci. U. S. A. 101: 11058-11063 [Abstract] [Full Text]
_________________________________________
Here is the link, I'd be interested to know whether anyone else can access it without being a 'paying' customer to NEJM.
http://content.nejm.org/cgi/content/ful ... lcode=nejm