Talk:Natalizumab/Archive 1

Archive

I have created an archive of the old discussions. I have copied back to this page the most recent conversations, in collapsible headers on the longer posts.

In case anyone needs to know in the future, I used the Move Page method. WhatamIdoing (talk) 03:11, 12 February 2008 (UTC)

Stem cells

An interesting property of natalizumab, and possibly even a therapeutic mechanism, it is ability of mobilising haematopoietic stem cells (CD34+ mononuclear population) from the bone marrow: doi:10.1182/blood-2007-10-120329 JFW | T@lk 10:46, 25 March 2008 (UTC)

I enquired today of colleagues if this had any significance, and apparently the drug will be trialled in multiple myeloma. Nothing on the clinicaltrials.gov site however.io_editor (talk) 01:50, 27 March 2008 (UTC)

FDA did not withdraw Tysabri nor cancel it's License

Reference #1 - from NEJM - withdrawal by Biogen -http://content.nejm.org/cgi/content/full/353/4/432

Reference #2 - FDA approval history - subsequent "re-approval" was actually a "supplemental" (Biological License); original License was in place - http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist ....io_editor (talk) 01:17, 29 March 2008 (UTC)

the PML deaths

From Io io editor

There were 3 PML cases; of which 2 died. Only in full-blown Aids is PML usually seen, and is usually fatal due to the absence of an immune system. So how did these patients die?

1. http://content.nejm.org/cgi/content/full/353/4/375?ijkey=b24b4864c7f8f2c41bcc31d8e021ff52b2f40430
2. http://content.nejm.org/cgi/content/full/353/4/369?ijkey=f3eceb18a94aa8b54237f55ba4a7286c8f4e071f
3. http://content.nejm.org/cgi/content/full/353/4/362

What all 3 had in common were 2 things:

1. con-committant drugs (avonex in 2 "MS" patients; and in the CD patient, not simultaneous but was
already chronically immuno-suppressed - had already low lymphocyte counts due to prior immuran and infliximab).
2. a bungling period 3 to 5 months of PML mis-diagnosis before death or partial recovery (in one
case of course the mis-diagnosis of a brain tumor continued for 2 years post-mortem). In this 3 to 5
months of PML mis-diagnosis, all 3 received massive amounts of powerful immuno-suppressive medications - all
for the wrong issues.

Treatment of PML in these non-Aids cases appears possible - http://archneur.ama-assn.org/cgi/content/abstract/64/2/169 - ....io_editor (talk) 01:33, 29 March 2008 (UTC)

How many "real" MS patients on N (and Avonex) got PML?

From Io io editor

By "original diagnosis", 2 is the answer; 1 died, 1 lived. However, a few months after the NEJM simultaneously published the case histories, it published a pair of letters (presumably, among many) which, to the embarrassment of the authors, cast doubt on the MS diagnosis of both patients - http://content.nejm.org/cgi/content/full/353/16/1744 - rather than explain all that, and for those who have no NEJM access, here is a full copy, minus the references -

<<<<<" To the Editor: According to the established definition of multiple sclerosis, the condition in the patient described by Kleinschmidt-DeMasters and Tyler (July 28 issue) should not have been diagnosed as multiple sclerosis. Apart from the unusual clinical findings, no oligoclonal bands were detected in two separate examinations of the cerebrospinal fluid, and repeated magnetic resonance imaging (MRI) scans obtained over the course of several years showed new and enlarging, but never enhancing, lesions. The most convincing argument against a diagnosis of multiple sclerosis is the neuropathology: no lesions that are characteristic for multiple sclerosis were detected. The patient described by Langer-Gould et al. in another article in the same issue may also raise concern about the diagnosis of at least "typical" multiple sclerosis. One to two oligoclonal bands in the cerebrospinal fluid would have to be considered negative, and repeated MRI scans would not show enhancing lesions. Therefore, it does not seem appropriate to conclude that patients with multiple sclerosis may be at risk for progressive multifocal leukoencephalopathy (PML) owing to treatment with natalizumab and interferon beta-1a. Is it possible to misdiagnose subclinical nonfatal cases of PML as multiple sclerosis in patients who are not obviously immunosuppressed? Further investigations of JC virus infections should extend our knowledge of this scenario.

Thomas Berger, M.D., M.Sc. Florian Deisenhammer, M.D., M.Sc. Innsbruck Medical University A-6020 Innsbruck, Austria

Dr. Berger reports having received unrestricted research-grant support, lecture fees, and consulting fees from Berlex, Biogen-Idec, Sanofi-Aventis, Schering, and Serono; and Dr. Deisenhammer, unrestricted research-grant support, lecture fees, and consulting fees from Biogen-Idec, Schering, and Serono.">>>>> (Io-Editors's note - this means almost all the MS DMD maker/ competition)

---

To the Editor: Kleinschmidt-DeMasters and Tyler described a patient with multiple sclerosis and PML that developed after she received natalizumab treatment. However, some of the findings in this patient are uncommon in multiple sclerosis. The absence of contrast enhancement in the MRI studies that were performed — almost a rule in patients with PML — is uncommon in multiple sclerosis. The lack of intrathecal synthesis of IgG is unusual in multiple sclerosis, although it is frequent in PML. Moreover, an autopsy study found no multiple sclerosis plaques but only PML lesions. Therefore, the pathological findings did not support a diagnosis of multiple sclerosis, which raises some questions. Can initial PML mimic multiple sclerosis? Was PML the only disease in this patient? To our knowledge, PML with a relapsing–remitting course has not been described. To clarify whether PML may have a relapsing–remitting course, it is necessary to study the cerebrospinal fluid in patients with relapsing neurologic disorders to rule out this disease. This seems particularly important for patients with suspected multiple sclerosis with atypical findings, such as early mental symptoms or an absence of oligoclonal bands. If it is demonstrated that PML can have an initial relapsing–remitting course, the risks of natalizumab treatment should be reevaluated.

José C. Álvarez-Cermeño, M.D. Jaime Masjuan, M.D. Luisa M. Villar, Ph.D. Hospital Ramón y Cajal 28034 Madrid, Spain

Note that these letters raise the possibility that, not only did one or both patients never had MS, but may have had "sub-clinical" PML. Perhaps in recognition of this (because the anomaly was raised at the FDA Advisory Committee Hearings - reference available), patients "who already have PML" are contra-indicated on the label for N treatment....io_editor (talk) 13:23, 29 March 2008 (UTC)

In actual practice, both in all trials and in 2 years of widespread availability, no MS patient (real or disgnosed) has contracted PML while on N alone - http://www.biogenidec.com/site/tysabri-information-center.html (by Dec '07, there were 21,000 MS patients on N)....io_editor (talk) 14:16, 29 March 2008 (UTC)

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I'm posting the third letter on that page, for completeness' sake: Drs. Kleinschmidt-Demasters and Tyler reply: We appreciate the comments of Drs. Berger and Deisenhammer and Dr. Álvarez-Cermeño and colleagues. Our involvement with this case began only post mortem; we were not involved in this patient's initial clinical evaluation, diagnosis, and treatment. The clinical and laboratory data presented were supplied by the patient's treating physician and supplemented by the Biogen company representative. Unfortunately, in some instances only the original MRI reports, not the actual scans, were available for independent review.

A variety of diagnostic criteria for multiple sclerosis have been proposed, including the widely accepted criteria of McDonald et al.1 These criteria do allow for the diagnosis of multiple sclerosis to be made solely on clinical grounds in a patient with two or more attacks and objective clinical evidence of two or more lesions. Criteria specific to MRI can provide supportive evidence of the dissemination of lesions over time; this criterion can be satisfied by the appearance of new T2-weighted lesions on appropriately spaced sequential scans. Oligoclonal bands on evaluation of the cerebrospinal fluid and enhancing lesions as shown on MRI are found in the majority of patients with definite multiple sclerosis; however, their presence is not absolutely required for diagnosis, nor does their absence completely rule out a diagnosis of multiple sclerosis.

We cannot resolve whether the absence of multiple sclerosis lesions at autopsy reflects obliteration of a limited number of multiple sclerosis plaques by the widespread and extremely destructive PML lesions, sampling error, or the presence of an alternative disease process. With regard to this last possibility, we believe it is unlikely that a chronic indolent or relapsing–remitting form of PML was the sole disease that this patient had or that it was responsible for this patient's symptoms early in her clinical course.

Our report, in combination with the others published in the same issue of the Journal,2,3 clearly indicates that natalizumab is associated with an increased risk of PML in patients without other recognized risk factors for this disease. The common denominator in all three reported cases, regardless of the underlying disease, was treatment with natalizumab.2,3

We hope that ongoing studies will clarify the pathogenesis of this disorder, including the viral factors and specific host factors responsible, and also the mechanisms by which natalizumab facilitates induction of PML.

B.K. Kleinschmidt-DeMasters, M.D. Kenneth L. Tyler, M.D. University of Colorado Health Sciences Center Denver, CO 80262 - Antelan^talk 16:14, 29 March 2008 (UTC)

Their long-winded excuses, for failing to note the strange diagnosis in their single-patient paper, doesnt help ths page much - but here is part of their conclusion - "we believe it is unlikely that a chronic indolent or relapsing–remitting form of PML was the sole disease that this patient had" - all the more remarkable given that all they had was an autopsy....io_editor (talk) 16:32, 29 March 2008 (UTC)

Today's MS Society (UK) 12-page pull-out on MS in London Times

From Io io editor

N mentioned twice, including general descriptions of efficacy and safety - http://doc.mediaplanet.com/projects/papers/Multiplesclerosis.pdf - notice that PML & Deaths are not mentioned at all - io_editor (talk) 17:24, 29 March 2008 (UTC)

So an article by the New York Times isn't appropriate, but an advertisement in the London Times is? Antelan^talk 17:47, 29 March 2008 (UTC)

I have alreaady dealt with the NYT - even this month they think N is "back in clinical trials" and appear to borrow the term "the sixth drug is Tysabri" http://query.nytimes.com/gst/fullpage.html?res=9C03E0DC123BF937A35750C0A96E9C8B63&sec=&spon=&pagewanted=2 - from the Wikipedia (Multiple sclerosis page) - but to call the London Times piece an advertisement is intellectually dishonest because there is no other a way that a national MS society can advance its agenda in so prominent a manner, and what they write reflects their policies...io_editor (talk) 18:53, 29 March 2008 (UTC)

No, to call it an advertisement is intellectually and in all other ways candid, since an advertisement is what that is. The fact that a robust and respected institution took out the advertisement doesn't change the fact that it is an advertisement. Antelan^talk 19:04, 29 March 2008 (UTC)

Well, if you have a point relative to N - any point at all - say what it is. I will leave it you and others to determine which has more relevance to encyclopedic-writing on N - this 12-page ad by the "robust and respected institution" or the current NYT article which appears to borrow from Wiki itself, and and get other basic facts wrong....io_editor (talk) 19:22, 29 March 2008 (UTC)

End of archive

Please add new topics for discussion to the bottom of the talk page. WhatamIdoing (talk) 22:01, 29 March 2008 (UTC)