Tysabri and PML  (Last update: 2009-July-25)

During clinical trials of Tysabri, three cases of PML occurred:
Patient # PML Date Status Combo? Prior Immunomodulators / Suppressants Washout Sex Diagnosis Tysabri doses Misc
1 Nov 2004-Feb 2005 Deceased: Feb 2005 (age 46) Avonex/Tysabri: April 2002-Jan 2005 Avonex: Feb 2000-Jan 2005 0 F No confirmation of MS 37 Colorado Springs, Colorado, USA Methylprednisolone: Mar 2001, Dec 2004, Jan 2005
2  Dec (?) 2004 Alive, Disabled Avonex/Tysabri: Oct 2002-Dec 2004 Avonex: 1998- Feb 2005 0 M MS About 30-34 San Francisco, California, USA Methylprednisolone: Feb 2005
3  July (?) 2003 Deceased: Dec 2003 (age 60) Azathioprine (Imuran)/Tysabri: Mar 2002-May 2002
+
5 doses of Tysabri monotherapy: Feb 2003-June 2003		 Azathioprine (Imuran): before Sep 1998-Nov 2002 3 months before the monotherapy? M Crohn's 3 combo + 5 mono Infliximab (Remicade):  3 infusions in 1999, 1 infusion in ~Nov 2001

Budesonide: 2000

Corticosteroids: Oct 2003-Dec 2003

The clinical trials were halted and Tysabri was voluntarily removed from the market in March 2005. 
Tysabri was re-introduced to the market  in July 2006, under risk-management programs.
 Since the re-introduction of Tysabri, the following cases of PML have been confirmed:

Patient # Patient #
post-re-intro		 PML Date Status Combo? Prior Immunomodulators / Suppressants Washout Sex Diagnosis Tysabri doses Approx date
of
first dose		 Misc
4 1  July 30, 2008 Alive, in rehab center near Stockholm, stabilized,  age 37 No Steroids only Unknown M Aggressive MS About 18 Jan 2007 Sweden
5 2  July 31, 2008 At home, bedridden, age 52 No 10 yrs (5 years?) Azathioprine (Imuran),  Beta-interferons*    Severely immunocompromised Unknown M MS About 15
May 2007		 Germany

MS for 30 years
6 3  Oct 29, 2008 Deceased: Dec 2008, age 59 No Methotrexate for rheumatoid arthritis, Beta-interferons* and glatiramer acetate (Copaxone) 4 months F MS 14 
Oct 2007 		 U.S. 
 
7 4  Dec 10, 2008 Alive, age 57, communicative, and improving No Prior disease-modifying therapies, including Beta-interferons* Unknown M MS About 26
Oct 2006		 Germany
 
8 5  Feb 5, 2009 Alive age 42, out of hospital No Novantrone (mitoxantrone) (12 months), Azathioprine (Imuran),  Beta-interferons*   Unknown F MS About 12 Feb 2008 Germany
9 6  April 15, 2009 Alive, age 43, on ventilator No Unknown Unknown F MS About 31 Sept 2006 E.U.
10 7  May 18, 2009 Alive, age 35, alert, walking, language problems No Rebif, Avonex, and Copaxone Unknown F MS 24 July 2007 U.S.
11 8  June 10, 2009 Alive, age 45, at home No Interferon beta 1-a (Avonex), and mitoxantrone (Novantrone) Unknown F MS 35 Nov 2006 E.U.
12 9  June 19, 2009 Alive, age 35 No Avonex, Rebif, and Novantrone Unknown F MS 34 Oct 2006 E.U.
13 10  June 23, 2009 Alive, age 27, stable No Interferon-beta, glatiramer acetate, and IVIG Unknown M MS About 30 Jan 2007 E.U.
14 11  July 24, 2009 Alive No Unknown   Unknown   MS 29 May 2007 U.S.

Cumulatively, in the combined clinical trial and post-marketing settings, approximately 61,200 patients have been treated with Tysabri. Of these, approximately 56,500 patients have been treated in the post-marketing setting, and approximately 43,300 patients are currently being treated. In the post-marketing setting only and since the reintroduction of TYSABRI in July 2006, approximately As of the end of June 2009, approximately 43,300 patients were on TYSABRI therapy worldwide; of these:
Color Coding
Dangerous Questionable Good

* Beta interferons: Avonex, Rebif

References

(Emphasis---underlining, bolding, red font---added to some quotations below.)

Patient #1:  Anita Louise Smith.  Was taking Tysabri in a clinical trial.  Four days after her death in 2005, Tysabri was pulled from the market.  Among some experts, there is serious doubt that she had MS.

 

http://articles.latimes.com/2006/feb/18/business/fi-drugtrial18 :   

  • "... some prominent neurologists contend that Smith shouldn't have been taking [Tysabri] to begin with -- because, they say, she didn't have MS."

  • "Dr. Bette KleinschmidtDeMasters, lead author of the article [NEJM, see below], said in an interview that she had found no evidence of the disease during her postmortem examination of Smith, though it was possible that the PML had obliterated signs of MS. "

  • "For me -- and a lot of other MS experts -- there is no doubt that at least this patient did not have MS," said Dr. Thomas Berger, head of neuroimmunology at Innsbruck Medical University in Austria.  Berger and a colleague said in a letter to the New England Journal of Medicine that Smith did not appear to have MS. Writing in the British Medical Journal this week, Dr. Abhijit Chaudhuri, a London neurologist who conducted one of the earliest clinical tests of Tysabri, called Smith's diagnosis "questionable."

 

Progressive Multifocal Leukoencephalopathy Complicating Treatment with Natalizumab and Interferon Beta-1a for Multiple Sclerosis, B.K. Kleinschmidt-DeMasters, M.D., and Kenneth L. Tyler, M.D., New England Journal of Medicine Volume 353:369-374, July 28, 2005. http://content.nejm.org/cgi/content/full/353/4/369

 

" ... an autopsy revealed that Smith never had MS."  http://www.newsinferno.com/archives/890

Patient #2:  A participant in the same clinical trial as Patient #1.  He survived the PML but suffered severe disabilities.

 

http://articles.latimes.com/2006/feb/18/business/fi-drugtrial18
 

Progressive Multifocal Leukoencephalopathy in a Patient Treated with Natalizumab, Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D, New England Journal of Medicine Volume 353:375-381 July 28, 2005. http://content.nejm.org/cgi/content/full/353/4/375

Patient #3:  A Crohn's patient and participant in a clinical trial of Tysabri.  His death was initially attributed to astrocytoma, but after the announcement of PML in Patients #1 and #2, his death was re-examined and was found to be PML.

 

Progressive Multifocal Leukoencephalopathy after Natalizumab Therapy for Crohn's Disease, Gert Van Assche, M.D., Ph.D., Marc Van Ranst, M.D., Ph.D., Raf Sciot, M.D., Ph.D., Bénédicte Dubois, M.D., Ph.D., Séverine Vermeire, M.D., Ph.D., Maja Noman, M.D., Jannick Verbeeck, M.Sc., Karel Geboes, M.D., Ph.D., Wim Robberecht, M.D., Ph.D., and Paul Rutgeerts, M.D., Ph.D., New England Journal of Medicine Volume 353:362-368 July 28, 2005.  http://content.nejm.org/cgi/content/full/353/4/362

 

"... [PML] has also been reported in immunocompromised patients receiving prolonged treatment with methotrexate, cyclophosphamide, and azathioprine.":  http://content.nejm.org/cgi/content/full/353/4/375

 

According to reports in the FDA's AERS database,  Remicade is the primary suspect in the death of this patient :  http://www.fdable.com/aers/advanced_query/b1ba2276db32#anchor_1957666

Patients #4 and #5: July 2008.

 

FDA ALERT [8/2008] (Cases 1 and 2 are Patients #4 and #5, respectively.) 
http://www.fda.gov/cder/drug/InfoSheets/HCP/natalizumab2008HCP.htm

 

SEC Form 8K.  Filing by Biogen Idec, Inc., July 31, 2008.
http://www.sec.gov/Archives/edgar/data/875045/000095013508005223/b714958ke8vk.htm

 

Biogen Idec Inc. Q3 2008 Earnings Conference Call Transcript, Oct 21, 2008. 
http://seekingalpha.com/article/100864-biogen-idec-inc-q3-2008-earnings-conference-call-transcript

 

Tysabri - Update on PML Risk and Recovery, by Lisa Emrich,Tuesday, September 23, 2008.
 http://www.healthcentral.com/multiple-sclerosis/c/19065/41962/tysabri  
 

Medscape news article: http://www.medscape.com/viewarticle/585770.  (Cases 1, 2, 3, and 4 in this article correspond to Patients #4, #5, #6, and #7, respectively.)
 

"... [PML] has also been reported in immunocompromised patients receiving prolonged treatment with methotrexate, cyclophosphamide, and azathioprine.":  http://content.nejm.org/cgi/content/full/353/4/375

Patient #6: October 2008.

 

SEC Form 8K.  Filing by Biogen Idec, Inc.,  Oct 29, 2008. http://www.sec.gov/Archives/edgar/data/875045/000095013508006776/b72762bie8vk.htm

 

Medscape news article: http://www.medscape.com/viewarticle/585770.   (Cases 1, 2, 3, and 4 in this article correspond to Patients #4, #5, #6, and #7, respectively.)
 

"... [PML] has also been reported in immunocompromised patients receiving prolonged treatment with methotrexate, cyclophosphamide, and azathioprine.":  http://content.nejm.org/cgi/content/full/353/4/375

Patient #7: December 2008.

 

Biogen IDEC Tysabri Update:   http://library.corporate-ir.net/library/14/148/148682/items/327618/79595964-371C-48B0-975C-EDA338E0B524_0306Tysabrimar09.pdf

 

http://www.fiercepharma.com/story/fourth-2008-pml-case-linked-tysabri/2008-12-16
 

Medscape news article: http://www.medscape.com/viewarticle/585770.   (Cases 1, 2, 3, and 4 in this article correspond to Patients #4, #5, #6, and #7, respectively.)
 

Biogen IDEC 8K filing December 15: http://tinyurl.com/br4gh7

Patient #8: February 2009.

 

Biogen IDEC Tysabri Update:   http://library.corporate-ir.net/library/14/148/148682/items/327618/79595964-371C-48B0-975C-EDA338E0B524_0306Tysabrimar09.pdf

 

Patient's husband's blog (in German): http://chefarztfrau.de/?page_id=418#comment-22427.   Translated excerpts: Chronological order since 1996: - Endoxan - has not helped (=Cyclophosphamide - Also known to be associated with PML) - Duration of prednisolone therapy - has not helped - Imurek - has not helped, but it gives pancreatic insufficiency (= Imuran = Azathioprine) - Betaferon - has helped a little - Mitoxantrone - the best way, had almost no relapses during this time unfortunately had to be discontinued because the life dose had been exceeded.

For patients #9 thru #14 (as well as all of the earlier patients since the re-introduction of Tysabri in July 2006), and any subsequent confirmed PML cases:

 

Any licensed physician can get more detailed information about all of these patients from Biogen Idec by emailing medinfo@biogenidec.com and asking for the Detailed Patient Case Histories of Post-Market PML.  (If detailed information was provided by the patients' physicians, Biogen Idec should have it.)