We have some preliminary answers on the medical history of the 3rd patient to have PML while on Tysabri treatment, and an investigative look at his medical history is extremely revealing.

It seems this patient undertook very serious, potentially toxic/carcinogenic, and immunosuppressive treatments for an extended period of time. Furthermore, the treatments were, among other things, themselves linked directly with the development of PML! To conclude from this case that Tysabri monotherapy was the primary cause of PML is in our opinion, extremely premature with the information available today.

Please click "read more" for our extended analysis-- you will likely be surprised by what you discover, and what the possible implications are for Tysabri's future as an MS therapy...

Advertisement

Full Article Text

3rd Patient had History of Severe Immunosuppression
Previous therapy linked directly to PML

A firestorm has erupted with the revelation on March 29, 2005 that a 3rd patient dosed with Tysabri had been discovered to have Progressive multifocal leukoencephalopathy (PML). PML is a demyelinating disease of the brain caused by the JC virus. This patient had 8 doses of Tysabri over the course of 18 months during a clinical trial for Crohn's disease, an autoimmune disorder that strikes the bowels. The doses were spaced out as follows: 3 months Tysabri, 9 months placebo, then 5 months Tysabri. The patient passed away in December of 2003, with his death originally attributed to a fatal brain tumor.

The recent revelation of 2 cases of PML found in extended combination therapy of Avonex and Tysabri prompted a reinvestigation of this death. The new conclusion was that the patient had actually died of PML, not a brain tumor. This has been viewed by many as devastating the chances of Tysabri ever returning to market, given that it seems on the surface that Tysabri can cause PML even when used alone (monotherapy).

However, This is MS became suspicious of the link between Tysabri and PML in this case, particularly given the low number of Tysabri doses that the patient had been exposed to, the spacing of those doses, and the mysterious mention of a past history of severe immunosuppresion. If PML were so "easy" to contract when exposed to Tysabri, why would we not see higher numbers of incidents in the multiple sclerosis Tysabri groups, who are more frequently dosed (monthly) over longer periods of time (over three years for the extended trial participants) with higher Tysabri circulation (when combined with Avonex, Tysabri clearance is reduced by ~30%). Something is clearly amiss...

The investigation is enlightening, and we believe, shows that Tysabri cannot easily be considered the critical factor for this case of PML. As you will see, it is not a foregone conclusion that this patient could be considered to have been on Tysabri monotherapy, given the long-term effects of his previous therapies. To preface this article, note that this is an opinion piece based upon information in the public domain and written by non-medical personnel, so all conclusions are meant to serve as discussion points and not definitive answers.

That being said, Elan disclosed the list of medications Patient #3 was treated with:

• Steroids No surprise here, and this relatively weak immunosuppressant is used commonly with most MSers.

• Remicade, which is a powerful drug used to treat Crohn's disease. Now things get more interesting. A *partial* list of warnings for Remicade: "Many people with heart failure should not take REMICADE...There are reports of serious infections, including tuberculosis (TB), sepsis and pneumonia. Some of these infections have been fatal. ...REMICADE can lower your ability to fight infections, so if you are prone to or have a history of infections, or develop any signs of an infection such as fever, fatigue, cough, or the flu while taking REMICADE, tell your doctor right away...There have been rare cases of serious liver injury in people taking REMICADE, some fatal...Blood disorders have been reported, some fatal...Nervous system disorders have also been reported. Tell your doctor if you have or have had a disease that affects the nervous system, or if you experience any numbness, weakness, tingling, or visual disturbances while taking REMICADE. Reports of lymphoma (a type of cancer) in patients on REMICADE and other TNF blockers are rare but occur more often than in the general population. Tell your doctor if you have or have had cancer." (Source).

  Clearly, Remicade is not a treatment to be undertaken lightly and has a number of ways of causing fatalities.

• Azathioprine (aka Imuran) -- This is where things get extremely interesting. The patient was treated for approximately five years (!) with this powerful drug commonly used for preventing the rejection of organ transplants (!) and in lower doses, rheumatoid arthritis and other inflammatory diseases such as Crohn's. Quoting Medline: "[Azathioprine] works by weakening the body's immune system so it will not attack the transplanted organ or the joints." It is not clear for what indication this patient took this drug, but it was likely taken off-label for what would obviously have to be a severe case of Crohn's disease. Let us examine this drug's mode of action and safety profile:

  "Imuran [is] used as an immunosuppressant antimetabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and procedures which influence the immune response. Therapeutic effect may be evident only after weeks or months..." Note that Imuran is commonly prescribed in combination with another immunosuppressant AND the effect of the drug-- severe immunosuppression-- is often delayed.

  Continuing on with the litany of grave warnings:

  "Severe leukopenia [an abnormal decrease of white blood cells] and/or thrombocytopenia [abnormal decrease of blood platelets] may occur in patients on azathioprine. Macrocytic anemia and severe bone marrow depression may also occur...Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in, or persistently low leukocyte count or other evidence of bone marrow depression [Tysabri works by preventing leukocytes from crossing the Blood-Brain-Barrier, so if they are already severely reduced...]...Serious infections are a constant hazard for patients on chronic immunosuppression...Fungal, viral, bacterial and protozoal infections may be fatal and should be treated vigorously...Azathioprine is mutagenic [causes mutations] in animals and humans, carcinogenic [causes cancer] in animals, and may increase the patient's risk of neoplasia [pre-cancerous cell growth]...acute myelogenous leukemia as well as solid tumors have been reported in patients...who have received azathioprine." (Source).

  Let us recap: Azathrioprine can be incredibly toxic, can decimate the immune system long after its dosing, and leaves the patient susceptible to potentially fatal infection. Could Imuran still have been exerting its effects during the Tysabri infusions? We don't have an answer to that, but if so, let us explore "the smoking gun":

  While looking at the reported adverse reactions for Azathioprine, we found this:

  "A case of progressive leukencephalopathy (PML) after a four year azathioprine therapy...was reported (Schnider,1991)." (Source). That's right-- a case of PML linked directly with long-term administration of azathioprine. Patient #3 was actually on azathioprine for one year longer than this PML-azathioprine case. This is not the only case, here's another:

  "A 71-year-old woman receiving azathioprine and glucocorticoid therapy experienced onset of right-sided hemiplegia within a few days, became comatose, and died within a few days...postmortem examination showed PML." (Source).

  Simply put, we are aghast that this ravaged individual, exposed to years of dosing with a cocktail of potentially lethal drugs-- that among other things, can cause delayed immunosuppression, cancer, and even PML itself(!), was participating in a clinical trial with another experimental immunosuppresant. Maybe his case was so bad, he had no other hope, but in such an extreme situation, the fault of his death cannot be placed squarely on Tysabri. That he died is of course tragic, but quite frankly, a serious adverse event is not entirely surprising given his cumulative medical history.

  To conclude that Tysabri is the key factor for his contraction of PML and ultimate death, based on the post-mortem analysis of a patient that clearly was severely ill (a gross understatement!) is to us, simply preposterous. While we are not doctors and so our opinion is purely non-medical, this situation cannot reasonably be viewed as akin to an otherwise healthy individual contracting PML after exposure to Tysabri monotherapy. In fact, given the latent effects of the Imuran treatment, without further information as to treatment start and stop dates, it cannot even be said definitively that this patient was on Tysabri monotherapy, as after five years of treatment, Imuran could still have been exerting its effects without being actively dosed.

  The contraindications for prescribing Tysabri are becoming clear, and coupled with the increased vigilance for PML that would be sure to accompany any Tysabri prescription, the risk factor would seem to be acceptable for many MSers anxious for a new treatment option. The fact that toxic drugs like Remicade and Imuran are tolerated but Tysabri would not be is at the very least extremely puzzling. Tysabri is extremely effective at what it does, and because of that potency, cannot be coupled with drugs that cause, or people who have, a history of immunosuppression, cancer and serious infections.

  Again, the above is a non-medical opinion and you are urged to form your own opinions. We hope this has been helpful to you.
  
  Note: Biogen stated today, April 1st, that this 3rd patient not only had a history of severe immunosuppression as stated within this article, but was actually taking the other immunosuppressive(s) while receiving the first series of Tysabri doses. This again casts serious doubt on Tysabri's role in the causation of PML in this case.