Tysabri is back on the market and, most importantly, presents an important additional alternative for multiple sclerosis patients and their physicians to choose from in their fight against this potentially debilitating disease.  However, over the years there has been a seemingly never-ending stream of misleading and sometimes downright false information spewing forth from various media sources when it comes to Tysabri.  If you have an interest in understanding the facts about Tysabri, it is likely you have been unduly influenced by this misleading and sometimes false information.  To help diagnose whether this may be the case, you may want to take the following Tysabri Challenge Quiz…..

1	In June 2006, the FDA granted re-approval for Tysabri sales in the U.S. Because of the risk for PML, Tysabri is only allowed to be prescribed to patients who have failed other existing therapies. True or false?

The answer is FALSE.  Although the updated label states that Tysabri “is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, alternate multiple sclerosis therapies,” the drug is APPROVED as a monotherapy for “the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations.”  In other words, the FDA is allowing the physicians and patients to decide among themselves whether Tysabri is the appropriate choice as a first-line therapy, and FDA has stated that the definition of “inadequate response” and inability to “tolerate” the older generation MS drugs was purposely left up to each doctor in consultation with the patient.

2	The FDA’s decision not to limit Tysabri to second-line usage goes against the recommendations of the advisory committee panel of experts following the March 2006 Tysabri advisory committee meeting. True or false?

The answer is FALSE.  The 12-member advisory committee panel voted unanimously for allowing Tysabri to return to market, and voted 7 to 5 in favor of permitting Tysabri to be prescribed as a first-line treatment (an arguably remarkable result in light of the intense scrutiny and publicity surrounding the PML issue at the time).  The panel also concluded that additional clinical safety trials should not be required before Tysabri is allowed to return.

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Which of the following is an accurate statement regarding Tysabri: a - In pivotal clinical trials, Tysabri demonstrated that it reduces MS relapses by about 68% over placebo, while the respective clinical trials of the other major MS treatments on the market today demonstrate about half that efficacy compared to placebo. b - Tysabri works by preventing a person’s immune T-cells from crossing the "blood-brain barrier" to the brain and central nervous system, where these T-cells attack the myelin sheath surrounding and covering the nerve fibers in the CNS. c - Tysabri is only the second prescription drug to be returned to the US market after being withdrawn for potential adverse side effects. d - All of the above.

The answer is (d).  In terms of efficacy of preventing relapses, Tysabri demonstrated 67% after one year and 68% after two years, improvement over placebo, while Betaseron, Avonex, Rebif, and Copaxone demonstrated improvements over placebo of 34%, 32%, 32%, and 29%, respectively.  Tysabri binds itself to a protein on T-cells called the “alpha 4-integrin,” which prevents the T-cells from passing through the blood-brain barrier.  When Tysabri was re-approved in June 2006, it became the only prescription drug other than Lotronex (an irritable bowel syndrome drug) to return to US market after being withdrawn for potential adverse side effects.

4	Tysabri has been clinically shown to improve the quality of life of MS patients.  In other words, not only does Tysabri help prevent patients from feeling worse, it actually makes them feel significantly better.  True or False?

The answer is TRUE.  In April 2006, data were presented at the American Academy of Neurology meeting that showed that Tysabri improved MS patients’ quality of life (QoL) based on three pre-specified health-related measures: (1) the MSQLI or Multiple Sclerosis Quality of Life Inventory, which is a battery of 10 scales that measure disease impact on quality of life including fatigue, pain, sexual function, bowel and bladder function, visual impairment health, and need for social support; (2) the SF-36 or Short Form-36 Health Survey, which is a component of MSQLI consisting of 36 questions designed to assess patients’ physical and mental well-being; and (3) the VAS or Visual Analogue Scale, which measures patients’ general well-being.

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On June 2, 2005, a Boston Globe headline sensationally trumpeted that “A fourth death may be tied to Biogen’s MS drug.”  What interesting fact was ultimately revealed regarding this “fourth death?” a - A subsequent autopsy showed that the patient didn’t die of PML, but of Creutzfeldt - Jakob disease, most likely from ingesting contaminated meat. b - This patient was also on a host of other immunosuppressants that could have been the true culprit of her PML. c - Not only did the patient not have PML, she was alive and out shopping when news reached her regarding her alleged demise. d - She actually died from a combination of a bad ulcer and whiplash from having been on Tysabri.

The answer is (c).  Shortly after the Boston Globe story broke, the patient’s doctor was quoted by Biogen-Idec as saying, “I just spoke to my patient’s daughter…and she is alive and out shopping.”  As it turned out, the patient did not have PML but an inflammatory ailment.  (Rumor is that the Boston Globe later tried to retract by stating, “What we meant to say was that the patient found shopping deals that were simply “to die for.”)   In fact, not only was there not a “fourth death” from PML, there was not even a third death.  See below.

6	How many patients with multiple sclerosis who had taken Tysabri in some form later died as a result of PML? a - Two b - Three c - Four d - Zero

The answer is (d).  This is kind of a tricky question.  In total, there were three Tysabri patients who developed PML, two of whom died.  Two of the patients developing PML received a combination of Tysabri and Avonex for multiple sclerosis (one of these patients died), and the other received Tysabri in a clinical trial for Crohn’s disease (this patient also passed away).  The patient who was given Tysabri and Avonex who later passed away was subsequently determined to have been most likely misdiagnosed with MS.  As such, no patients with confirmed MS who were treated with Tysabri died from PML.

7	An overview of safety data from the double-blind, placebo-controlled MS trials for Tysabri suggest that patients taking Tysabri have an overall increased risk of adverse side effects.  True or false?

The answer is FALSE.  The 2-year overview of adverse events seen in the clinical trials suggests that Tysabri does NOT result in additional adverse events / serious adverse events compared to placebo.  In fact, numbers-wise, the data actually show that patients on Tysabri showed FEWER adverse events than the placebo group.  For instance, of the total 1,617 patients given Tysabri and 1,135 patients given placebo on these trials, there were actually LOWER percentages of adverse events (unwanted health problems), serious adverse events (severe health problems including death and prolonged hospitalization), malignancy, and deaths in the Tysabri group relative to the placebo group.

8	Data show that taking Tysabri leads to an alarmingly higher number of cases of infections, particularly herpes. True or false?

The answer is FALSE.  While data from the placebo-controlled MS trials suggest that patients given Tysabri had an increased risk for infections including herpes, the increase in risk was quite small.  For common infections (influenza, pharyngitis, tonsillitis, etc.), the percentage of Tysabri patients developing such infections was 73.7%, versus 73.9% for the placebo patients, or about a 0.2% increase.  For serious infections (appendicitis, urinary tract infections, pneumonia, etc), the percentages were 2.4% for Tysabri patients versus 2.3% for placebo patients, a 4% increase.  In terms of herpes infections, the percentages were 7.2% for Tysabri patients versus 6.1% for placebo patients, an 18% increase.  The herpes infection numbers are even smaller if one discounts the patients who took Tysabri in combination with Avonex: examining only the AFFIRM Tysabri monotherapy clinical trial, the patients given Tysabri had a 6.4% incidence of herpes infections, while the placebo group had 6.0%, a difference of about 6.7%.

9	Currently, the risk of developing PML from extended use of Tysabri is specified as approximately 1 in 1000, or 0.1%.  General expectations are that the actual incidences of PML will exceed this ratio once Tysabri is more widely prescribed. True or false?

The answer is FALSE.  The “1 in 1000” ratio is based on the fact that three people developed PML out of about 3000 patients who received Tysabri over an extended time.  However, two factors would indicate that actual risk should prove lower going forward.  The first factor is that the three patients who developed PML were either (a) given Tysabri in combination with Avonex, which likely compromised the patients’ immune system to a degree that allowed PML to occur, or (b) already on very strong immunosuppressive medications, including Imuran and Remicade, which are themselves associated with PML.  The second factor is that all Tysabri patients (and prescribing doctors) must now be enrolled in a comprehensive risk management plan called the TOUCH program.  This TOUCH program, combined with the fact that Tysabri is only to be administered as monotherapy, should theoretically reduce the PML risk significantly.  The TOUCH program also requires screening both before a patient is approved for Tysabri and throughout the treatment process to exclude patients at higher risk of PML and react to potential symptoms of PML immediately.  Previously, PML was not even a suspected risk, so the doctors were not alert to the possibility.  Only time will verify whether the TOUCH program is effective in reducing the risk of PML, but it is likely it will be quite effective.

10	What does TOUCH stand for anyway? a - Tysabri Outreach: Unified Commitment to Health. b - Tysabri Objective: Upgraded Community Health. c - Tom on Oprah: Unrestrained Couch-Hopping. d - The best album Sarah McLachlan ever recorded.

The answer is (a).  This comprehensive Tysabri risk management program includes: mandatory enrollment into the program for all prescribers, pharmacies, infusion centers and patients; controlled and centralized distribution of Tysabri in authorized infusion centers; mandatory educational tools for patients and physicians; and a 5000 patient cohort observational study over five years. (Coincidentally, there have been anecdotal reports that Tysabri makes some MS patients feel so good that they hop more excitedly than Mr. Cruise finding an impressionable young woman who actually likes him.)

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In February 2006, a research abstract from researchers at the University of Texas was circulated, stating that Tysabri can deplete immune-system cells by the same level as the HIV virus.  It generated some concern among MS patients awaiting Tysabri’s return as well as the investment community (Elan’s stock fell materially on the day the report was circulated).  It was later learned that this report was circulated by: a - A concerned neurologist who feared an epidemic of PML. b - An FDA official who wanted to prepare the world for its anticipated decision to not re-approve Tysabri. c - A publicist for Teva Pharmaceuticals, maker of competing MS drug Copaxone. d - Reporter Jeff Krasner of the Boston Globe in an effort to prevent the death of a fifth PML patient tied to Biogen’s MS drug.

The answer is (c).  It probably was only a coincidence that the Teva publicist circulated this potentially inflammatory research abstract about a week before the FDA advisory committee meeting was scheduled to decide whether to recommend to the FDA that Tysabri should return to market.  Was this report truly cause for concern?  As Motley Fool writer Bill Mann commented a few days later, “the report doesn’t say that Tysabri is as dangerous as HIV.  It says that it lowers immune systems to similar levels.  Well, hello! Tysabri is an immunosuppressant.  This is how the drug combats MS . . . imagine that - an immunosuppressant that suppresses the immune system!”