This (hopefully) marks the end of Tysabri's epic and volatile journey from lab to market, and the beginning of patients benefitting from a potent, if controversial, new weapon against multiple sclerosis progression and disability...

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"Today marks an important step forward for the European MS patient community," said James C. Mullen, Chief Executive Officer, Biogen Idec. "TYSABRI represents one of the most significant advances in MS treatment in nearly 10 years and provides patients living with this disabling disease an important new therapeutic choice."

"This decision means that patients in Europe who are suffering from this chronic, debilitating disease now have an effective new treatment alternative," said Kelly Martin, President and Chief Executive Officer, Elan.

Click "read more" for the full press release...

The wholesale price will be, brace yourself, $2184.62 per vial. One vial entails one treatment, and 13 vials will be needed per year (assuming an infusion every 4 weeks). This yields a total price of $28,400 per year wholesale! For those keeping track, this represents a nearly 21 percent price increase versus the original wholesale price at launch in November of 2004.

"The increase takes account of...

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This is a huge day for MS'ers, as the volatile Tysabri story finally seems to be settled, with availability scheduled for July. While this article will focus on the various aspects of the reapproval, we strongly encourage you to read our accompanying story on the recent history of Tysabri.

There are a number of interesting aspects to this reapproval, which found its genesis in the meetings held by the FDA Advisory Committee on Drugs for Peripheral and Central Nervous Systems March of 2006. The committee recommended the drug be reintroduced, and further to that, even allowed the drug as a first-line therapy (the first thing one might use when diagnosed with MS), and without any specific requirements for MRIs or spinal taps while still recommending a risk minimization plan inclusive of patient registration, tracking and periodic followups.

While the FDA usually follows its committees recommendations, they have deviated...

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For those that have not been actively tracking developments on Tysabri (known generically as natalizumab and co-owned by BiogenIdec and Elan), the story essentially begins when the drug was approved for use in MS patients in November of 2004. It was met with great fanfare, due to its...

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More specifically, Elan said that the drug was still on track for final review by June 28th, 2006, which was the United States FDA's extended deadline for determining the medication's fate and "finalized" risk profile. Recall that though the FDA's advisory committee recommended the drug be re-introduced, the FDA..

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"The companies have been informed by the FDA that the Agency requires additional time to review information regarding the Tysabri risk management plan," Tysabri creators Biogen and Elan noted in a joint statement.

This is a not altogether surprising development and does not seem to jeopardize the return of the drug in any way. 90 days seems like a long time, but it is actually the minimum amount of time the FDA will grant for extensions in these circumstances-- in other words, they may not need the full amount of time. Furthermore, it seems quite ambitious in retrospect for a governmental agency to finalize a complex and critical risk management plan in the mere three weeks between the advisory committee meeting and the previous committed decision date of March-end.

In short, with this move the FDA has certainly delayed Tysabri's re-introduction to market, but this delay does not seem to be a point of concern in terms of the FDA preventing the drug from coming back altogether.

Click "read more" for some related articles...

The United States Food and Drug Administration Advisory Committee voted UNANIMOUSLY (12-0) that Tysabri should be returned to market, on the condition that Biogen/Elan maintain a tracking database on all patients exposed to Tysabri to quickly observe and react to any side effects, particularly that of PML. At this point, there have been no requirements stated in terms of periodic spinal taps or MRIs.

Furthermore, the panel voted 7-5 on whether Tysabri should be considered a "first-line" treatment for MS'ers, which is a somewhat surprising result given the usually conservative nature of a government agency.

"Most people in (Tysabri) studies did not have a relapse and did not have disability progression," panel chairman Dr. Karl Kieburtz was quoted as saying.

The panel continues to meet through the day to discuss further scientific issues related to Tysabri. Of particular interest is being able to discern the early signs of PML versus "normal" MS symptoms, as that will be a critical part of the patient care given by a prescribing neurologist. We will keep you updated as we learn more.

Remember, the FDA is not *required* to follow the recommendations of their panel, but almost always does. Without getting ahead of ourselves, it seems rather certain that for those that want it and are willing to accept a PML risk that has been preliminarily quantified as 1 in 1000 (indeed this number comes from patients exposed to Tysabri *and* Avonex, but the conservative estimate assumes the risk comes from Tysabri), the once-a-month infusion with relatively better patient outcomes than the currently available NCRABs should be available again shortly.

Any day that involves more treatment options being made available to the MS community-- with appropriate risk management-- is a good day for all of us.

Stay tuned... in the meanwhile, links to some source articles are available by clicking "read more".

• Testimony was heard from MS patients, many tearful, who made the general point that they would risk a potentially fatal side effect for the more certain chance at relief from MS symptoms. Some Examples:
• Heather Smith, a 36 year old mother said, "I know Tysabri worked for me when all other MS drugs failed. Each patient has the right to make their own choice," Smith said.
• MS'er Marcy Canavan said "I have no treatment options left, and the way things are progressing, in a few years my life won't be worth living ... I want Tysabri badly," Marcy Canavan said.
• A particularly poignant comment made by one of the MS patients testifying: "There is a one-in-1,000 chance of developing MS. After winning that lottery, I am fully willing to become one of the 999 who don't develop PML while taking Tysabri"
• Dr. Robert Temple, head of the FDA's Office of Medical Policy, called the testimonies "heart-wrenching" and helped clarify how much risk patients would accept. "I thought it was extremely, extremely useful."
• The National Multiple Sclerosis Society came out strongly in favor of Tysabri and urged its speedy return to the MS patient's toolbox. Dr. John Richert: "We will applaud the addition of this treatment to our arsenal. If the FDA does not approve Tysabri's return to the market, or if it does so with significant restrictions, we will work tirelessly to find ways to satisfy the safety concerns so that more effective treatments can be readily available for the benefit of people with MS."
• The Multiple Sclerosis Association of America came out against Tysabri's return, arguing that more trials are necessary first.
• This should not be relevant, but as many of our readers will ask for this information, here is the corporate sponsorship information for the: MSAA and NMSS.
• The committee seemed highly interested in the potential misdiagnosis of Anita Smith, one of the two PML victims who in time has been revealed to most likely not ever have had MS in the first place. In particular, they were calling into question why she was allowed to participate in a trial for an experimental therapy when her health status was either unclear or in no obvious danger from MS. Tempering things, the chairman of the AC concluded: "It is inevitable that people are misdiagnosed with neurological diseases" Expect more on this salient but offshoot issue.
• The panel should make its recommendation to the US FDA on Wednesday. The FDA generally follows the advice of its expert panels.

• Tysabri's sponsors, Biogen and Elan, have obviously asked the FDA to allow Tysabri back onto the market.
• They have proposed restrictions including creating a mandatory patient registry to track side effects (Accutane is an example of a drug with a registry), and providing the drug only to MS patients that do not have "weakened" (definition of 'weakened' not clear from our sources) immune systems *and are not taking other MS drugs* (Interesting, as this closes off entirely the Biogen-promoted Avonex+Tysabri combo that in the trials was associated with PML in MS patients)
• In another potentially surprising move, the companies actually proposed the infamous "black box" warning be applied to Tysabri, indicating in the strongest terms available that patients could develop the devastating illness we have all unfortunately become familiar with: Progressive Multifocal Leukoencephalopathy, or PML.
• Biogen's Executive Vice President of Development, Dr. Burt Adelman, says these proposed steps "will enable us to proactively detect new safety signals."
• In very blunt terms, Dr. Russell Katz, director of the FDA's Neurology products division, said that "We fully expect additional cases of PML, many likely to be fatal." It is unclear to us (thisisms) where this assertion is coming from, given PML was never seen in MS patients undergoing monotherapy (Tysabri only).

We will provide a deeper analysis soon, but for now we wanted to get you the links to these critical new abstracts as soon as possible.

In short, Tysabri continued to demonstrate strong efficacy in terms of disability progression and relapses, a relatively low side effect profile, and (hold your breath)-- a risk of PML that has been preliminarily quantified as approximately 1 in 1000, when a person is given nearly 18 months of exposure to Tysabri. This data is of course artificially limited due to the clinical trials being halted last year; the true number can only be known in time.

Click "read more" for the links to the NEJM abstracts.

• The Effects of Natalizumab Monotherapy on Multiple Measures of Disability Progression in MS Patients: This one is potentially huge. Of particular interest is the reduction in T1-hypointense lesions, also known as "black holes" which are areas of the brain that are irreversibly damaged. Previously, Copaxone has been shown to reduce these as well, but to a lesser extent than what has been seen with Tysabri in previously announced results (though remember it is difficult to compare trial results directly due to myriad variables).
  
  "OBJECTIVE: To report the effects of natalizumab monotherapy (TYSABRI) on multiple measures of disability and burden of disease in patients with relapsing multiple sclerosis (MS). RESULTS: Over 2 years of treatment in AFFIRM, natalizumab delayed the onset of sustained disability progression by 42% compared with placebo...In addition, natalizumab reduced disability progression as measured by change from baseline in MSFC...the percentage of patients who reached an EDSS of 4.0 (5% vs. 13%...) or an EDSS of 6.0 (2% vs. 6%...), and mean (standard deviation) change in EDSS (0.04 0.86 vs. 0.41 1.09...). Furthermore, natalizumab reduced T2 lesion volume...and the number of new T1-hypointense lesions...over 2 years... CONCLUSIONS/RELEVANCE: Natalizumab monotherapy reduces disability progression and suppresses changes on MRI that represent, in part, irreversible axonal damage in MS."

As the history goes, the drug was voluntarily suspended from dosing, in clinical trials and to the public, in February of 2005, after three Tysabri-exposed patients developed progressive multifocal leukoencephalopathy (PML). Two of those patients died, while little is known about the welfare of the third asides from clinical stabilization.

There are many interesting facets at play here-- we would in fact expect no less from the drug known in the multiple sclerosis community as much for its drama as its promised efficacy.

• The drug has only been cleared for clinical trial usage *in patients previously on Tysabri.* In other words, this particular decision is not opening the door for widespread post-marketing (Phase IV) clinical trials on new patients.
• That being said, re-dosing in clinical trials is a necessary but not sufficient step towards eventual re-introduction to the broad market. In short, this is a highly positive (and in fact required) move for those that would like access to Tysabri in the future.
• The re-initation of this trial may lead to allowing the various trials of other drugs similar to Tysabri that were halted after the PML discoveries. One such drug is Novartis' FTY720.
• The FDA advisory committe, tasked with determining whether Tysabri should be allowed to be brought back onto the public market or not, is to be held on March 7.
• In their note on the release of the clinical trial hold, the FDA continued to express natural reservations about the the PML risk: "FDA remains very concerned about the potential for PML associated with natalizumab (Tysabri) use."
• FDA feels the clinical trials will help illuminate that risk:"Therefore, if a study is done in a manner that provides as much safety monitoring as feasible, it is reasonable to resume studying this product under IND to obtain more safety-related information that may permit us to begin to better understand how large or small the true risks associated with natalizumab are."
• That statement makes it seem like the trials will need to run for a significant time before re-marketing the drug to the public. However, the FDA then says: "the existing efficacy data with natalizumab indicate this is a very effective product and multiple sclerosis is a devastating neurologic disease."
• Unconfirmed, but interesting: During the Biogen investor conference call held today, it was apparently announced that the advisory committee meeting has been extended an extra day. Speculation as to why more time is necessary is rampant, but the most obvious explanation might be the large amount of public testimony that is expected to occur via the patient community.

Elan and Biogen, the co-sponsors of Tysabri, submitted a supplemental Biologics License Application (sBLA) at the end of September, 2005. This was, of course, after the dramatic removal of the drug from the market in early 2005 following the development of 3 cases of the usually fatal brain wasting disease known as Progressive Multifocal Leukoencephalopathy (PML).

The FDA responded to the sBLA by granting Tysabri priority review status. This was seen as favorable for Tysabri, given that the FDA reserves this status only for drugs that they deem provide a significant unmet need for patients. Ultimately, the designation shaves about 4 months from the submission to the FDA decision.

Included in the sBLA are complete 2 year data from the Phase III AFFIRM monotherapy (Tysabri versus placebo) trial, as well as the SENTINEL trial that added on Avonex (Interferon beta-1a) to the Tysabri dose. Also included are a suggested revised label for the drug, as well as a risk management plan to prevent future cases of PML from either developing, or progressing to disability and/or mortality. Finally, the sBLA integrates the safety data from all 3,000 patients ever-dosed with Tysabri (including those taking it for Crohn's disease and Rheumatoid Arthritis indications), an investigation which discovered no further PML cases beyond the 3 widely mentioned.

The meeting with the FDA's commission will be held on March 7th, and a final decision is expected by the end of that month. A momentous day for MS'ers, as a therapy that has shown much promise, and unfortunately much mystery, will get its day in court.

Please click "read more" for the official press release, as well as a link introducing the committee member's that will decide Tysabri's fate.

The application was submitted on September 26, 2005, which would imply that the review would be over, and the drug potentially back on the market, by the end of March, 2006.

"We believe that the acceptance of the sBLA for Priority Review is another step in our ongoing commitment to provide TYSABRI as a treatment option for MS patients in need," said Lars Ekman, MD, executive vice president and president, Research & Development, Elan. "We will continue to work closely with the FDA as they review the filing so that TYSABRI can be made available with an appropriate benefit-risk profile."

Click "read more" for the official press release...