A new study released yesterday provides compelling statistics behind that claim, saying in short that Vitamin D seems to reduce the risk of developing MS in Caucasians.. While the study does not make any claims about people who already have MS benefiting from Vitamin D supplementation...

Story continues, please click 'read more'...

Fingolimod (which, by the way, wins our award for Most Unintentionally Humorous Drug Name) works by keeping the immune system's T cells in the lymph nodes and away from the central nervous system, which is for reasons yet unknown, vulnerable to attack in an MS patient.

The trial enrolled over 250 patients. In the first six months, patients were randomized to receive either one of two doses of fingolimod, or a placebo. For the following six months, all the placebo patients were randomized to one of the two fingolimod doses.

The results...

Story continues, please click "read more"...

"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...

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...

Story Continues... please click 'read more'

"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...

• 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.

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.

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...

This means that in the end, amongst all those exposed to Tysabri and who underwent PML screening, there were a final total of 3 cases of PML, 2 of which were fatal. In other words, after the initial reports, no new cases have been discovered across multiple sclerosis, Crohn's and rheumatoid arthritis patients dosed with Tysabri during clinical trials. This additional data will be added to the supplementary Biologics License Application submitted to the FDA for multiple sclerosis.

With no additional cases found, certainly these findings must bolster the case for Tysabri's return as a monotherapy, though to an unknown degree. As a next milestone, the FDA will rule by October 26th whether they will grant Tysabri an accelerated review (6 months maximum) or a standard review (10 months).

Click "read more" to view the full press release.

The supplement contains the following information:

- Final 2-year data from the AFFIRM monotherapy (Tysabri only) trial
- Final 2-year data from the SENTINEL Tysabri + Avonex trial
- Safety assessment of clinical trial patients treated with Tysabri
- The suggested revised label and risk management plan

What will be truly interesting for us to see will be the content of the label revision (e.g., will it be a "black box" warning reserved for the most dangerous drugs or something less severe), as well as the risk management plan (e.g., simple blood tests or spinal taps?).

Also note that the FDA has up to 10 months to respond to this application, although Elan and Biogen have requested priority review which would shorten the FDA's lead time to 6 months. Tysabri originally received priority review when it first came out. Elan and Biogen have simultaneously submitted this information to the European Medicines Agency as well.

So the sage continues-- we now have all the gathered information in the hands of the agency responsible for medicine, and we await the bureacratic wheels to turn to provide a verdict. Much speculation will certainly arise as to whether the FDA will take its allotted time or instead expedite the review of the application even further. Though we are all biased here to the plight of the MS community, this is a disease where days count. If the FDA has compelling data that this drug is reasonably safe to use, one has to hope that they will continue to be sensitive to the needs of our community-- as they earlier attempted to do by fast-tracking the original Tysabri application.

"We are very encouraged by this filing. We strongly believe in the therapeutic benefit of TYSABRI and the difference it could make in the lives of patients with MS. We are committed to working closely with regulatory authorities to define a path forward for TYSABRI as a treatment choice for patients who struggle with the debilitating effects of the disease," said Lars Ekman, MD, executive vice president and president, Research and Development, Elan.

Click "read more" to see the official press release...

Today, the parent companies published an update on their plans for Tysabri. For the multiple sclerosis indication, they plan to submit a Supplemental Biologics License Application in the "coming weeks." A Supplemental BLA is defined by the FDA as:

"An application to allow a company to make changes in a product that already has an approved new drug application (NDA). Center for Drug Evaluation and Research must approve all important NDA changes (in packaging or ingredients, for instance) to ensure the conditions originally set for the product are still met."

In other words, they will attempt to amend the labelling information (in currently unknown ways) to account for the discovered PML risk and to return the product to market.

On a related note, Tysabri was also being used for the treatment of the digestive disorder Crohn's disease, and for Rhuematoid Arthritis. The safety evaluation for those two indications is yet to be completed, and should be done on the same time frame as the submission of the MS supplemental BLA. This means either or both of the following: MS is viewed as the most important application of Tysabri and/or the data in MS is clear enough to understand the PML risk to the point the product could be returned to market in a relatively safe manner.

Overall good news, though the timeline for submission, FDA action, and resumption of marketing (if the FDA agrees with the supplement, of course) is nebulous at this moment.

Please click "read more" for the full press release...

Campath is a cancer treatment that is currently approved to treat the rare cancer called B-cell chronic lymphocytic leukemia. Trials in MS have shown promise-- and in this latest round of results, Campath patients were only 25% as likely to have a relapse of symptoms as patients taking the interferon Rebif. Campath also showed some indicators of slowing long-term disease progression, but not enough to be seen as statistically significant.

Unfortunately with the two steps forward, comes one back: There were 3 serious adverse events reported, with one of those leading to a patient death. 3 of 219 MS patients dosed with Campath were diagnosed with a blood condition called idiopathic thrombocytopenic purpura, a highly dangerous drop in blood platelets that help clot wounds.

This possible side-effect is already on the label for the cancer treatment indication. The patient who died had shown symptoms of the condition for a month before seeking medical care. The other two patients were diagnosed more quickly and are responding to treatment.

Genzyme said it intends to continue testing the drug, but only after working with regulators to improve the safety of the trials. Obvious changes include monitoring patients more closely, as well as instructing them to look for symptoms of the blood condition before it becomes irreversible.

And so the dance continues...

Click "read more" for more information...

Daclizumab, also known as Zenapax, is curently in Phase II studies (see clinical trial recruiting information). It is an intravenous injection consisting of engineered human antibodies that block the interleukin-2 (IL-2) receptor on immune cells. IL-2 is a potent immune stimulator and thus by blocking it, you theoretically dampen the immune response. It is currently FDA approved for use in transplant patients. In a tiny, 11 person trial of daclizumab or Zenapax combined with an interferon, results were promising: ( see our coverage of this study here

"Ten patients showed a dramatic reduction in both the severity and number of brain lesions as demonstrated by magnetic resonance imaging. The decrease in new lesions, as well as the total decrease in lesions, occurred gradually over a 2-month span. Improvement was also seen on a neurological rating scale and in a test of hand function. The clinical improvement was unexpected in such a small trial, since a larger number of patients is usually required to show clinical effects."

All that being said, putting the weight of Biogen behind daclizumab is excellent news in terms of getting daclizumab through trials, and if warranted, to the market expeditiously. Does this have any implications on Tysabri or Avonex? Not likely-- Biogen is most probably simply filling its drug development pipeline with promising candidates in markets it already knows well.

Continuing with all things ending in "zumab," this deal also covers the early stage therapy fontolizumab, also known as "HuZAF" (we couldn't make these names up if we tried). Fontolizumab is an anti-interferon-gamma. Interferon-gamma is likewise an immune stimulator, so blocking it might have a potential benefit to multiple sclerosis.

Of course, all of these therapies are premised on the inherently auto-immune nature of multiple sclerosis, which is still controversial. Happily, Biogen is not placing all of its bets on this single line of thought, but is also looking at myelin regeneration.

Click 'read more' to see the full press release from Biogen and Protein Design Labs.