This Is MS Multiple Sclerosis Knowledge & Support Community

Denver,

I agree with you that the FDA has to minimize the risk of litigation, but I wish posting a blackbox warning about the possible link to PML would suffice. Hopefully a test for early detection of PML is right around the corner...as in next week!

Posting the Black Box warning is the easy part.....but somebody has to come up with a scientific relationship between PML and Tysabri in order to establish some kind of reference in the warning. Otherwise, the lawyers could have a field day in any kind of litigation they might bring forth.

Harry

Harry

Perhaps this is an answer to your question, posted today by an virologist.

"Dear analyst community

I think it is time that you latch onto what Bill Rastetter said yesterday in the BIIB conference call - he is telling you how av + ty has a synergistic immune suppressive effect that could lead to immune suppression in some patients via supersaturation of VLA-4 caused by avonex reducing tysabri clearance by 30% while increasing tysabri half life by 30% and it does this in the face of avonex reducing VLA-4 expression on lympocytes while avonex also reduces Th1 lymphocyte movement across the blood brain barrier

Thus av + ty risk is much higher than ty monotherapy - that is what we have seen and that is why the affirm two year data is so clean - be the first one on the block to figure it out "

Regards
Better

Better,

There has always been the suspicion of the Av + Ty correlation in possibly causing the PML. But one also has to look at the Crohn's patient who was on monotherapy plus previously using other immune suppressive drugs.

It is looking like Tysabri used on patients who have previously been on any kind of immune system altering drugs could be in a higher risk category. I go back to what my wife's neuro said last December...Tysabri looks like it may be prescribed for newly diagnosed MS patients who have a mild case of the disease.

Bottom line so far.....the researchers don't quite have a handle on all of this other than a number of theories. And until any of the theories can be proven, the FDA, I would imagine, is quite nervous!

Harry

I wouldn't go so far as to say <em>any</em> immune-modulating drugs, as I would assume most, if not all, of the Ty+Avonex trialist have taken steroids either before or during the trial, yet no outbreak in PML has been seen, likewise with the monotherapy trials. It is fairly obvious, though, that strong immunosuppressants that have a latent effect (e.g., Imuran, which can still suppress the immune system months after its last dose) are to be avoided at all costs when Tysabri is in consideration.

Arron,

That's the problem....nobody at this point knows and that is one reason why they are going over each of the trial patient files with a fine toothed comb. The researchers have to try and find some kind of data that would indicate to them what the Tysabri/PML connection may be. Not an easy task when so little is known about PML.

Harry

that's an interesting point-- i bet more research has gone on into PML in the last 6 months than in the last 5 years. If you're a glass-half-full kind of person, well then that's the power of the MS community!

Arron,

What intrigues me is that PML is very rare (and more devastating than MS), but the scientists know the virus that causes PML. It is suspected that EBV plays a role in MS, but the scientists can't get conclusive proof even with all the tissue donations etc.


Bromley

Discussions about Tysabri to resume by the end of the summer

Dow Jones

NEW YORK (Dow Jones)--James Mullen, Biogen Idec Inc. (BIIB) president and chief executive, said he expects discussions about its multiple-sclerosis drug Tysabri to resume by the end of the summer.

Tysabri was pulled from the market earlier this year after two patients from clinical trials were diagnosed with a debilitating and often deadly brain infection.

In a CNBC interview Monday, Mullen said since the drug was pulled Biogen has done a re-evaluation of clinical trials to understand what risk the drug poses and what can be done.

"We are well into that process and by the end of the summer we will be back to discussions with the FDA as well as regulators in other countries [about Tysabri]" he said.

Mullen also spoke about two of Biogen's other drugs, Rituxin and Avonex, saying that despite the developments with Tysabri "we never took our attention off those products."

Avonex is the leading product in multiple sclerosis, he said, however "we believe that Tysabri would replace that and may still will in the future."

Rituxin, he said, is aimed at non-Hodgkin's lymphoma and has revolutionized the treatment in that therapy. In addition, he added that last month the company filed for approval of Rituxin for rheumatoid arthritis.

-By Jen Ryan, Dow Jones Newswires; 201-938-5294


(END) Dow Jones Newswires

06-20-05 1235ET

30 June 2005

TYSABRI(R) Phase III Induction Trial in Crohn's Disease Meets Primary Endpoint;
TYSABRI Induced Statistically Significant Response and Remission in Patients with Active Disease

DUBLIN, Ireland & CAMBRIDGE, Mass.--(BUSINESS WIRE)--June 30, 2005--

Study Showed Reduction in Signs and Symptoms of Crohn's Disease;
Ongoing Safety Evaluation Remains on TrackElan Corporation, plc and Biogen Idec announced today that ENCORE, the second Phase III induction trial of TYSABRI(R) (natalizumab) for the treatment of moderately to severely active Crohn's disease (CD) in patients with evidence of active inflammation, met the primary endpoint of clinical response as defined by a 70 point decrease in baseline Crohn's Disease Activity Index (CDAI) score at both weeks 8 and 12.

In addition, ENCORE met all of its secondary endpoints including clinical remission at both weeks 8 and 12. Clinical remission was defined as achieving a CDAI score of equal to or less than 150 at both weeks 8 and 12.

There were no notable differences in the overall rates of adverse events or serious adverse events between the TYSABRI and placebo treatment groups. The most common adverse events seen in the trial were headache, nausea, abdominal pain and nasopharyngitis.

On February 28, 2005, Elan Corporation, plc and Biogen Idec announced that they voluntarily suspended TYSABRI from the U.S. market and all ongoing clinical trials. This decision was based on reports of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal, demyelinating disease of the central nervous system. Elan and Biogen Idec's comprehensive safety evaluation concerning TYSABRI and any possible link to PML is ongoing. At the time of the dosing suspension, all ENCORE study patients had completed dosing based on the study protocol and collection and analysis of data followed.

The full data from ENCORE, including further sub-analysis of response and remission rates as well as clinical effect at other time points, effect on inflammatory markers and quality of life data will be presented at an upcoming medical meeting.

"The results of the ENCORE study are encouraging because patients treated with TYSABRI achieved a significant improvement in symptoms of this devastating, chronic immune disease," said Lars Ekman, MD, executive vice president and president, Research and Development, Elan. "Patient safety remains our top priority. We plan to share the data from ENCORE and our other Phase III TYSABRI Crohn's studies with the FDA and other regulatory agencies to determine the appropriate path forward for TYSABRI as a potential new treatment option for this underserved patient population."

"These data provide further evidence of the benefit of TYSABRI in treating immune-mediated diseases. We are committed to a thorough safety evaluation so we can better define the benefit-risk profile of TYSABRI. We hope to have findings from the evaluation by the end of the summer," said Burt Adelman, MD, executive vice president, Development, Biogen Idec.

The ENCORE Study

ENCORE was a Phase III, international, double-blind, placebo-controlled study of 510 patients at 114 sites to evaluate the safety and efficacy of intravenous TYSABRI in patients with moderately to severely active Crohn's disease (based on a confirmed diagnosis of CD and a CDAI score of greater than or equal to 220 and less than or equal to 450) and evidence of active inflammation (as evidenced by elevated C-reactive protein (CRP) levels of CRP greater than 2.87 mg/l, the upper limit of normal). Patients were randomized 1:1 to treatment with TYSABRI (300mg) or placebo infusions at weeks 0, 4, and 8. Efficacy and safety assessments were performed at weeks 4, 8 and 12, and the study remains ongoing for safety follow-up.

About TYSABRI

Elan and Biogen Idec are collaborating equally on the development of TYSABRI in MS, Crohn's disease, and rheumatoid arthritis. On February 28, 2005, Biogen Idec and Elan announced that they voluntarily suspended TYSABRI from the U.S. market and all ongoing clinical trials. Worldwide regulatory agencies are being kept informed of developments related to TYSABRI.

About Crohn's Disease

Approximately one million people worldwide have Crohn's disease, a chronic and progressive inflammatory disease of the gastrointestinal tract, which commonly affects both men and women. The disease usually causes diarrhea and crampy abdominal pain, often fever, and at times rectal bleeding. Loss of appetite and weight loss also may occur. Complications include narrowing of the intestine, obstruction, abscesses, and fistulas (abnormal channels connecting the intestine and other organs, including the skin), malnutrition and decreased growth rate in children.

http://www.elan.com/News/full.asp?ID=725210

Elan's Tysabri Link to Death May Be From `Overdose,' NCB Says
2005-07-06 06:43 (New York)

By Carey Sargent

July 6 (Bloomberg)

Elan Corp.'s multiple sclerosis drug
Tysabri may have led to patient deaths because interaction with
another treatment, Avonex, led to a build-up of the medicine in
the body and an overdose, an NCB Stockbrokers analyst said.
An interaction of Tysabri and Avonex, an older MS drug
sold by Elan's U.S. partner Biogen Idec Inc., ``essentially
leads to almost double the intended Tysabri concentration after
only 20 weeks,'' NCB analyst Orla Hartford said today in a note
to investors. ``Patients on Tysabri alone did not accumulate
the drug.''

Tysabri was recalled Feb. 28 after being linked to
progressive multifocal leukoencephalopathy, a rare neurological
disease in two patients. Both of these patients had been taking
a combination of the two drugs. Elan and Biogen Idec are
reviewing medical records of patients who have taken the drug,
and have said they expect to complete the review at the end of
June or July. The companies will meet with the FDA to determine
whether the drug can be sold again.

Tysabri is the cornerstone of Elan Chief Executive Kelly
Martin's plan to reach profitability and repay debt due in 2008
and 2011. He said in May he's confident the drug will return to
the market.
Analysis of data submitted to the U.S. Food and Drug
Administration during the approval process suggests that
treatment with the two drugs leads to a ``rapid accumulation of
Tysabri along with a reduced ability to clear the drug from the
body,'' Hartford said.

This accumulation may have led to a suppressed immune
system in the brain and may have been a key pre-disposing
factor in the two-cases of PML seen in combination therapy,
Hartford said.
She added that she expects that the effect Avonex has on
Tysabri will ``form a central part of the case made to the FDA
for Tysabri's relaunch.''

A third patient, identified in March, wasn't taking Avonex
but was on azathioprine, another immunosuppressive drug.
Hartford said a combination of Tysabri with any other
immunosuppressive drug may ``have to be avoided.''

--Editor: Roth

To contact the reporter on this story:
Carey Sargent in London at (44) (20) 7073-3126 or
csargent3@bloomberg.net.

To contact the editor responsible for this story:
Christopher Elser at (44) (20) 7673 2284

http://www.bloomberg.com/apps/news?pid= ... tkr=eln:US

Better,

Analysis of data submitted to the U.S. Food and Drug
Administration during the approval process suggests that
treatment with the two drugs leads to a ``rapid accumulation of
Tysabri along with a reduced ability to clear the drug from the
body,'' Hartford said.

This is very interesting in that Biogen/Elan researchers appeared to know of the "rapid accumulation" of Tysabri when combined with Avonex....yet
chose to continue the fast track process. I ask the question "why" and was this the action of a responsible pharmaceutical company?

Harry

From Jewish World Review

Lewis A. Fein


July 12, 2005

The search for a cure


Typically, I write columns about politics or foreign policy, issues that generate passionately supportive or vehemently oppositional feedback.

But I am also a person who feels - yes, feels - deeply concerned about an attitude that affects not only my life but the lives of millions of people nationwide. This forum thus enables me, because of my shared religious heritage and ethnic background, to make an important confession, which is itself a plea.

I have Crohn's Disease, a chronic condition that causes physical pain, weight loss, fever and fatigue. (Crohn's disproportionately strikes Ashkenazi Jews, and - though fatalities are no longer as common as decades before - it requires a lifetime of prescription medication and a doctor's care.) Yet, my case has its own political message, a metaphor for regulatory change and economic action.

First, let me praise the very existence of an institution like the Food and Drug Administration (FDA). The agency performs a valuable public service, bestowing its credibility upon - or withdrawing its support for - products that grace pharmacies and store shelves throughout the country. The agency provides consumers with needed information about a drug's safety, efficacy, trial history or side effects. A delicate balance nonetheless exists between the FDA's authority and people's medical needs, which alarmism or media extremism must not upset.

Think, for a moment, about the consequences of this brand of regulatory fear and journalistic hysteria. The manufacturers of the MS treatment Tysabri, which also has excellent clinical results for patients with Crohn's, stands before the FDA's imperial whims. Despite this medication's impressive history, the public may not purchase this new drug. Awaiting the results of a comprehensive data review -- encouraged by the culture of indecision (or negative action) that predominates throughout the FDA -- punishes the sick.

Perhaps I should mention the consequences of inaction, something I can recount with vivid detail: The unavailability of new drugs for Crohn's left me hospitalized and prepped for surgery, a long procedure that required the supervision of a pancreatic specialist and a team of nurses.

After more than a month in a quarantined room, and with a surgical scar across my lower torso, I slowly began to regain my strength. This operation, which newer and more effective medication could have prevented, was necessary because of an absence of choice; regulatory hurdles prevented me from using more successful remedies.

Patients with MS also appreciate these comments because Tysabri represents a major breakthrough in treatment of this disease, focusing on halting its progression rather than merely providing symptom relief. And, given the degenerative nature of their condition, submission before the altar of regulatory "wisdom" is something few MS patients can afford. These individuals deserve improved quality of life, not legalistic obstacles or bureaucratic delays. Absent a compelling scientific reason to the contrary, we should elevate informed consent above the government's false protection.

People with MS, Crohn's, arthritis and other inflammatory diseases routinely deal with serious chronic conditions that require extensive treatment options. If a drug like Tysabri works, which MS patients can confirm and my fellow sufferers of Crohn's fervently believe, then we have an ethical responsibility to remove any restrictions toward scientific progress. Patients and physicians deserve choice, the greatest preserver of life.

It is rare that we directly sense the power of government, its ability to complicate or terminate (indirectly) life. The FDA has such power, an awesome responsibility that transcends its regulatory dominion over beef or aspirin or cough syrup. The existence of a drug like Tysabri, medication that can greatly improve the lives of my own friends and family, is reason for action. We need a vigilant government, but we must not have an intrusive government. Let patients and physicians decide these issues for themselves. Government, heal thy self.


http://jewishworldreview.com/0705/fein1.asp

Better,

Thank you for posting a very well written article.

I'm sure the situation that Lewis finds himself is duplicated many times over with patients who have either Crohn's or MS. Both these diseases are a chronic burden to those who suffer from them and live each and every day under pain and discomfort. It is understandable for patients to crave for a medication that will alleviate this pain and allow them to live some quality of life.

Unfortunately I and many others don't share the level of optimism that many others have for Tysabri. It is mentioned that Tysabri has an impressive history and that it is a shame that the FDA does not make it available for MS and Crohn's patients. I feel that Biogen/Elan have terribly overstated the effect of this medication which has only been tested for a very short period of time, mostly on mild MS patients. I won't speak about Crohn's disease because I haven't really followed it's use with this disease.

I am not going to re-hash the differences of opinion that a number of experts have had with Tysabri and MS. Both sides have expressed these several times and of course, the patient is caught in the middle. The FDA now has no choice but to demand all kinds of additional data from Biogen/Elan regarding Tysabri and it's relationship to PML. And we all know how slowly the wheels of government agencies turn!

I often wonder how different the course of action with Tysabri might have been if Biogen/Elan had waited another 6-9 months before obtaining their accelerated FDA approval. PML would have been a known risk before approval had been granted and perhaps the long waiting period now that exists might have been avoided. We won't ever know that.

What we do know is that Tysabri has a definite risk factor with PML under certain conditions, most of which aren't fully understood. And that leaves the FDA in a very precarious position of balancing risk and benefit, especially with a benefit that has been questioned.

I know the pain and suffering that MS gives to patients...I watch it daily in my wife. The hundreds of thousands of MS patients (the numbers grow daily) are desperate for some kind of relief but how Biogen/Elan introduced Tysabri and ended up with all the problems isn't the answer either.

Harry

Harry

My last post is not from me, but from Lewis A. Fein.
Sorry for the confusion.

Better

Better,

better2gether wrote:Harry

My last post is not from me, but from Lewis A. Fein. Sorry for the confusion.

Better

The confusion begins with "me" since I did not carefully read the first part of the message which states Lewis Fein as the author. It is an excellent article and I have edited my response to reflect who wrote it. Again, thanks for the posting.

Harry