TYSABRI® TWO-YEAR MONOTHERAPY DATA

A board to discuss the newly-released drug Tysabri, (formerly known as Antegren) as a treatment for Multiple Sclerosis

TYSABRI® TWO-YEAR MONOTHERAPY DATA

Postby better2gether » Tue Apr 12, 2005 1:29 pm

TYSABRI® TWO-YEAR MONOTHERAPY DATA SUPPORT POSITIVE ONE-YEAR EFFICACY FINDINGS AND SHOW SIGNIFICANT REDUCTION IN RISK OF DISABILITY PROGRESSION
Data Presented at American Academy of Neurology Meeting

Cambridge, MA and Dublin, Ireland - April 12, 2005 -Two-year data from the AFFIRM Phase III monotherapy trial presented today for the first time, showed that treatment with TYSBARI® (natalizumab) led to a significant reduction in disability progression, the rate of clinical relapses and brain lesions in patients with relapsing forms of multiple sclerosis (MS). These data were presented at the 57th annual American Academy of Neurology (AAN) meeting in Miami Beach, FL.

AFFIRM met all primary and secondary endpoints, including disability progression and relapse rate. TYSABRI treatment was also associated with a low level of immunogenicity.

TYSABRI treatment led to a 42 percent (p=0.0002) reduction in the risk of disability progression compared to placebo. TYSABRI also reduced the rate of clinical relapses by 67 percent (p<0.0001) compared to placebo, which was sustained and consistent with the previously reported one-year results.

On February 28, 2005, Biogen Idec and Elan Corporation, plc 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 frequently fatal, demyelinating disease of the central nervous system. Biogen Idec and Elan's comprehensive safety evaluation concerning TYSABRI and any possible link to PML is ongoing. The results of this safety evaluation will be discussed with regulatory agencies to determine possible re-initiation of dosing in clinical trials and future commercial availability.

"While an evaluation is underway to better understand recent developments with TYSABRI, these data confirm the efficacy of TYSABRI on clinical relapse and define its impact on disability progression," said Chris Polman, MD, PhD, lead investigator of the AFFIRM study, professor of Neurology at Free University Medical Centre, and clinical and scientific director of the Multiple Sclerosis Centre at the VU Medical Centre, Amsterdam. "Disability progression is an important consideration in managing MS. The efficacy of TYSABRI underscores its importance for MS patients."

Results From Two-Year AFFIRM

AFFIRM is a two-year, randomized, multi-center, placebo-controlled, double-blind study of 942 patients conducted in 99 sites worldwide, evaluating the effect of TYSABRI on the progression of disability as measured by at least a one-point increase on the Expanded Disability Status Scale (EDSS) sustained for three months, and the rate of clinical relapses. Progression of disability is a sustained change that has a long-term impact on a patient's functional and ambulatory performance. Patients in AFFIRM were randomized to receive either a 300 mg IV infusion dose of TYSABRI (n=627) or placebo (n=315) every four weeks.

Disability

TYSABRI-treated patients were less likely to experience progression of disability. The risk of disability progression sustained for three months was reduced by 42 percent relative to placebo (p=0.0002), the two-year primary endpoint. Additionally, after two years, 29 percent of placebo-treated patients had progressed, while only 17 percent of TYSABRI-treated patients progressed, representing a 41 percent reduction in the proportion of patients progressing (p<0.0001).

TYSABRI also slowed the progression of disability as demonstrated by the mean Multiple Sclerosis Functional Composite (MSFC) score. The MSFC consists of three tests that evaluate ambulation, upper extremity dexterity and cognitive function.

A pre-defined sensitivity analysis of the primary endpoint defined progression as at least a one-point increase on the EDSS sustained for six months. Using this definition, the risk of disability progression was reduced by 54 percent with TYSABRI treatment.

Relapse Rate

Data also demonstrated a 67 percent reduction in the rate of clinical relapses relative to placebo (p<0.0001) over two years, which was sustained and consistent with the previously reported one-year results. The annualized relapse rate was 0.22 for TYSABRI-treated patients compared to 0.67 for placebo-treated patients. The proportion of patients who remained relapse free was 67 percent in the TYSABRI-treated group compared to 41 percent in the placebo-treated group (p<0.0001).

MRI measures

MRI analysis examining different types of brain lesions is used in the initial diagnosis of MS and is a marker of ongoing and previous disease activity and damage. TYSABRI treatment resulted in sustained and statistically significant reductions in the number and volume of gadolinium enhancing, T2-hyperintense and T1-hypointense lesions compared to placebo. The pre-specified secondary endpoint MRI measures were the volume of T2-hyperintense lesions and the number of new T1-hypointense lesions.

Over two years, there was a significant difference in the burden of disease as measured by change in T2-hyperintense lesion volume. Placebo-treated patients experienced an increase in burden of disease while TYSABRI-treated patients had a decrease. In addition, TYSABRI demonstrated a 76 percent reduction in the mean number of new T1-hypointense lesions compared to placebo.

AFFIRM Safety Summary

The two-year adverse event profile in AFFIRM was consistent with previously reported one-year results. Common events included headache, fatigue, urinary tract infection, depression, lower respiratory tract infection, limb and joint pain, and pharyngitis. The rate and incidence of infections in TYSABRI-treated and placebo-treated patients were similar. Serious infections occurred in 3.2 percent and 2.6 percent of TYSABRI-treated and placebo-treated patients, respectively. TYSABRI has also been associated with hypersensitivity reactions, including serious systemic reactions that occurred at an incidence of less than 1 percent of patients.

Immunogenicity

All biologics have the potential to induce antibody formation. Analysis of the two-year data from the AFFIRM study indicated a low level of immunogenicity associated with TYSABRI. Patients were tested for antibodies every 12 weeks. Antibodies were detected in approximately 9 percent of patients at least once during treatment, with 6 percent of patients remaining persistently positive. Persistently positive antibodies were associated with a substantial decrease in efficacy and an increase in certain infusion-related adverse events. Almost all patients who tested positive for antibodies did so within the first 12 weeks of treatment.

"We believe in the significant therapeutic benefit of TYSABRI in MS, a disease with high unmet need," said Burt Adelman, MD, executive vice president, Development, Biogen Idec. "Biogen Idec and Elan are working diligently to evaluate extensive data from our clinical trials, consulting with leading experts and with regulatory agencies throughout this process. We hope to define a path forward for this product, and our future steps, as always, will be guided by our commitment to people living with MS."

"We are very encouraged by the two-year results which support the efficacy of TYSABRI in MS," said Lars Ekman, MD, PhD, executive vice president and president, Research and Development, Elan. "Patient safety is our top priority, and we are working closely with the regulatory agencies to define the appropriate benefit-risk profile for TYSABRI as a new option to treat MS."

About TYSABRI

Biogen Idec and Elan 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.

Information about TYSABRI, including the voluntary suspension of marketing, U.S. prescribing information and support services, is available through a single toll-free number (1-800-456-2255), and via www.TYSABRI.com.

About Multiple Sclerosis

MS is a chronic disease of the central nervous system that affects approximately 400,000 people in North America and more than one million people worldwide. It is a disease that affects more women than men, with onset typically occurring between 20 and 40 years of age. Symptoms of MS may include vision problems, loss of balance, numbness, difficulty walking and paralysis.

http://www.biogenidec.com/news/BiogenIDECPR_075.htm
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Postby DenverCO » Tue Apr 12, 2005 3:50 pm

Woo Hoo!
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Postby Arron » Tue Apr 12, 2005 5:49 pm

this is covered on the front page as well :)
Disclaimer: Any information you find on this site should not be considered medical advice. All decisions should be made with the consent of your doctor, otherwise you are at your own risk.
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Re: TYSABRI® TWO-YEAR MONOTHERAPY DATA

Postby HarryZ » Tue Apr 12, 2005 9:30 pm

Better,

A rather knowledgeable fellow over on the Brain Talk MS forum looked at the two year numbers and made this comment....17% of the patients taking Tysabri had disease progression while 29% of the placebo group progressed. That meant that only 12% of the Tysabri patients really benefitted from using the drug during the two year trial. He thought that was rather disappointing. I guess it's how one interprets the numbers.

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Tysabri

Postby bromley » Wed Apr 13, 2005 1:23 am

Harry,

The interpretation of the numbers is of course the key and will, I imagine, be different depending on whether or not you have this disease. For those with this disease, the CRAB drugs reduce the number of relapses by 30ish%, Tysabri reduces the number of relapses by 67ish% (I know these are averages). Tysabri is therefore substanially better at reducing the number of relapses. For those with RR MS such an improvement can make life a little more bearable.

In terms of disability, the difference between Tysabri and the placebo was not so substantial. However, for an MS sufferer, Tysabri offers a small chance of slowing the progression of the disease - small chances are what MS sufferers cling on to.

Tysabri also appeared to reduce the number of lesions. Who knows what this means in terms of disability etc, but I would rather have less lesions on my brain and spinal cord.

Tysabri also had provided an option to daily / weekly injections, and many who took it said that it allowed them to forget their MS for a bit by having monthly infusions.

Of course Tysabri was very expensive and three on the trial died. Who knows what will happen to this treatment in the future. But for a while it offered MS sufferers hope.

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Postby LarryLDN » Wed Apr 13, 2005 3:08 am

Yep Hope. That's what my red bracelet says. H O P E That's what they offered.

I want a pill that I can take every day that costs less than half a cup of coffee that will keep me exacerbation free for years.

Perhaps another new H O P E will come out... we can H O P E it does better than this one did.
-- LarryGC/LarryLDN http://www.larrygc.com/ms
-- My LDN journal http://www.larrygc.com/mystory
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Re: Tysabri

Postby HarryZ » Wed Apr 13, 2005 6:42 am

Bromley,

The interpretation of the numbers is of course the key and will, I imagine, be different depending on whether or not you have this disease. For those with this disease, the CRAB drugs reduce the number of relapses by 30ish%, Tysabri reduces the number of relapses by 67ish% (I know these are averages). Tysabri is therefore substanially better at reducing the number of relapses. For those with RR MS such an improvement can make life a little more bearable.


Yes, I can imagine the different interpretations that will come out of this data. The Brain Talk poster went on to give this info....."As I have argued here, I believe Avonex is the weakest of the interferons. And yet in the Avonex FDA trial, 22% of the Avonex patients progressed versus 35% of the placebo patients. Thus 13% of the Avonex patients benefited over the two years of the trial.

But the Avonex participants were sicker than the Tysabri participants -- as shown by the fact that 6% more of the Avonex trial placebo patients progressed (not sure if the difference was significant).

Based on these numbers, one could certainly make the case that Avonex is as effective as Tysabri in slowing disability progression.

The other numbers are better than seen in the interferon and Copaxone trials, but the bottom line for me is: how effectively does a drug prevent disability? "

So you see that the data must be peer reviewed and many questions asked.

In terms of disability, the difference between Tysabri and the placebo was not so substantial. However, for an MS sufferer, Tysabri offers a small chance of slowing the progression of the disease - small chances are what MS sufferers cling on to.


This supports what my wife's neurologist told me last December about Tysabri and he was conducting the trials at the MS Clinic here. He stated that Tysabri had no impact on the EDSS scores for their patients.

Tysabri also appeared to reduce the number of lesions. Who knows what this means in terms of disability etc, but I would rather have less lesions on my brain and spinal cord.


One of these days they may be able to find a correlation between the MRI lesions and symptoms. Until then it remains a very hit-and-miss exercise.

Of course Tysabri was very expensive and three on the trial died. Who knows what will happen to this treatment in the future. But for a while it offered MS sufferers hope.


If it ever makes it back, it will be under strict testing controls which of course will likely add to the already huge price tag. Unless of course, Biogen/Elan drop the price..an unlikely scenario.

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Postby amelia » Wed Apr 13, 2005 8:47 am

a couple of years ago, my husband, Gary, had to stop Betaseron due to the antibody thing. Copaxon was new and on lottery at the time. He chose NOT to take it. He started having attacks, at the end of his Betaseron days, every month to 6 weeks. This is when a cane became a permanent attachment to him. This is when the vison in his right eye went from normal to almost nothing. This is when he FELL down the Disability Scale. He started Copaxon and his attacks went to every 3-4 months, then over a year. Finally he has one every several years. Yes he still has attacks, BUT Copaxon cut them back. Tysabri shows to do a little better. Tysabri for now and then something better next. We all would like to see the "cure in pill form" come along today, but reality shows otherwise. But 20 years ago you had NO HOPE for slowing progression. So I'll take the Tysabri #'s being just a little bit better.
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Boston Globe article about neurologists' Tysabri assessment

Postby Arcee » Wed Apr 13, 2005 8:50 am

Doctors doubt Tysabri will make big comeback
They say the risks outweigh benefits of Biogen Idec drug
By Jeffrey Krasner, Globe Staff | April 13, 2005

MIAMI BEACH, Fla. -- Tysabri, the once-promising multiple sclerosis drug that has been linked to a potentially fatal brain disease, probably won't return to the market for widespread use, according to many neurologists here attending their largest national convention.

Doctors said the drug, made by Biogen Idec Inc. of Cambridge, might come back in a severely curtailed form, addressing a small minority of MS patients, with numerous warnings to doctors about prescribing the drug.

''It won't come back," said Dr. Douglas R. Jeffery, associate professor of neurology at the Wake Forest University School of Medicine in Winston-Salem, N.C.

Biogen Idec took the drug off the market this year after the discovery of three cases of a potentially deadly brain disease among the 3,000 patients who participated in clinical trials of the drug. The disease, progressive multifocal leukoencephalopathy, or PML, has killed two of the three patients diagnosed with it in Tysabri trials.

''When you study a very small population and then you move a drug to a broad patient population, you see things you didn't see before," Jeffery said. ''You're going to be hearing about more PML cases coming out."

Dr. Mark Freedman, director of the multiple sclerosis research unit at the University of Ottawa in Canada, said, ''I think the risk of Tysabri outweighs any perceived benefit. So far, we haven't had drugs that kill people. Given that it's a lifelong disease, nobody is showing that Tysabri can cure multiple sclerosis."

Ironically, the skeptical comments came as Biogen Idec and its partner, Elan Corp. PLC, presented positive data from their trials of Tysabri at the annual meeting of the American Academy of Neurology here.

The two companies last year said they would seek approval based on one year's worth of trial results, a year ahead of schedule. The Food and Drug Administration gave the drug accelerated review and approved it in late November based on the single year's results.

Yesterday's data showed that the one-year results weren't flukes. The two-year data showed Tysabri continued to prevent MS relapses by 67 percent, compared to patients given a placebo, and slowed the rate progression of disability. The trial involved 942 patients at 99 medical sites worldwide .

The companies submitted the data to the neurology academy last year, long before it heard of the cases of PML.

Tim Hunt, a Biogen Idec spokesman, said, ''Right now we need to continue our safety evaluation, and in the months ahead, examine the results, work with the FDA, and hopefully craft a risk-benefit profile that will allow us to bring the drug back to the MS community."

Biogen Idec and Elan introduced Tysabri shortly after its approval.

The drug is administered by a once-a-month intravenous infusion, making it more convenient than competing treatments that require frequent injections.

Doctors and patients were crestfallen when Biogen Idec and Elan suspended distribution of Tysabri Feb. 28 and halted all clinical trials using the drug. Both company's stocks have dropped by more than 50 percent.

''It's really a pity," said Dr. Juha-Matti Seppa, a neurologist from the Central Hospital of Satakunta in Finland. ''I'm afraid at the moment it seems Tysabri has no possibility to come back onto the market."

Other physicians were more optimistic, noting that other drugs for complex disease often have serious side effects.

''Tysabri is not going to have a large future," said R. Philip Kinkel, director of the Multiple Sclerosis Center at Beth Israel Deaconess Medical Center in Boston. ''It's going to be used for a select group of patients for a defined period of time."

Meantime, Biogen Idec continues to investigate the link between Tysabri and PML. The first two cases involved patients that were also taking the company's Avonex treatment for multiple sclerosis. The third was in a trial for Crohn's disease, an intestinal ailment.

Dr. Al Sandrock, Biogen Idec's vice president of medical research, said the company has hired consultants including a virus specialist, a neurologist with a specialty in PML, and a an expert in reading brain scans.

All 3,000 patients who participated in Tysabri trials are undergoing new physical exams, neurological evaluations, and new brain scans to search for signs of PML.

Clinical investigators who oversaw patients in Tysabri trials are also conducting spinal taps to search for the virus that causes PML. They are also looking for the virus in blood plasma.

''What we're trying to find out is what is the risk, who is at risk, and can we mitigate the risk," said Sandrock. ''We hope to have some results from the safety evaluation by the second half of the year."

Jeffrey Krasner can be reached at krasner@globe.com.



© Copyright 2005 The New York Times Company
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Postby Arron » Wed Apr 13, 2005 9:29 am

Unless backed by insider information, comments such as, "It won't come back" or, "It will definitely come back" are inflammatory speculation. Everyone is certainly entitled to their own opinion, but I am shocked that a highly-educated neurologist can make such a controversial blanket statement to the media.

some info on Dr. Jeffery, from http://www.wfubmc.edu/neurology/departm ... ffery.html :

"Dr. Jeffery's area of clinical and research interest is Multiple Sclerosis. His current grant support includes Teva Marion's "Evaluation of Injected Glatiramer Acetate in Primary Progressive Multiple Sclerosis," Teva Marion's "Evaluation of Oral Glatiramer Acetate in Relapsing Remitting Multiple Sclerosis," Pfizer's "Evaluation of Donepezil in the Treatment of Cognitive Dysfunction in Multiple Sclerosis," Immunex's and Berlex's "Evaluation of Mitoxantrone in Treatment of Multiple Sclerosis," and Elan's "Evaluation of Zanaflex Modified Release in the Treatment Spasticity in Multiple Sclerosis and Spinal Cord Injury."
Disclaimer: Any information you find on this site should not be considered medical advice. All decisions should be made with the consent of your doctor, otherwise you are at your own risk.
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Postby HarryZ » Wed Apr 13, 2005 11:03 am

Arron,

Arron wrote:Unless backed by insider information, comments such as, "It won't come back" or, "It will definitely come back" are inflammatory speculation. Everyone is certainly entitled to their own opinion, but I am shocked that a highly-educated neurologist can make such a controversial blanket statement to the media.


Don't be shocked about these comments. One of the doctors quoted stated many months ago in private that Tysabri could be dangerous and Biogen wasn't doing things the right way. If you can recall I posted similar comments but did not reveal sources. I kept on telling people that I wasn't making this stuff up but continued to be called a rumor monger and Biogen trasher!

The docs making these comments work with the disease every day and have been involved with MS for years. They usually have some idea of what they are talking about and don't live in Biogen's pocket.

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Postby DenverCO » Wed Apr 13, 2005 11:15 am

I am currently reading Jock Murray's book on the history of MS (thank you, Boston Cure...see Art's post under the Reading Nook forum). Throughout history there have been educated researchers and clinicians with polar opposite opinions on every new development and theory regarding MS. We need to bear that in mind when we read the opinions of the "experts" quoted in newspaper articles.

Another interesting observation...if there were 99 testing sites for Tysabri, then there were probably twice that many doctors involved in the trials. We need to remember when someone on a message board quotes their trial doc as having a certain opinion about Tysabri, there were more than just a handful of physicians involved in the trials. That is one doctor's opinion.
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Postby HarryZ » Wed Apr 13, 2005 1:15 pm

Denver,

Throughout history there have been educated researchers and clinicians with polar opposite opinions on every new development and theory regarding MS.


Talk about hitting the proverbial nail on the head!! The variance and discrepancy of opinions among MS docs is rather large and it certainly makes it very difficult for the MS patient to feel totally comfortable with a course of action in fighting the disease. I guess it depends on what kind of experience a MS doc has with a particular drug.

Keeping this variance in mind, it was one reason why I have been so skeptical towards Biogen. From the beginning they made Tysabri out to be the absolute saviour for most MS patients and their marketing department spared no adulation along the way in promoting it this way. I always had a feeling that something bad might happen, despite what Biogen had been saying along the way. Unfortunately the feeling became a reality and we have the mess today.

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