Biogen's Tysabri May Cause Liver Injury, U.S. Says (Update2)

By Luke Timmerman and Catherine Larkin

Feb. 27 (Bloomberg) -- Biogen Idec Inc. and Elan Corp.'s multiple sclerosis medicine Tysabri may cause significant liver injury within six days of the first dose, U.S. regulators said.

Patients should stop taking Tysabri if they develop jaundice or other symptoms of liver injury, according to a letter to doctors from the drugmakers that was posted today on the Food and Drug Administration's Web site. Doctors should warn patients about the drug's liver risk, the FDA said.

Tysabri, Biogen's fastest-growing product, generated $129 million in worldwide sales in the fourth quarter and was being taken by 21,000 patients at year-end, according to Biogen. The companies pulled the drug from the market in February 2005 because two patients developed fatal brain infections. The drug was reintroduced in July 2006 after the FDA decided the benefits in slowing multiple sclerosis relapses outweighed the risks.

``At Biogen and Elan, patient safety is our highest priority,'' the companies said in the letter to physicians that is dated this month. ``We are committed to ensuring that health- care professionals continue to receive the necessary information to prescribe Tysabri appropriately.''

Biogen fell 76 cents, or 1.2 percent, to $60.77 at 12:59 p.m. New York time in Nasdaq Stock Market composite trading, after touching $57.95. That 5.8 percent decrease would be the biggest drop in more than two months. The stock has gained 30 percent in the 12 months before today. Elan climbed 11 cents, to 16.59 euros in Dublin trading.

The companies, which market the product together, issued the warning letter after patients developed unusually high levels of liver enzymes in the blood, a sign of liver injury, according to the letter. The injury recurred in some patients after they were given another dose of the drug, ``providing evidence that Tysabri caused the injury,'' according to the letter.

Previous Reports

In July, the FDA cited 28 cases of liver injury associated with Tysabri since November 2004, four of them potentially serious. Elan spokesman Andrew Lewis said at the time the cases were from ``post-marketing experience.'' Tysabri won an additional approval for Crohn's disease in January, after the FDA considered the liver injuries.

Revised prescribing information approved in January includes the liver risks.

Biogen is counting on sales of Tysabri to fuel its growth. The company said this month that it expects 100,000 patients to be taking Tysabri by the end of 2010, which translates to about $2.8 billion in annual sales at current prices.

Biogen is based in Cambridge, Massachusetts. Elan is based in Dublin, Ireland.

To contact the reporters on this story: Luke Timmerman in San Francisco at +1- ltimmerman@bloomberg.net ; Catherine Larkin in Washington at clarkin4@bloomberg.net .

MRI findings predict evolution of preclinical multiple sclerosis

Date: Tue, 19 February 2008
by Will Boggs, MD

Patients with subclinical demyelinating lesions fulfilling MRI Barkhof-Tintoré criteria with a normal neurological examination are likely to develop multiple sclerosis (MS), according to a report in the February issue of the Journal of Neurology, Neurosurgery, and Psychiatry.

"Patients who fulfill the Barkhof and Tintoré MRI criteria, combined with CSF study, can be considered high risk for MS and have early treatment," Dr. Christine Lebrun-Frenay from CHU de Nice, France told Reuters Health.

Dr. Lebrun-Frenay and colleagues note that the concept of preclinical MS is now recognized. Silent brain T2 lesions are often seen on incidental MRI, they point out, but patients fulfilling Barkhof-Tintoré criteria are relatively uncommon.

The researchers report clinical and MRI findings after a five-year follow-up in 30 patients with subclinical demyelinating lesions fulfilling Barkhof criteria seen on MRI performed for medical complaints such as headache or trauma.

All patients had a normal examination and biological screening, the authors report, but all patients had increased CSF immunoglobulin levels (including nine with oligoclonal bands) and eight patients had abnormal asymptomatic visual evoked potentials.

Eleven patients clinically converted, including five with optic neuritis, three with diplopia or internuclear ophthalmoplegia, two with paresthesias in the lower limbs, and one with cognitive deterioration.

Four of these patients had their first clinical events during the first year after the first abnormal MRI, three during the second year, three during the third year, and one at five years. The mean time between the abnormal MRI and the clinically isolated syndrome was 2.3 years.

All 17 patients who underwent a second MRI during the first year showed MRI dissemination, the researchers note, as did eight of 12 patients whose second MRI was done between 12 and 24 months.

"For the pre-MS patient, without clinical events but with evidence of dissemination to time and space, medical discussion on the therapeutic options of immunomodulatory agents for reducing the risk of MS should be conducted, with the knowledge that subclinical MS can evolve into relapsing remitting MS in the majority of cases or more rarely into progressive MS," the investigators advise.

"Physicians and especially neurologists must really know Barkhof and McDonald criteria to not overestimate the diagnosis of MS," Dr. Lebrun-Frenay said. "A lot of abnormal MRI with T hyperintensities are classified MS, but a lot of physicians forget what Barkhof and Tintoré said in their principal publications on the way to interpret brain MRI."

If the patient does fulfill the Barkhof-Tintoré criteria, "then a simple workup for other inflammatory conditions would seem to be in order," writes Dr. Jeremy Chataway from St. Mary's Hospital, London, UK in a related editorial. "From there on, time and clinical evaluation would perhaps guide subsequent investigation."


Source: Reuters

Antisense Therapeutics Ltd Licenses ATL1102 to Teva

11 February 2008

• ATL1102 licensed to Teva Pharmaceutical Industries Ltd
• ANP to complete current Phase IIa trial, results due mid-year
• Teva to fund and perform all future development of ATL1102 beyond the current trial

Antisense Therapeutics Ltd. (ASX:ANP) is pleased to announce that it has entered an exclusive, world-wide license agreement with Teva Pharmaceutical Industries Ltd. (Teva), a top 20 global pharmaceutical company, to develop and commercialise ATL1102, a drug discovered by Isis Pharmaceuticals Inc. (Nasdaq: ISIS) and licensed to ANP.

Under the terms of the agreement, ANP will receive an initial $US2m up-front payment. ANP also has the potential to receive payments related to the continued clinical development of ATL1102 for MS upon certain future development milestones, with more significant milestone payments for entry into the market, and sales targets in particular territories. The License includes potential milestone payments of up to $US100m for the MS indication which is contingent upon completion of R&D,
successful commercialization and meeting certain sales milestones and bears inherent risks as does all pharmaceutical R&D. Teva would fund and perform all future development of ATL1102 beyond the current trial, should they decide to continue beyond that point.

If ANP fails to meet a particular development milestone regarding completion of the current ongoing, fully enrolled Phase IIa study by the agreed date in mid 2008, Teva may terminate the agreement and receive a $US2m termination fee.

Royalties are payable on net sales of ATL1102 are in the low double digit range and are tiered according to annual net sales achieved.

The agreement also provides an option for Teva to in-license ATL1102 as an aerosol drug for asthma.

Under a separate Collaboration and License Agreement between ANP and Isis Pharmaceuticals Inc., ANP pays Isis one third of sublicense fees and milestone payments received from Teva as well as a percentage of any royalties ANP receives.

ANP’s Managing Director Mark Diamond said, “We are delighted to have signed this significant licensing deal with one of the world’s leading pharmaceutical companies. Clinical stage deals such as this are subject to very stringent selection criteria and we are particularly pleased that Teva has recognised the drug’s commercial potential. Teva is a company with tremendous expertise in developing drugs, and is our partner of choice.”

ANP will continue to manage and fund the current Phase IIa clinical trial in relapsing-remitting MS patients, which is on track for completion of dosing, unblinding of the clinical trial, and reporting of results in mid 2008.

Antisense Therapeutics makes no representations with respect to the outcome of the Phase IIa trial and, like all other clinical trials in pharmaceutical R&D, there are inherent risks in terms of clinical outcomes, efficacy, cost and timeframes. As such, no assurance can be given that ANP’s drug development efforts will translate to successful commercialisation.

Background Information

ATL1102 is a second generation antisense inhibitor of CD49d, a subunit of VLA-4 (Very Late Antigen-4), and is currently in
Phase IIa clinical trials as a treatment for MS. In inflammation, white blood cells (leukocytes) move out of the bloodstream
into the inflamed tissue, for example, the CNS in MS, and the lung airways in asthma. The inhibition of VLA-4 may prevent
white blood cells from entering sites of inflammation, thereby halting progression of the disease. VLA-4 is a clinically
validated target in the treatment of MS. Antisense inhibition of VLA-4 has demonstrated positive effects in a number of
animal models of inflammatory disease including MS (Myers et al. J Neuroimmunol 160, p12-24, 2005).

Multiple sclerosis is a life long chronic disease of the central nervous system which is believed to affect as many as 2.5
million people worldwide. Global drug sales for MS exceeded US$5 billion in 2005 and are expected to grow with the
introduction of novel treatment options. There remains a high demand for more effective and better tolerated treatments.
Antisense Therapeutics Limited (ASX: ANP) is an Australian publicly listed biopharmaceutical drug discovery and
development company. Its mission is to create, develop and commercialise antisense pharmaceuticals for large unmet
markets. ANP has two drugs in development and two drugs in pre-clinical research. Its lead drug, ATL1102, is in the
advanced stages of a Phase IIa trial as a potential treatment of multiple sclerosis.

Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) is exploiting its expertise in RNA to discover and develop novel drugs for its
product pipeline and for its partners. The Company has successfully commercialized the world's first antisense drug and has
18 drugs in development. Isis' drug development programs are focused on treating cardiovascular and metabolic diseases.
Isis' partners are developing drugs for a wide variety of diseases. Ibis Biosciences, Inc., Isis' wholly owned subsidiary, is
developing and commercializing the Ibis T5000™ Biosensor System, a revolutionary system to identify infectious organisms.
Isis is a joint owner of Regulus Therapeutics LLC, a joint venture focused on the discovery, development and
commercialization of microRNA therapeutics. As an innovator in RNA-based drug discovery and development, Isis is the
owner or exclusive licensee of over 1,500 issued patents worldwide. Additional information about Isis is available at
http://www.isispharm.com.

For more information:

Website: www.antisense.com.au
Managing Director – Mark Diamond +61 3 9827 8999
Investor Relations – Market Connect Pty. Ltd. (Simon Watkin) +61 3 9863 7797 or 0413 153 272

New MS Drug Target Shows Promise

By Jeffrey Perkel
HealthDay Reporter
Monday, February 18, 2008; 12:00 AM

MONDAY, Feb. 18 (HealthDay News) -- A high-tech molecular fishing expedition has led researchers to two potential therapeutic targets for the treatment of multiple sclerosis.

The data implicate a pathway more typically associated with wound healing -- the blood clotting cascade -- than in the development of multiple sclerosis (MS).

"There is no coagulation component to MS," explained Patricia O'Looney, vice president of biomedical research at the National Multiple Sclerosis Society.

But coagulation factors also play a role in inflammation, whichisa component of the disease, she noted.

"If you can use this pathway and engineer some new drug therapy that will turn on the anti-inflammatory pathway, that could benefit people with MS," O'Looney concluded. "So, this perhaps reveals new therapeutic targets."

The research was published Feb. 17 in the advance online edition of Nature.

In the study, a team led by Dr. Lawrence Steinman of Stanford University School of Medicine grouped MS brain lesions from six autopsied human subjects into three classes based on histological criteria. They then probed those samples, along with samples from two healthy controls, using a technique called mass spectrometry, which essentially identifies the proteins in a tissue based on their mass.

The result was a "proteome" -- a sort of protein index of the tissues. Of the 2,574 proteins the team identified from all the samples, they found a few hundred that were unique to MS. More than half of those proteins were of unknown function, but five were known players in blood coagulation -- a pathway not previously recognized as being involved in the origin and development of the disease. All five were found in a single type of lesion, called a "chronic active plaque."

Puzzled by that observation, Steinman's team then tested whether drugs that targeted two of the five coagulation pathway members, called tissue factor and protein C inhibitor, could alleviate the symptoms of MS in a mouse model of the disease.

They seemed to have succeeded: Mice formerly paralyzed by an MS-like illness regained walking ability after the treatments, the researchers said. "They went from paralysis involving hind limbs to a much more functional score," Steinman said. The effect lasted at least two months, he added.

According to the National Multiple Sclerosis Society, MS affects at least 400,000 Americans. The disease results from loss of the insulating myelin sheath that surrounds nerve fibers, thereby disrupting nerve transmission, and causing damage to the nerve fibers themselves. Symptoms vary from patient to patient but can include blurred vision, slurred speech, loss of coordination and paralysis. Disease course can also vary, with four distinct disease forms recognized, the most common of which is relapsing remitting MS.

According to O'Looney, that variability is "the biggest challenge" of the disease.

"The symptoms may vary from person to person, the disease course will be variable, and we don't understand why there is this difference among people with MS," she said.

"And so," she added, "what is terrific about this study is that it compares the different forms of MS."

Six MS treatments have been approved for use by the US Food and Drug Administration, but there is as yet no cure for the disease, according to O'Looney. The two drugs Steinman used have been approved by the FDA for use in treating other diseases, however. Hirulog is an anti-coagulant protein fragment derived from leeches; Xigris is a recombinant form of activated protein C, for use against severe sepsis.

Those approvals should give researchers a head-start in getting these compounds into clinical testing for MS, Steinman said. "We can already jump past toxicity testing, because they are already approved," he noted.

But that doesn't mean doctors should administer these drugs to their MS patients right now, Steinman cautioned.

"It needs to be tested in clinical trials. We need evidence, and these drugs have serious potential side effects," he said. "But organized, well-run clinical trials should be done, because these drugs may be of immense potential benefit to people with MS."

Praising the study's use of donated human samples, O'Looney added that, "it's a perfect example of how we can learn so much from the use of tissue samples. We are so indebted to people with MS who leave the message that their bodies are available to researchers. So, this is the perfect example of how valuable that is. That's what drove this study."

More information

For more on multiple sclerosis, visit the National Multiple Sclerosis Society.

SOURCES: Larry Steinman, M.D., professor, neurology and neurological sciences, and chair, Interdepartmental Program in Immunology, Stanford University School of Medicine; Patricia A. O'Looney, Ph.D., vice president of biomedical research, National Multiple Sclerosis Society; Feb. 17, 2008, advance online publication,Nature

© 2008 Scout News LLC. All rights reserved.

Marijuana ups MS problems

[Posted: Fri 15/02/2008]

People with multiple sclerosis (MS) who smoke marijuana are more likely to have emotional and memory problems, the results of a new study indicate.

Around 6,000 people in Ireland have MS, which affects the brain and the spinal cord. There is currently no cure and the condition is characterised by a slowly progressing disablement.

According to the Canadian researchers, these findings are important because a ‘significant minority’ of people with MS smoke marijuana as a treatment for the disease, ‘even though there are no scientific studies demonstrating that it is an effective treatment for emotional difficulties’.

The study involved 140 people with MS. Of these, 10 had smoked marijuana within the last month and were considered current users. They were compared to people with MS who did not smoke marijuana.

The participants were evaluated for emotional problems and psychiatric disorders, including depression and anxiety. They were also evaluated in other areas such as speed at processing information and memory.

The researchers found that marijuana smokers performed 50% slower in information processing tests, compared to MS patients who did not smoke marijuana.

There was also a significant link between smoking marijuana and emotional problems such as depression and anxiety,

“Since marijuana can induce psychosis and anxiety in healthy people, we felt it was especially important to look at its effects on people with MS. This is the first study to show that smoking marijuana can have a harmful effect on the cognitive skills of people with MS”, said lead researcher Dr Anthony Feinstein of the University of Toronto.

Details of these findings are published in the medical journal, Neurology.

Rituxan Shows Promise for MS

Cancer, Arthritis Drug May Help People With Multiple Sclerosis
By Salynn Boyles

WebMD Medical News Reviewed by Louise Chang, MD

Feb. 13 -- The novel cancer and rheumatoid arthritis drug Rituxan may prove to be a highly effective treatment for the most common form of multiple sclerosis, if results from a small, phase II trial are confirmed.

In the study, sponsored by the drug's manufacturers, patients with relapsing-remitting MS who were treated with a single course of Rituxan showed rapid reductions in the inflammatory brain lesions that are a hallmark of the disease.

And after nearly a year of follow-up, half as many patients treated with the drug had experienced clinically significant relapses as patients in the placebo arm of the study.

If the findings are confirmed in larger, phase III studies, the Rituxan research opens a new frontier for the study of the cause and treatment of MS, says lead author Stephen L. Hauser, MD, of the University of California, San Francisco (UCSF).

The study is published in the Feb. 14 issue of The New England Journal of Medicine.

"No matter what happens with Rituxan down the road, this represents a paradigm shift that has profound implications for our understanding of MS," he tells WebMD.

T Cells and B Cells
The leading treatments for MS target the T cells. The thinking has been that T-cell-mediated inflammation sends the immune system into overdrive, causing the body to attack itself.

MS occurs when this attack targets the protective insulation known as myelin, which protects nerve fibers of the central nervous system. Myelin helps nerve fibers transmit electrical signals.

Instead of targeting T cells, Rituxan targets specific immune cells called B cells.

Studies by the UCSF researchers and others suggest that B cells and related pathways play a key role in destroying myelin.

The study included 104 patients with relapsing-remitting multiple sclerosis treated with either two infusions of Rituxan separated by two weeks, considered one course of treatment, or placebo infusions.

The patients were followed for 48 weeks, and brain imaging was performed to look for areas of inflammatory lesions at weeks 4, 12, 16, 18, and 24.

The imaging revealed dramatic and very rapid improvements in these lesions.

By week 24, the Rituxan-treated patients showed 91% fewer lesions, compared with the placebo-treated patients, and the results were similar at week 48.

"What we found so stunning was not only that the drug worked, but that it worked almost immediately," Hauser says.

The patients who got Rituxan showed improvement in lesions with the first post-infusion MRI scan, taken just weeks after treatment ended.

"This could only have happened if the B cells themselves are the culprit and not the antibody," he says. "It sends us back to the lab to discover what it is about the B cell, independent of its impact on antibodies, that is at the center of what causes MS flares."

Rituxan Safety Concerns
Hauser says there were few treatment-related side effects among the patients in the study, but questions about the long-term safety of Rituxan remain.

Rituxan is approved for the treatment of non-Hodgkin's lymphoma (NHL) and rheumatoid arthritis.

Use of the drug has been linked to a rare but fatal brain infection known as progressive multifocal leukoencephalopathy (PML). But it is not clear if PML is caused by the drug or by the patients' underlying disease.

Until more is known and until Rituxan is approved for the treatment of MS, patients with multiple sclerosis should not use it, says John Richert, MD, the National Multiple Sclerosis Society's executive vice president for research and clinical programs.

"We really want to discourage off-label use," he tells WebMD. "We just don't know enough about its long-term safety."

But Richert agrees that the early findings offer the hope of a new direction in the study and treatment of MS.

"Within the limitations of what you would expect with a small trial of short duration, the (UCSF) results are very exciting," he says. "We are cautiously optimistic that the phase III trials will show the same degree of efficacy."

SOURCES:
Hauser, S.L., The New England Journal of Medicine, Feb. 14, 2008; vol 358: pp 676-688.
Stephen L. Hauser, MD, department of neurology, University of California, San Francisco.
John Richert, MD, executive vice president for research and clinical programs, National Multiple Sclerosis Society.
© 2008 WebMD, LLC. All rights reserved.

Multiple Sclerosis Drug May Be Linked to Melanoma

Doctors report 2 cases of the deadly skin cancer developing in patients taking Tysabri

By Amanda Gardner
Posted 2/6/08

WEDNESDAY, Feb. 6 (HealthDay News) -- Almost immediately after a 46-year-old woman with multiple sclerosis received her first dose of the drug Tysabri, a mole that had been on her shoulder for years suddenly took on a dangerous new character.

It turned out to be a melanoma that spread like wildfire. The woman now has just a few months to live.

At almost the same time, a 45-year-old woman who also has multiple sclerosis developed melanoma in her retina after receiving several doses of Tysabri. She had a family history of melanoma and also had atypical moles on her body; the mole on her retina went back at least nine years.

Although these are just two -- albeit dramatic -- examples, the authors of a letter in the Feb. 7 issue of the New England Journal of Medicine are cautioning doctors who care for MS patients to keep this potential risk in mind.

"Neurologists who have patients who report a family history of melanoma or have funny moles should send them to a dermatologist first. Don't just start them on drugs [Tysabri]," said Dr. John Thomas Mullen, co-author of the letter and a surgical oncologist with Beth Israel Deaconess Medical Center, in Boston.

"I can't say it's cause-and-effect definitively because it's just an observation, but the first patient had had that mole forever. She took the drug and almost instantaneously the lesion changed," added Mullen, who saw both patients.

"We don't know if the two are related right now," said Patricia O'Looney, vice president of biomedical research at the National Multiple Sclerosis Society. "There are so many people taking Tysabri, we should go forward with caution... One should always consult with their doctor and go over their personal family history and decide what is best."

Tysabri (natalizumab), a monoclonal antibody that helps treat autoimmune disorders such as MS and Crohn's disease, has had a clouded history. It first received U.S. Food and Drug Administration approval in November 2004, only to be pulled from the market three months later after several patients in clinical trials developed a rare but deadly viral infection of the brain called progressive multifocal leukoencephalopathy.

In June 2006, the FDA allowed the drug back on the market but with strict conditions governing its use.

Just last month, the FDA approved Tysabri to treat people with a moderate to severe form of Crohn's disease.

But there is basic science to support Mullen's observations.

One of the participants in an earlier study of Tysabri had developed (and subsequently died of) a metastatic melanoma that appeared as soon as he got his first dose of the drug, Mullen said.

And in a study done before Tysabri received FDA approval, melanomas in mice that were given the drug had an increased tendency to detach from the primary tumor and spread.

Tysabari may have a dampening effect on the immune system that encourages the formation of the potentially deadly skin cancer, the letter stated.

And now that Tysabri has been approved for people with Crohn's disease, more people may be at risk, although those with no family history of melanoma and no moles probably don't need to worry, Mullen said.

"Doctors should ask for a family history of melanoma and do a quick skin check," he said. "Tysabri isn't the only drug in our arsenal. You could give the patient something else if you were concerned about that."


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