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Interesting update on FTY720 and their speculation that that it could be available for organ transplant patients -- and therefore also available for off-label use -- by 2007. Also the official results of their phase II trial are being released tomorrow.



Novartis Is Seeking to Beat Serono to First MS Pill

June 20 -- Bloomberg -- Serono, Europe's biggest biotechnology company, Novartis AG, Switzerland's largest drugmaker, and Paris-based Sanofi-Aventis SA are racing to develop the first pill for MS patients, a market that Lombard Odier Darier Hentsch analysts foresee growing 60 percent to $8 billion by 2010. Novartis, which currently relies on products such as the eight-year-old Diovan heart drug for growth, tomorrow releases data on its new oral MS treatment. The drug may be available as early as next year.

``There's a good chance for a filing in 2006 and it could be a threat to everyone, including Serono, Schering AG, and Biogen,'' said Romain Pasche, a fund manager at Vontobel Asset Management in Zurich who oversees about $800 million in health- care stocks. ``That would change the landscape.''

Novartis will present data at the European Neurological Society meeting in Vienna on a study of the medicine, called FTY720, in 281 patients with relapsing forms of the debilitating illness. Existing medicines including Rebif, Avonex and Betaseron all have to be injected. Oral treatments may capture as much as 40 percent of the market, Serono Deputy Chief Executive Jacques Theurillat said April 12.

The Novartis drug has a number of hurdles to overcome. The data being presented is only from the second of the three stages of testing generally required before approval. Regulators are also likely to be cautious following the early approval and then recall of Biogen Idec and Elan Corp.'s Tysabri, Lombard Odier analyst Karl Heinz Koch said.

Analysts at Lehman Brothers estimate FTY720 will garner about $1 billion in sales as an MS treatment, and currently give it just a 30 percent chance of approval. Novartis had $28.2 billion in revenue last year.

According to the Boston-based Tufts Center for the Study of Drug Development, it costs about $802 million to get a drug from discovery to market, from $237 million in 1987. Of every 5,000 potential medicines discovered in laboratories, only about five make it to human testing, and only one of those will actually make it to the market.

``What's important about this study is that you establish safety'' for FTY720, Lombard Odier's Koch said. ``That's of course the focus after the Tysabri withdrawal.''

Preliminary data released earlier this month showed that FTY720 cut the rate of MS relapses by about 55 percent compared with placebo. Seventy percent of the patients on placebo were relapse-free, compared with 86 percent of the patients in both groups taking the drug, the study, led by Ludwig Kappos at the University Hospital in Basel, Switzerland, Novartis' hometown, showed.

In a different study, Tysabri cut the rate of MS relapses by 66 percent compared with a placebo in a trial of 942 patients. Data from clinical trials show that interferons like Avonex and Rebif reduce relapses by about 30 to 40 percent.

Analysts are looking for details of the FTY720 study results, including information on how advanced the disease was in the patients included in the trial and on side-effects.

The Novartis product may have an advantage over competitors because it's also being tested for use in organ transplantation, Koch said. Novartis has said that as many as 200 patients have been on the medicine for two years and more in testing for that use.

UBS analysts including David Beadle forecast sales of $225 million in both transplant and MS by 2009. They say their forecast is ``conservative given the $2 billion potential of the product in both indications.''

Novartis plans to ask regulators to approve the drug for use in organ transplantation by ``early 2006.'' Koch said convincing data on MS combined with the drug's availability on the market may lead to ``significant off-label use'' starting in 2007. This would make the treatment available before Serono's Mylinax or Sanofi's teriflunomide, a variant of the company's rheumatoid arthritis treatment Arava.

Serono is working with U.S. partner Ivax Corp. to develop Mylinax, which is in the final round of testing usually required. The company has said it will seek approval of the medicine in 2007. Sanofi-Aventis' teriflunomide is also in phase III trials.

http://quote.bloomberg.com/apps/news?pi ... refer=home

" Analysts at Lehman Brothers estimate FTY720 will garner about $1 billion in sales as an MS treatment, and currently give it just a 30 percent chance of approval. Novartis had $28.2 billion in revenue last year. "

How do these companies find out about these drugs and their results in advance of the publication of the results? Why only 30 % chance of approval? I need more details and can't wait until tomorrow for the results of phase ll studies.

Thanks for the find Dignan, I am suppose to be on the phase lll studies of this drug..... Carole[/b]

Unfortunate about the slight delay in the phase III trial, but these results sound good. A pill that could possibly be more effective than the CRABs.



Novartis MS pill data promising but Phase III delayed

June 21 -- Reuters -- Swiss drugmaker Novartis has pushed back the start of a late-stage trial of its FTY720 pill for multiple sclerosis (MS) after U.S. regulators asked for a safety analysis of the drug's use in transplant patients.

Investors and analysts have been watching the experimental drug's progress carefully, believing it could be a potential blockbuster seller for Novartis, as well as being one contender in the race to bring the first pill for treating MS to the market.

Over 2 million people worldwide are thought to have MS, a disabling disorder of the central nervous system in which the immune system is thought to attack healthy nerve tissue.

Symptoms include slurred speech, numbness, pain, poor balance and blurred vision. Most MS patients have a relapsing form of the disease, meaning symptoms come and go, and most current treatments are injected.

Novartis said on Tuesday that Phase II data on FTY720 in MS was promising but the Phase III trial would now start in the fourth quarter of 2005, rather than mid-2005 as previously announced.

Details of the six-month, Phase II study released on Tuesday in Vienna were promising, Novartis said, showing a more than 50 percent reduction in relapses and up to an 80 percent reduction relative to placebo in terms of brain lesions seen in scans.

However, Novartis said that the U.S. Food and Drug Administration had asked the firm to conduct a safety analysis of data from Phase III trials of the drug's use as a treatment to prevent organ rejection in kidney transplant patients.

Some cases of macular edema, or swelling in the eye, had been observed in the transplant trial but not in the MS trial, a Novartis spokesman said, adding that the transplant trial had used higher dosages of FTY720 than the MS trial.

"As a result, the Phase III programme in MS is expected to be launched in the fourth quarter of 2005 involving centres in North America and Europe," Novartis said.

The Phase II trial, involving daily 1.25 mg or 5 mg doses of FTY720, showed the drug was well-tolerated with 92 percent of patients completing the six-month trial. The most frequent side effects included headaches, respiratory problems and diarrhoea.

"There was no real drop-out rate and a clear-cut, highly statistically significant advantage of the drug over placebo at both doses," Ludwig Kappos, chief investigator of the trial, told Reuters.

"There was a tendency as you would expect in a drug that acts on the immune system towards a somewhat higher rate of infection especially with a higher dose but not serious infection," he said.

Swiss biotech company Serono is also working on a pill to treat MS, dubbed Mylinax, while British-based GlaxoSmithKline plans to file a competitor for regulatory approval in 2008.

Serono hopes its Rebif drug, co-marketed with Pfizer in the United States, will become the number one MS treatment in time, despite competition from rivals made by Germany's Schering and Biogen.

http://www.alertnet.org/thenews/newsdesk/ZAT004957.htm

Good post Dignan.

This drug looks promising, but an oral treatment still looks some years off. The Tysabri issue has certainly had an impact and the authorities are more cautious.

There are a number of oral treatments in the pipelines of the various drugs companies but one has to wonder how they can keep recruiting triallists. It's about time that they gave some thought to ditching the placebo arms of the trial. I wonder why they needed it on this trial, as comparable efficacy data is available from the CRAB drugs (relapse rates / number of lesions) as is data on safety / side effects.

Bromley

What makes you think we are some years off for an oral treatment? I know I am overly optimistic. Once this gets approved for organ transplants, doctors can start prescribing it off-label for MS. Before the delay, speculation was that it would be available early next year off-label. This delay pushes the MS trial back six months because of the safety evaluation. If the safety evaluation in organ transplants (which is higher that what would be prescribed for MS) comes back positive, we could theoretically see this medicine being prescribed for MS as soon as mid- to late 2006.

Xenova,

You might be right on dates but I'm a natural pessimist. Things seem to take a long time after the end of the Phase III trials - pulling together the results, applying for approval from FDA etc. I don't expect to see any of the oral treatments on the market until late 2007 at the earliest. But by this time they might have worked out what causes this disease and have identified some more effective treatments to eliminate it (this is the little bit of optimist in me).


Bromley

This article has some more info about research into S1P and its relation to MS and FTY720.


Discovery of T-cell 'traffic control' boosts new drug promise

July 14, 2005 - University of California - San Francisco - Scientists have begun to clarify how one of the body's molecules controls the trafficking of T cells through the blood, lymph nodes and on to tissues to fight infection -- a crucial response that sometimes goes awry, attacking the body's own tissues and causing autoimmune diseases.

The traffic control system -- composed of a fat-like compound called S1P and its receptor on T cells -- usually prevents T cells from launching harmful reactions. But when the S1P traffic cop reacts incorrectly, T cells can swamp healthy tissue. The new research explains how a promising experimental drug treats the autoimmune disease multiple sclerosis by blocking excess S1P action. The research also shows the promise of similar strategies to prevent rejection of transplanted organs and tissues without compromising essential immune defenses.

The emerging view brings together research findings on S1P's effect on both the immune system and the blood-circulating vascular system, showing how the two systems interact to regulate T cell circulation and prevent a constant and potentially dangerous release of T cells, or lymphocytes.

The research is presented this month in a special issue of Nature Reviews Immunology. Authors are Edward Goetzl, MD, at UCSF and Hugh Rosen, MD, PhD, at the Scripps Research Institute, scientists who have pioneered the new understanding. Goetzl is the Robert L. Kroc Professor of Medicine and Immunology at UCSF. Rosen is a professor of immunology at Scripps.

Goetzl and Rosen participated in the discovery of S1P's role in T cell trafficking. Goetzl has also shown that S1P regulates T cell trafficking by occupying a receptor on the T cell surface that suppresses the cells' normal response to a "forward march" signal.

T cells respond by chemotaxis -- moving from areas of lower to higher concentration of a signaling molecule known as a chemokine. Studies by the two scientists have shown that S1P and its T cell receptors block this signaling. They slow the flood of T cells "called into" lymph nodes by chemokines.

The scientists made a second discovery about T cell movement: S1P, like chemokines, can also act as a chemotactic attractant to T cells. Once T cells enter lymph nodes -- the sites where they encounter antigens for microbes and other infectious agents -- they sense S1P in the outflowing blood and so migrate into the blood and onto tissues where they are needed to fight infection.

In a key experiment, Goetzl's and Rosen's labs showed that by chemically displacing S1P, its natural braking effect is released, stimulating T cell traffic into lymph nodes. Because this also blocks S1P's chemotactic influence, migration of T cells out of the lymph nodes is greatly reduced. T cells are essentially sequestered in the nodes. Such an effect would prevent T cells from swamping newly transplanted organs or launching a harmful autoimmune reaction, the scientists suggest in the paper.

They think this mechanism underlies the promising clinical trial results of a new drug against multiple sclerosis (MS) recently reported by other researchers. That study showed that the experimental drug, FTY720, significantly reduced the destructive autoimmune process in patients with MS, a debilitating disease in which the body's T cells attack the myelin coating of nerve cells and disrupt their function. Neither Goetzl nor Rosen is involved in the on-going clinical trials of the new drugs and neither has financial ties to the companies that manufacture them.

Controlling this process with drugs offers "enormous potential" against devastating immune reactions, Goetzl says.

"Transplanting organs or even cells, such as insulin-producing Beta cells, into a patient triggers immune reactions that reject the transplant, but a drug such as FTY720 controls S1P function and slows the rush of T cells to the transplantation site without blocking normal immune response against bacteria and other infectious agents," he says. Similarly, such a drug should slow the autoimmune response that occurs in MS, a hypothesis recently confirmed in phase 2 clinical trials, he says.

Such drugs do not interfere with essential protective immune function since bacterial proteins that normally trigger immune defense do so when they enter lymph nodes -- "where the T cells are essentially trapped by the drug for a few days, but still are working fine and allowing new antibody formation," he explains.

Treatment using this drug strategy does not come without risks, Goetzl cautions. Current drugs that affect one type of S1P receptor affect all others as well, and some of these control heart rate and muscle development. In clinical trials of some of these kinds of drugs, a number of patients have tired easily, experienced lower blood flow and a tendency for airways to constrict as muscle walls develop abnormally, Goetzl says.

"Fully exploiting this approach for treatment of autoimmune diseases and transplant rejection will depend on developing new drugs that block only the immune type of S1P receptor," he adds. "But early studies by a number of researchers are quite promising."

Progress will also come from finding "uniquely effective combinations of these agents with other immunosuppressive drugs," he says.

In animal studies and clinical research with patients over more than a decade, scientists have come to understand that millions of T cells and B cells are "called" into lymph nodes by other immune molecules called chemokines.

"But we began to wonder why T cells don't always swarm into lymph nodes and flood on into blood vessels that lead to all parts of the body," Goetzl says. "We asked ourselves, 'What is the brake?'"

In research with mice that have T cells that lack S1P receptors or have over-expressed receptors, the Goetzl and Rosen labs and others determined that T cells have on their surfaces what are known as G protein-coupled receptors, which when occupied by chemokines -- their natural binding partners -- prompt the T cells to rush into lymph nodes. But S1P, they found, can act through its own G-coupled receptors to prevent chemokines from triggering T cell movement. In ways not yet fully understood, this process is reversible, providing the body with a crucial control over when and how much of the potent T cell soldiers to release into the blood stream.

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Research support for both Goetzl and Rosen comes from the National Institutes of Health.

NOTE: S1P is an abbreviation for Sphingosine1-phosphate, one of a family of fat-like molecules that affect proliferation and diverse functions of many cell types.

http://www.eurekalert.org/pub_releases/ ... 071405.php