New Drugs in late-stage trials offer promise for sufferers of the chronic and crushing disease multiple sclerosis

Two Steps Forward

New drugs in late-stage trials offer promise for sufferers of the chronic and crushing disease multiple sclerosis

Mary Ellen Egan 08.07.08, 6:00 PM ET
Forbes Magazine dated September 01, 2008




Robin and Clifford Giese, with Kevin Giese at right.


Robin Giese, 59, kicks off each day by getting out of her wheelchair for a half-hour ride on a stationary bike followed by 30 minutes of stretching exercises. Most afternoons she visits friends or one of of her five grandchildren, and in the evenings she and her husband, Clifford, entertain guests or go out to dinner.

Giese hasn't always been so active. She has multiple sclerosis, the degenerative disease of the central nervous system that afflicts 400,000 Americans. In MS the immune system attacks myelin, a fatty substance that protects nerve fibers much the way insulation protects electrical wires. When the unprotected nerve fibers, or axons, are damaged, signals are blocked or delayed traveling to and from the brain. This causes a variety of symptoms that can include blurred vision, incontinence, difficulty walking and paralysis.

Over three decades multiple sclerosis has slowly robbed Giese of her mobility and weakened her muscles, and without treatment she would be all but immobilized in her wheelchair. But an experimental drug has changed the course of her disease--and her husband's career path.

The compound, called dirucotide, is a chain of 17 amino acids that mimics a portion of the protein in myelin. It works by acting as a decoy to divert the attacking immune cells. It has had such a profound impact on Robin's condition that her husband has started a company, BioMS Medical, to bring it to market. Today dirucotide is one of two novel MS drugs in late-stage clinical trials. The other, from a small firm called Acorda, improves muscle strength.

There are four kinds of MS. Most sufferers are first given a diagnosis of a mild relapsing form of the disease marked by occasional flare-ups followed by months or years without symptoms. Ninety percent of patients with this condition eventually develop a progressive MS characterized by continuous deterioration. The two remaining types of MS, less common, entail a rapid decline.

Most existing MS therapies work by suppressing the immune system, and they're generally effective only when the disease is at an early stage. They include Biogen Idec (nasdaq: BIIB - news - people )'s monoclonal antibody Tysabri, beta interferons and anticancer drugs. They can be helpful (there is no cure), but their side effects can range from flu-like symptoms to fatal viral infections of the brain.

Dirucotide began with research conducted at the University of Alberta by doctors Kenneth Warren and Ingrid Catz. In 1989 Warren developed a synthetic peptide that mimics myelin protein. He began testing his compound on MS patients in 1994, and Robin Giese, who became a patient of his that same year, received her first infusion in 1996. Three weeks later, she says, her energy level had increased dramatically, and her head, which had felt "fuzzy" for years, was suddenly "clear." "It was the best I'd felt in years," she says.

Even though the drug didn't allow her to throw away her wheelchair, she credits it with restoring her zest in life. "Before I started taking it, I couldn't predict how I'd feel or what I could do each day. Now I wake up feeling great and have energy for the entire day." She gets dirucotide infusions twice a year.

The university lacked money for clinical trials, so Clifford, who had made a fortune with a chain of Canadian oil-change stores, stepped in to help. He and his brother, Kevin, licensed the drug from the university and founded BioMS in September 2000. The following year they started selling shares to the public, and they've raised $180 million so far on top of the $1 million that they estimate they invested themselves at the outset. Kevin took the role of chief executive, and Clifford became chairman.

BioMS moved to late-stage clinical trials of dirucotide in January 2005 and has done them with 611 patients with the progressive form of MS. Testing should wrap up in mid-2010.

The results so far have been very promising. Patients with either of two genes associated with autoimmune disorders, HLA-DR2 and HLA-DR4, have gone five years without any progression of the disease. Those genes are found in 65% to 75% of all MS patients, and because of that analysts estimate that the potential market for drugs like dirucotide, effective for patients at later stages of the disease, could reach $10 billion a year. The current market for all existing MS drugs is $6 billion.

Acorda's drug, Fampridine-SR, works differently from dirucotide and specifically addresses one of the most devastating symptoms of the disease, loss of muscle strength. Its key compound, 4-aminopyridine, has been around for 100 years. Academic researchers originally used the synthesized chemical to study nerve cell conduction. Not until the 1980s did they figure out how it works and how it might help with MS.

In MS the damage to myelin exposes channels on the surface of the axon, allowing potassium ions to leak out and thus dissipate the electrical current that carries nerve signals. The 4-aminopyridine molecule patches the exposed channels so the current can pass through.

But, early on, using the compound in humans proved to be tricky. Dosages were hard to control, and patients given too much had seizures. The drug languished until the mid-1980s, when Elan Corp. (nyse: ELN - news - people ), an Irish firm, began looking for ways to reformulate it.

In 1994, after a decade of tinkering, Elan began testing a sustained-release version in patients with MS. A year later Acorda, then privately held, approached Elan for permission to test Fampridine-SR, as the new version was named, in spinal cord injury patients. Acorda began clinical trials in 1998 and, five years later, when Elan was struggling, secured the rights for Fampridine-SR for all applications.

Acorda started its tests of Fampridine-SR in MS patients in late 1999, and in June this year the now public company completed late-stage trials in 540 patients with all four types of MS. The results are impressive: 43% of the patients showed consistent improvement in walking speed, as against 9% of patients on a placebo.

"One of the first questions patients ask is if they'll be in an wheelchair. Anything that helps to keep them out of a wheelchair longer is very important," says Dr. Hillel Panitch, one of the drug's clinical investigators and director of the University of Vermont's Multiple Sclerosis Center. Acorda plans to submit its data to the FDA early next year and ask the agency for fast-track approval.

"One of the first questions patients ask is if they'll be in an wheelchair. Anything that helps to keep them out of a wheelchair longer is very important," says Dr. Hillel Panitch, one of the drug's clinical investigators and director of the University of Vermont's Multiple Sclerosis Center. Acorda plans to submit its data to the FDA early next year and ask the agency for fast-track approval.

Adult Stem Cells Reprogrammed To Become Myelin-Making Cells

Research published in Nature Neuroscience , electronic publication ahead of print) has shown that adult stem cells in mice that are developing into nerve cells can be redirected to turn into myelin-making cells by changing a single gene . This type of research may some day help repair the damage to myelin which occurs in multiple sclerosis (MS).

In people with MS the immune system can attack both myelin and myelin making cells (oligodendrocytes). Limiting the number of myelin making cells impairs the capacity to repair the damage to myelin. One potential treatment option currently being investigated involves encouraging immature stem cells that reside in the adult brain, called neural stem cells, to move to areas of damage and repair myelin.

When neural stem cells are grown in the laboratory scientists have been able to reprogramme them to develop into several different types of brain cells, including oligodendrocytes. This latest research which took place in The Salk Institute for Biological Studies in California sought to determine if it would be possible to repeat these experiments in the brain.

A gene called Asc1 which is associated with oligodendrocyte development was introduced into the stem cells in the brain and caused neural stem cells to develop into oligodendrocytes.

This study confirms that adult stem cells in the brain retain their ability to be converted to certain other types of brain cells. Further research is needed to determine the significance of these finding to myelin repair in people with MS.

Dr Laura Bell at the MS Society said: 'Finding a way to cause stem cells which are already present in the brain to repair damaged myelin is an attractive potential treatment option for people with MS. This is early research but it is an important step and we look forward to seeing how the work progresses.'

Scientists Show Monoclonal Antibody Leads to Repair of Myelin Sheath in Laboratory Study of Multiple Sclerosis

HAWTHORNE, N.Y.--(BUSINESS WIRE)--Oct. 16, 2007--Researchers at Mayo Clinic have presented details from a preclinical study showing that a recombinant human monoclonal antibody, administered in a single low dose in a laboratory mouse model of multiple sclerosis, can repair myelin, the insulating covering over nerve fibers in the central nervous system.

The study was presented on October 9, 2007 at the American Neurological Association meeting in Washington, D.C.

"We are excited to be collaborating with Mayo on the development of this therapy," noted Andrew R. Blight, Ph.D., Chief Scientific Officer at Acorda. "The options for treatment of MS are still quite limited, and a new approach that could repair damage to the central nervous system would represent an important advance for the individuals who live with this disease."

In multiple sclerosis and some other disorders of the central nervous system, the immune system attacks and destroys the myelin sheath, causing the nerve to lose its ability to conduct electrical impulses from the brain to the body, resulting in the disabilities associated with those conditions.

The antibody, which was genetically engineered for large-scale production, binds to myelin and the surface of cells in the brain and spinal cord, triggering the cells to begin the repair process called remyelination. The study was conducted using a laboratory mouse model of chronic progressive multiple sclerosis in humans. The antibody was delivered alone and in combination with the steroid methylprednisolone; remyelination was detected in both instances.

The antibody is being developed by Mayo Clinic and Acorda Therapeutics. Under a license agreement between Acorda and Mayo Clinic, Acorda holds exclusive worldwide rights to certain patents and other intellectual property for this antibody related to use and treatment of central nervous system disorders, including multiple sclerosis. Both Acorda and Mayo will be working on the steps leading to a future Investigational New Drug Application (IND) and a Phase 1 clinical trial.

About Multiple Sclerosis

Multiple sclerosis is a chronic, usually progressive disease of the central nervous system in which the immune system attacks and destroys the structure, and therefore degrades the function, of nerve cells. According to the National Multiple Sclerosis Society, approximately 400,000 Americans have MS, and every week about 200 people are newly diagnosed. Most are between the ages of 20 and 50, and women are affected two to three times as much as men. Worldwide, MS may affect 2.5 million individuals.

The NMSS estimates the direct costs of medical care for MS patients in the United States to exceed $6 billion annually. Additionally, a recent NMSS analysis estimated the total cost of MS, including medical and non-medical care, production losses, and informal care, at more than $47,000 per U.S. patient per year. Complications from MS may make it harder for people to work and may interfere with their ability to perform common, daily activities.

For most people with MS, the disease slowly progresses with a series of unpredictable flare-ups, also called relapses or exacerbations. But for some, the progression of the disease is rapid. Each relapse tends to lead to increasing disabilities such as walking impairment, muscle weakness or speech or vision impairments.

About Acorda Therapeutics

Acorda Therapeutics is a biotechnology company developing therapies for spinal cord injury, multiple sclerosis and related nervous system disorders. The Company's marketed products include Zanaflex Capsules(TM) (tizanidine hydrochloride), a short-acting drug for the management of spasticity. Acorda's lead clinical product, Fampridine-SR, is in a Phase 3 clinical trial to evaluate its safety and efficacy in improving walking ability in people with MS. The Company's pipeline includes a number of products in development for the treatment, regeneration and repair of the spinal cord and brain.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, regarding management's expectations, beliefs, goals, plans or prospects should be considered forward-looking. These statements are subject to risks and uncertainties that could cause actual results to differ materially, including Acorda Therapeutics' ability to successfully market and sell Zanaflex Capsules, the risk of unfavorable results from future studies of Fampridine-SR, delays in obtaining or failure to obtain FDA approval of Fampridine-SR, competition, failure to protect its intellectual property or to defend against the intellectual property claims of others, the ability to obtain additional financing to support Acorda Therapeutics' operations, and unfavorable results from its preclinical programs. These and other risks are described in greater detail in Acorda Therapeutics' filings with the Securities and Exchange Commission. Acorda Therapeutics may not actually achieve the goals or plans described in its forward-looking statements, and investors should not place undue reliance on these statements. Acorda Therapeutics disclaims any intent or obligation to update any forward-looking statements as a result of developments occurring after the date of this press release.

CONTACT: Acorda Therapeutics
Media:
Erica Wishner, 914-347-4300 ext. 162
ewishner@acorda.com
or
Investor:
Tierney Saccavino, 914-347-4300 ext. 104
tsaccavino@acorda.com

SOURCE: Acorda Therapeutics

Calcium ions activate enzymes in MS

Learning exactly how the myelin sheath is degraded might enable scientists to determine how to halt disease progress and reverse damage by growing new myelin, said Ji-Xin Cheng, an assistant professor in Purdue University's Weldon School of Biomedical Engineering and Department of Chemistry.

"Although multiple sclerosis has been studied for many years, nobody knows exactly how the disease initially begins," he said. "The pathway is not clear."

Purdue researchers used an imaging technique called coherent anti-Stokes Raman scattering, or CARS, to study how the myelin sheath is degraded by a molecule called lysophosphatidylcholine, known as LPC. The LPC does not cause multiple sclerosis, but it is used extensively in laboratory research to study the deterioration of myelin, which insulates nerve fibres and enables them to properly conduct impulses in the spinal cord, brain and peripheral nervous system throughout the body.




The findings suggest that LPC causes sheath degradation by allowing an influx of calcium ions into the myelin. The increased concentration of calcium ions then activates two enzymes - calpain and cytosolic phospholipase A2 - that break down proteins and lipids.

"It is possible that the same pathway causes myelin degradation in people suffering from multiple sclerosis and spinal cord injuries," Cheng said.

The research demonstrates that CARS microscopy is a valuable research tool and could become a future clinical method to diagnose multiple sclerosis and detect damage to the spinal cord from accident trauma, which also causes the myelin to degrade, he said.

The researchers used CARS to study and take images of healthy and diseased myelin. The researchers showed that an enzyme called cytosolic phospholipase A2 contributes to myelin degradation by snipping off one of the two tails that make up lipid molecules contained in the myelin. Cutting off one of the tails turns the lipid molecules into LPC, amplifying the effect and further degrading the myelin.

The research was carried out in spinal cord tissues extracted from animals and in the sciatic nerves of living mice.

Findings were confirmed by comparing CARS results with electron microscope images and measurements of electrical impulses in spinal cord tissue that distinguish between normal and diseased myelin.

CARS imaging takes advantage of the fact that molecules vibrate at specific frequencies. In a CARS microscope, two laser beams are overlapped to produce a single beam having a new frequency representing the difference between the original two beams. This new frequency then drives specific molecules to vibrate in phase, amplifying the signals from those molecules.

Contact: Purdue University's Weldon School of Biomedical Engineering

Insight into myelination process

In a host of neurological diseases, including multiple sclerosis (MS) and several neuropathies, the protective covering surrounding the nerves is damaged. Scientists at the Weizmann Institute of Science have discovered an important new line of communication between nervous system cells that is crucial to the development of myelinated nerves – a discovery that may aid in restoring the normal function of the affected nerve fibres.

Weizmann Institute scientists Prof. Elior Peles, graduate student Ivo Spiegel, and their colleagues in the Molecular Cell Biology Department and in the United States, have provided a vital insight into the mechanism by which glial cells recognize and myelinate axons.

The Weizmann Institute team found a pair of proteins that pass messages from axons to glial cells. These proteins, called Necl1 and Necl4, belong to a larger family of cell adhesion molecules.

Peles and his team discovered that even when removed from their cells, Necl1, normally found on the axon surface, and Necl4, which is found on the glial cell membrane, adhere tightly together. When these molecules are in their natural places, they not only create physical contact between axon and glial cell, but also serve to transfer signals to the cell interior, initiating changes needed to undertake myelination.

The scientists found that production of Necl4 in the glial cells rises when they come into close contact with an unmyelinated axon, and as the process of myelination begins. They observed that if Necl4 is absent in the glial cells, or if they blocked the attachment of Necl4 to Necl1, the axons that were contacted by glial cells did not myelinate. In the same time period, myelin wrapping was already well underway around most of the axons in the control group.

“What we’ve discovered is a completely new means of communication between these nervous system cells,” says Peles. “The drugs now used to treat MS and other degenerative diseases in which myelin is affected can only slow the disease, but not stop or cure it. Today, we can’t reverse the nerve damage caused by these disorders. But if we can understand the mechanisms that control the process of wrapping the axons by their protective sheath, we might be able to recreate that process in patients.”

Contact: Weizmann Institute of Science

New strategies to treat neurological disorders

By Mike Nagle

20/06/2007 - Experts from around the world have gathered this week to discuss the best emerging therapies for a number of neurological disorders such as multiple sclerosis and stroke.

Thousands of scientists and clinicians have descended on the island of Rhodes, Greece for the European Neurological Society (ENS) congress and the latest drugs are the centre of attention.

One central topic at the scientific conference is multiple sclerosis (MS), a chronic inflammatory disease that attacks the central nervous system (CNS).

"About 400,000 people in Europe have MS and about one million worldwide," said the ENS president, Professor Giancarlo Comi.

"MS is still not curable. A number of new findings have been made in recent years, however, with regard to the origins of the disease and new therapeutic strategies. These new insights help us to mitigate the course of the disease and delay the development of permanent disabilities."

The scientists took time to focus on the mechanisms underlying the process of axonal degeneration which characterise the progressive phase of the disease. There is some evidence that some of these mechanisms are at least partially independent from inflammation.

According to Prof. Comi, modulating and suppressing the immune system only has a modest effect at best on the progressive phase of the disease.

"One important goal in the treatment of this severe disease has to be to develop therapies that repair the damage MS causes in nerve cells," Professor Comi said. "There is increasing scientific evidence that the course of MS is shaped by different disease mechanisms in its early and late phase."

Researchers from France, Germany and Switzerland believe they have proof for a hypothesis first posited in the late 19th century. According to this new evidence, certain stem cells differentiate very early on in human development into nerve cells or into glia cells - the maintenance and support cells in the CNS.

They showed that there are two different types of stem cells that differentiate into either glia or nerve cells. This finding from Dr Zalc, Hôpital Pitié Salpêtrière, Paris, and colleagues, contradicts the viewpoint that nerve cells form first and that glia cells then develop from them.

Prof. Comi said: "Key fundamental research findings like these could well enable MS therapy to advance in significant ways."

Professor Martin Schwab, from the University of Zurich, presented promising results for his antibody therapy that can restimulate nerve growth in animals, following injury or stroke. In the human brain, nerve fibre growth is restricted to distances below 2mm as it is inhibited by several substances found in myelin sheaths - the protective coverings found on nerves.

One of these substances is the membrane protein Nogo-A. Prof. Schwab and his team have developed an antibody that blocks this target. When they tested its effect in animals, they found that the drug stimulated nerve fibre growth over comparatively long distances substantially improved "functional restoration", such as running, swimming or gripping.

Professor Ioannis Milonas, chairman of the ENS Congress, said: "The new agent is currently being tested in a Phase I clinical study in a European network of centres for spinal cord injuries."

Another possible stroke therapy discussed at the event was developed by a group of Swiss scientists from University Hospital Zurich. Annett Spudich and her colleagues are examining the effectiveness of multidrug resistance-associated protein 1 (MRP1) as a stroke therapy in mice. They injected mice subjected to stroke injury with MRP1 substrates 17betaEG and GSNO immediately and saw a dose-dependent decrease (17betaEG) or increase (GSNO) in brain injury. If MRP1 expression was knocked out completely, these injury effects were also blocked. This indicated that MRP1 was needed by the two substrates in order to gain access to the brain.

"Strokes are the third most common cause of death and the most common cause of severe disability for adults in industrialised countries," said Professor Gerard Said, secretary general of the ENS.

He continued: "They have found that MRP1 might be a substance for transporting drugs across the blood cerebrospinal fluid barrier, a physiological barrier between the central nervous system and the blood stream."

If this proves to be the case, MRP1 could be used as a gateway through which drugs could travel directly to the brain regions affected by a stroke.

MS Treatment May Lie in the Eye

Protein Found in the Human Eye Shows Promise as a Multiple Sclerosis Treatment in Mice

By Miranda Hitti

WebMD Medical News

Reviewed by Louise Chang, MD

June 13, 2007 -- A protein called CRYAB, which is found in the eye, may help treat multiple sclerosis (MS).

That's according to preliminary lab tests done on mice. It's too soon to know if the same strategy will work in people. But if it does, it may lead to new MS treatments.

The researchers included Stanford University's Lawrence Steinman, MD, and Shalina Ousman, PhD. Steinman is a professor in Stanford's neurology and neurosciences department, where Ousman also works.

With colleagues from various other institutions, Steinman and Ousman studied CRYAB, which is found in the eye's lens.

Previous research has shown that when MS develops, CRYAB turns up in the brain. That's a problem -- but it also inspired an intriguing solution that may help tame MS.

Protein Power

In MS, the body's immune system attacks myelin, the fatty sheath that insulates nerves. As a result, nerves can't communicate as well as they normally would.

The new study focuses on mice with a brain condition similar to MS. Some of the mice were genetically unable to make CRYAB.

The researchers found that the mice that couldn't make CRYAB had more brain inflammation and a hypersensitive immune system response to that inflammation than normal mice.

The scientists injected human CRYAB into those mice. That eased the mice's symptoms and even reversed paralysis caused by their disease.


How It Works

In their study, the scientists argue that when CRYAB first appears in the brain, it's a troublemaker.

"For some reason, the protein [CRYAB] gets turned on in the brain where it's not expected to be," Steinman says in a Stanford news release.

Because CRYAB isn't expected in the brain, the immune system attacks it. That spurs a cascade of inflammatory chemicals, making matters worse.

But adding more CRYAB to the brain has the opposite effect. Additional CRYAB calms brain inflammation, according to the researchers.

"Remarkably, addition of that very same stress protein, akin to restoring the brakes that were failing, returns control," they write, calling CRYAB a "critical tipping point" in the development of MS.

The study appears in the advance online edition of the journal Nature.

SOURCES: Ousman, S. Nature, June 13, 2007; advance online edition. News release, Stanford University Medical Center.

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