New drugs in late-stage trials offer promise for sufferers of the chronic and crushing disease multiple sclerosis
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 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 2.5 million people worldwide. 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'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., 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 U.S. Food and Drug Administration early next year and ask the agency for fast-track approval.‹
A new study finds that Genzyme's drug Campath may be an effective treatment for multiple sclerosis
By Catherine Arnst
Campath, a Genzyme (GENZ) drug already approved for leukemia, may turn out to be one of the most effective treatments for multiple sclerosis, and it's the first medication to show potential for reversing the disease, according to a study reported Oct. 22 in The New England Journal of Medicine. In a three-year trial involving 334 patients in early stages of the nerve disease, Campath reduced the number of relapses by 74% when compared with Rebif, a form of interferon that's commonly used to treat MS. Campath also lowered the risk of sustained disability by 71% over Rebif, which is co-marketed by EMD Serono and Pfizer (PFE).
The researchers also noted that patients on Campath showed some recovery of lost motor functions and were less disabled after three years than at the beginning of the trial, while those on interferon worsened. Those results, researchers say, suggest Campath may allow damaged nerve tissue to repair, a first for a disease that afflicts about 400,000 people in the U.S. and several million worldwide. Side Effects
As encouraging as the results may be, Campath can cause very serious side effects, in particular a rare blood condition called immune thrombocytopenic purpura (ITP) that can lead to abnormal bleeding and even death. Six patients on Campath developed ITP during the trial, and one died. Genzyme temporarily stopped the trial after the death and started closely monitoring all patients on Campath for ITP, which can be reversed if treated promptly. The trial was sponsored by Genzyme and Bayer Schering Pharma, which holds marketing rights to Campath.
Despite the danger of ITP, MS specialists welcomed the results. "These outcomes are really pretty remarkable," says Patricia O'Looney, vice-president for biomedical research at the National Multiple Sclerosis Society. "They still have to be confirmed by further trials, but I think it is a very, very promising drug."
Campath is also appealing because it only needs to be administered once a year, intravenously, while Rebif must be given by injection three times a week, O'Looney says. Interferon can also produce severe flu-like symptoms. "There are a lot of patients who cannot tolerate interferon or do not like the shots, so this drug would be an appealing alternative," O'Looney says. Hope for MS Sufferers
The Campath results provided some rare good news to the MS community. In April, Rituxan, a promising MS drug made by Genentech (DNA) and Biogen-Idec (BIIB), failed in a clinical trial against a particularly tough form of MS. This summer, two more cases of a rare and sometimes deadly brain disorder were reported in patients on Tysabri, an MS drug marketed by Biogen-Idec and Elan (ELN). Sales growth of the drug slowed in the third quarter as a result. Because of reports of a few deaths from the brain disease, Tysabri was taken off the market in 2005, just months after it won Food & Drug Administration approval. The FDA allowed it back on in 2006 on the condition that patients be closely monitored.
Both Tysabri and Campath are antibodies that manipulate the immune system, making it almost a given that serious side effects will arise. But many MS patients are so desperate for better treatments that they are often willing to take risks that would be unacceptable in drugs for less serious diseases.
In cases of MS, an autoimmune disease, the body's immune system attacks myelin, the protective coating around the nerves. The nerves are then destroyed, resulting in physical and mental impairments that can become crippling as the disease progresses. Further Trials Planned
Campath, first developed at the University of Cambridge in England, works by inhibiting a portion of the immune system that attacks the myelin. Dr. Alasdair Coles of the University of Cambridge, lead investigator of the study, says he was particularly excited by the drug's ability to promote brain repair. "We are witnessing a drug which, if given early enough, might effectively stop the advancement of the disease and also restore lost function," he says. That would be unprecedented, he adds.
Genzyme is now recruiting patients for two additional trials of Campath, and it will likely be three years or so before the company can seek an additional approval for the drug for the treatment of MS.
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