In the pipe line

In the pipe line – multiple sclerosis research

Martha King

Think Trans-Alaska Pipeline System, 800 miles of it. Think crude oil, and how slowly it moves. When it reaches the terminus, it needs to be shipped to a refinery. And even when it has been made into the clear liquid gasoline that makes your car go, there’s the time for delivery to a gas station near you. That’s the pipeline metaphor–often used as a figure for the research process.

Fifty years ago, to learn the basics of MS, researchers concocted a complex molecule called a copolymer which they believed would cause an MS-like disease in lab mice. Instead, the animals were protected by it. In 1996–after 40 years in the pipeline–that substance, glatiramer acetate, was approved for people with MS as Copaxone. The interferon story, resulting in Rebif, Betaseron, and Avonex, is nearly as long. Today, more potential treatments are emerging–while still others are up the line.

Five years ago, Dr. Jack Strominger, Higgins Professor of Biochemistry at Harvard University, and his colleagues began tinkering with the Copaxone molecule to see which one or two of its components might be the actual active ingredient. If sub-units proved to be the source of the anti-MS effect, they might be turned into a more effective drug. But the lab was unable to establish “active” sub-units.

Does that mean five years of research, paid for in part by grants from the National MS Society, went down the tube?

Not exactly. In the course of the search, Dr. Strominger’s team created a number of new copolymers. So far, two of them appear to prevent mice from ever developing an MS-like disease. They seem to stop the disease completely, rather than simply reduce its effects.

But mice are not people. No lab animal ever develops actual MS. According to a report prepared by Pfizer Global Research and Development, only seven of every 100 discoveries in laboratory animals prove safe and helpful for a human disease. The odds for Strominger’s team may be a little better, since a similar copolymer has already proved to be an effective human therapy.

We’re presenting here a round-up of news from the action end of the pipeline–news about potential therapies that are safe and promising enough to be studied in people who have MS.


The monoclonal antibodies (MABs), stars of the biotech revolution, are among the newer MS treatments. These designer proteins are brewed in large, identical batches, all from one clone. Hence, the fancy “monoclonal” name. Each MAB homes in on one specific receptor on the surface of a particular cell or type of cell. Some have reduced MS disease activity in the brain by 75% in very small studies. Antegren is the trade name for natalizumab, an antibody that targets a protein on immune cells. Once the antibody sticks onto this protein, the cell’s ability to get through a special blood vessel barrier and enter the brain is blunted. If it does get into the brain, this immune cell can mastermind MS inflammation and the destruction of myelin.

Antegren is given once a month by IV infusion. In several small trials in the U.S. and the U.K., it dramatically reduced the number of actively inflamed lesions in the central nervous system. Specialists generally agree this is a good indicator of reduced MS activity. Like the current disease-modifying drugs, Antegren appears to slow down MS. It doesn’t stop it completely.

Right now, 900 volunteers with relapsing-remitting MS are in a two-year international, double-blind, placebo-controlled study, which should provide definitive data on how well it Works. (This is the gold standard for scientific trials. Neither the volunteers nor the health-care personnel know who is getting the active drug and who is getting an inert placebo until the testing period is over.)

Antegren plus Avonex

Antegren s early trials were sufficiently exciting for the two sponsoring pharmaceutical companies, Biogen and Elan, to also fund a study of the combination. Currently, 1,200 people with relapsing-remitting MS are taking Avonex alone or Avonex with Antegren.

Campath (alemtuzumab) is another bioengineered MAB. This one latches onto immune cells with CD52 proteins on their surfaces and kills off all the CD52 positive T cells. The drastic drop in immunity is offset by infusing another type ofT cell when the drug is administered. Campath is taken once a year–by IV infusion–over three days. In one small study in the UK and Europe for people with secondary-progressive MS, it virtually eliminated new MS lesions in about half of the people treated. The others continued to progress rapidly.

The drug is FDA approved, but only for use in leukemia at this point. In previous trials it produced a serious side effect. One third of the people with MS who took it developed Graves’ disease, an autoimmune disorder of the thyroid.

Graves’ disease can be well controlled by taking thyroxin, a synthetic thyroid hormone. If Campath proves to dramatically control MS, the trade-off might be obvious, but this is a significant consideration.

A multi-center trial called CAMMS221 begins this year in the U.S. and Britain comparing high- and low-dose Campath to Rebif in 400 people with early relapsing-remitting MS. This trial, funded by Millennium & Ilex, L.P., will continue for three years. Schering AG/Berlex, which markets Betaseron, has the marketing rights for this potential therapy.

Other MABs still in early small-scale studies include Rituxan (rituximab), WA-J695, CNTO 1275, and Zenapax (daclizumab).

New Combos of Proven Agents

If one drug reduces MS activity by 30% and a different drug does the same, can a combination deliver the proverbial one-two punch? First, researchers need to know about safety.

Novantrone plus Avonex vs Novantrone plus Copaxone: This study, involving only 50 volunteers, is funded by the manufacturer of Novantrone. Open to people with secondary progressive and rapidly worsening relapsing-remitting MS, it will analyze how well people tolerate taking two drugs. Novantrone has significant side effects and a lifetime dose limit. Both Avonex and Copaxone are safe for long-term regular use. This trial is not blinded.

Novantrone plus Betaseron: The French Health Ministry and Schering AG are jointly supporting the study of this combination–in 220 people with relapsing-remitting MS in France and Italy. The three-year trial began in 1999, but results typically undergo lengthy analysis and review following the end date of the trial.

Copaxone plus Avonex: A preliminary study proved this combination is also safe–so a three-year trial with 750 volunteers is getting underway at many MS centers. It is a gold-standard trial; the volunteers cannot know if they are receiving the double treatment or not.

The Hormones

Based on intriguing research findings on gender differences in MS, a very small study on hormone safety was completed recently. Women with early relapsing-remitting MS took a daily pill containing estriol, a form of estrogen common in late pregnancy. Results released this past September show that the hormone shrank the number and size of brain lesions as seen on MRI during the time it was being taken. When the women stopped the pill, their MS lesions grew again.

The findings indicate that larger trials are merited to see if estriol works as well as currently approved therapies. A pilot trial of a testosterone gel is also underway in men. These studies are funded by the National MS Society.

Disease-modifiers for people who might develop MS

People with just one attack of symptoms suggesting loss of myelin cannot be definitely diagnosed as having MS. Many of them may never develop it. Physicians tend to be reluctant to prescribe MS-modifying therapy to people in this kind of diagnostic limbo despite all the evidence that these drugs fight MS best the sooner they are used. But treatment of “clinically isolated syndrome” with Avonex has already been approved in Europe, based on two definitive international trials called CHAMPS and ETOMS.

While CHAMPS and ETOMS data are under consideration by the FDA, which is expected to approve it in the U.S., a multi-center trial of Betaseron for people who might have MS has just begun in Europe, Canada, and Israel. This study, called the BENEFIT trial, will follow 400 people for two years to see if this interferon drug can also delay a second attack.


What can be done for MS fatigue?

Provigil (modafinil) is an FDA-approved pill for narcolepsy–a sleep disorder that causes uncontrollable drowsiness. It may reduce MS fatigue. Early studies produced positive results. Cephalon is the manufacturer. In Europe, Provigil is marketed as Modiodal and is also being studied there for its ability to combat MS fatigue. A larger gold-standard trial in France will look at the experiences of 100 people with fatigue and relapsing or secondary-progressive MS.

Fampridine has been around in its generic form as 4-AP for decades, causing controversy. It apparently relieves MS fatigue, bladder dysfunction, pain, and spasticity in possibly one-third of the people who use it. It is a powerful nervous system stimulant, with the potential for causing seizures, and it is currently available only from “compounding” pharmacists who make drugs from scratch. (Most pharmacists dispense factory-made medications.)

Acorda Therapeutics has developed a timed-release formulation called Fampridine SR that may be safer because it prevents “spiking” drug levels. A trial in 360 people with spinal cord injury is in progress at 70 centers in the U.S. and Canada–and a trial in 120 people with MS is now in its second year.

Rehabilitation is under study in a Society-funded project at the Cleveland Clinic’s MS Center. Data are being collected on how well people recover from attacks (or relapses) when they are given intensive outpatient rehabilitation. This trial is following 160 people with secondary-progressive or relapsing-remitting MS as they recover from the effects of a documented MS attack. Half of the participants are receiving outpatient rehabilitation; the other half are not. The study is expected to be closely watched by patient advocates because insurance plans traditionally resist covering intensive rehabilitation for MS.


Progress in MS research depends critically on volunteers. All clinical trials have rigid requirements with respect to the person’s stage and type of MS, age, gender (sometimes), and geography. While trials typically cover expenses related to the therapy under investigation, most do not cover other medical expenses or travel costs for partners or caregivers.

Participants in trials typically don’t know if they are receiving the active treatment or a placebo. Now that there are approved therapies for treating relapsing MS, some trials may take a different form. Instead of a placebo group to serve as the “control” against which the effects of a new treatment are measured, the control group may be composed of people taking one of the disease modifiers.

People interested in clinical trials should discuss it thoroughly with their physician. Information about trials currently enrolling volunteers can be found on the Society’s Web site at nationalms

Potential volunteers may also want to register with NARCOMS, a comprehensive MS patient database at Yale University. Authorized researchers with specific needs sometimes use NARCOMS to invite people who appear to match their needs to volunteer. Telephone 800-253-7884, or e-mail

For more about the pipeline–including information on current Society-funded projects in all stages of development–telephone your chapter at 1-800-FIGHT-MS [1-800-344-4867] or explore the Research section of our Web site.

Martha King is editor of this magazine.

COPYRIGHT 2003 National Multiple Sclerosis Society

COPYRIGHT 2003 Gale Group