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Mycophenolate Found No Better Than Placebo for Myasthenia Gravis in Two Trials: Study Design May Be the Reason for Results, Study Authors Say


doi: 10.1097/01.NT.0000337665.59903.c8
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Investigators of two placebo-controlled studies of mycophenolate for myasthenia gravis said the study period was too short to realize the positive results they had hoped to find.

A decade ago, a case report described the successful use of an immunosuppressive drug in treating a patient with myasthenia gravis (MG), sparking widespread use in patients who had not responded to traditional treatments. Reports of similar success with mycophenolate mofetil (CellCept) followed.

Now, results of two placebo-controlled studies suggest that the drug may not be as beneficial as neurologists and patients had hoped. But even the lead investigator of one of the studies, Donald Sanders, MD, professor of neurology at Duke University Medical School, is pointing the finger at the study design, suggesting that it was impossible to find an effect of the medicine in the short time period used for patients who qualified to receive the medication. Both studies were published in the August 5 Neurology.

“There are a lot of feelings in the community (of patients with MG and the doctors treating them) that the drug works,” said Dr. Sanders. “There is strong evidence that patients are better. We believe it would be a mistake to make a final conclusion about the effects of mycophenolate mofetil on myasthenia gravis based on these studies.”

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Dr. Sanders called for new studies designed to avoid the problems of the two new studies. Some retrospective case studies found benefit from the medicine, as well as one small placebo-controlled study and the decade-long experience with hundreds of individual patients, he said.

Three years after the case study appeared in Neurology in 1998, Dr. Sanders, one of the investigators of the multicenter Muscle Study Group, developed a protocol and submitted the design to the FDA Orphan Products Development Program. Because of concerns about patient safety the study was shortened to 12 weeks to protect patients in the placebo arm and whose condition might worsen if an effective drug were withdrawn for the study.

Similar concerns led investigators to include only patients who had mild to moderate symptoms. Also excluded were patients who had been given the drug in the past, or those who had received steroids, IV immunoglobulin or plasmapheresis in the preceding three months, or had a thymectomy in the prior year.





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The Muscle Study Group trial included 80 subjects at eight medical centers around the world. The patients were randomized to receive the experimental medicine or placebo in addition to a steroid.

Dr. Sanders and his colleagues reported that patients in both arms of the study improved; 85 percent in the drug group and 77 percent of those on placebo. More than a third of the patients in both groups showed “marked improvement” on a test used to measure MG symptoms, Dr. Sanders said. The improvement carried over through the open phase of the study in both groups — even with the tapered doses of prednisone.

The other randomized trial was initiated by Aspreva Pharmaceuticals, under an agreement with the makers of the immunosuppressant drug. The results were also negative. The Aspreva-sponsored study compared the drug versus a titrated dose of steroid therapy on 176 patients.

Aspreva Pharmaceuticals began its study in 2004, enrolling patients with mild to moderate disease. They received mycophenolate mofetil or placebo plus tapering doses of prednisone throughout the nine-month study. About 40 percent of patients in both groups improved. At the end of the day, both studies failed to show an added benefit of mycophenolate mofetil. They did find that patients fared just as well on lowered doses of prednisone.

Dr. Sanders, who has seen many of his treatment-resistant patients improve on mycophenolate mofetil, has been trying to explain why the clinical experience and the study results don't add up. “Tell our patients that the medication is not the reason why they can now walk, talk, breathe and swallow better,” Dr. Sanders said. He now believes that the treatment phase of the study should have been at least 18 months. He added that patient selection could have biased against sicker people who may have been more responsive to the treatment.

“Obviously, these studies have major implications for myasthenia gravis patients taking mycophenolate mofetil — today and in the future,” Dr. Sanders said. In a paper written with colleague Zaeem A. Siddiqi, MD, PhD, of the University of Alberta, and published in the New York Academy of Sciences in June, they added: “The risk is that a potentially useful drug is prematurely set aside because of factors related to the study designs.”

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An editorial written in Neurology by Michael Benatar, MBChB, Dphil, assistant professor of neurology and director of the Muscular Dystrophy Association Clinic at Emory University, and Lewis P. Rowland, MD, professor of neurology at Columbia University and editor in chief of Neurology Today, also came to the same conclusion. “It is regrettable …that what remains unanswered is whether mycophenolate offers long-term benefits with respect to myasthenic weakness or steroid-sparing effect. The answer to these questions will have to await further study.”

They pointed to the brevity of the trial as a problem because immunosuppressant therapy may take months to take effect and they remarked on the high rates of placebo response — 40 per cent in one trial and 77 per cent in the other.

Myasthenia gravis is an autoimmune disease and immunosuppressive drugs should be effective therapy. Prednisone has been the main treatment, but the adverse effects have led to the pursuit of new options. That this study also found that patients benefited from lowered doses of prednisone could also change treatment for patients with myasthenia gravis.

Doctors who use mycophenolate worry that it will become harder to get reimbursement without studies that show benefit. “It is so hard to conduct a short-term clinical trial and determine whether a drug is effective or not,” said David Richman, MD, a neurologist at the University of California-Davis, who was a lead investigator in the Aspreva study. Dr. Richman said that he has many patients on mycophenolate mofetil who have been able to reduce their steroid dose or get off it altogether.

The new reports do not advocate cessation of mycophenolate therapy for myasthenia. Emma Ciafaloni, MD, an associate professor of neurology at the University of Rochester in New York, said that she has no plans for switching medicines. She said that it is now used for the majority of the patients they treat in upstate New York. “I have so many examples of patients going into remission,” she said. “I am not ready to throw it out.”

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Want to hear more about the findings of the international phase 3, randomized trial of mycophenolate mofetil for myasthenia gravis? Visit for a podcast interview with Dr. Donald B. Sanders by editorialists Dr. Lewis P. Rowland and Michael Benatar.

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Sanders DB, Hart IK, Richman, DP, et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 2008;71:400–406.
    Benatar M, Rowland LP. Editorial: The muddle of mycophenolate mofetil in myastyhenia. Neurology 2008;71:390–391.
      The Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 2008;71: 394–399.
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          Hauser, RA, Malek, AR, Rosen R. Successful treatment of a patient with severe refractory myasthenia gravis using mycophenolate mofetil. Neurology 1998;51:912–913.
            ©2008 American Academy of Neurology