Tarnished 'Gold Standard' Trials: Mycophenolate in Myasthenia

April 28, 2008


Science Editorials and Reviews - Edited by Vinay Chaudhry, MD, FAAN

By Daniel B. Drachman, MD, FAAN
Author Disclosure


Two clinical trials of treatment of myasthenia gravis (MG) with mycophenolate mofetil (MMF) in Neurology® report lack of efficacy. Unfortunately, both trial protocols were flawed, with relatively short durations of treatment, unexpectedly good responses to concomitant steroid treatment, and problems in the efficacy measure. However, excellent results, and a favorable profile of side effects, observed in numerous myasthenic patients treated by experienced clinicians require that these published trials be considered in context. In the meantime, MMF must remain available for treatment of MG. Future trial designs should consider prolonged time course, interactions of other immunosuppressive agents, and a more appropriate outcome method.

Two Negative MMF Trials

Two reports in Neurology®—and a thoughtful critique to be published in Annals of the New York Academy of Science by two of the investigators—raise critical questions about the validity and purposes of so-called "gold standard" drug trials of mycophenolate mofetil (MMF, CellCept®) in myasthenia gravis (MG). It is almost a matter of faith that double blind randomized controlled trials based on "intent to treat" are the ultimate criteria for assessing the efficacy of therapeutic agents. However, these two investigations—conducted with flawed, or at best questionable, designs—underscore the risks that such Gold Standard trials may produce misleading results that could have important adverse consequences.

These trials were undertaken with the expectation that they would confirm the independent observations of numerous experienced clinicians regarding the effectiveness and minimal side effects of MMF in the treatment of MG 1,2. Experts in MG must now question the cause of the negative results, and consider both what they mean and how to deal with their consequences.

Already, insurance companies—and even Medicare—have begun to refuse payment for MMF for treating MG. These denials result in serious consequences for patients whose health depends on the medication, and unnecessary demands by insurers for justifications by physicians to cover payment for its use. The financial issues are not trivial. If only half the estimated 50,000 myasthenic patients in the United States were to use MMF at the average dose of 1 gram twice a day, the retail cost per year would be $234 million. Without FDA approval, MMF could continue to be prescribed in the United States off label, as are all other drugs currently used for the immunosuppressive treatment of MG.

MG involves autoantibodies. In most patients, these are directed against acetylcholine receptors (AChRs), while in a minority they are directed against muscle specific kinase (MuSK) at neuromuscular junctions. The antibodies are produced by B cells and require collaboration by T cells. A variety of immunotherapeutic strategies directed against antibodies, B cells, and T cells have greatly improved the prognosis of MG.

Immune Suppression with MMF

The introduction of MMF for long-term immunosuppression has been reported to provide safe immunosuppression and clinical benefit in MG, with minimal adverse side effects. The mechanism of action of MMF is to inhibit the proliferation of both B and T lymphocytes. MMF blocks inosine monophosphate dehydrogenase, which is required for purine synthesis by the de novo pathway. This is the only pathway available to lymphocytes, whereas all other cells have an alternative "salvage pathway" for purine synthesis.

Thus, MMF inhibits the production of new lymphocytes, but does not eliminate pre-existing lymphocytes, or affect other somatic cells. This explains why MMF is rapidly effective in preventing rejection of organ transplants, but takes so long to work in MG. In transplants, a new antigen never before "seen" is presented to the immune system, and MMF inhibits the production of new lymphocytes that would otherwise reject it.

By contrast, patients with MG already have a large number of pre-existing autoreactive lymphocytes that can survive for variably long periods of months to years, and continue to produce autoantibodies against AChR (or MuSK), until they eventually die off. MMF is used to prevent the recruitment of new autoreactive lymphocytes, but does not eliminate those that are already there. That is why treatment with another immunosuppressive agent (for example, prednisone), which eliminates or inactivates the pre-existing lymphocytes, is often used in the initial treatment of MG in addition to MMF.

Although MMF may take a very long time—many months or even years—to achieve maximum benefits, it offers many advantages as an immunosuppressive agent:

  • It has a remarkably low profile of adverse side effects.
  • It can be stopped abruptly during infection or immunization, to allow the immune system to respond rapidly.
  • It suppresses both B and T cells, which minimizes the risk of developing B cell lymphomas.

Flawed Clinical Trials

In both of the reported clinical trials, MMF was given together with prednisone (or prednisolone), and both trials were designed to be practical—that is, capable of being carried out within a limited period of time, and without excessive cost. In one trial, the timeframe was three months, in conjunction with prednisone and pyridostigmine, while the other took place over nine months, during which the patients' pre-existing prednisone treatment was reduced on a schedule.

The problems inherent in the design of those trials included:

  • A timeframe that was too short
  • The concurrent use of steroids, which proved more effective than anticipated
  • A primary measure of efficacy ("Quantitative MG Score"—QMGS 3) that evaluates the whole patient rather than the specific area of weakness in each individual

One of the most difficult issues raised by these trials is the question of how to test a drug in a condition such as MG, for which reasonably effective medications—are already available, albeit with unfortunate side effects. A truly critical trial of MMF in the treatment of MG would involve long-term follow up, possible observation of the effect of discontinuing medication, and establishment of criteria of efficacy that take into account the individual's specific areas of involvement. This would be a prolonged and costly endeavor indeed, and may not be feasible.

In the meantime, it is essential that MMF remain available for use in MG, and that insurance companies not use these unfortunately flawed trials to reject claims for payment for this important treatment.

Author Disclosure

Within the past 24 months, the author received personal compensation from the company Revimmune for consultation concerning the use of high-dose cyclophosphamide in treatment of neurological conditions. In addition, Dr. Drachman served as a member of the editorial advisory board for the Journal of Autoimmunity, and has reviewed three legal cases during the past 24 months (none related to the subject of the present article). He has also received support from the NIH, MDA, ALSA, and the Packard ALS Center for research on myasthenia gravis and ALS.


  1. Chaudhry V, Cornblath DR, Griffin JW, O'Brien R, Drachman DB. Mycophenolate Mofetil: a Safe and Promising Immunosuppressant in Neuromuscular Diseases. Neurology 2001;56: 94–96.
  2. Meriggioli MN, Ciafaloni E, Al-Hayk KA, et al. Mycophenolate for Myasthenia Gravis: an Analysis of Efficacy, Safety and Tolerability. Neurology 2003;61:1438–4140.
  3. Jaretzki A, Barohn RJ, Ernstoff RM, et al. Myasthenia Gravis: Recommendations for Clinical Research Standards. Neurology 2000;55:16–23.