2012 AAN Meeting: Myasthenia Gravis Briefs

The 2012 annual meeting of the American Academy of Neurology, held in New Orleans April 21-28, included findings related to myasthenia gravis (MG).

Eculizumab safe and effective in severe MG

Neurologist James F. Howard Jr., from the University of North Carolina at Chapel Hill, presented positive results from a phase 2 pilot trial of eculizumab (Soliris) in people with severe, generalized (affecting muscles throughout the body) MG whose disease could not be adequately treated with at least two standard immunosuppressant medications for more than one year.

Eculizumab is a type of immunosuppressant known as a complement inhibitor. The drug is on the market to treat two conditions unrelated to MG (paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome).

This multicenter, double-blind, placebo-controlled study included 14 people who had moderate to severe muscle weakness despite treatment with immunosuppressants for more than a year.

Among the findings:

• Six of the seven people treated with eculizumab for 16 weeks (86 percent) saw a three-point reduction in their quantitative myasthenia gravis (QMG) score. On this assessment, lower scores reflect better muscle strength.

• During the first 16 weeks, the average change in QMG score was an improvement of 7.43 points in the eculizumab group and an improvement of 2.71 points in the placebo group.

• Four of the seven people treated with eculizumab had an eight-point improvement in the total QMG score compared with one of seven in the placebo group.

• When data from all patient visits were assessed, the overall change in average QMG total score was significantly better in the eculizumab group compared to the placebo group. The average improvement in the treated group was 6.43 points; in the placebo group, it was 3.18 points.

• Eculizumab was well-tolerated. No one discontinued treatment.

The conclusions:

• The positive data from this trial highlight the important role of "uncontrolled complement activation" in severe, generalized MG that is resistant to treatment. The complement system is a group of proteins that enhances an immune response. In MG, there is an undesirable, destructive immune response that attacks the place where nerve and muscle fibers interact.

• The data show that eculizumab is apparently safe and beneficial in severe, generalized MG that has not responded to other treatments.

GM-CSF may have helped patient in myasthenic crisis

Neurologist Julie Rowin from the University of Illinois College of Medicine at Chicago described how the use of an experimental drug called GM-CSF may have contributed to an improvement in the condition of a 77-year-old man with a prolonged myasthenic crisis that was resistant to conventional treatments.

A myasthenic crisis involves MG-related weakening of the respiratory muscles so that breathing is not possible without mechanical ventilation.

There is evidence that GM-CSF (granulocyte-macrophage colony-stimulating factor) can "rebalance" the immune system by stimulating cells that dampen (regulate) an immune response. These cells are known as T regulatory cells, or Tregs. (MG involves an inappropriate immunologic attack on the place where nerve and muscle fibers meet, and dampening this immune response would presumably improve the disease course.)

GM-CSF (also known as sargramostim and marketed by Genzyme as Leukine) is approved by the U.S. Food and Drug Administration for use after chemotherapy to improve the white blood cell count and for use during harvesting of peripheral blood stem cells to be used for bone marrow transplantation. MDA is supporting the development of this drug for possible use in MG.

Experiments in mice with an MG-like disease have shown that GM-CSF can suppress a misdirected immune response and expand the number of functional Tregs.

Prior to treatment with GM-CSF, the Tregs of the patient in this one-person study were not optimally functional. After the treatment, there was an increase in the number of functional Tregs and in their ability to suppress an immune response. This coincided with an improvement in the patient's clinical status.

The investigators reached several conclusions:

• Clinical improvement in this patient after GM-CSF treatment was associated with enhanced Treg function.

• The observed effects of GM-CSF on Tregs are consistent with previously reported effects of GM-CSF on the immune system.

• Although limited to a single patient, these observations, combined with data from mouse experiments, support the study of GM-CSF in MG in a larger clinical trial.

• Tregs may play an important role in MG, and monitoring these cells might be a good way to measure disease progression and response to treatment.

In an April 30, 2012, email to Quest, Julie Rowin said the patient in this study has regained the ability to breathe on his own and is now in remission on 1,000 milligrams per day of the immunosuppressant mycophenolate. He has resumed his usual activities, including square dancing and mowing the lawn.

However, she noted, "I just don't think we have the data to say that his clinical improvement is clearly or solely due to the GM-CSF, since he was on multiple treatments concurrently."