“Chemical Plasmapheresis” Drug for Myasthenia Gravis Is Safe, Lowers Antibodies, and Produces Hints of Efficacy in Phase 2 Trial
Article In Brief
In a phase 2 trial, researchers found that efgartigimod was safe and effective in patients with generalized myasthenia gravis with a history of anti-acetylcholine receptor autoantibodies.
The monoclonal antibody efgartigimod is safe for use in patients with myasthenia gravis (MG), according to a phase 2 study published in the June 4 online issue of Neurology. The drug rapidly and dramatically lowered the level of circulating immunoglobulin G (IgG) antibodies, and improved scores on several MG rating scales.
“This was a very important phase 2 trial that opened up a promising new mechanism of action for the treatment of autoimmune myasthenia gravis, and potentially other antibody-mediated neurologic diseases,” said Amanda C. Guidon, MD, instructor in neurology at Harvard Medical School and director of the Myasthenia Gravis Clinic at Massachusetts General Hospital in Boston, who was not involved in the trial.
Efgartigimod targets the neonatal Fc receptor (FcRn), which prevents lysosomal degradation of IgG antibodies, including those against the acetylcholine receptor (AchR), keeping them in circulation. By binding to the FcRn, efgartigimod interrupts this recycling process and lowers the level of IgG antibodies in the bloodstream. Because it depletes circulating antibodies, it has been called “chemical plasmapheresis.”
The treatment proved safe and reduced anti-AchR antibodies in a phase 1 trial in healthy volunteers, but whether it could similarly reduce them in patients receiving immunosuppressive therapy, and remain safe in an immunocompromised population, were the open questions that the phase 2 trial intended to address.
Study Design, Findings
In the trial, 24 patients with MG on stable treatment were enrolled and randomized 1:1 to receive four weekly two-hour infusions of efgartigimod or placebo. Patients were followed out to 16 weeks after the first treatment. Among other exclusion criteria, patients could not enroll who had received immunoglobulin, plasmapheresis, or plasma exchange within the prior four weeks.
The primary endpoints were safety and tolerability. Secondary endpoints included reduction in anti-AchR antibodies and change from baseline to week 11 of the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Quantitative Myasthenia Gravis (QMG) score, and Myasthenia Gravis Composite (MGC) disease severity score, as well as of the revised Myasthenia Gravis Quality of Life (MGQoL) scale.
All patients receiving placebo, and 11 of 12 patients receiving efgartigimod, completed the study; one patient withdrew for lack of efficacy.
No deaths or serious adverse events occurred. Treatment-emergent adverse events were similar between the two groups, with headache being the most common event, affecting three patients taking placebo and four taking efgartigimod. One patient on efgartigimod developed an episode of shingles on the arm receiving the infusion.
Treatment with efgartigimod led to a 40 percent reduction in total serum IgG within one week, and a maximum of about 71 percent after dosing was complete. Anti-AchR antibodies were reduced by 40 to 70 percent in all but one patient, whose level of this antibody was only slightly reduced by treatment. Following the last dose, the levels of total IgG and anti-AchR IgG rose gradually, returning to near baseline about eight weeks after the final dose.
While the study was not powered to test the efficacy of efgartigimod, there were signals from the clinical scales that favored its use during at least part of the trial, even in the face of the recognized strong placebo effect in MG patients. The MG-ADL score was significantly better for active treatment than for placebo two weeks following the final dose, and the MG-QoL score favored active treatment for three of four weeks following the final dose. There was no significant difference between groups for the MGC at any time, and the QMG favored efgartigimod at only one time point, one week into treatment. Within the active treatment group, improvements in multiple scores were sustained for up to eight weeks after the final infusion.
“This drug, and other drugs with a similar mechanism of action, may be playing a role in our future treatment of immune-mediated disorders,” said Gil I. Wolfe, MD, FAAN, Irvin and Rosemary Smith Professor and Chairman of Neurology at Jacobs School of Medicine and Biomedical Sciences at SUNY Buffalo, who participated in this study as a member of the Efgartigimod MG Study Group. “This could be another option for treatment of our MG patients, with a safety profile perhaps even better than IVIg, with easier vascular access than plasma exchange.”
Dr. Wolfe noted that the lack of infectious disease issues in this trial was to be expected, based on experience with plasma exchange. Headaches may be part of the treatment picture, as it is with other infused medications, he said.
“This trial established safety to proceed with a larger trial,” said Dr. Guidon of Massachusetts General Hospital, noting that a phase 3 trial of efgartigimod is currently underway. “The risk of shingles is known to be elevated in immunosuppressed patients, and the mechanism of action of efgartigimod would raise particular concerns about shingles risk,” she said.
“The secondary MG-specific efficacy outcomes were promising,” she added, “and what was most interesting, though not surprising, was that the clinical benefit lasted longer than the period of active treatment in most patients.”
One limitation of the trial, Dr. Guidon said, is that “it did not provide enough baseline data on the patients to understand whether the treatment group was a refractory or nonrefractory population of patients with myasthenia gravis. This would be important in assessing where this drug may fit into the treatment paradigm.”
One possibility is that it may be a rescue therapy for patients in myasthenic crisis, as an alternative to plasmapheresis, since, as Dr. Guidon put it, “It is an agent with a similar end result, but without the potential limitations of venous access and availability of plasmapheresis.”
But that determination will have to await not only proof of efficacy in the phase 3 trials, she said, but also clinical experience with efgartigimod used in this manner.
“This study demonstrated excellent safety results,” commented Henry J. Kaminski, MD, FAAN, professor and chair of neurology at George Washington University School of Medicine and Health Sciences in Washington, DC, who was not involved in the trial. “There was a clear demonstration of target engagement, with a rapid drop in antibody levels, and some evidence of efficacy.”
One important point, he added, is that the administration “is somewhat tough on the patients,” given that it is a weekly two-hour infusion. It is likely to be tolerable, “but it's not as easy as some of the other agents that are in development.”
And there are multiple other drugs in various stages of development for MG, including another FcRn receptor antagonist. “This is a remarkable era in the history of the disease,” Dr. Kaminski said. “We have a pretty well-developed understanding of the autoimmune reaction, and so there can be these highly targeted approaches that remove antibody with the expectation that there will be a therapeutic effect.”
In addition, he said, experts have developed clinical research standards and quantitative outcome measures, including those used in this trial, “so the clinical trial community has been much more rigorous overall over the past ten to fifteen years.” As a result, he said, “this is really a golden age for therapeutic development in MG.”
The study's senior investigator, Nicholas Leupin, MD, is a full-time employee of argenx BVBA. Dr. Guidon has received consulting fees and clinical support from Momenta Pharmaceuticals. Dr. Wolfe receives honorarium fees from argenx for consulting work. Dr. Kaminski serves on the advisory board for UCB and RA Pharmaceuticals, and is chief executive officer of ARC Biotechnology, LLC.