Phase III results demonstrate improvements in activities of daily living

Efgartigimod, an investigational antibody fragment engineered to reduce pathogenic immunoglobulin (IgG) auto-antibodies, showed benefit in patients with generalized myasthenia gravis (MG) and was well tolerated, the phase III ADAPT study found.

Among 129 generalized MG patients who had antibodies to acetylcholine receptor (AChR), the efgartigimod responder rate was 68% after one cycle of treatment versus 30% for placebo (OR 4.95, 95% CI 2.21-11.53; P<0.0001), reported James Howard, Jr., MD, of University of North Carolina at Chapel Hill, and co-authors in Lancet Neurology.

Results were independent of use of nonsteroidal immunosuppressive therapies (NSISTs) in exploratory analyses. Muscle specific tyrosine kinase (MUSK) auto-antibodies were seen in 4% of both groups.

Serious adverse events occurred in 5% of efgartigimod group and 8% in the placebo group. Three participants in each group discontinued treatment, and no deaths occurred.

“The results of the phase III ADAPT trial suggest that the novel mechanism of selective IgG reduction through blocking of the neonatal Fc receptor (FcRn) with efgartigimod is an effective and well tolerated treatment for patients with generalized myasthenia gravis,” Howard and colleagues wrote.

The researchers identified patients with generalized MG between September 2018 and November 2019, whom they randomized to efgartigimod (n=84) or placebo (n=83). Mean ages were 46 and 48 for treatment and placebo groups, respectively, with 75% and 66% women. Overall, 77% of participants were acetylcholine receptor antibody-positive.

One cycle of treatment included four weekly infusions of 10 mg/kg each. Assessment in the first treatment cycle with the Myasthenia Gravis Activities of Daily Living (MG-ADL) score defined AChR antibody-positive participants with improvements of ≥2 points that was sustained for ≥4 consecutive weeks as responders on the primary outcome. (MG-ADL scores range from 0-24, with higher scores indicating more disability). All patients had a baseline MG-ADL of 5 or more.

Results in the overall population were similar to those in the acetylcholine receptor antibody-positive population, with a responder rate of 68% in the efgartigimod group and 37% for placebo (OR 3.70, 95% CI 1.85–7.58; P<0.0001).

Additional treatment cycles were considered in follow-up to 26 weeks based on clinical response. With additional cycles, the responder rate for AChR antibody positive patients increased from 68% to 78% by week 26.

“One question raised by these results is whether efgartigimod is more effective than eculizumab in patients with acetylcholine receptor-positive MG,” noted Shigeaki Suzuki, MD, PhD, of the Keio University School of Medicine in Tokyo, in an accompanying editorial.

The phase III REGAIN trial of eculizumab found no significant difference between eculizumab and placebo at 26 weeks, Suzuki noted, but this result “is significant if the evaluation method used in the ADAPT trial is applied to the REGAIN trial.”

Efgartigimod (ARGX-113) is a human IgG1 antibody Fc-fragment that binds FcRn and facilitates lysosomal recycling of pathologic antibodies. Binding reduces recycling and accelerates removal of pathologic antibodies. The phase II study of efgartigimod in generalized MG demonstrated prompt decrease in total IgG and AChR antibody levels and clinical improvement.

In the present study, baseline total MG-ADL score was 9.2 in the efgartigimod group and 8.8 in the placebo group. Baseline treatment status for the efgartigimod and placebo groups, respectively, was any steroid (71% versus 81%), any NSIST (61% for both groups), steroid and NSIST (51% versus 53%), or no steroid or NSIST (19% versus 8%).

“The MG-ADL scores and other clinical measures “demonstrate substantial disease burden despite ongoing generalized myasthenia gravis treatment,” Howard and co-authors noted.

Mean score improvements in MG-ADL in cycle 1 showed significant differences from baseline observed from week 1 and sustained through week 7 in all measures. “Most patients had a clinically meaningful improvement in MG-ADL within 2 weeks of starting treatment,” the researchers wrote.

More patients in the efgartigimod (70%) than placebo group (43%) had prior thymectomy, and the proportion of patients who were MG-ADL responders was lower in patients with previous thymectomy. An increased prevalence of thymectomy in the efgartigimod group did not appear to favor efgartigimod, Howard and colleagues said.

Any adverse event was seen in 77% of the efgartigimod group and 84% of the placebo group. The most common was any infection (46% and 37%, respectively), with upper respiratory infection occurring in 11% and 5%, and urinary tract infection in 10% and 5%. Headache (29% and 28%) and nasopharyngitis (12% and 18%) also were common.

“The rate of infections is of special interest because patients with myasthenia gravis are predisposed to infections, probably exacerbated by concomitant immunosuppressive treatments,” Howard and colleagues observed. “Most infections were mild to moderate, with only two graded as severe in the efgartigimod-treated patients. Although longer term data are required to assess the risk of infection, these results are reassuring.”

“Additionally, the action of efgartigimod is selective, with transient and incomplete reduction of IgG and no effect on other immunoglobulins,” they added. “Efgartigimod-treated patients should retain the potential to mount an IgG immune response.”

“Several additional complement inhibitors and FcRn antagonists have entered phase III clinical trials,” Suzuki noted. “The therapeutic landscape for the management of patients with myasthenia gravis is expanding year by year.”

Study limitations include a relatively short follow-up period. An open label extension study, ADAPT+, is ongoing.

  1. Efgartigimod, an investigational antibody fragment engineered to reduce pathogenic immunoglobulin (IgG) auto-antibodies, showed benefit in patients with generalized myasthenia gravis (MG) and was well tolerated, the phase III ADAPT study found.

  2. The therapeutic landscape for the management of myasthenia gravis is expanding, with more new agents entering phase III trials.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was funded by argenx.

Howard has received research support from Alexion Pharmaceuticals, argenx, the CDC, the Muscular Dystrophy Association, the NIH, Patient Centered Outcomes Research Institute, and Ra Pharmaceuticals (now UCB); honoraria from Alexion Pharmaceuticals, argenx, Immunovant, Ra Pharmaceuticals (now UCB), Regeneron Pharmaceuticals, and Viela Bio; and non-financial support from Alexion Pharmaceuticals, argenx, Ra Pharmaceuticals (now UCB), and Toleranzia.

Suzuki reported receiving speakers’ fees from Alexion Pharmaceuticals, the Japan Blood Products Organization, and Asahi Kasei Medical, and has participated on advisory board meetings of Alexion Pharmaceuticals.

Cat ID: 130

Topic ID: 82,130,730,130,192,925