Potential First-in-Class, Targeted Therapy for Myasthenia Gravis

Megan Brooks

June 17, 2021

Efgartigimod (argenx) is an effective and well-tolerated therapy for patients with generalized myasthenia gravis (gMG), new research suggests.

Results from the phase 3, randomized, placebo-controlled ADAPT trial showed that reduction in disease burden and improvement in strength and quality of life in patients with gMG were consistent across four MG-specific scales for those receiving the novel treatment.

In addition, these benefits were observed early and were reproducible and durable, the researchers note.

Efgartigimod is a "very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work; and the side effect profile is much like placebo," principal investigator James Howard, Jr, MD, Department of Neurology, University of North Carolina at Chapel Hill, told Medscape Medical News.

The ADAPT results are "important for the MG community and I am hopeful efgartigimod will provide a first-in-class targeted therapy that can be dosed in an individual way for people living with this chronic autoimmune disease," Howard added in a news release.

The findings were published online June 17 in Lancet Neurology.

Targeted Molecular Therapy

The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have immunoglobulin G (IgG) antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.

Efgartigimod is an investigational antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.

The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.

The ADAPT trial was conducted at 56 neuromuscular academic and community centers in 15 countries in North America, Europe, and Japan.

The study included 167 adults with gMG, regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (> 50% non-ocular) on a background of a stable dose of at least one MG drug.

For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as 4 infusions per cycle at 1 infusion per week. The process was repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.

ADAPT was designed to allow an individualized treatment approach with an initial treatment cycle followed by a variable number of subsequent treatment cycles, the investigators note.

Primary Endpoint Met

The primary efficacy endpoint was number of acetylcholine receptor antibody-positive (AChR-Ab+) patients who achieved a clinically meaningful response on the MG-ADL score. This was defined as at least a 2-point improvement from baseline for 4 or more consecutive weeks.

Forty-four (68%) of 65 AChR-Ab+ patients treated with efgartigimod met this endpoint versus 19 (30%) of 64 patients treated with placebo (odds ratio [OR], 4.95; 95% CI 2.21 - 11.53; P < .0001).

Many of the patients treated with efgartigimod showed improvement "beyond the clinically meaningful threshold, achieving up to 9-point reductions in MG-ADL," the investigators report.

In addition, 40% of the efgartigimod group attained an MG-ADL score of 0 or 1 (minimal symptom expression) in cycle 1 versus 11% of the placebo group (P < .0001).

Nearly two thirds (63%) of AChR-Ab+ patients responded to the first cycle of efgartigimod and most of these patients (83%) responded to treatment within the first 2 weeks.

Among the AChR-Ab+ participants who responded to efgartigimod in cycle 1, the duration of responder status was 6 to 7 weeks in 32% of patients, 8 to 11 weeks in 23% of patients, and 12 weeks or more in 34% of patients. 

Safety Profile

"Some patients never required retreatment over the 26-week period that they were under observation," Howard said.

"Patients want to be individuals. They don't want to be assigned to a regimented therapy and I think these results show that this therapy can be tailored to the individual patient, rather than simply giving it to them in a cookbook fashion," he added.

The safety profile of efgartigimod was comparable to placebo. Most adverse events were mild or moderate in severity. The most commonly reported adverse events were headache, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, and urinary tract infection. 

Four (5%) efgartigimod-treated patients had a serious adverse event, which included thrombocytosis, rectal adenocarcinoma, worsening MG, and depression.

The novel agent is currently under review with the US Food and Drug Administration (FDA) for the treatment of gMG, with a Prescription Drug User Fee Act target action date of December 17. If approved, it would become the first FDA-approved FcRn antagonist.

Expanding Therapeutic Landscape

In a linked commentary, Shigeaki Suzuki, MD, PhD, Department of Neurology, Keio University School of Medicine, Tokyo, Japan, notes that the therapeutic landscape for patients with MG is "expanding year by year," with several additional complement inhibitors and FcRn antagonists now in phase 3 testing.

"Biological drugs should be preferentially used as the treatment for patients with refractory myasthenia gravis, although the definition of refractory myasthenia gravis is different depending on the criteria used," Suzuki writes.

He noted that when "cost-effectiveness is not taken into account, targeted molecular therapy might be used widely" in patients with MG.

"Risks of myasthenic exacerbation and crises should be substantially decreased, particularly in patients with refractory myasthenia gravis," Suzuki adds.

The ADAPT study was supported by argenx. Howard has reported receiving research support from argenx, Alexion Pharmaceuticals, the Centers for Disease Control and Prevention, the Muscular Dystrophy Association, the National Institutes of Health, Patient-Centered Outcomes Research Institute, and Ra Pharmaceuticals; honoraria from argenx, Alexion, Immunovant, Ra, Regeneron Pharmaceuticals, and Viela Bio; and nonfinancial support from argenx, Alexion, Ra, and Toleranzia. Disclosures for the other investigators are listed in the original article. Suzuki has reported relationships with Alexion Pharmaceuticals, Japan Blood Products Organization, and Asahi Kasei Medical.

Lancet Neurol. Published online June 17, 2021. Article, Commentary

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