Subcutaneous Efgartigimod Demonstrates Efficacy, Safety in Seronegative Myasthenia Gravis

Ratna Bhavaraju-Sanka, MD

A newly presented analysis of the phase 3 ADAPT-SC study (NCT04818671) revealed that treatment with subcutaneous efgartigimod PH20 (Vyvgart Hytrulo; Argenx) was safe and efficacious in patients with seronegative generalized myasthenia gravis (gMG). Seronegative gMG, which makes up about 5-10% of all patients, has been typically left out of the drug development world because of their small population size and unclear diagnostic criteria.¹

Presented at the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, held October 15-18, in Savannah, Georgia, the analysis included 184 participants rolled over from ADAPT-SC (n = 105) and ADAPT+ (n = 79), the original phase 3 trial. Of the 179 patients receiving at least 1 dose of subcutaneous efgartigimod in ADAPT-SC+ through December 2022, 38 were anti-acetylcholine receptor antibody negative (AChR-Ab-). Of these group, 84.9% of participants had at least 1 adverse event (AE), which were mostly mild/moderate in nature.

Led by Ratna Bhavaraju-Sanka, MD, the John H. Doran Endowed Chair in Peripheral Neuropathy at The University of Texas Health, the most commonly reported AEs in seronegative patients were injection site erythema, COVID-19, and headache. Additionally, injection site reactions were mild/moderate, did not lead to treatment discontinuation, and decreased in incidence with subsequent cycles. Overall, the safety profile in this patient population was similar to the one observed in the study’s original cohort, as injections site reactions were the most frequent AE, resolving over time.

In the analysis, AChR-Ab- participants demonstrated improvements in Myasthenia Gravis-Activities of Daily Living (MG-ADL), the study’s primary end point, and Myasthenia Gravis Quality of Life 15-item Questionnaire (MG-QoL 15r) at week 1 of cycle 1. Specifically, patients demonstrated mean changes of –3.6 (SE, 0.49) and –3.5 (SE, 0.81) in these respective assessment outcomes. These consistent improvements were observed through 9 cycles of treatment with subcutaneous efgartigimod.

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Efgartigimod was originally FDA-approved in an intravenous formulation in December 2021 using results from ADAPT as the basis for the decision. Years later, in 2023, the agency approved the subcutaneous formulation of the therapy, marketed as Vyvgart Hytrulo.² This optimized route is coformulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme's ENHANZE drug delivery technology, which allows for subcutaneous delivery of biologics that are typically administered via infusion. It was approved in a 1000-mg fixed dose administered over 30 to 90 seconds in cycles of once-weekly injections for 4 weeks.

An interim analysis of ADAPT-SC+ presented at AANEM 2023 showed that patients with seropositive gMG demonstrated improvements in daily function through efgartigimod. The analysis featured 164 patients who received at least 1 dose of the therapy, with an average of approximately equal to 3 treatment cycles over a mean study duration of 170 days, resulting in 72 patient-years of observation. In the first cycle, at week 4, investigators recorded a –4.0 (SE, 0.25) reduction in MG-ADL total score from cycle baseline.³

Similar to the newly presented analysis, the AEs observed in the 2023 analysis of efgartigimod were predominantly mild or moderate. The most common AEs included injection site erythema (25.6%), headache (15.2%), and COVID-19 (11.6%). Patients who had site reactions were also mild or moderate in severity, did not lead to any discontinuation of treatment, and reduced in the incidence of subsequent cycles.

In the original ADAPT-SC study, subcutaneous formulation of efgartigimod was associated with a mean total reduction in IgG of 66.4% at day 29 compared with 62.2% with the IV formulation (P <.0001 for noninferiority). These results were consistent across the overall study cohort and were no different between patients with or without AChR antibodies. Supplementary key secondary end points were also met, and were consistent with the efficacy results observed in ADAPT. On MG-ADL scores, 69.1% of those treated with the subcutaneous form were deemed responders, having at least a 2-point improvement for 4 consecutive weeks.⁴

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REFERENCES
1. Bhavaraju-Sanka R, Howard JF, Vu T, et al. Long-term safety and efficacy of efgartigimod PH20 SC in generalized myasthenia gravis: interim analysis of anti-acetylcholine receptor antibody seronegative participants in ADAPT-SC+. Presented at: 2024 AANEM Annual Meeting; October 15-18; Savannah, GA. Abstract 144.
2. argenx Announces U.S. Food and Drug Administration Approval of VYVGART Hytrulo (efgartigimod alfa and hyaluronidase-qvfc) Injection for Subcutaneous Use in Generalized Myasthenia Gravis. News release. Argenx. June 20, 2023. Accessed November 20, 2024. https://www.globenewswire.com/news-release/2023/06/20/2691658/0/en/argenx-Announces-U-S-Food-and-Drug-Administration-Approval-of-VYVGART-Hytrulo-efgartigimod-alfa-and-hyaluronidase-qvfc-Injection-for-Subcutaneous-Use-in-Generalized-Myasthenia-Grav.html
3. Li Y, Howard JF Jr, Li G, et al. Long-Term Safety, Tolerability, and Efficacy of Subcutaneous Efgartigimod PH20 in Patients With Generalized Myasthenia Gravis: Interim Results of the ADAPT-SC+ Study. Presented at: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting; November 1-4, 2023; Phoenix, AZ. Abstract 222.
4. Argenx Announces Positive Topline Phase 3 Data From ADAPT-SC Study Evaluating Subcutaneous Efgartigimod for Generalized Myasthenia Gravis. News release. March 22, 2022. Accessed November 20, 2024. https://www.argenx.com/news/argenx-announces-positive-topline-phase-3-data-adapt-sc-study-evaluating-subcutaneous