Dose Selection and Clinical Development of Efgartigimod PH20 Subcutaneous in Patients with Generalized Myasthenia Gravis
George Li1, Yuebing Li2, Tuan Vu3, Denis Korobko4, Marek Smilowski5, Li Liu6, Sophie Steeland6, Benjamin Van Hoorick6, Jana Podhorna6, Jenna Casey6, Jan Noukens7, Tonke Van Bragt7, Kimiaki Utsugisawa8, Heinz Wiendl9, Jan De Bleecker10, Renato Mantegazza11, James Howard12, in collaboration with the ADAPT-SC Investigator Study Group
1Medsol Clinical Research Center Inc, 2Cleveland Clinic, 3Department of Neurology, University of South Florida, Morsani College of Medicine, 4State Budgetary Healthcare Institution of Novosibirsk Region "State Novosibirsk Regional Clinical Hospital", 5Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, 6argenx, 7Curare Consulting BV, 8Department of Neurology, Hanamaki General Hospital, 9Department of Neurology, University of Münster, 10Ghent University Hospital, 11Department of Neuroimmunology and Neuromuscular Diseases, Fondazione Istituto Neurologico Carlo Besta, 12Department of Neurology, The University of North Carolina
Objective:

To confirm dose selection and rationale of using the reduction of total immunoglobulin G (IgG) levels as a pharmacodynamic (PD) marker of noninferiority for subcutaneous (SC) efgartigimod PH20 (coformulated with recombinant human hyaluronidase PH20).

Background:

Efgartigimod intravenous (IV) was evaluated in the phase 3 ADAPT study, where it demonstrated clinical efficacy and was well tolerated in patients with generalized myasthenia gravis (gMG). Based on the observed association between reductions in total IgG levels (including pathogenic autoantibodies) and improvement in MG-ADL in the phase 2 study, a population PK/PD approach was utilized for dose selection of efgartigimod PH20 SC, that would result in a similar PD effect as efgartigimod IV (10 mg/kg).

Design/Methods:

PK and PD data from a phase 1 study where healthy participants (n=32) received a single injection of efgartigimod PH20 SC at various fixed doses or 10 mg/kg, were used for the PK/PD analysis. Based on the model, simulations were performed for a typical participant of 70 kg for a dose range of 750-1750 mg (25 mg increments). The selected dose was subsequently evaluated in healthy participants and patients with gMG (ADAPT-SC study), as treatment cycles of 4 weekly injections.

Results:

The 1000 mg dose of efgartigimod PH20 SC was predicted to result in comparable reduction in total IgG on day 29, one week after the fourth injection, and was selected for evaluation in the ADAPT-SC study. Patients ranging in weight from 42.0 to 150.2 kg (median=78.3) received one treatment cycle of efgartigimod PH20 SC 1000 mg and achieved similar total IgG reductions as those treated with efgartigimod IV. These reductions were also associated with improvements in MG-ADL clinical outcome measure.

Conclusions:

ADAPT-SC study demonstrated that the dose selection was appropriate as treatment with efgartigimod PH20 SC 1000 mg resulted in noninferior reduction in total IgG to efgartigimod IV at day 29.

10.1212/WNL.0000000000203765