SUN-328 - Phase 3 Randomized-Controlled Trials Evaluating Efficacy and Safety of Subcutaneous Efgartigimod PH20 using Pre-Filled Syringes in Patients with Graves' Disease Inadequately Controlled with Antithyroid Drugs: Trials in Progress

Graves’ disease (GD) is an IgG-mediated autoimmune disease with debilitating symptoms and multiorgan complications that impair daily function and significantly diminish patient quality of life (QoL). In GD, thyroid-stimulating hormone receptor IgG antibodies (TSHR-Abs) chronically stimulate TSHR, causing hyperthyroidism which can impact multiple organ systems (ie, cardiovascular, metabolic, gastrointestinal) and cause significant morbidity. The main extrathyroidal manifestation of GD is Graves’ orbitopathy/thyroid eye disease (GO/TED). Preferred treatment is antithyroid drugs (ATD), but only 50% of patients adequately respond and relapse can frequently occur. There remains a significant unmet need for therapies targeting the underlying GD pathophysiology. Efgartigimod (EFG) is a human IgG1 antibody Fc fragment that selectively reduces IgG by blocking neonatal Fc receptor (FcRn)-mediated IgG recycling. Based on the underlying pathophysiology of GD and the extensive clinical data supporting use of EFG in other IgG-mediated autoimmune diseases, our hypothesis is that EFG may provide therapeutic value for GD patients.
Two identical parallel phase 3 studies will enroll participants with active GD and suppressed TSH after ≥3 months of ATD treatment prior to the screening period (≤5 weeks). In the first stage, ~230 participants will be randomized 2:1 to receive weekly subcutaneous (SC) EFG PH20 (coformulated with recombinant human hyaluronidase PH20 [rHuPH20]) 1000 mg administered via pre-filled syringe (PFS) or placebo PH20 SC PFS for a 24-week double-blinded period. During this stage, the primary objective is to evaluate the ability to achieve euthyroidism and to stop ATD treatment. Thereafter, participants will enter another 24-week treatment period, dependent on their clinical response at Week 24. The study will conclude with an 8-week safety follow-up after the final administration.
The primary endpoint will be the percentage of participants who are euthyroid and off ATDs at Week 24. Key secondary efficacy endpoints include time to becoming euthyroid off ATDs by Week 24, and the percentage of participants who are euthyroid off ATDs and TSHR-Ab seronegative at Week 24. Other secondary efficacy objectives include durability of response, ability to induce remission, and impact on health-related QoL and patient-reported outcome measures. Safety and tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of the EFG PH20 SC PFS will also be assessed. Exploratory objectives will include efficacy in preventing development or worsening of GO/TED, ability to reduce TSHR-Ab levels, and effect of retreatment with EFG after loss of euthyroidism upon ATD discontinuation.
These parallel trials will investigate the efficacy and safety of EFG PH20 SC PFS in adults with GD and explore its potential to target the pathogenic IgG antibodies underlying GD pathophysiology.

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