ORF49-05 - Results from a Phase 1b Trial Evaluating CD40-Ligand Blocker Lu AG22515 in Patients with Moderate-to-Severe Thyroid Eye Disease

Background: Thyroid eye disease (TED) is an autoimmune disorder characterized by inflammation and proliferation of orbital tissue causing proptosis, diplopia, pain, and disfigurement, and can result in disordered visual function or loss of vision. Current treatments are not fully effective and are associated with severe adverse effects. Lu AG22515, a novel anti-CD40L immunomodulator targeting the CD40/CD40L pathway, has demonstrated pharmacological modulation of proximate autoimmune drivers and is currently in clinical development for TED.

Objective: To evaluate the efficacy, safety, and pharmacodynamics (PD) of Lu AG22515 in patients with TED.

Methods: This ongoing, open-label, single-arm phase 1b trial (NCT06557850) enrolled adults with active moderate-to-severe TED (proptosis ≥3 mm above normative values; clinical activity score (CAS) ≥3; symptom onset < 12 months). During the treatment period, participants receive intravenous Lu AG22515 for 24 weeks followed by 28 weeks of safety monitoring. The primary efficacy endpoint is the change from baseline (CfB) of proptosis, measured by Hertel exophthalmometry. Other efficacy endpoints included CfB in CAS and diplopia (assessed by the Gorman Score). PD assessments include thyroid-stimulating hormone receptor autoantibody (TSH-R-Ab) levels. Safety is being monitored including collection of adverse events. Statistical analysis was performed using a mixed model for repeated measures of the primary endpoint and descriptive statistics were used for the remaining endpoints.

Results: Interim data was based on 15 participants, of whom 6 have completed 24 weeks of Lu AG22515 treatment. In the trial eye, the estimated mean CfB in Hertel-determined proptosis was –2.06 mm at Week 24. The absolute mean CfB in the CAS score at Week 24 was –3.8 (n=6). All the 6 completers had a Gorman score ≥1 at baseline, of these 33% demonstrated ≥1 grade improvement in diplopia. The geometric mean ratio of post-baseline to baseline TSH-R-Ab was reduced by an estimated 45% at Week 24. No clinically relevant safety trends were observed.

Conclusion: Interim analyses demonstrated clinically meaningful reduction in proptosis and pharmacodynamic response to Lu AG22515 in patients with moderate-to-severe, active TED. These data support the therapeutic potential of Lu AG22515 and the CD40/CD40L pathway as a novel therapeutic target for TED. Final efficacy, PK/PD, and partial safety results from the ongoing trial will be available and presented at ENDO 2026.