(W-022) Simulations to Inform Dose Selection for a Phase 2b Trial Investigating TOUR006, a Fully Human Anti-IL6 Antibody, for Treatment of Thyroid Eye Disease

Kristine Erickson, OD, PhD – Vice President and TA Head, Opthalmology, Tourmaline Bio; Craig Comisar, PhD – Senior Director, Integrated Drug Development, Certara; Stuart Seiff, MD – Professor Emeritus, Opthalmology, University of California San Francisco; Yung Chyung, MD – Chief Medical Officer, Tourmaline Bio; Ryan Iarrobino, BA – Senior Vice President, Product Development, Tourmaline Bio; Emil DeGoma, MD – Senior Vice President, Medical Research, Tourmaline Bio; Paul Martin, PhD – Senior Director, Integrated Drug Development, Certara

Objectives: Thyroid eye disease (TED) is an autoimmune disease in which the eye muscles and fatty tissue behind the eye become inflamed leading to bulging of eyes. Due to the key role of Interleukin 6 (IL-6) in the pathogenesis of TED, IL-6 inhibition has been used off label as a treatment. TOUR006 (previously known as PF-04236921) is a selective fully human IgG2 mAb that binds IL-6 with high affinity. It has been dosed in >400 subjects to date. We predicted effective dosing regimens of TOUR006 for TED, using a population PK/PD model of C-reactive protein (CRP), a marker of IL-6 pathway activity.

Methods: A PK and PK/PD (CRP) model for TOUR006 was developed by Li et. al, based on 5 clinical studies conducted with PF-04236921 in healthy volunteers and patients with autoimmune conditions other than TED [1]. Serum CRP, widely used as a surrogate for IL-6 pathway activity was selected as a biomarker. Several combinations of dosing frequencies (q4w or q8w) and dose levels (10 to 50 mg) were evaluated. Simulations were used to identify optimal subcutaneous (SC) dosing scenarios targeting ≥90% CRP suppression from baseline or < 2 mg/L for the virtual TED population assuming modeled inflammatory behavior similar to rheumatoid arthritis. Any simulated subject with a CRP level less than 2 mg/L was set to 90% CRP reduction for analysis purposes. The simulations were performed by sampling the participants from a subpopulation with baseline serum CRP of >2 mg/L to 10 mg/L, comparable to most TED patients. Sensitivity analysis was performed to estimate response for population with higher bodyweight.

Results: Simulations predict that a dosing schedule of 20 mg SC q8w and 50 mg SC q8w will result in ≥90% CRP suppression (or < 2 mg/L) in most virtual participants with TED. Further, the 20 mg q8w regimen may achieve the targeted efficacy in participants with moderate levels of IL-6 pathway activation (baseline CRP of 2 to 10 mg/L), while the 50 mg q8w regimen may be needed if IL-6 pathway activation is greater in TED or there are participants with relatively higher levels of IL-6-driven inflammation. Additionally, fixed subcutaneous dosing for TOUR006 without weight-based adjustment was found to be appropriate.

Conclusion: The simulations for 20 mg and 50 mg q8w of SC TOUR006 predict that these doses/regimens are likely to target ≥90% CRP suppression from baseline in most TED subjects, thus producing a robust therapeutic effect.

Citations: [1] Li C, et al. Pharmacokinetics and C-reactive protein modelling of anti-interleukin-6 antibody (PF-04236921) in healthy volunteers and patients with autoimmune disease. Br J Clin Pharmacol (2018) 84;2059–2074.