Safety, Tolerability, Pharmacokinetics, and Immunogenicity of a BTLA Agonist Antibody (Venanprubart) in Healthy Participants, Patients with Systemic Lupus Erythematosus, and Patients with Psoriasis: Results From Three Phase 1 Studies.

Venanprubart (LY3361237), an agonist antibody to B and T lymphocyte attenuator (BTLA), was developed as a potential treatment for autoimmune disorders, including systemic lupus erythematosus (SLE) and psoriasis. We tested venanprubart in three human Phase 1 safety studies: a single ascending dose (SAD) study in healthy participants (1/2/5/15/50/150 mg subcutaneously, or 150/400 mg intravenously; n = 64), a multiple ascending dose study in patients with SLE (six doses every 2 weeks at 50/150/450 mg subcutaneously; n = 28), and a randomized controlled study in patients with psoriasis (six doses every 2 weeks at 450 mg subcutaneously; n = 24). Key endpoints across studies included safety and tolerability, pharmacokinetics, receptor occupancy of BTLA on B cells, CD4+ T cells, CD8+ T cells, and immunogenicity as measured by treatment-emergent anti-drug antibodies (TE ADA). Venanprubart was well tolerated in healthy participants and in patients with SLE and psoriasis. No participants discontinued treatment due to adverse events, and nearly all treatment-emergent events were mild or moderate. The pharmacokinetic profile of venanprubart was nonlinear. Serum concentrations of venanprubart increased greater than dose proportionally at lower doses, but exposure became more linear after target binding was nearly saturated. Higher doses led to high levels of receptor occupancy on B cells, CD4+, and CD8+ T cells, indicating a high level of target engagement. Irrespective of titer, TE ADA incidence was 79%, 71%, and 71% for healthy participants, patients with SLE, and patients with psoriasis, respectively. ADA titers were lower in the repeat-dose studies compared to the SAD study, especially at higher doses.