Maximal and sustained TYK2 inhibition: The key to higher efficacy with oral allosteric inhibitors

Summary: Abstract Body: ESK-001 is a highly selective allosteric TYK2 inhibitor targeting inflammatory cytokine pathways involved in diseases like psoriasis. This study examines whether sustained ESK-001 exposure to achieve maximal TYK2 inhibition impacts clinical efficacy outcomes. Pharmacokinetic (PK) and PD data, including IFNα-induced pSTATs, were collected from Phase 1 healthy volunteers and Phase 2 psoriasis patients. Efficacy data (PASI score) and biomarker data (TYK2-responsive SIGLEC1) were obtained from Phase 2 and Open-Label Extension studies. Data were analyzed for 40 mg QD and 40 mg BID dosing regimens, evaluating the relationship between pSTAT inhibition, SIGLEC1 suppression, and clinical efficacy. ESK-001 demonstrated a strong correlation between exposure and efficacy. At week 12, PASI 75 and PASI 90 responses for the 40 mg BID dose were 14% and 50% higher, respectively, than those for the 40 mg QD dose. Similar efficacy differences were observed during the Open-Label Extension as well. The 40 mg BID dose maintained >24-hour IC90 coverage for IL-12/IL-23 and IFNα pathways. RNA-seq analysis confirmed maximal inhibition of the type I IFN signature and the TYK2 biomarker SIGLEC1 in both Phase 1 healthy subjects and Phase 2 psoriasis patients. The 40 mg BID dose of ESK-001 achieved >24-hour IC90 coverage and complete SIGLEC1 suppression in patients, suggesting that maximal inhibition results in higher efficacy. These findings support 40 mg BID as the optimal regimen for treating psoriasis. Sibel Ucpinar², Joyce K. Kwan³, Mera K. Tilley³, Nicole Narayan³, Roman G. Rubio¹, Philip A. Nunn⁴, Claire L. Langrish³ 1. Clinical Science, Alumis, South San Fransisco, CA, United States. 2. Clinical Pharmacology and DMPK, Alumis, South San Fransisco, CA, United States. 3. Translational Science, Alumis, South San Fransisco, CA, United States. 4. Early Clinical Development, Alumis, South San Fransisco, CA, United States. Clinical Research: Interventional Research