TL-925, a First-in-Class, Topical, Bruton’s Tyrosine Kinase Inhibitor (BTKi) in Subjects (Subjs) with Moderate to Severe Dry Eye Disease (DED)

Abstract

Purpose : DED, a chronic inflammatory disorder of the lacrimal unit, causes ocular discomfort, pain, and visual disturbances. Mast cells (MCs), found in the lacrimal functional unit, are key initiators and amplifiers of the inflammatory cascade. Our novel approach to treating DED targets BTK, critical for MC activation and immune response. TL-925 (925), an ocular formulation of the potent, irreversible BTKi TL-895, aims to prevent MC degranulation, block the inflammatory response, and restore lacrimal unit homeostasis, offering the potential for disease modification.

Methods : This phase 2, multicenter, randomized, double-masked, vehicle-controlled study evaluated 925 in subjs with DED using the Ora Controlled Adverse Environment (CAE) Challenge Model. After a 2-week, single-masked vehicle (Veh) run-in, subjs were randomized 1:1 to receive 925 or Veh bilaterally twice daily for 28 days. The primary and secondary objectives were safety and efficacy (signs and symptoms by an intention-to-treat analysis [pre/post CAE]), respectively.

Results : The study randomized 107 subjs across two arms well matched and representative of a DED population. The most common treatment-emergent adverse event was instillation site irritation. Other safety assessments were unremarkable. On Day 15, mean drop comfort score was 2.6 (Scale: 0-10) in both arms two minutes after instillation.

After 28 days, 925 significantly improved the signs of DED, including fluorescein staining central (p=0.01) and total corneal sum (p=0.034). Positive trends were seen in inferior (p=0.053) and total sum regions (p=0.077). Schirmer’s responders (≥10mm) were higher with 925 vs Veh in both Study and Fellow Eye (13.2% vs 5.6% and 13.2% vs 3.7%, respectively). 925 also significantly improved the symptoms of DED, including Pain (visual analog scale; p=0.014), Dryness (Ora Ocular Discomfort 4-symptom Questionnaire [OD4SQ] p=0.026), Burning (OD4SQ; p=0.034), and trended positively on the Ora Ocular Discomfort Scale (p=0.052).

Conclusions : The consistency of results across ocular regions, rapid onset of improvements in signs and symptoms, confirmation in different settings (pre/post CAE), and novel therapeutic approach underscore the promise of 925 as a safe, well-tolerated, effective treatment for DED, with disease-modifying potential.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Table 1: Ocular Events Safety Population

 

Table 2: Efficacy Results ITT