Tropomyosin-Related Kinase Receptor Type B Agonism in Geographic Atrophy-The Translational Challenges from Preclinical Data to a First-in-Human Trial.

Objective: To report results of the first-in-human trial of intravitreal tropomyosin-related kinase receptor type B (TrkB) agonist BI 754132 in participants with geographic atrophy (GA). To discuss BI 754132 clinical data in the context of the preclinical findings and their translation into human data. Design: An open-label, uncontrolled, nonrandomized phase I trial (NCT04002310) assessing the safety, tolerability, and pharmacokinetics of BI 754132 in participants with GA supported by preclinical data. Participants: Participants with GA recruited between July 2019 and August 2022 in the United States and UK. Methods: Clinical trial comprising a single rising dose (SRD) part (n = 15) and multiple dose (MD) part (n = 3). Of 18 participants treated, 16 received a single dose of BI 754132 0.3 to 6 mg (SRD, n = 15; MD, n = 1) and 2 received 3 doses each of BI 754132 6 mg (MD part). Main Outcome Measures: The primary SRD endpoint was the incidence of ocular and systemic dose-limiting events until day 100; the primary MD endpoint was treatment-related adverse events (AEs) until day 155. Exploratory endpoints included change from baseline in best-corrected visual acuity (BCVA), GA lesion area, central retinal thickness, and selected electroretinogram parameters. Results: Preclinical data supported a potential treatment effect and a favorable safety profile of BI 754132, supporting clinical development. In the phase I study (SRD and MD parts), 12 of 18 (67%) participants had an AE; of which, 4 had ischemic optic neuropathy in the study eye. Considering the frequency of ischemic optic neuropathy in the absence of efficacy data, the benefit-risk assessment of BI 754132 could not be considered as positive, and the clinical study was terminated. There was a mild increase in central retinal thickness (≤25 μm) of all study eyes. No relevant changes in BCVA, GA lesion area, or electroretinogram parameters were noted. Conclusions: Clinical data suggested a potential association between BI 754132 and development of ischemic optic neuropathy. Although the underlying mechanisms remain unclear, these data warrant caution during further exploration of TrkB agonism in GA and highlight the role of monitoring safety data during early clinical development, especially when studying new modes of action. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.