ERM-123 is an orally bioavailable bi-specific RBP4 inhibitor that stabilizes TTR similarly to Tafamidis

Abstract

Purpose : Orally bioavailable inhibitors of Retinol Binding Protein 4 (RBP4) are promising therapeutics for atrophic age-related macular degeneration (dAMD) and Stargardt Disease (STGD1), but it has not been determined whether disrupting the RBP4/TTR complex leads to increased TTR aggregation and TTR amyloidosis. We determined whether a bi-specific RBP4 inhibitor / TTR stabilizer could stabilize human TTR to a similar extent as Tafamidis, an approved TTR stabilizer for treatment of cardiomyopathy caused by TTR amyloidosis. We find that daily oral dosing of ERM-123 reduces both circulating RBP4 and retinal bisretinoid accumulation in an ABCA4-/- genetic mouse model of STDG1. Further, we see comparable stabilization of TTR by both ERM-123 and Tafamidis in an in vitro assay with human TTR present at a normal serum concentration.

Methods : TTR stabilization
Purified human TTR was incubated for 48h at pH4 with compounds as shown, and aggregation quantified by absorbance at 330 nm.

RBP4 inhibition
ABCA4-/- mice were dosed orally with ERM-001 and serum taken for RBP4 quantification by ELISA.

Bisretinoid accumulation
ABCA4-/0 mice were dosed orally q.d. with ERM-001 for 4 months, then retinas were pooled and the bisretinoid A2E levels were measured by LC-MS.

Results : ERM-123 stabilized TTR similarly to Tafamidis, significantly depleted circulating RBP4, and significantly reduced retinal bisretinoid A2E levels.

Conclusions : We conclude that bi-specific RBP4 inhibitors that also stabilize TTR hold promise to treat dAMD and STGD1 while also mitigating the risk of TTR amyloidosis.

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

 

Inhibition of TTR Aggregation. A) Purified human TTR was incubated at pH 4.0 for 48h with compounds as indicated, then protein aggregation was quantified at A330. B) Structures of ERM-123 (Bi-Specific), Tafamidis (TTR stabilizer), and Belite Bio Compound 1 (RBP4 inhibitor).

 

Effect of ERM-123 on RBP4 and bisretinoids in ABCA4-/- mice. ABCA4-/- mice were dosed with ERM-123 once per day by oral gavage with the indicated daily dose. A) After 4 weeks of dosing, serum samples were taken and RBP4 quantified by ELISA. B) After 12 weeks of dosing, A2E bisretinoid levels were quantified in eyecups. Mean +/- SEM is shown and statistical significance calculated as one-way ANOVA with Tukey’s multiple comparison post-test.