Next-generation ocular topical SBT-272 demonstrates optimized retina tissue exposure: building upon elamipretide for treating dry AMD

Abstract

Purpose : Advances in mitochondrial research have illuminated the development potential for mitochondria-targeted therapeutics like elamipretide and next-generation therapeutic SBT-272 for the treatment of age-related macular degeneration (AMD). We studied the optimized topical ocular pharmacokinetic (PK) profile of next-generation SBT-272, which retains the core functional characteristics of elamipretide and restores the structure and function of dysfunctional mitochondria in AMD.

Methods : Either ocular topical SBT-272 (various concentrations up to 2% BID in both eyes) or a single subcutaneous (SC) dose of elamipretide (1.5 mg/kg) were administered in male Dutch Belted rabbits (n=12/group). At 0.5, 1, 2, 4, 8, or 24 hrs post final dose, blood samples were collected and both eyes harvested following euthanasia (n=2). Plasma and eye tissue concentrations were analyzed by LC-MS/MS (lower limit of quantification=0.400 ng/mL). PK parameters were calculated using noncompartmental analysis (Phoenix WinNonlin).

Results : Both SBT-272 and elamipretide reached T_max at 2 hrs in retina tissue; however, SBT-272 reached ~4-6x higher concentrations (C_max=123±39.4 ng/g, AUC_0-last=1,840 ng*h/g vs C_max=30.8±12.5 ng/g, AUC_last=320 ng*h/g). Higher retina tissue concentrations were maintained through 24 hrs in SBT-272-treated rabbits compared to elamipretide (42.1±10.6 ng/g vs 11.4±5.17 ng/g). Systemic exposure was minimal with SBT-272 treatment compared to elamipretide (plasma C_max=9.23 ng/mL vs 672 ng/mL at 0.5 hrs) with both agents being below the LLOQ after 4 hrs. Overall, SBT-272 had enhanced retinal exposure and minimal plasma exposure compared to elamipretide.

Conclusions : Our in vivo results suggest that topical ocular SBT-272 has an advanced PK profile relative to SC elamipretide, with optimized delivery into retinal tissue resulting in increased retinal tissue concentrations while reducing systemic exposure. SBT-272 is a next-generation compound in development that follows the foundational studies and mechanism of action of SC elamipretide. Additional animal studies are ongoing, and the results will inform future development decisions. The optimized PK activity of SBT-272 could offer an advancement in the development of a topical therapeutic for dry AMD.

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