SBT-272, a novel small molecule in development for treating mitochondrial dysfunction in neurodegenerative diseases, preferentially associates with membranes rich in cardiolipin. Cardiolipin is the inner mitochondria membrane (IMM) phospholipid responsible for the structural integrity of the IMM folds, or cristae, harboring protein complexes of the electron transport chain (ETC) and are essential for oxidative phosphorylation and ATP generation. SBT-272 data includes non-clinical/Phase 1 clinical trial data.
SBT-272’s activity was established by assaying restoration of mitochondrial function invitro in rat cardiac cells, post anoxia reoxygenation, and invivo in rat kidney after ischemia-reperfusion. In an experimental stroke model using rat brains, SBT-272 restored mitochondrial respiratory-control ratio after endotoxin-1 stereotactic injection. Pharmacokinetics in mice indicate a favorable exposure profile, i.e., 10nM to 100nM trough level concentrations in brain homogenates after five single daily-subcutaneous doses of 1, 5 and 7.5mg/kg/day, doses producing therapeutic benefit in various mouse ALS models.
Despite a short plasma elimination half-life in rats (≤3hr, 4600ng/mL Cmax, and 11ng/mL C24h after a 10mg/kg dose), SBT-272 brain levels are maintained (201ng/g Cmax and 136ng/g C24hr in the same animals), supporting once-daily dosing; also evident from CSF measurements of SBT-272. CSF:plasma ratios in rats/monkeys increase ~100-fold over 24hours (final ratios 0.55 and 0.23, respectively). We present plasma, CSF, and brain homogenate pharmacokinetic results from non-clinical studies using single doses, and chronic dosing steady state. Emerging clinical plasma pharmacokinetic data are consistent with non-clinical species at allometrically-scaled doses. Plasma exposures observed in the Phase 1 study (doses deemed generally safe and well tolerated), are anticipated to result in therapeutic concentrations in the brain based on the observed relationship between plasma and brain pharmacokinetic in the rodent. Non-clinical brain-specific translational pharmacology and efficacy in preclinical models, along with results of human plasma pharmacokinetics, encourage the further development of SBT-272 as a treatment for ALS.