A randomized, double-blind, placebo controlled, phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of LB-102, a selective dopamine D2/3/5-HT7 inhibitor.

LB-102 is an N-methylated analogue of amisulpride under development to treat schizophrenia. LB-102 was evaluated in a Phase 1, double-blind, placebo-controlled, clinical study to evaluate safety and pharmacokinetics. This was a first-in-human study examining single and multiple doses of LB-102 administered orally in 64 healthy volunteers. Dosing in the single ascending dose (SAD) portion of the study was initially planned to be 50, 100, 200, and 400 mg, with doses in the multiple ascending dose (MAD) portion to be determined based on observations in the SAD portion. As a result of two cases of EPS (acute dystonia) at 200 mg in the MAD portion of the study, dosing of that arm was discontinued and doses for the remaining cohort were decreased to 150 mg/day. Dose escalation was guided by safety and plasma concentrations of LB-102 compared to a translational model. LB-102 was generally safe and well-tolerated, and clinical lab values were unremarkable at all doses, save for prolactin which was transiently elevated in the majority of subjects treated with LB-102; there were no clinical observations associated with the increases in prolactin elevation. There was evidence of transient QT interval prolongation at the 200 mg dose, none of which resulted in clinical observation or triggered stopping criteria. There were four instances of EPS (acute dystonia), typically associated with dopamine receptor occupancy in excess of 80%, one at 100 mg QD, one at 75 mg BID, and two at 100 mg BID. A phase 2 clinical study of LB-102 in schizophrenia patients with PANSS as primary endpoint is being planned.

Antipsychotic Benzamides Amisulpride and LB-102 Display Polypharmacy as Racemates, S Enantiomers Engage Receptors D2 and D3, while R Enantiomers Engage 5-HT7.

Benzamide antipsychotics such as amisulpride are dosed as racemates though efficacy is assumed to be mediated through S enantiomer binding to D2 receptors. At prescribed doses, the benzamides likely display polypharmacy since brain exposure should be sufficient to engage the 5-HT7 receptors, as well. Curiously, the studies herein reveal that racemic dosing is required to engage both targets since the D2 receptor has an almost 40-fold selectivity for the S enantiomer, while the 5-HT7 receptor has greater than 50-fold preference for the R enantiomer.

Fosmetpantotenate (RE-024), a phosphopantothenate replacement therapy for pantothenate kinase-associated neurodegeneration: Mechanism of action and efficacy in nonclinical models.

In cells, phosphorylation of pantothenic acid to generate phosphopantothenic acid by the pantothenate kinase enzymes is the first step in coenzyme A synthesis. Pantothenate kinase 2, the isoform localized in neuronal cell mitochondria, is dysfunctional in patients with pantothenate kinase-associated neurodegeneration. Fosmetpantotenate is a phosphopantothenic acid prodrug in clinical development for treatment of pantothenate kinase-associated neurodegeneration, which aims to replenish phosphopantothenic acid in patients. Fosmetpantotenate restored coenzyme A in short-hairpin RNA pantothenate kinase 2 gene-silenced neuroblastoma cells and was permeable in a blood-brain barrier model. The rate of fosmetpantotenate metabolism in blood is species-dependent. Following up to 700 mg/kg orally, blood exposure to fosmetpantotenate was negligible in rat and mouse, but measurable in monkey. Consistent with the difference in whole blood half-life, fosmetpantotenate dosed orally was found in the brains of the monkey (striatal dialysate) but was absent in mice. Following administration of isotopically labeled-fosmetpantotenate to mice, ~40% of liver coenzyme A (after 500 mg/kg orally) and ~50% of brain coenzyme A (after 125 µg intrastriatally) originated from isotopically labeled-fosmetpantotenate. Additionally, 10-day dosing of isotopically labeled-fosmetpantotenate, 12.5 µg, intracerebroventricularly in mice led to ~30% of brain coenzyme A containing the stable isotopic labels. This work supports the hypothesis that fosmetpantotenate acts to replace reduced phosphopantothenic acid in pantothenate kinase 2-deficient tissues.