Discussion
axonal degeneration, death, neuronal hypertrophy, SAD
OXIDATIVE STRESS, ASSOCIATED DISEASE
The safety profile of OCS-05 in healthy subjects was favorable at the tested doses in the SAD and MAD parts of this study. With the exception of TEAEs that tended to be higher following placebo during the MAD, there were no other treatment or dose-related trends in safety parameters observed during either part of the study. Pharmacokinetic data for OCS-05 in the SAD and MAD parts of the study demonstrate that the CPreclinical pharmacokinetics studies of i.v. OCS-05 in rats and dogs have shown that a value of blood concentration (CThe doses in this study were chosen based on the human equivalent doses related to animal toxicology studies and based on the NOAEL. As such, we started with a dose × 10 under the NOAEL. The PK data indicate that Cmax is reached within approximately 2 h of single and 5-day multiple-dosing, occurring at or near the end of the 2 h OCS-05 infusion. The AUC%extrap (< 5%) indicates that the large majority of exposure was accounted for during the sampling period (to 24 h post-dose) following both single and multiple dosing. In the study, the t1/2 (geometric mean) ranged from 3.35 to 8.23 h across the 0.2–3.2 mg/kg OCS-05 dose range in Part A and 12.2 and 8.63 h for 2.4 and 3.0 mg/kg OCS-05 in Part B respectively. In both parts of the study, Vz (geometric mean) ranged from 120.0 (120,000 mL/kg) to 320.0 (320,000 mL/kg) L/kg in Part A and Vss (geometric mean) 60.2 (60,200 mL/kg) to 63.6 (63,600 mL/kg) L/kg in Part B, suggesting that OCS-05 is widely distributed to perfused tissues. This study has limitations such as not having collected cerebrospinal fluid samples for measuring OCS-05 concentrations after BBB crossing, not being able to reach the maximum Cmax planned because the AUC reached the stopping rule and not having validated biomarkers of target engagement and pharmacodynamics. Considering the PK profile from this study, the toxicology studies, and that OCS-05 is crossing the BBB by active transportation after IV infusion, we have determined that starting doses for the phase 2 trial being between 2–3 mg/kg (NCT04762017 and EUDRACT: 2020-003147-29). Regarding the mechanism of action of OCS-05 for promoting neuroprotection, we have previously shown that it activates SGK2Downstream effects of SGKs include the E3 ubiquitin ligase Nedd4-2, the FOXO3 and other kinases such as GSK-3B and NRDG1-2. In addition, SGKs regulates ion channels such as Epithelium ion channel (ENaC), CLC2, acid-sensing ion channel 1 (ASIC1), Kv1.3, Kv1.5, Kv4.3, ROMK1, TRVP5, CIC2, SCN5A, KCNE1/KCNQ1, KCNQ4, 4F2/LAT, GluR1 and GluR6, NHE3, as well as glucose transporters SGLT1, GLUT1, aminoacids transporter ASCT2, glutamate transporter EAAT1-5, CreaT, Na–K ATPaseSGK2 induces a broad spectrum of neurotrophic effects on neurons, including induction of neuronal hypertrophy, protection from neuron death and axonal degeneration and promoting axonal regenerationPhosphorylation by SGK induces FOXO3 translocation from the nucleus. FOXO3 contributes to the regulation of various processes such as cell cycle progression, cell size determination, cell death, cell differentiation, resistance to nutrient and oxidative stress, immune response, stress resistance, energetic metabolism and longevityIn summary, the results of this phase 1 study in healthy subjects with i.v. OCS-05 for up to 5 days showed a safe profile and linear pharmacokinetics, supporting testing it as a neuroprotective therapy for AON and MS. OCS-05 is currently being tested in a phase 2 trial in patients with AON of idiopathic origin or due to MS or MOG associated disease (MOGAD) (NCT04762017 and EUDRACT: 2020-003147-29).