LB-029 - POPULATION PHARMACOKINETICS (PK) AND PHARMACODYNAMIC (PD) ANALYSES OF MULTIPLE INTRAVENOUS INFUSIONS OF NX210C PEPTIDE IN HEALTHY ELDERLY VOLUNTEERS (HEVS)

G. Pasculli¹, P. Bambury², J. Le Douce³, S. Marie³, D. Dumas⁴, F. Sips⁵, M. Lovern⁶, Y. Godfrin³, A. Janus³, R. Bursi⁷; ¹InSilicoTrials Technologies, InSilicoTrials Technologies S.p.A, Trieste, Friuli Venezia Giulia, Italy, ²InSilicoTrials Technologies S.p.A, Trieste, Italy, InSilicoTrials Technologies S.p.A, Trieste, Friuli-Venezia Giulia Italy, Italy, ³Axoltis Pharma, Axoltis Pharma, Lyon, France, France, ⁴Centre for Human Drug Research, Leiden, The Netherlands, Centre for Human Drug Research, Leiden, The Netherlands, The Netherlands, ⁵InSilicoTrials Technologies B.V., s' Hertogenbosch, The Netherlands, InSilicoTrials Technologies B.V., s' Hertogenbosch, The Netherlands, The Netherlands, ⁶InSilicoTrials Technologies LLC, Stafford, USA, InSilicoTrials Technologies LLC, Stafford, USA, USA, ⁷InSilicoTrials Technologies B.V., s' Hertogenbosch, The Netherlands, InSilicoTrials Technologies B.V., s' Hertogenbosch, The Netherlands.

Background: NX210c, a cyclic peptide derived from subcommissural organ-spondin (SCO-spondin), has been shown in preclinical development to improve synaptic transmission, repair the blood brain barrier and protect against neurodegradation, and is in clinical development for neurodegenerative diseases. The importance of neurofilament light chain (NfL) as a regulatory approved biomarker for Amyotrophic Lateral Sclerosis (ALS) progression and its potential to enhance clinical trial efficiency has been recently evidenced (Witzel et al., 2021; Mullard, 2023). This study aimed to explore and characterize NX210c population PK and PD, capitalizing on the predictive power of NfL to monitor neurodegenerative diseases progression and therapeutic response.

Methods: We used nonlinear mixed effects (NLME) modeling to analyze PK and PD of NX210c, based on data from the AXO-CLI-210c-02 double-blind, randomized, placebo-controlled, Multiple Ascending Dose (MAD) study on HEVs. 29 HEVs (18 males, 11 females, average age 68.8 years) received intravenous infusions of NX210c (10 mg/mL in glucose 5%) over 10 minutes, thrice weekly for four weeks, covering a total of 26 days, at doses of 5 mg/kg and 10mg/kg. Wagner Target-Mediated Drug Disposition (TMDD) (Gibiansky et al., 2008) PK associated with an indirect response model was used to describe the NX210c time-concentration profiles and its effects on NfL levels, collected at days -1, 12, 26 and 40 of the study. Key data, unavailable before September 14, 2023, were analyzed on October 1, 2023.

Results: A two-compartments Wagner TMDD model described well the time-concentration profiles of NX210c. Population PK/PD analyses by means of an Imax indirect response model revealed a sigmoidal effect of NX210c concentrations on the inhibition of NfL production, resulting in the decrease of NfL plasma levels. The IC50 value was determined to be 5.41 nM, and the effect increased with higher NX210c concentrations, reaching an IC90 of 48.69 nM, suggesting a robust PD response at clinically relevant doses.

Conclusion: The two NX210c peptide dose groups were able to achieve an NfL levels decrease, with all subjects in the highest dose group reaching the effect plateau. These data analyses support NX210c potential upcoming ALS phase II clinical trial settings.