Background and Objectives Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that can lead to hemorrhage, focal neurologic deficits, and seizures. Rho-associated kinase (ROCK) overactivation plays a critical role in the development of CCMs, and a novel, selective ROCK2 inhibitor, NRL-1049, mitigated lesion burden and bleeding in mouse models of CCM. This study examined the safety, tolerability, and pharmacokinetics of NRL-1049 in healthy volunteers. Methods In this first-in-human, randomized, double-blind, single-ascending dose study, participants received a single, oral dose of NRL-1049 (25, 75, 150, or 250 mg) or placebo in a fasted state (period 1). In period 2, participants received 150 mg NRL-1049 or placebo 30 min after a standardized high-fat, high-calorie meal. Blood samples for pharmacokinetic analysis were collected pre-dose and at post-dose time points from 5 min to 48 h. Treatment-emergent adverse events (TEAEs) were recorded and pharmacokinetic parameters determined, including maximum drug concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve (AUC) from time 0 to last quantifiable concentration (AUC0–t) and extrapolated to infinity (AUC0–∞). Results Of the 24 participants in period 1 who received NRL-1049 (fasted), 9 (37.5%) experienced ≥ 1 TEAE, with 8 (33.3%) reporting ≥ 1 treatment-related TEAE. TEAEs appeared to correlate with dose, and 150 mg was the maximum tolerated dose following single-dose administration in this study. The most common TEAEs (> 5%) were dizziness (16.7%), headache (8.3%), and syncope (8.3%). In period 2 (n = 10), four (40.0%) participants who received 150 mg NRL-1049 (fed) reported ≥ 1 TEAE, and three (30.0%) reported a treatment-related TEAE. There were no reports of serious TEAEs or discontinuations due to a TEAE. NRL-1049 was rapidly absorbed in the fasted state, with median tmax ranging from 0.50 to 0.75 h. Mean Cmax increased over the dose range of 25–250 mg (3.66–58.0 ng/mL). As NRL-1049 dose increased in a ratio of 1:3:6:10, mean Cmax similarly increased (1:5:10:16), while AUC0–t and AUC0–∞ increased in a greater-than-dose proportional manner (1:5:11:25 and 1:4:10:21, respectively; P < 0.001). In the fed state (150 mg NRL-1049), mean Cmax (18.5 ng/mL) was lower compared with the fasted state (34.9 ng/mL). For the active metabolite, NRL-2017, in the fasted state, median tmax was 0.88–1.63 h, and mean Cmax increased over the dose range (54.2–1520 ng/mL). Mean Cmax (1:6:14:28), AUC0–t (1:4:7:14), and AUC0–∞ (1:3:6:13) of NRL-2017 increased in a greater-than-dose proportional manner (P < 0.001). In the fed state, mean Cmax was lower compared with the fasted state. Conclusions The maximum tolerated dose of 150 mg NRL-1049 was associated with a favorable safety profile in healthy adult volunteers. Exposure of NRL-1049 and its active metabolite, NRL-2017, increased in a dose proportional or greater-than-dose proportional manner. These results support continued investigation and development of NRL-1049.

Safety, Tolerability, and Pharmacokinetics of NRL-1049, a Rho-Associated Kinase Inhibitor, in Healthy Volunteers: A Phase 1, First-in-Human, Single-Ascending Dose, Randomized, Placebo-Controlled Trial

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2025年7月8日

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Stuart Madden,
Issam Awad,
Miguel A. Lopez-Toledano,
Leslie Morrison,
Juan Gutierrez,
Leock Y. Ngo,
Enrique Carrazana,
Adrian L. Rabinowicz

摘要

Background and Objectives

Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that can lead to hemorrhage, focal neurologic deficits, and seizures. Rho-associated kinase (ROCK) overactivation plays a critical role in the development of CCMs, and a novel, selective ROCK2 inhibitor, NRL-1049, mitigated lesion burden and bleeding in mouse models of CCM. This study examined the safety, tolerability, and pharmacokinetics of NRL-1049 in healthy volunteers.

Methods

In this first-in-human, randomized, double-blind, single-ascending dose study, participants received a single, oral dose of NRL-1049 (25, 75, 150, or 250 mg) or placebo in a fasted state (period 1). In period 2, participants received 150 mg NRL-1049 or placebo 30 min after a standardized high-fat, high-calorie meal. Blood samples for pharmacokinetic analysis were collected pre-dose and at post-dose time points from 5 min to 48 h. Treatment-emergent adverse events (TEAEs) were recorded and pharmacokinetic parameters determined, including maximum drug concentration (C_max), time to C_max (t_max), and area under the concentration-time curve (AUC) from time 0 to last quantifiable concentration (AUC_0–t) and extrapolated to infinity (AUC_0–∞).

Results

Of the 24 participants in period 1 who received NRL-1049 (fasted), 9 (37.5%) experienced ≥ 1 TEAE, with 8 (33.3%) reporting ≥ 1 treatment-related TEAE. TEAEs appeared to correlate with dose, and 150 mg was the maximum tolerated dose following single-dose administration in this study. The most common TEAEs (> 5%) were dizziness (16.7%), headache (8.3%), and syncope (8.3%). In period 2 (n = 10), four (40.0%) participants who received 150 mg NRL-1049 (fed) reported ≥ 1 TEAE, and three (30.0%) reported a treatment-related TEAE. There were no reports of serious TEAEs or discontinuations due to a TEAE. NRL-1049 was rapidly absorbed in the fasted state, with median t_max ranging from 0.50 to 0.75 h. Mean C_max increased over the dose range of 25–250 mg (3.66–58.0 ng/mL). As NRL-1049 dose increased in a ratio of 1:3:6:10, mean C_max similarly increased (1:5:10:16), while AUC_0–t and AUC_0–∞ increased in a greater-than-dose proportional manner (1:5:11:25 and 1:4:10:21, respectively; P < 0.001). In the fed state (150 mg NRL-1049), mean C_max (18.5 ng/mL) was lower compared with the fasted state (34.9 ng/mL). For the active metabolite, NRL-2017, in the fasted state, median t_max was 0.88–1.63 h, and mean C_max increased over the dose range (54.2–1520 ng/mL). Mean C_max (1:6:14:28), AUC_0–t (1:4:7:14), and AUC_0–∞ (1:3:6:13) of NRL-2017 increased in a greater-than-dose proportional manner (P < 0.001). In the fed state, mean C_max was lower compared with the fasted state.

Conclusions

The maximum tolerated dose of 150 mg NRL-1049 was associated with a favorable safety profile in healthy adult volunteers. Exposure of NRL-1049 and its active metabolite, NRL-2017, increased in a dose proportional or greater-than-dose proportional manner. These results support continued investigation and development of NRL-1049.