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

  • CNS Drugs. 2025 Sep;39(9):865-877. doi: 10.1007/s40263-025-01198-0.
Stuart Madden  1 ,  Issam Awad  2 ,  Miguel A Lopez-Toledano  3  4 ,  Leslie Morrison  5 ,  Juan Gutierrez  6 ,  Leock Y Ngo  3 ,  Enrique Carrazana  3  7 ,  Adrian L Rabinowicz  3  4
Affiliations
  • 1. Neurelis, Inc., San Diego, CA, USA. [email protected].
  • 2. Department of Neurological Surgery, University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
  • 3. Neurelis, Inc., San Diego, CA, USA.
  • 4. Center for Molecular Biology and Biotechnology, Charles E. Schmidt College of Science, Florida Atlantic University, Jupiter, FL, USA.
  • 5. Department of Neurology, University of New Mexico, Albuquerque, NM, USA.
  • 6. Formerly of Neurelis, Inc., San Diego, CA, USA.
  • 7. University of Hawaii John A. Burns School of Medicine, Honolulu, HI, USA.
PMID: 40627117 DOI: 10.1007/s40263-025-01198-0
Abstract

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.

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