Stuart Madden, Issam Awad, Miguel A Lopez-Toledano, Leslie Morrison, Juan Gutierrez, Leock Y Ngo, Enrique Carrazana, Adrian L Rabinowicz
{"title":"rho相关激酶抑制剂NRL-1049在健康志愿者中的安全性、耐受性和药代动力学：一项1期、首次人体、单次递增剂量、随机、安慰剂对照试验","authors":"Stuart Madden, Issam Awad, Miguel A Lopez-Toledano, Leslie Morrison, Juan Gutierrez, Leock Y Ngo, Enrique Carrazana, Adrian L Rabinowicz","doi":"10.1007/s40263-025-01198-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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<sub>max</sub>), time to C<sub>max</sub> (t<sub>max</sub>), and area under the concentration-time curve (AUC) from time 0 to last quantifiable concentration (AUC<sub>0-t</sub>) and extrapolated to infinity (AUC<sub>0-∞</sub>).</p><p><strong>Results: </strong>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<sub>max</sub> ranging from 0.50 to 0.75 h. Mean C<sub>max</sub> 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<sub>max</sub> similarly increased (1:5:10:16), while AUC<sub>0-t</sub> and AUC<sub>0-∞</sub> 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<sub>max</sub> (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<sub>max</sub> was 0.88-1.63 h, and mean C<sub>max</sub> increased over the dose range (54.2-1520 ng/mL). Mean C<sub>max</sub> (1:6:14:28), AUC<sub>0-t</sub> (1:4:7:14), and AUC<sub>0-∞</sub> (1:3:6:13) of NRL-2017 increased in a greater-than-dose proportional manner (P < 0.001). In the fed state, mean C<sub>max</sub> was lower compared with the fasted state.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":""},"PeriodicalIF":7.4000,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"Stuart Madden, Issam Awad, Miguel A Lopez-Toledano, Leslie Morrison, Juan Gutierrez, Leock Y Ngo, Enrique Carrazana, Adrian L Rabinowicz\",\"doi\":\"10.1007/s40263-025-01198-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objectives: </strong>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.</p><p><strong>Methods: </strong>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<sub>max</sub>), time to C<sub>max</sub> (t<sub>max</sub>), and area under the concentration-time curve (AUC) from time 0 to last quantifiable concentration (AUC<sub>0-t</sub>) and extrapolated to infinity (AUC<sub>0-∞</sub>).</p><p><strong>Results: </strong>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<sub>max</sub> ranging from 0.50 to 0.75 h. Mean C<sub>max</sub> 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<sub>max</sub> similarly increased (1:5:10:16), while AUC<sub>0-t</sub> and AUC<sub>0-∞</sub> 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<sub>max</sub> (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<sub>max</sub> was 0.88-1.63 h, and mean C<sub>max</sub> increased over the dose range (54.2-1520 ng/mL). Mean C<sub>max</sub> (1:6:14:28), AUC<sub>0-t</sub> (1:4:7:14), and AUC<sub>0-∞</sub> (1:3:6:13) of NRL-2017 increased in a greater-than-dose proportional manner (P < 0.001). In the fed state, mean C<sub>max</sub> was lower compared with the fasted state.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":10508,\"journal\":{\"name\":\"CNS drugs\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":7.4000,\"publicationDate\":\"2025-07-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CNS drugs\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40263-025-01198-0\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS drugs","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40263-025-01198-0","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
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.
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.
期刊介绍：
CNS Drugs promotes rational pharmacotherapy within the disciplines of clinical psychiatry and neurology. The Journal includes:
- Overviews of contentious or emerging issues.
- Comprehensive narrative reviews that provide an authoritative source of information on pharmacological approaches to managing neurological and psychiatric illnesses.
- Systematic reviews that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement.
- Adis Drug Reviews of the properties and place in therapy of both newer and established drugs in neurology and psychiatry.
- Original research articles reporting the results of well-designed studies with a strong link to clinical practice, such as clinical pharmacodynamic and pharmacokinetic studies, clinical trials, meta-analyses, outcomes research, and pharmacoeconomic and pharmacoepidemiological studies.
Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in CNS Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.
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