Introduction

Pain affects an estimated one in five individuals worldwide and represents a major global health challenge.1 While acute pain serves as a protective mechanism, persistent or severe pain can profoundly diminish quality of life and lead to significant disability.2 Current pharmacotherapies, including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, are frequently limited by insufficient efficacy, gastrointestinal or cardiovascular toxicity, and the risks of dependence and respiratory depression.3–5 Collectively, these limitations underscore a pressing and unmet need for novel, non-opioid analgesics with improved safety profiles.

The development of such novel analgesics requires a deeper understanding of the molecular mechanisms underlying pain signal transmission. Voltage-gated sodium channels (VGSCs) in peripheral sensory neurons play a critical role in this process.6,7 Among the nine known subtypes (Nav1.1–Nav1.9), Nav1.8 has emerged as a particularly promising therapeutic target.8,9 It is preferentially expressed in dorsal root ganglion (DRG) and trigeminal ganglion neurons,10 which are primary sites for pain signal transduction. Nav1.8 is uniquely responsible for the majority of the depolarizing current during the action potential upstroke in these nociceptors. It is also relatively resistant to inactivation at depolarized membrane potentials—a property crucial for sustained firing under pathological conditions.11,12 This peripheral-restricted expression offers a compelling theoretical advantage. Selective Nav1.8 blockade may achieve potent analgesia while minimizing the central nervous system and cardiac side effects that have plagued earlier, non-selective sodium channel inhibitors such as carbamazepine, lidocaine, and mexiletine.13–15

The clinical validation of the Nav1.8 target has been demonstrated by selective inhibitors such as VX-150 and VX-548,16–18 which have shown promising analgesic efficacy in human trials for acute and neuropathic pain. Most notably, on January 30, 2025, the US Food and Drug Administration approved suzetrigine, the first Nav1.8 inhibitor, for the treatment of moderate to severe acute pain, marking a major milestone in the field.19,20 HRS-2129 is a novel, orally active, and highly selective Nav1.8 inhibitor jointly developed by Shandong Shengdi Pharmaceutical Co., Ltd. and Shanghai Hengrui Pharmaceutical Co., Ltd. Extensive non-clinical studies conducted by the sponsor have characterized HRS-2129 as a potent and highly selective blocker of Nav1.8 (IC50 values of 0.19–0.32 nM). It concentration-dependently reduced action potential firing in isolated rat DRG neurons and exhibited robust, dose-dependent analgesic effects in rodent models of inflammatory and post-surgical pain. Furthermore, non-clinical safety pharmacology and toxicology studies from the sponsor indicated a wide safety margin, with no significant effects on the hERG channel, neurobehavior, or respiration at relevant exposures, supporting its progression to human trials. (The preclinical data described above were provided by the sponsor from their internal non-clinical studies).

Here, we report the first-in-human (FIH) study of HRS-2129, comprising Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) components. The primary objectives were to evaluate the safety, tolerability, and pharmacokinetics (PK) of HRS-2129 in healthy subjects. Secondary and exploratory objectives included assessing food effect on PK, QTc interval prolongation, and pharmacodynamic (PD) profiles (heat/cold pain detection thresholds and pain tolerance). These findings provide the critical foundation for the continued clinical development of HRS-2129 as a novel non-opioid analgesic.

Methods Study Design

This early-phase clinical trial comprised two independent, randomized, double-blind, placebo-controlled studies conducted in healthy adult volunteers. Study 01: A Phase I, single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HRS-2129 following a single dose, with an integrated cohort to assess the potential effects of food on its bioavailability. Study 02: A Phase I, single-center, randomized, double-blind, placebo-controlled, multiple-ascending dose (MAD) study designed to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HRS-2129 following repeated administrations. Both studies were prospectively registered on ClinicalTrials.gov (NCT06619392 and NCT06742840).

Both studies were conducted in full accordance with the ethical principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice (ICH-GCP) guidelines. The clinical protocol, informed consent forms, and other relevant documents were reviewed and approved by the Independent Ethics Committee of the Third Xiangya Hospital, Central South University (Changsha, Hunan, China). Prior to participating in any study-related procedure, all subjects provided written informed consent.

To ensure blinding integrity, an independent biostatistician generated the randomization schedule using SAS software (SAS Institute Inc., Cary, NC, USA). All investigational products (HRS-2129 and placebo) were identical in appearance. Through standardized operating procedures, investigators, site staff, subjects, and sponsor personnel remained blinded to treatment assignments throughout the study period.

Participants

Healthy male and female volunteers of East Asian descent (Chinese population) aged 18 to 55 years, with a body mass index (BMI) between 19 and 28 kg/m2, were enrolled from multiple regions across China. Female subjects were required to be non-pregnant and non-lactating. Additional inclusion criteria specified that the skin at the pain stimulation site must be free of wounds or dermatological conditions, and that subjects must be willing and trained to complete pain testing procedures.

Key exclusion criteria included: a history or presence of clinically significant cardiovascular, endocrine, neurological, digestive, or psychiatric diseases; symptomatic arrhythmia or personal/family history of long QT syndrome; abnormal laboratory values at screening (eg, AST, ALT, total bilirubin, or creatinine above the upper limit of normal, QTcF >450 ms); known hypersensitivity to the drug or its excipients; use of any prescription or over-the-counter medications within 14 days prior to dosing; participation in another clinical trial within 3 months prior to screening; and positive tests for drugs of abuse, alcohol, hepatitis B/C, HIV, or syphilis.

Dose Escalation

The starting dose for the SAD phase was set at 25 mg, determined based on the no-observed-adverse-effect-level (NOAEL) from 4-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, incorporating body surface area conversion and application of a safety factor. Allometric scaling from canine toxicokinetic data (predicting human CL/F of 1040 mL/h, V/F of 34679 mL, and Ka of 0.25/h) further supported this selection. The dose selection rationale, including NOAEL-based calculations, allometric scaling factors, safety margins, and predicted human therapeutic exposures, is summarized in Supplementary Table S1.

For the MAD phase, non-parametric superposition simulation of steady-state exposure, informed by preliminary pharmacokinetic data from the 25 mg SAD cohort, indicated an acceptable safety window for a 25 mg BID regimen. The anticipated therapeutic dose range for continuous administration was projected to be 25—150 mg QD. The original MAD protocol planned dose escalation from 25 mg BID to 75 mg QD, followed by 50 mg BID, 100 mg BID, and 200 mg BID.

After completion of the 25 mg BID cohort, dermatological AEs—including rash (2 cases), pruritus (2 cases), and skin irritation (1 case)—were observed. Following a comprehensive safety review by the investigators and the sponsor, these events were deemed manageable and did not meet the protocol-defined stopping criteria; thus, the 25 mg BID dose level was considered safe for continued exploration. Nonetheless, to better characterize the relationship between dermatological events and exposure levels before proceeding with further escalation, the protocol was amended to introduce an intermediate 25 mg QD cohort, allowing for a direct comparison with the BID regimen at the same total daily dose. The 25 mg QD cohort was completed with acceptable safety findings, after which the originally planned 75 mg QD cohort was conducted. Given the long elimination half-life of HRS-2129 (approximately 28.5–35.7 hours) and the similar plasma concentrations observed at 12 and 24 hours post-dose, a QD regimen was selected for all subsequent dosing cohorts. The treatment duration was set at 12 days for the initial BID cohort and 14 days for all QD cohorts.

Treatment Allocation and Escalation Criteria

The SAD phase comprised five sequential cohorts with geometrically increasing doses of 25, 75, 150, 300, and 600 mg. The 25 mg cohort enrolled 4 subjects (3 HRS-2129: 1 placebo), while all other cohorts included 10 subjects (8 HRS-2129: 2 placebo). The 150 mg cohort incorporated a two-period crossover design to evaluate food effect, with a 14-day washout between periods (Figure 1a). For the MAD phase, each cohort enrolled 10 subjects (8 HRS-2129: 2 placebo).

Interim safety and PK data were reviewed by the investigators and the sponsor after each cohort, and dose-escalation decisions were made collaboratively according to the protocol. Advancement to the next dose cohort was contingent upon a comprehensive review of safety and tolerability data from the preceding cohort for at least 72 hours post-dose. Pre-defined dose escalation stopping criteria included: ≥50% of subjects in a cohort experiencing a related moderate or severe adverse event (AE); ≥2 subjects with related severe AEs in the same organ system; the occurrence of any related serious adverse event (SAE); or the anticipation of PK saturation or lack of further exposure gain with dose escalation.

The screening and randomization outcomes for both studies are summarized in Figure 1b. A total of 276 healthy volunteers were screened for the SAD study, of whom 44 were randomized; the primary reasons for screening failure included not meeting inclusion criteria or meeting exclusion criteria (n=227), with 5 additional candidates excluded for other reasons. For the MAD study, 291 volunteers were screened, yielding 23 randomized participants.

Study Procedures

In the SAD study, subjects were confined to the clinic from the day before dosing until completion of the scheduled safety and PK assessments. Dosing occurred after an overnight fast (≥10 hours), except for the fed arm of the 150 mg cohort, which received a high-fat, high-calorie meal 30 minutes before dosing. Serial blood samples for PK analysis were collected up to 216 hours post-dose. Additionally, in the 300 mg dose cohort, all urine and fecal samples were systematically collected from subjects over 216 hours post-dose to evaluate the excretion characteristics and mass balance of HRS-2129.

In the MAD study, subjects were admitted to the Phase I clinical research unit from the day before dosing until completion of the scheduled study assessments. PK samples were collected on Day 1 and the last day of dosing (Day 12 for BID, Day 14 for QD), with sparse sampling on intermediate days to assess trough concentrations.

Safety and Tolerability Assessments

Safety was evaluated throughout the studies based on the incidence and severity of treatment-emergent adverse events (TEAEs), clinical laboratory tests (hematology, serum chemistry, urinalysis, coagulation, thyroid function), vital signs, 12-lead electrocardiograms (ECGs), physical examinations, and abdominal ultrasonography. AEs were graded for severity (mild, moderate, severe) and relationship to study drug. To specifically assess the proarrhythmic potential, a Concentration-QT (CQT) analysis was embedded within the SAD study. Continuous Holter monitoring was employed to extract ECGs at predefined timepoints relative to dosing, and the relationship between the Fridericia-corrected QT interval (QTcF) and HRS-2129 plasma concentration was characterized using a linear mixed-effects modeling approach.

Pharmacokinetic Analysis Sample Collection and Processing

In the SAD study, serial blood samples for PK analysis were collected up to 216 hours post-dose. In the 300 mg cohort, all urine and fecal samples were systematically collected over 216 hours post-dose to evaluate the excretion characteristics and mass balance of HRS-2129. In the MAD study, PK samples were collected on Day 1 and the last day of dosing (Day 12 for BID, Day 14 for QD), with sparse sampling on intermediate days to assess trough concentrations. Blood samples were collected in K2-EDTA tubes. Plasma was separated and stored at ≤ −60°C until analysis.

Bioanalytical Method

Plasma concentrations of HRS-2129 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method (Shanghai WuXi AppTec). The lower limit of quantification (LLOQ) was 20.0 ng/mL, with quality control (QC) concentrations of 60.0, 600, 8000, and 15000 ng/mL. Across all analytical batches, assay accuracy ranged from 97.2% to 104.2%, and precision (coefficient of variation) was ≤3.8%, confirming the reliability of the method for quantitative analysis of HRS-2129 in plasma.

Pharmacokinetic Parameters

Non-compartmental analysis (WinNonlin® version 8.3) was used to estimate PK parameters. For the SAD study, the following parameters were calculated: maximum plasma concentration (Cmax), time to maximum concentration (Tmax), area under the concentration-time curve from time zero to the last quantifiable concentration (AUC0–t) and to infinity (AUC0–∞), elimination half-life (t1/2), apparent clearance (CL/F), apparent volume of distribution (Vz/F), and mean residence time (MRT). For the 300 mg cohort, urine and fecal samples were analyzed to determine cumulative amount excreted in urine (Ae), cumulative excretion percentage (fe), and renal clearance (CLmax). Dose proportionality for Cmax and AUC was assessed using a power model.

For the MAD study, the following parameters were estimated: Cmax,1 and AUCτ,1 after the first dose; Cmax,2 and AUCτ,2 after the second dose (BID regimen only); and at steady state (Day 12 for BID, Day 14 for QD): Cmax,ss, Ctrough,ss, Cavg,ss, AUC0–τ,ss, AUC0–t,ss, AUC0–∞,ss, Tmax,ss, t1/2, CLss/F, Vz/F, MRT, fluctuation index (DF), and accumulation ratios (Rac,AUC and Rac,Cmax). Steady-state attainment was evaluated by analysis of variance (ANOVA) of predose trough concentrations at Days 8, 10, 11, and 12 (BID) or Days 8, 12, 13, and 14 (QD).

Metabolite Identification and Excretion

For the 300 mg cohort in the SAD study, pooled plasma, urine, and fecal samples were subjected to metabolite profiling using UPLC-UV/Q-TOF MS to identify the major metabolic pathways of HRS-2129 in humans. Excretion characteristics were assessed based on the cumulative recovery of unchanged HRS-2129 in urine and feces over 216 hours post-dose.

Pharmacodynamic Assessment

Exploratory pharmacodynamic (PD) assessments included the cold pressor test (ice-water bath) and the Pathway Pain and Sensory Evaluation System (Medoc Ltd., Israel). Pain tolerance was assessed by recording the time until the cold stimulus became intolerable, defined as Pain Tolerance Time (PTT). To ensure participant safety, the immersion time was limited to a maximum of 120 seconds. Pain thresholds were assessed using the Pathway system to measure cold pain detection threshold (CPDT) and heat pain detection threshold (HPDT).

To improve consistency and minimize measurement variability, all PD assessments were performed according to a standardized procedure at the same time of day in a temperature-controlled room. Participants received a training session before baseline assessments to reduce potential learning effects. All PD evaluations were conducted by the same trained operator throughout the study. PD assessments were performed at baseline and at multiple post-dose time points. The relationship between PD endpoints and HRS-2129 plasma exposure was explored descriptively and graphically.

Statistical Analysis Analysis Sets

Safety analyses were performed on the Safety Set (SS). Pharmacodynamic (PD) analyses were conducted using the PD Analysis Set (PDS), defined as all randomized subjects who received study drug and had at least one valid PD measurement. PK analyses were performed on the PK Concentration Set and PK Parameter Set. The Concentration-QTc (CQT) Analysis Set comprised subjects with both evaluable Holter ECG data and corresponding plasma concentration data at matched time points.

Statistical Methods

Descriptive statistics were used for continuous and categorical variables. PK parameters were estimated using non-compartmental analysis (WinNonlin® 8.3), including Cmax, Tmax, AUC, t1/2, CL/F, Vz/F, and accumulation ratio (Rac). For the 300 mg cohort, Ae, fe, and CLr were also calculated.

The concentration-QTc analysis was performed using a linear mixed-effects model, with QTcF as the dependent variable, time-matched plasma concentration as a fixed effect, and subject as a random effect. Model-predicted ΔΔQTcF at Cmax with 90% CIs was calculated. Missing data were not imputed; the analysis was based on observed matched pairs.

PD endpoints included CPDT, HPDT, and PTT. PD data were summarized descriptively by treatment group and time point, with values presented as mean ± SD or mean change from baseline. Treatment-group comparisons were examined through descriptive summary statistics and graphical visualization, including mean change–time curves, in line with the exploratory nature of this first-in-human study. The exposure–PD relationship was explored graphically.

All statistical analyses were performed using SAS® version 9.4 or higher.

Results Demographic Characteristics

A total of 67 healthy subjects were randomized and received at least one dose of HRS-2129 or placebo across the two studies. In the SAD study, all 44 randomized subjects (35 received HRS-2129, 9 received placebo) completed the study. In the MAD study, 23 subjects were randomized (18 received HRS-2129, 5 received placebo); one subject in the 75 mg QD group discontinuing due to a SAE, While the remaining 22 completed the study. Detailed demographic data are presented in Table 1.

Safety and Tolerability

In the SAD phase, HRS-2129 demonstrated favorable safety and tolerability across the dose range of 25–600 mg. All TEAEs were mild or moderate in severity, with no SAEs, deaths, or discontinuations due to AEs. The overall incidence of TEAEs was comparable between the HRS-2129 group (91.4%, 32/35) and the placebo group (88.9%, 8/9). The spectrum and incidence of the most frequently reported TEAEs are summarized in Table 2. No clear dose-dependent trend in TEAE incidence or severity was observed.

During the MAD phase, the safety profile remained generally consistent with the SAD phase under lower doses. In the initial 25 mg BID cohort, mild dermatological AEs were observed, including rash (2 cases), pruritus (2 cases), and skin irritation (1 case). These events did not meet the predefined dose-escalation stopping criteria and were considered manageable, prompting an adaptive protocol amendment to insert a 25 mg QD cohort for further safety characterization before proceeding to higher doses. TEAEs were common but predominantly mild, with an incidence of 100% in both the HRS-2129 and placebo groups, which is not unexpected in longer-duration Phase I studies. Treatment-related AEs occurred in 100% (18/18) of the HRS-2129 group compared to 80% (4/5) of the placebo group. Dermatological events, specifically pruritus and rash, were identified as the most notable TRAEs (Table 2).

Importantly, the moderate drug rash observed in the 75 mg QD MAD cohort represents a critical, dose-limiting safety signal. The affected subject was a 38‑year‑old female who developed pruritus on Day 3 of dosing, followed by scattered erythematous papules that partially subsided but recurred on Day 9 (one day after the last dose) with generalized erythema and targetoid lesions, leading to hospitalization. Laboratory findings were unremarkable except for transient lymphopenia and neutrophilia. The event was classified as a Grade 2 (moderate) SAE per CTCAE v5.0 criteria and as a protocol‑defined AESI. Causality was assessed as “probable” by the investigators based on temporal relationship, positive dechallenge, and absence of alternative etiologies. The rash resolved completely following treatment with systemic corticosteroids and antihistamines, with no sequelae. Because this treatment-related SAE directly triggered the pre-specified protocol safety stopping criterion (defined as ≥1 subject experiencing a treatment-related SAE within a cohort), the MAD escalation was operationally terminated, establishing 25 mg BID as the maximum safe dose under the conditions of this study.

Concentration-QTc Analysis

In the SAD phase, a dedicated concentration-QTc (C-QTc) analysis was conducted using a linear mixed-effects model to evaluate the potential effect of HRS-2129 on cardiac repolarization. The analysis confirmed the absence of any clinically relevant effect on the QTc interval. At the maximum plasma concentration (Cmax) following the highest evaluated single dose of 600 mg (mean Cmax of 6234 ng/mL), the model-predicted placebo-corrected change-from-baseline Fridericia-corrected QT interval (ΔΔQTcF) was 0.13 ms, with a two-sided 90% confidence interval (CI) of −1.95 to 2.30 ms, which is well below the 10 ms regulatory threshold of concern. Similarly, at the 300 mg dose level (mean Cmax of 4589 ng/mL), the model-predicted ΔΔQTcF was 0.26 ms (90% CI: −1.45 to 2.08 ms). The estimated slope of the concentration–ΔΔQTcF relationship was flat and showed no statistically significant relationship (p>0.05), demonstrating that increasing systemic exposure of HRS-2129 does not correlate with QTc interval prolongation. The predicted ΔΔQTcF values and their corresponding 90% CIs at Cmax across all dose cohorts are summarized in Table 3.

Pharmacokinetic and Dose-Exposure Relationship

The pharmacokinetic profile of HRS-2129 was characterized across the dose ranges studied. After single oral administration in the fasted state, HRS-2129 was rapidly absorbed, with a median time to maximum plasma concentration (Tmax) ranging from 1.00 to 1.75 hours across the 25 to 600 mg dose levels. The mean t1/2 was long, ranging from 28.38 to 35.57 hours, supporting a once-daily dosing regimen. Key pharmacokinetic parameters are summarized in Table 4, and the plasma concentration versus time curves on linear and semi-logarithmic scales are presented in Figure 2a for the 25–600 mg dose groups and in Figure 2b for the 150 mg dose under fasted and fed conditions. Dose proportionality was assessed over the 25–600 mg range. The results indicated that systemic exposure, as measured by Cmax and AUC, increased in a less-than-dose-proportional manner. The slope estimates (90% CI) from the power model were below 1 for both Cmax and AUC parameters.

Administration of a 150 mg dose with a high-fat meal significantly delayed absorption, prolonging the median Tmax from 1.75 hours to 7.00 hours. However, the overall extent of exposure was not significantly altered, as the geometric mean ratios (fed/fasting) and their 90% confidence intervals for both AUC0-inf (105.63%) and Cmax (89.88%) fell within the conventional bioequivalence range of 80–125%.

In the MAD phase, steady-state conditions were achieved by approximately Day 8 of dosing. The pharmacokinetic profile at steady state was consistent with that observed after a single dose. As anticipated for a drug with a long half-life, accumulation was observed upon multiple dosing. The Rac for AUC were 3.1 for the 25 mg BID regimen and 2.4 for the 75 mg QD regimen. Key pharmacokinetic parameters are summarized in Table 5, and the plasma concentration versus time curves at steady state are presented in Figure 3a (25 mg BID) and Figure 3b (25 mg QD and 75 mg QD).

In the 300 mg SAD cohort, excretion and biotransformation profiles were characterized. Excretion of the unchanged parent drug was minimal, with mean cumulative recoveries of only 4.71% in urine and 2.11% in feces over 216 hours post-dose (detailed in Supplementary Table S2), indicating that metabolic clearance is the primary elimination pathway. Metabolite profiling identified 31 metabolites in human biomatrices, with principal biotransformation pathways comprising reduction, demethylation, oxidative deamination, and glucuronidation. Importantly, the unchanged parent compound was the highly predominant circulating species in plasma, representing approximately 90.52% of total drug-related UV peak area, with no single metabolite exceeding 10% of systemic exposure. Excretion kinetics are illustrated in Supplementary Figure S1 and S2, and the full metabolite profiles are compiled in Supplementary Table S3.

Pharmacodynamic and Exposure-Effect Relationship

The pharmacodynamic effects of HRS-2129 were evaluated through quantitative sensory testing in healthy volunteers. In the single ascending dose study, doses from 75 mg to 600 mg increased PTT in the ice-water bath test compared to baseline and placebo groups. The time-course profile of PTT changes is shown in Figure 4a. In contrast, neither HPDT (Figure 4b) nor CPDT (Figure 4c) showed consistent changes from baseline across the same dose range.

During multiple ascending dose administration, sustained enhancement of pain tolerance was observed with all regimens (25 mg BID, 25 mg QD, and 75 mg QD). The temporal pattern of PTT changes during repeated dosing is presented in Figure 4d. Consistent with single-dose results, multiple administrations of HRS-2129 did not produce significant alterations in either HPDT (Figure 4e) or CPDT (Figure 4f).

Exploratory exposure-response analysis indicated a positive correlation between plasma concentrations of HRS-2129 and the degree of PTT prolongation. However, this relationship demonstrated considerable inter-individual variability and exhibited a trend toward plateau at higher exposure levels, consistent with the absence of a clear dose-response relationship across the 75–600 mg dose range in the single-dose study. These findings provide preliminary evidence of target engagement consistent with Nav1.8 channel blockade.

Discussion

This first-in-human study demonstrates that HRS-2129, a novel selective Nav1.8 inhibitor, exhibits favorable safety, tolerability, and pharmacokinetic properties in healthy subjects, along with preliminary evidence of analgesic activity. The favorable safety profile of HRS-2129 represents a significant finding. The absence of severe adverse events or study discontinuations in the single-ascending-dose study, provides substantial reassurance regarding the compound’s initial safety characteristics. It is noteworthy that the dermatological events observed in the multiple-ascending-dose study (primarily manifested as rash), while requiring attention in future clinical development, established a clear maximum tolerated dose (25 mg BID) that provides crucial guidance for subsequent trials. Furthermore, the safety profile of HRS-2129 shows similarities with suzetrigine, another Nav1.8 inhibitor approved for clinical use. In three Phase 3 clinical trials involving 2,447 participants, suzetrigine was demonstrated to have no potential for addiction, with its most common adverse reactions including pruritus, muscle spasms, elevated blood creatine phosphokinase levels, and rash.12,21,22 Similarly, in clinical trials of the investigational compound VX-128, rash was observed across multiple dose groups, including one SAE of angioedema that led to premature study termination. While the initial interpretation of such events in early-phase trials often attributes them to compound-specific or metabolic characteristics,23,24 the recurrence of dermatological findings across multiple Nav1.8 inhibitors—including an approved therapy—suggests a need to consider a potential class-related dimension. The distinct exposure-response relationship observed for HRS-2129’s dermatological events, which allowed for the establishment of a clear maximum tolerated dose rather than prompting study termination, indicates that this risk may be manageable within a defined therapeutic window. This distinction is clinically meaningful and supports continued development while mandating vigilant monitoring in future trials.

The dose‑limiting SAE of drug eruption in the 75 mg QD cohort warrants further discussion. The affected subject developed pruritus on Day 3 of dosing, with scattered papules on Day 4 that partially subsided. However, on Day 9 (one day after the last dose), the rash recurred with generalized erythema and targetoid lesions, leading to hospitalization. Laboratory findings were unremarkable except for transient lymphopenia and neutrophilia, consistent with a drug‑induced hypersensitivity reaction. The subject received systemic corticosteroids and antihistamines, with complete resolution by Day 28 and no sequelae except mild post‑inflammatory hyperpigmentation. The event was classified as Grade 2 (moderate) per CTCAE v5.0 and causality was assessed as “probable.” This temporal pattern—initial mild symptoms that partially resolved, followed by a more extensive recurrence after continued dosing—suggests a sensitization mechanism rather than a direct toxic effect. This case underscores the importance of vigilant monitoring for dermatological AEs in future trials, particularly with QD regimens at higher doses, and supports that the 25 mg BID regimen, which demonstrated a manageable safety profile in this study, represents the maximum safe dose for repeated administration.

Regarding C-QTc assessment, the C-QTc study results for HRS-2129 were negative at single doses up to 600 mg (corresponding to a Cmax of 6234 ng/mL). Furthermore, across the entire studied dose range (25–600 mg), HRS-2129 did not demonstrate a trend of QTc prolongation with increasing dose. Therefore, HRS-2129 is considered to have a low risk of inducing QTc prolongation. In subsequent clinical development, the risk of QTc prolongation associated with this agent should be further evaluated based on the clinical dose and exposure levels.

The pharmacokinetic characteristics of HRS-2129 demonstrate distinct advantages for both acute and chronic pain management. Its rapid absorption (median Tmax 1–2 hours) suggests a potential for fast onset of action, which is notably faster than that of the approved Nav1.8 inhibitor suzetrigine (median Tmax 3.0 hours).21 Meanwhile, the long elimination half-life of HRS-2129 (approximately 28–35 hours) supports once-daily dosing—a feature similar to suzetrigine (effective t½ 23.6 hours). The less-than-dose-proportional increase in exposure observed across the 25–600 mg dose range may reflect solubility-limited absorption or saturable processes, a factor that should be considered in dose selection for future studies. It is worth noting that administration after a high-fat meal significantly delays the absorption rate of HRS-2129: compared with fasting administration, the median lag time increases from 0 h to 0.25 h, and the median Tmax is prolonged from 1.75 h to 7.00 h, although overall exposure remains comparable between the two administration conditions. These findings indicate that for the initial dose in acute pain management, fasting administration is recommended to avoid delayed onset and ensure timely analgesic effect.

In addition, as a selective NaV1.8 sodium channel blocker, the pharmacokinetic characteristics of suzetrigine are significantly influenced by its active metabolite, M6-SUZ. The in vivo metabolism of both suzetrigine and M6-SUZ is primarily mediated by the CYP3A pathway, necessitating careful consideration of CYP3A-related drug-drug interactions in its clinical use. Consequently, co-administration with strong CYP3A inhibitors is contraindicated due to a marked increase in plasma concentrations, moderate CYP3A inhibitors require dose adjustment, and CYP3A inducers can substantially reduce suzetrigine exposure, leading to diminished efficacy.21 Given the critical role of CYP3A-mediated interactions in the clinical application of suzetrigine, elucidating the metabolic pathways of HRS-2129 and its potential for interactions with CYP enzymes is of great importance. This study systematically characterized, for the first time in humans, the metabolism and excretion profile of HRS-2129. Following a single oral dose of 300 mg HRS-2129, a total of HRS-2129 and 31 metabolites were detected in plasma, urine, and feces. Unchanged parent drug predominated in plasma, accounting for approximately 90.52% of the total drug-related exposure, with no single metabolite present at a high proportion. This suggests that HRS-2129 exists primarily as the parent compound in humans, and the contribution of metabolites to the overall pharmacological activity may be limited. The primary metabolic pathways of HRS-2129 included reduction, demethylation, oxidative deamination, and glucuronidation, while secondary pathways involved oxidation, deamination, defluorination, and hydrolysis. Excretion studies revealed that within 216 hours post-dose, the mean cumulative urinary excretion of unchanged drug was 4.71%, and the mean cumulative fecal excretion was 2.11%. These results indicate that renal and fecal excretion of the parent drug are not the major elimination routes for orally administered HRS-2129, and the drug is primarily eliminated via bodily fluids in the form of metabolites. Based on the preclinical CYP enzyme study results for HRS-2129, this compound demonstrated reversible inhibition of CYP3A4/5 and exhibited potential induction of CYP3A4 across a concentration range of 0.3 to 3 μM, indicating a clear in vitro interaction profile with CYP3A4. However, when considered alongside the human metabolism data from this study—where unchanged parent drug accounted for over 90% of plasma exposure and no single high-proportion CYP3A4-mediated metabolite was identified—raise the hypothesis that CYP3A4 may not be the predominant metabolic clearance pathway for HRS-2129 in humans; however, definitive elucidation of the metabolic enzyme phenotype requires dedicated drug-drug interaction and mass balance studies with radiolabeled material in future investigations. This discovery stands in stark contrast to suzetrigine, which is predominantly metabolized by CYP3A, indicating that the drug-drug interaction risk profile of HRS-2129 may differ fundamentally from that of suzetrigine. Nevertheless, whether the inhibitory/inductive effects of HRS-2129 on CYP3A4 observed in preclinical studies translate into clinically meaningful drug-drug interactions remains to be determined. When HRS-2129 is co-administered with CYP3A substrate drugs, its potential role as a CYP3A4 inhibitor/inducer may affect the exposure levels of the concomitant medications. Conversely, since HRS-2129 itself is not a major substrate of CYP3A4, the impact of strong CYP3A inhibitors or inducers on its own exposure may be limited. Therefore, future studies should further quantify changes in HRS-2129 exposure when co-administered with CYP3A inhibitors or inducers, assess its effects on the pharmacokinetics of sensitive CYP3A substrates, and identify the key drug-metabolizing enzyme phenotypes involved in its biotransformation. Such investigations will help refine the clinical pharmacological profile of HRS-2129 and provide an evidence-based foundation for individualized dose adjustments and safety management of concomitant medications in its subsequent clinical application.

The pharmacodynamic evaluation of HRS-2129 demonstrated a significant prolongation of pain tolerance time in the ice-water bath test, providing preliminary evidence of analgesic activity aligned with its mechanism as a selective Nav1.8 inhibitor. This is consistent with the established role of Nav1.8 channels in mediating affective pain processing and sustaining repetitive neuronal firing in nociceptors under pathological conditions such as neuropathic pain.25–27 However, the pharmacodynamic profile of HRS-2129 exhibits notable distinctions from other agents in this class. For instance, VX-128 has been reported to modulate both pain tolerance and detection thresholds,23 while VX-150 significantly affects cold pressor pain tolerance and heat pain detection thresholds without altering pressure pain tolerance.23,28 In contrast, HRS-2129 did not produce measurable changes in heat or cold pain detection thresholds as assessed by the Pathway system, suggesting that this particular quantitative sensory testing model may lack sensitivity for capturing its pharmacodynamic effects. The observed insensitivity may be attributed to several factors, including potential differences in drug exposure or target engagement between healthy volunteers and pain patients, the specific stimulus modalities employed in the Pathway paradigm, and the inherent inter-individual variability compounded by the limited sample size of this early-phase study. Future investigations in clinically relevant pain populations, incorporating broader pharmacokinetic-pharmacodynamic analyses and possibly alternative sensory testing approaches, will be essential to fully characterize the analgesic profile of HRS-2129 and to identify optimal endpoints for evaluating its efficacy.

Several limitations of this initial evaluation should be acknowledged. While the healthy volunteer population is essential for preliminary safety assessment, it may not fully predict efficacy in patients with pathological pain states characterized by peripheral and central sensitization. The relatively small sample size across both the single and multiple ascending dose studies, as is typical in early-phase trials, limits the generalizability of findings and the ability to detect less common adverse events. Of the 67 randomized subjects, only 8 were female, resulting in a predominantly male composition of the enrolled cohorts. This further restricts the extrapolation of results to female populations, particularly given known sex-related differences in pain perception and drug metabolism. Furthermore, although the ice-water bath test has demonstrated sensitivity to Nav1.8 inhibitors, its predictive validity for clinical efficacy requires confirmation in patient studies. Additionally, this study did not systematically evaluate the metabolic enzyme phenotype of HRS-2129 or its potential for drug-drug interactions; in particular, whether it is primarily metabolized by CYP3A4 remains unclear. These gaps in pharmacological characterization should be addressed in subsequent development.

In conclusion, HRS-2129 demonstrates a promising risk-benefit profile supporting its continued development for pain management. The established safety margins, favorable pharmacokinetics, and evidence of analgesic activity without sensory impairment position HRS-2129 as a potentially valuable addition to the non-opioid analgesic arsenal. Future studies in patient populations with neuropathic or inflammatory pain conditions will be crucial to fully characterize the therapeutic potential of this novel Nav1.8 inhibitor.

Conclusion

As the first-in-human trial of HRS-2129, this study systematically evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of this novel selective Nav1.8 inhibitor in healthy subjects. The results indicate that HRS-2129 was generally safe and tolerable within the dose range of up to 600 mg for single administration and 25 mg BID for multiple administrations, with manageable dermatological reactions being the primary adverse events. Pharmacokinetic analysis revealed rapid absorption and a long half-life, supporting once-daily dosing. The pharmacodynamic evaluation provided preliminary signals suggestive of analgesic activity, warranting further exploration in patient populations. These findings establish a critical foundation for the continued clinical development of HRS-2129, supporting its further investigation as a non-opioid analgesic for both acute and chronic pain conditions.

Table 1 Demographic and Baseline Characteristics

Table 2 Summary of TEAEs and Key TEAEs by Dose Group

Table 3 ΔΔQTcF with Two-Sided 90% CI at Cmax by HRS-2129 Dose Group

Table 4 PK Parameters of of HRS-2129 Following Single-Dose Administration Across Dose Groups. Values are Presented as Mean ± SD, Except for Tmax Which is Reported as Median (min, max)

Table 5 Key Steady-State Plasma PK Parameters of HRS-2129 After Multiple Dosing

Figure 1 Study design and participant flow diagram. (a) Dose-escalation study design schematic for SAD (25–600 mg) and MAD (25 mg Bid, 25 mg QD, 75 mg QD) cohorts. (b) Flow diagram of participant screening, randomization, and allocation for both studies.

Figure 2 Plasma Concentration-Time Profiles of HRS-2129 Following a Single Dose. (a) Linear and semi-logarithmic plasma concentration-time curves of HRS-2129 (25–600 mg). (b) Linear and semi-logarithmic plasma concentration-time curves of HRS-2129 (150 mg) under fasted and fed conditions.

Figure 3 Pharmacokinetics of HRS-2129 After Multiple Doses. (a) Plasma concentration-time curve of HRS-2129 (25 mg Bid). (b) Plasma concentration-time curves of HRS-2129 (25 mg QD and 75 mg QD).

Figure 4 Pharmacodynamic Effects of HRS-2129 Assessed by Quantitative Sensory Testing. (a-c) Single-dose administration of 75–600 mg or placebo: (a) Ice-water pain tolerance time (PTT), (b) Heat pain detection threshold (HPDT), and (c) Cold pain detection threshold (CPDT). (d–f) Repeated administration of 25 mg Bid, 25 mg QD, 75 mg QD, and matching placebo: (d) PTT, (e) HPDT, and (f) CPDT.

Data Sharing Statement

The data supporting the findings of this study are available from the corresponding author (Prof. Guoping Yang) upon reasonable request.

Ethics Statement

This study was approved by the Institutional Review Board/Ethics Committee of the Third Xiangya Hospital of Central South University (approval numbers: 24137 for the single-ascending dose study and 24179 for the multiple-ascending dose study). The study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to enrollment.

Acknowledgments

The authors sincerely thank all participants, clinical coordinators, and support staff for their contributions to this trial. We acknowledge Shandong Shengdi Pharmaceutical Co., Ltd. and Shanghai Hengrui Pharmaceutical Co., Ltd. for providing HRS-2129 and supporting the study design and data analysis.

Author Contributions

Jie Huang: Data acquisition, data analysis and interpretation, and drafting of the manuscript. Qian Wu: Data acquisition, supervision, and critical review of the manuscript. Saiying Wang: Data acquisition, supervision, and critical review of the manuscript. Jinlian Xie: Data acquisition, supervision, and critical review of the manuscript. Kunhong Deng: Data acquisition, supervision, and critical review of the manuscript. Shuang Yang: Treatment of participants and data acquisition. Xiaoyan Yang: Treatment of participants and data acquisition. Chuanpin Chen: Study design, data analysis and interpretation, and drafting of the protocol. Guoping Yang: Study design, data analysis and interpretation, and drafting of the protocol. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was funded by Shandong Shengdi Pharmaceutical Co., Ltd. and Shanghai Hengrui Pharmaceutical Co., Ltd.

Disclosure

JH, QW, SYW, JLX, KHD, SY, XYY, CPC, and GPY declare no conflicts of interest.

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