Abstract
Firsekibart is an anti‐IL‐1β monoclonal antibody for treating acute gout flares in adults. This randomized, double‐blind, placebo‐controlled study assessed the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of multiple ascending doses of firsekibart in healthy Chinese adults. Participants were assigned to one of the two firsekibart cohorts (120 or 200 mg) every 4 weeks for three doses and randomized in a 5:1 ratio to receive firsekibart or placebo. Twenty‐four participants completed the study. After a single dose, the median Tmax was 7.0 days for both firsekibart groups. Mean Cmax was 16.0 and 29.2 µg/mL; AUC0–t was 350.6 and 600.0 d·µg/mL for the 120 and 200 mg groups. Following multiple doses, the median Tmax,ss was 4.0 days and 5.5 days, Cmax,ss was 31.5 and 54.1 µg/mL, AUC0–t,ss was 1213.3 and 1975.8 d·µg/mL, and AUC0–∞,ss was 1445.3 and 2355.4 d·µg/mL. Accumulation ratios for Cmax and AUC were <2 in both groups. Serum total IL‐1β levels showed no dose‐related trends and immunogenicity was low. Treatment‐emergent adverse events (TEAEs) occurred in 65.0% of firsekibart‐treated participants and 75.0% of placebo‐treated participants. TEAEs were mostly grade 1 or 2. Firsekibart was safe, well tolerated after multiple administrations in healthy participants, with dose‐proportional exposure and modest accumulation.
Keywords: firsekibart, multiple ascending dose, pharmacokinetics, phase 1 study, safety
Interleukin‐1β (IL‐1β), a key member of the IL‐1 cytokine family, is primarily produced by activated monocytes and macrophages. 1 , 2 As a pivotal proinflammatory cytokine, IL‐1β plays a crucial role in various immune responses and can potentially mediate multiple autoinflammatory and non‐hereditary chronic diseases. 3 Excessive IL‐1β is particularly associated with autoimmune‐inflammatory diseases, including gouty arthritis, adult‐onset Still's disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), and rheumatoid arthritis. 4 , 5 , 6 , 7
Through binding to IL‐1 receptors, IL‐1β promotes a cascade of inflammatory signaling that contributes to systemic symptoms and organ damage. 3 Given its central role in IL‐1 driven inflammation and tissue damage, therapeutic targeting of the IL‐1β pathway has emerged as a promising approach.
Canakinumab, a fully human monoclonal antibody targeting IL‐1β, has been approved for the treatment of several inflammatory diseases, including gout flares. 8 , 9 In patients with recurrent gout flares requiring repeated treatment, the interval between doses should be at least 12 weeks, supporting the feasibility of intermittent or repeated subcutaneous administration in long‐term management. 9
Firsekibart (formerly known as Genakumab) is a fully human IgG4/λ monoclonal antibody that specifically binds to IL‐1β and blocks its interaction with the IL‐1 receptors, thereby effectively suppressing downstream inflammatory response. Recently, a randomized phase 3 clinical trial confirmed that firsekibart is effective and well tolerated for acute gout flares in patients unsuitable for standard therapy, demonstrating non‐inferiority in rapid pain relief and superiority in preventing flare compared with compound betamethasone. 10 Based on clinical evidence, it was approved in China in July 2025 for the treatment of acute gout flares in adults who have contraindications, intolerance, or inadequate response to nonsteroidal anti‐inflammatory drugs and/or colchicine, and for whom repeated use of corticosteroids is not appropriate. Currently, clinical trials are being actively conducted for other gout‐related indications and sJIA.
To support broader clinical development and assess the safety of repeated dosing, we conducted a randomized, double‐blind, placebo‐controlled, multiple ascending dose (MAD) phase 1 study of firsekibart in healthy Chinese participants. The study aimed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of firsekibart following three subcutaneous doses administered at 4‐week intervals.
Methods
Participants
The study was conducted at Chengdu Xinhua Hospital, affiliated to North Sichuan Medical College from March 14, 2023, to November 14, 2023. Eligible participants were healthy adults aged 18 to 45 years (inclusive), with a minimum body weight of 45 kg for females or 50 kg for males, and a body mass index (BMI) between 19.0 and 26.0 kg/m2. Detailed inclusion and exclusion criteria were provided in Table S1.
The study protocol was approved by the Ethics Committee of Chengdu Xinhua Hospital. The trial was conducted in accordance with the study protocol, Good Clinical Practice (GCP), the Declaration of Helsinki, and applicable regulatory requirements. All participants had signed informed consent forms (ICF) before participating in the study. The trial was registered at ClinicalTrials.gov (NCT05894148).
Study Design
This was a randomized, double‐blind, placebo‐controlled, MAD phase 1 trial. Two sequential dose cohorts of firsekibart (120 and 200 mg) were evaluated, each comprising 12 participants randomized in a 5:1 ratio to receive firsekibart (n = 10) or placebo (n = 2). Each participant received three subcutaneous injections at 4‐week intervals (on Days 1, 29, and 57). Dose escalation from 120 to 200 mg cohort proceeded only after a blinded safety assessment confirmed acceptable tolerability in the lower dose group, which was conducted after all participants had completed the third dose administration and the subsequent 28‐day safety follow‐up, to allow adequate assessment of cumulative and delayed adverse events associated with multiple dosing (Figure 1).
Figure 1.
Schematic study design. SC, subcutaneous.
The screening period lasted up to 14 days to assess eligibility through clinical, laboratory, and imaging evaluations. Participants who met the inclusion criteria were admitted to the study center the day before dosing. Participants were not confined at the study site for the entire treatment period; instead, they were admitted intermittently around dosing visits and key assessment time points for safety monitoring and PK/PD sampling and followed as outpatients between these visits. The treatment period lasted 12 weeks, followed by an 8‐week safety follow‐up, during which visits occurred on Days 85, 113, and 141.
Safety assessments, PK blood sampling, PD measurements (serum total IL‐1β), and immunogenicity testing were performed according to the study protocol. Firsekibart and matching placebo were provided by Changchun GeneScience Pharmaceutical Co., Ltd.
PK Analysis
Blood samples for PK analysis were collected at prespecified time points throughout the study, including pre‐dose (within 2 h before administration) and on Days 2, 3, 5, 8, 15, and 22 of the first treatment cycle; on the day before dosing in the second cycle; on the day before dosing in the third cycle, Days 2, 3, 5, 8, 15, 29, 57, and 85. Additional samples were collected upon premature withdrawal, if applicable. Approximately 2 mL of blood was collected at each time point.
Serum concentrations of firsekibart were quantified using a validated enzyme‐linked immunosorbent assay (ELISA) in human serum. The assay calibration curve was linear over the concentration range of 25.0 to 2000 ng/mL, with a lower limit of quantification (LLOQ) of 25.0 ng/mL. A logistic regression model with 1/Y2 weighting was used for curve fitting. Intra‐ and inter‐assay precision, expressed as coefficient of variation (CV), ranged from approximately 2.5% to 12.9% and from 6.9% to 12.3%, respectively, while assay accuracy was within predefined acceptance criteria.
PK parameters were calculated using a non‐compartmental analysis model (Phoenix WinNonlin Version 8.3). PK parameters after the first dose included Cmax (peak concentration), Tmax (peak time), AUC0–t (area under the concentration–time curve from 0 to 28 days), AUC0–∞ (area under the concentration–time curve from 0 to ∞), t1/2 (half‐life), λz (first‐order terminal elimination rate constant or apparent first‐order terminal elimination rate constant), CL/F (apparent clearance), Vz/F (apparent volume of distribution), and MRT (mean residence time).
Steady‐state PK parameters were calculated after the third dose and included Cmax,ss (peak concentration at steady state), Cτ,ss (trough concentration at steady state), Cavg,ss (average concentration at steady state), Tmax,ss (time to reach Cmax,ss), AUC0–t,ss (area under the concentration–time curve at steady state from 0 to t), AUC0–∞,ss (area under the concentration–time curve at steady state from 0 to ∞), AUC0–τ (area under the concentration–time curve at steady state from 0 to τ, τ = 28 days), t1/2,ss (half‐life at steady state), λz,ss (first‐order terminal elimination rate constant or apparent first‐order terminal elimination rate constant at steady state), Vz,ss/F (apparent volume of distribution at steady state), CLss/F (apparent clearance at steady state) and MRTss (mean residence time at steady state). The accumulation ratios for Cmax and AUC0–28 days (Rac,Cmax, Rac,AUC) were calculated by comparing steady‐state and first‐dose PK parameters.
PD Analysis
Blood samples for PD analysis were collected from each participant at the following time points: pre‐dose (within 2 h before administration) and on Day 8 of the first treatment cycle, on the day before dosing in the second cycle, on the day before dosing in the third cycle, Days 8, 29, 57, and 85 of the third cycle. Additional samples were collected upon premature withdrawal, if applicable. Approximately 3 mL blood was collected at each time point. The PD parameters were the serum total IL‐1β levels.
Serum total IL‐1β concentrations were quantified using a validated single molecule array (Simoa) immunoassay in human serum. The assay calibration curve covered the concentration range of 0.800 to 200 pg/mL, with an LLOQ of 0.800 pg/mL. A logistic regression model with 1/Y2 weighting was applied for curve fitting, and samples were analyzed at a minimum required dilution of two‐fold. Intra‐ and inter‐assay precision (CV%) and accuracy (%RE) were within predefined acceptance criteria throughout validation and sample analysis.
Immunogenicity Assessment
Blood samples for immunogenicity assessments were collected from each participant at the following time points: the day before dosing, Day 15 of the first cycle, the day before dosing of the second cycle and the third cycle, Days 29, 57, and 85 of the third cycle, and premature patient withdrawal visit. A blood sample of approximately 2 mL was collected at each time point. Immunogenicity was evaluated by determining the presence of anti‐drug antibodies (ADA) and neutralizing antibodies (NAb) in the serum.
ADAs were detected using a validated affinity capture elution (ACE) electrochemiluminescence immunoassay on the MSD platform, following a tiered approach consisting of screening and confirmatory assays. The screening cut point was defined as 1.17 × the mean negative control signal, and the confirmatory cut point was based on percent inhibition (45.2%). The assay sensitivities were 7.81 ng/mL for screening. NAbs were assessed using a validated competitive ligand‐binding assay (CLBA)‐based ACE method on an ELISA platform. Samples were classified as NAb‐positive based on a predefined assay cut point of 13.9% inhibition, with an assay sensitivity of 98.26 ng/mL. Assay performance characteristics, including precision, drug tolerance, and specificity, met predefined acceptance criteria.
Safety Assessments
Safety assessments included recording of adverse events (AEs), physical examinations, vital signs, laboratory tests, and 12‐lead electrocardiogram (ECG). All AEs were coded using the MedDRA 26.0 version and categorized by system organ class (SOC) and preferred term (PT). All safety data were summarized descriptively without statistical analysis.
Statistical Analysis
All statistical analyses were conducted using SAS 9.4 version. For quantitative data, descriptive statistics were provided using numbers, mean, standard deviation, median, quartiles (first quartile and third quartile), minimum, and maximum. Total numbers and percentage were used for qualitative data, and the calculation of percentage was based on the number of individuals of each group.
For PK parameters, descriptive statistics of serum concentration data at scheduled time points were performed. Serum concentration–time profiles were plotted on both linear and semi‐logarithmic scales based on PK data. PK calculations were performed using Phoenix WinNonlin version 8.3. For samples with serum concentration lower than the LLOQ, it was calculated as 0 before reaching the Cmax, and missing after reaching the Cmax.
The PD analysis characterized serum total IL‐1β concentrations at prespecified time points through descriptive statistics. Concentration–time curves were plotted based on the serum total IL‐1β levels.
For immunogenicity, the incidence and timing of ADA and NAb positivity were summarized descriptively by treatment group (firsekibart 120 mg, firsekibart 200 mg, and the total firsekibart group). Additionally, the overall post‐treatment positivity was also summarized.
Results
Baseline Characteristics
A total of 24 healthy participants were enrolled in this study and randomized into firsekibart 120 mg group (n = 10), firsekibart 200 mg group (n = 10), and placebo group (n = 4) (Figure 2). The baseline characteristics were summarized in Table 1. A total of 22 participants (91.7%) completed the trial, while 2 participants (8.3%) withdrew from the study. One participant in the 120 mg group (10.0%) withdrew consent due to unwillingness to continue. One participant in the placebo group (25.0%) was lost to follow‐up.
Figure 2.
Flow chart of participant distribution.
Table 1.
Baseline Characteristics of Participants.
| Statistical Description |
Firsekibart‐120 mg (N = 10) |
Firsekibart‐200 mg (N = 10) |
Placebo (N = 4) |
Total (N = 24) |
|
|---|---|---|---|---|---|
| Age (years) | Mean (SD) | 25.2 (7.52) | 26.6 (4.99) | 29.3 (7.37) | 26.5 (6.41) |
| Median (Q1, Q3) | 22.5 (21.0, 26.0) | 26.0 (23.0, 30.0) | 29.0 (23.0, 35.5) | 24.0 (22.0, 30.5) | |
| Min, Max | 18, 42 | 20, 36 | 22, 37 | 18, 42 | |
| Gender | male | 5 (50.0%) | 4 (40.0%) | 2 (50.0%) | 11 (45.8%) |
| female | 5 (50.0%) | 6 (60.0%) | 2 (50.0%) | 13 (54.2%) | |
| Ethnicity | Han | 10 (100%) | 10 (100%) | 4 (100%) | 24 (100%) |
| Other | 0 | 0 | 0 | 0 | |
| Height (cm) | Mean (SD) | 165.66 (11.105) | 163.27 (4.888) | 159.58 (10.186) | 163.65 (8.709) |
| Median (Q1, Q3) |
164.70 (155.20, 177.60) |
162.45 (158.70, 168.10) |
155.85 (153.70, 165.45) |
161.65 (156.80, 169.65) |
|
| Min, Max | 150.0, 180.0 | 157.3, 170.0 | 152.0, 174.6 | 150.0, 180.0 | |
| Weight (kg) | Mean (SD) | 62.94 (11.778) | 61.24 (7.090) | 59.68 (5.259) | 61.69 (8.890) |
| Median (Q1, Q3) |
66.65 (52.70, 73.50) |
60.00 (56.70, 66.80) |
60.95 (55.80, 63.55) |
62.15 (53.95, 68.30) |
|
| Min, Max | 45.4, 79.1 | 50.7, 71.9 | 52.5, 64.3 | 45.4, 79.1 | |
| BMI (kg/m2) | Mean (SD) | 22.78 (2.389) | 22.94 (1.992) | 23.50 (2.093) | 22.97 (2.103) |
| Median (Q1, Q3) |
23.00 (20.20, 25.10) |
23.10 (22.00, 24.70) |
23.45 (21.90, 25.10) |
23.00 (21.55, 24.80) |
|
| Min, Max | 19.0, 25.8 | 19.3, 25.6 | 21.1, 26.0 | 19.0, 26.0 |
max, maximum; min, minimum; N, total number; Q1, first quartile; Q3, third quartile; SD, standard deviation.
Pharmacokinetics
The mean serum concentration–time profiles of firsekibart following administration of 120 and 200 mg are shown in Figure 3 and Figure 4, respectively. Serum concentration increased with dose after single and multiple subcutaneous administrations.
Figure 3.
Firsekibart serum concentration–time curves after the first dosing.
Figure 4.
Firsekibart serum concentration–time curves after the last dosing.
After a single subcutaneous injection of firsekibart 120 and 200 mg in healthy participants, the median Tmax was 7.0 days for both doses. The mean (±SD) Cmax was 16.0 (±4.4) and 29.2 (±11.5) µg/mL, and the mean (±SD) AUC0–t was 350.6 (±95.1) and 600.0 (±209.8) d·µg/mL, respectively, indicating dose‐proportional increases in exposure.
Following multiple doses, the median Tmax,ss was 4.0 days in firsekibart 120 mg group and 5.5 days in firsekibart 200 mg group, with mean (±SD) Cmax,ss 31.5 (±7.8) and 54.1 (±18.7) µg/mL. Systemic exposure, as measured by AUC0–τ reached 674.4 (±156.1) and 1101.3 (±353.6) d·µg/mL, AUC0–t,ss reached 1213.3 (±300.6) and 1975.8 (±625.3) d·µg/mL, while the mean (±SD) AUC0–∞,ss was 1445.3 (±419.1) and 2355.4 (±1006.1) d·µg/mL, respectively, suggesting dose‐proportional increases in exposure. Additionally, t1/2,ss was 31.0 (±5.2) and 30.4 (±10.8) days, CLss/F was 0.187 (± 0.047) and 0.206 (± 0.093) L/d, and Vz,ss/F was 8252 (±1918) and 8440 (±2878) mL, respectively.
The accumulation ratios for Cmax (Rac,Cmax) were 1.94 and 1.92, and for AUC (Rac, AUC) were both 1.88, indicating modest accumulation after multiple dosing. The PK parameters after the first dose and steady‐state PK parameters after the third dose are shown in Table 2.
Table 2.
PK Parameters After the First Dosing and the Third Dosing.
| PK Parameters |
Firsekibart‐120 mg (N = 10) |
Firsekibart‐200 mg (N = 10) |
|
|---|---|---|---|
| After the first dosing | Tmax (d) a | 7.0 (4.0, 14.0) | 7.0 (4.0, 14.0) |
| Cmax (µg/mL) | 16.0 ± 4.4 | 29.2 ± 11.5 | |
| AUC0–t (d·µg/mL) | 350.6 ± 95.1 | 600.0 ± 209.8 | |
| After the third dosing | Cmax,ss (µg/mL) | 31.5 ± 7.8 | 54.1 ± 18.7 |
| Tmax,ss (d) a | 4.0 (2.0, 14.0) | 5.5 (2.0, 7.0) | |
| t1/2,ss (d) | 31.0 ± 5.2 | 30.4 ± 10.8 | |
| AUC0–t,ss (d·µg/mL) | 1213.3 ± 300.6 | 1975.8 ± 625.3 | |
| AUC0–∞,ss (d·µg/mL) | 1445.3 ± 419.1 | 2355.4 ± 1006.1 | |
| AUC0–τ (d·µg/mL) | 674.4 ± 156.1 | 1101.3 ± 353.6 | |
| λz,ss (per hour) | 0.000953 ± 0.000137 | 0.00102 ± 0.000232 | |
| CLss/F (L/d) | 0.187 ± 0.047 | 0.206 ± 0.093 | |
| Vz,ss/F (mL) | 8252 ± 1918 | 8440 ± 2878 | |
| MRT0–inf,ss (d) | 44.6 ± 6.7 | 43.9 ± 7.3 | |
| Rac,AUC | 1.88 ± 0.218 | 1.88 ± 0.319 | |
| Rac,Cmax | 1.94 ± 0.267 | 1.92 ± 0.392 | |
AUC0–t, area under the concentration–time curve from 0 to t; AUC0–t,ss, area under the concentration–time curve at steady state from 0 to t; AUC0–∞,ss, area under the concentration–time curve at steady state from 0 to ∞; AUC0–τ, area under the concentration–time curve at steady state from 0 to τ, τ = 28 days; Cmax, peak concentration; Cmax,ss, peak concentration at steady state; CLss/F, apparent clearance at steady state; MRT0–inf,ss, mean residence time at steady state from 0 to infinity; N, total number; Rac,AUC, accumulation ratio for AUC0–28 days; Rac,Cmax, accumulation ratio for Cmax; t1/2,ss, half‐life at steady state; Tmax, peak time; Tmax,ss, time to reach Cmax,ss; Vz,ss/F, apparent volume of distribution at steady state; λz,ss, first order terminal elimination rate constant or apparent first order terminal elimination rate constant at steady state.
Tmax is shown as median (minimum, maximum), all other data are mean ± standard deviation.
Pharmacodynamics
Serum total IL‐1β concentration–time profiles following administration of firsekibart 120 and 200 mg are presented in Figure 5. In healthy participants, no apparent dose‐dependent change in IL‐1β levels was observed after either single or multiple subcutaneous administrations of firsekibart.
Figure 5.
Serum concentration–time curves of IL‐1β (C1, the first treatment cycle; C2, the second treatment cycle; and C3, the third treatment cycle).
Immunogenicity
All 20 participants who received firsekibart tested negative for ADA at baseline. Following treatment, one participant (5.0%) in the 200 mg group developed treatment‐emergent ADA on Day 15 after the first dose, with an ADA titer of 1:20, while NAb was negative. Subsequent ADA tests were all negative, and all other participants remained ADA negative throughout the study. No apparent differences in overall PK, PD, or safety profiles were observed in the participant with treatment‐emergent ADA.
Safety Assessments
During the trial, a total of 16 participants (66.7%) experienced treatment‐emergent adverse events (TEAEs). Among those receiving firsekibart, TEAEs were reported in 13 participants (65.0%), including 5 participants in the 120 mg group and 8 in the 200 mg group. In the placebo group, TEAEs were reported in three participants (75.0%). Thirteen participants (54.2%) experienced treatment‐related adverse events (TRAEs), which occurred in 10 participants (50%) in the total firsekibart group and 3 participants (75%) in the placebo group.
The most common reported TRAEs (occurred in ≥10% of participants) in the total firsekibart group were blood bilirubin increased, neutrophil count decreased, alanine aminotransferase increased, blood uric acid increased, white blood cell count increased, and nasopharyngitis. In the placebo group, most common (occurred in ≥10% of participants) TRAEs were blood triglycerides increased, blood bilirubin increased, neutrophil count decreased, alanine aminotransferase increased, and supraventricular extrasystoles.
One participant (4.2%) of grade ≥3 TEAEs was reported in the 120 mg firsekibart group. The event was blood creatine phosphokinase increased and classified as Common Terminology Criteria for Adverse Events (CTCAE) grade 4. It occurred following strenuous exercise and was assessed as “probably unrelated” to the study drug. No therapeutic intervention or dose modification was required. Re‐examination confirmed normalization of blood creatine phosphokinase levels, with the adverse event ultimately classified as “recovered.”
There were no serious adverse events (SAEs), TEAEs leading to treatment discontinuations, or death. Most TEAEs were CTCAE grade 1 or 2. The overall incidence of AEs was similar between the placebo and firsekibart groups, as well as between firsekibart 120 mg group and 200 mg group. A summary of all AEs is provided in Table 3.
Table 3.
Overall Adverse Events.
|
Variables, n (%) |
Firsekibart‐120 mg (N = 10) |
Firsekibart‐200 mg (N = 10) |
Total Firsekibart (N = 20) |
Placebo (N = 4) |
Total (N = 24) |
|---|---|---|---|---|---|
| TEAE | 5 (50.0) | 8 (80.0) | 13 (65.0) | 3 (75.0) | 16 (66.7) |
| TRAE | 5 (50.0) | 5 (50.0) | 10 (50.0) | 3 (75.0) | 13 (54.2) |
| SAE | 0 | 0 | 0 | 0 | 0 |
| TRAE reported in ≥10% of participants in total firsekibart group or placebo group | |||||
| Blood bilirubin increased | 1 (10.0) | 1 (10.0) | 2 (10.0) | 1 (25.0) | 3 (12.5) |
| Neutrophil count decreased | 1 (10.0) | 1 (10.0) | 2 (10.0) | 1 (25.0) | 3 (12.5) |
| Alanine aminotransferase increased | 2 (20.0) | 0 | 2 (10.0) | 1 (25.0) | 3 (12.5) |
| Blood uric acid increased | 1 (10.0) | 1 (10.0) | 2 (10.0) | 0 | 2 (8.3) |
| Blood triglycerides increased | 1 (10.0) | 0 | 1 (5.0) | 2 (50.0) | 3 (12.5) |
| White blood cell count increased | 1 (10.0) | 1 (10.0) | 2 (10.0) | 0 | 2 (8.3) |
| Nasopharyngitis | 1 (10.0) | 1 (10.0) | 2 (10.0) | 0 | 2 (8.3) |
| Supraventricular extrasystoles | 0 | 0 | 0 | 1 (25.0) | 1 (4.2) |
N, total number of participants per group; n, number of participants with associated adverse event; TEAE, treatment‐emergent adverse event; TRAE, treatment‐related adverse event.
Discussion
In this study, multiple subcutaneous doses of firsekibart (120 and 200 mg) administered every 4 weeks for 3 cycles were safe and well tolerated in healthy Chinese participants and showed predictable PK with moderate accumulation (accumulation ratios <2). No SAEs, injection‐site reactions, or discontinuations were reported, and most TEAEs were CTCAE grade 1 or 2. Firsekibart exhibited low immunogenicity, with only one participant showing transient ADA with negative neutralizing activity or no impact on PK, PD, or safety outcomes.
The current findings are consistent with previous studies of firsekibart. In a single ascending dose (SAD) phase 1 trial in Chinese healthy adults, doses of 0.3–6 mg/kg (18–360 mg for a 60‐kg individual) demonstrated dose‐proportional exposure and favorable tolerability. 11 In addition, a phase 3 randomized, double‐blind, positive‐controlled, multicenter trial in patients with gouty arthritis identified 200 mg as the optimal dose by integrating safety and efficacy outcomes. 10 Further support was provided by an unpublished phase 1b/2a study in sJIA, in which repeated dosing every 4 weeks resulted in accumulation ratios of approximately 1.5–2.3.
Based on these data, 200 mg was selected as the high dose for this study to ensure potential efficacy and safety for future clinical use. This MAD study was conducted after an earlier Ib/II study in patients with sJIA, which was performed between August 2021 and December 2022 using a Q4W dosing regimen. The present study in healthy adults was subsequently designed to support further development in adult indications involving recurrent inflammatory diseases, where repeated dosing is anticipated. Considering the drug product specification (150 mg/vial), 120 mg was chosen as the low dose to allow accurate administration while maintaining a clinically meaningful dose range, with a 67% difference between the low and high doses. This dose‐escalation strategy consists of pharmacological modeling and prior clinical evidence, ensuring both scientific rationale and clinical feasibility.
PK results in the present study confirmed dose‐proportional increases in Cmax and AUC0–t for both single and multiple doses, with accumulation ratios of 1.94 and 1.92 for Cmax, and 1.88 for AUC after repeated dosing. These findings align with those from another phase 1 study of firsekibart in Chinese healthy adults aged 18–50 years, who were divided into five dose‐escalated groups (0.3, 1.0, 2.0, 4.0, and 6.0 mg/kg). 11
Regarding PD, no dose‐dependent changes in serum total IL‐1β were observed. Baseline serum total IL‐1β levels observed in this study were very low and consistent with previously reported values in healthy adults. 11 This finding is partially distinct from canakinumab, which often leads to measurable increases in total IL‐1β due to antibody‐stabilized complexes. Two potential explanations are: (1) free IL‐1β is rapidly cleared from circulation, and (2) low baseline IL‐1β levels in healthy subjects may limit detectability despite tissue‐level cytokine production. 12
In terms of safety, AEs were mostly related to routine laboratory or clinical evaluations, with no meaningful difference between the placebo and firsekibart groups. One participant in the 120 mg group experienced elevated serum creatine phosphokinase after strenuous exercise, which was deemed possibly unrelated to the investigational drug. Overall, the use of IL‐1 inhibitors may be associated with a moderate increase in the risk of infection, but such events are generally mild or moderate. 13 In this study, three TEAEs of infections and infestations were reported, all grade 2 in severity, which resolved with appropriate management and were within the expected range.
Firsekibart is the first IL‐1β monoclonal antibody developed in China and has recently been approved for the treatment of acute gout flares in adults who have contraindications, intolerance, or inadequate response to nonsteroidal anti‐inflammatory drugs and/or colchicine, and for whom repeated use of corticosteroids is not appropriate. The data from this MAD study, combined with prior SAD and phase 3 trials, provide robust support for the 120 and 200 mg every 4 weeks dosing regimen and form a basis for further exploration in IL‐1 driven conditions such as gouty arthritis, sJIA, and other indications for multiple dosing.
This study has several limitations. As an early‐phase trial with a relatively small sample size, the safety and PK findings require confirmation in larger and more diverse patient populations. The treatment and follow‐up periods were relatively short, which limits the evaluation of long‐term safety and immunogenicity. Future clinical studies with extended treatment durations and broader patient cohorts are warranted to further validate these findings and optimize dose strategies.
Conclusion
Firsekibart exhibited well‐characterized PK profiles following multiple doses in healthy participants. Following administration at 4‐week intervals, systemic exposure increased with dose and showed modest accumulation, with low immunogenicity and good tolerability. The results support further evaluation of repeated dosing regimens in future clinical trials.
Conflicts of Interest
Tianhong Luo, Qian Xu, and Xiaoyan Zhu are employees of Changchun GeneScience Pharmaceutical Co., Ltd. The other authors have no conflicts of interest to declare.
Funding
This study was funded by Changchun GeneScience Pharmaceutical Co., Ltd.
Supporting information
Table S1 Inclusion/Exclusion criteria
Acknowledgments
We extend our sincere appreciation to the participants who agreed to participate in this study and the contribution of all site investigators. Comprehensive support in manuscript review and revision was provided by Huiwen Jiao from Changchun GeneScience Pharmaceutical Co., Ltd.
Data Availability Statement
The data can be obtained from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1 Inclusion/Exclusion criteria
Data Availability Statement
The data can be obtained from the corresponding author upon reasonable request.