ABSTRACT
Olamkicept is a first‐in‐class fully human fusion protein that selectively inhibits trans interleukin (IL)‐6 signaling. Previous phase I clinical trials demonstrated that single doses up to 750 mg and multiple doses up to 600 mg were safe and well tolerated in healthy men and women. The clinical efficacy of the 600 mg dose has been demonstrated in inflammatory bowel disease. This phase I, single‐center, within‐group randomized, double‐blind, dose‐extension trial examined the safety, pharmacokinetics (PK), and immunogenicity of single (SAD) and multiple ascending doses (MAD) of olamkicept. Healthy men aged 18–45 years were randomized 3:1 in panels of eight individuals to receive either olamkicept (1200 mg, 1800 mg, or 2400 mg) or placebo as either SAD or MAD every 2 weeks over a 6‐week period. The primary objective was to assess the safety of olamkicept based on treatment‐emergent adverse events, vital signs, electrocardiogram, clinical chemistry, hematology, and hemostasis. Secondary outcomes included PK and immunogenicity. Forty‐nine participants were randomized. Four treatment‐emergent adverse events (TEAEs) and one adverse drug reaction were reported in the SAD, and 16 TEAEs were reported in the MAD part. No treatment or dose‐related trends were observed across dose groups in any safety measure. Exposure increased in a dose‐proportional manner and there was no evidence of accumulation. New anti‐olamkicept antibodies were identified in 4/18 participants (22.2%) across all dose levels in the MAD part. SAD and MAD administration of up to 2400 mg olamkicept were well tolerated by healthy men and demonstrated dose‐proportional increases in exposure.
Keywords: inflammatory bowel disease, interleukin 6, olamkicept, pharmacokinetics, phase I, safety
Study Highlights
What is the current knowledge on the topic?
The inflammatory bowel diseases (IBDs) remain an area of unmet medical need. Olamkicept is a first‐in‐class, fully human, fusion protein that specifically inhibits trans interleukin‐6 (IL‐6) signaling. Olamkicept, administered as a 600 mg intravenous infusion every 2 weeks, has demonstrated evidence of clinical efficacy in phase II trials involving IBD patients with active disease. The treatment of bioexposed, moderate‐to‐severe IBD, however, may require higher doses of olamkicept to induce and maintain remission.
What question did this study address?
This phase I trial assessed the safety, PK, and immunogenicity of olamkicept in healthy men following single and multiple intravenous doses of 1200 mg, 1800 mg, and 2400 mg.
What does this study add to our knowledge?
This trial demonstrated that single and multiple doses of olamkicept at up to 2400 mg were well tolerated and showed dose‐dependent increases in exposure in healthy men.
How might this change clinical pharmacology or translational science?
These data are supportive of testing higher dosages of olamkicept in future efficacy trials. Based on positive outcomes in future phase II trials, higher doses of olamkicept, up to 2400 mg, may offer a novel treatment option for patients with IBD for whom current treatments may be suboptimal.
1. Introduction
Inflammatory bowel diseases (IBDs) reflect dysregulation of the immune system, resulting in chronic intestinal inflammation [1]. While pathogenesis is not fully understood, inherent genetic susceptibility and environmental factors may combine to cause alterations in gut microbiota, dysbiosis, and immune dysregulation [1, 2]. A systematic review and meta‐analysis of studies published from 2000 to 2022 estimated the global prevalence of IBD as approximately 230 cases per 100,000, including ulcerative colitis (120 cases per 100,000) and Crohn's disease (84 cases per 100,000) [3]. While treatment options for IBD have improved with the introduction of targeted biologic therapies, limitations remain in terms of suboptimal effectiveness, loss of treatment response, and adverse side effects, which highlight the need for novel therapeutic approaches [4].
Interleukin‐6 (IL‐6) is a key mediator in chronic inflammation and is thought to signal by at least two distinct signaling pathways. The classic signaling pathway involves IL‐6 binding to membrane‐bound IL‐6 receptor (mIL‐6R), which is expressed by certain immune cell populations, intestinal epithelial cells, hepatocytes, and osteoclasts [5, 6]. Binding of IL‐6 to mIL‐6R causes the recruitment and formation of a high‐affinity hexameric complex with the signal transducing element, glycoprotein 130 (gp130) [7]. Trans IL‐6 signaling involves complexes of soluble IL‐6 receptor (sIL‐6R) and IL‐6 binding to membrane‐bound gp130, which is almost ubiquitously expressed [5]. IL‐6 has been associated with both physiological and pathological effects, and it is hypothesized that these are mediated by classic and trans signaling, respectively [5].
Olamkicept is a first‐in‐class fully human fusion protein that specifically inhibits trans IL‐6 signaling by binding and neutralizing the IL‐6/sIL‐6R complex [8, 9]. In the phase I, first‐in‐human trials, single intravenous doses of olamkicept up to 750 mg and multiple dosages up to 600 mg were safe and well tolerated [10]. Olamkicept had an elimination half‐life of approximately 5 days, with dose‐dependent PK and no accumulation during multiple dosing. Olamkicept exposure was comparable in men and women (unpublished data). Ex vivo stimulation of peripheral blood mononuclear cells indicated that STAT3 phosphorylation was fully abrogated at concentrations ≥ 1 μg/mL, in an exploratory pharmacodynamic (PD) assay. PK modeling revealed that olamkicept 300–600 mg administered every 2 weeks maintained trough concentrations of approximately 1 μg/mL. Phase II trials, including patients with active IBD, provided evidence of efficacy at the 600 mg dose level [11]. Exploratory exposure response analyses of trial data revealed a trend toward greater efficacy with higher trough concentrations (unpublished data). Modeling of exposure indicated that olamkicept 600 mg administered every 4 weeks failed to maintain trough olamkicept concentrations of 1 μg/mL (unpublished data). Together, these analyses highlighted the need to explore the safety and PK of higher olamkicept dosages before investigating therapeutic efficacy further.
Therefore, this trial in healthy men was performed to address the need for safety, PK, and immunogenicity data for olamkicept at dose levels beyond those currently evaluated in the first‐in‐human phase I trial [10]. Single and multiple olamkicept doses of 1200 mg, 1800 mg, and 2400 mg were selected based on phase I and II data, in silico modeling and simulation, and non‐clinical toxicology data [8, 10, 11, 12, 13, 14] and tested to inform future clinical trials. Modeling indicated that doses of ≥ 1200–1800 mg were required to maintain concentrations above the PD threshold [14]. Therefore, 2400 mg was selected as the upper boundary to characterize linearity, safety, and tolerability at the highest feasible exposure.
2. Methods
2.1. Trial Design
This was a phase I, within‐group randomized, double‐blind trial investigating the safety, PK, and immunogenicity of olamkicept in healthy men (NCT06298032). The trial was conducted at a single site (Charité Research Organization GmbH, Berlin, Germany). Permission to perform the trial was obtained in accordance with applicable regulatory requirements. The trial was performed in accordance with the Declaration of Helsinki and International Council for Harmonization Good Clinical Practice (GCP) guidelines. Participants were informed of the risks and benefits of the trial, and that they could withdraw from the trial at any time for any reason. Written consent was obtained before the trial‐related activities started. The trial protocol, the informed consent form, and all written information that was shared with trial participants were reviewed and approved by an independent ethics committee before trial initiation (Ethik‐Kommission des Fachbereichs Medizin der Goethe Universität; EU Clinical Trial Number: 2023‐507882‐24‐00; approval date: 8 February 2024).
2.2. Trial Population
The trial recruited healthy men aged between 18 and 45 years, with no history of chronic inflammatory disease. Key exclusion criteria included the history of clinically significant medical conditions and alcohol or drug abuse. For full eligibility criteria, please see Table S1.
2.3. Randomization and Blinding
Randomization and treatment allocation were performed by an electronic data capture system. Unblinded pharmacy staff prepared olamkicept and placebo in identical intravenous (IV) infusion bags based on the randomization list provided by the sponsor. The trial investigators, their associated clinical trial team, and trial participants were blinded to treatment allocation throughout the trial.
2.4. Treatment
Olamkicept powder was reconstituted in 5 mL of water for injection and was diluted to 250 mL in 0.9% saline solution. The placebo group received 250 mL of 0.9% saline solution alone. Three dose levels of olamkicept (1200 mg, 1800 mg, and 2400 mg) were evaluated in each part of the trial. Both olamkicept and placebo were infused by IV over 2 h in the morning of the dosing days; this infusion duration was selected to maintain a similar milligrams‐per‐minute infusion rate as in the first‐in‐human trial [10] and minimize the risk of infusion‐related reactions at substantially higher total doses. A dosing interval of 2 weeks was selected for the MAD part of the trial, as this was the most frequent dose schedule aimed for in the current development plan. Three dose administrations over 6 weeks were expected to enable assessment of steady‐state exposures, given that olamkicept has a terminal half‐life of approximately 5–6 days.
Dose groups were randomized in a 3:1 ratio to either olamkicept or placebo. Sentinel dosing was performed in the single ascending dose (SAD) part of the trial. Forty‐eight‐hour safety data for the first two participants (randomized 1:1 to olamkicept and placebo) were evaluated by the investigator before continuing administration to the remaining six participants in each dose group (randomized 5:1 to olamkicept and placebo). A safety review committee (SRC) was established to evaluate safety and PK of olamkicept for each dosing regimen and dose level during the conduct of the trial. Decisions to escalate dose were based on a minimum of 10 days safety data and 4 days systemic exposure data. Infusion of multiple ascending doses (MAD) was only permitted if safety for the same dose level was confirmed by the SRC during the SAD part.
In the SAD part, treatment period (TP)1 included a residential stay from Day −1 to Day 3 and ambulatory visits on Days 4, 5, 8, and 11 (Figure S1a). Follow‐up visits were scheduled on Days 15, 22, 29, and 36 ± 2 days. Olamkicept or placebo was administered on Day 1 of the TP. In the MAD part, participants received olamkicept or placebo on Day 1 of each of three, 2‐week TPs1–3 (Figure S1b). All TPs included residential stays from Day −1 to Day 3 of each TP; TP1 included ambulatory visits on Days 4, 5, 8, and 11, and TP3 included ambulatory visits on trial Days 32, 33, 36, and 39. Follow‐up visits in the MAD part were scheduled on trial Days 43, 50, 57, and 64 ± 2 days.
2.5. Primary Safety Endpoints
The primary objective of the trial was to assess the safety of olamkicept in healthy men after single and multiple IV infusions. The frequency, type, intensity, and causality of treatment‐emergent adverse events (TEAEs) were recorded throughout the trial (Figure S1a,b). Changes in vital signs, 12‐lead electrocardiogram (ECG), hematology, clinical chemistry, hemostasis, and urinalysis parameters from baseline to Day 36 after a single dose infusion or Day 64 after multiple dose infusions were analyzed. The timings of assessments are detailed in Figure S1a,b.
2.6. Secondary PK Endpoints
Secondary endpoints of the trial included PK analyses following SAD and MAD dosing. Blood samples for PK analysis were taken at prespecified intervals after SAD and MAD dosing (Figure S1a,b).
Serum olamkicept concentrations were quantified using a validated sandwich electrochemiluminescence immunoassay (Meso Scale Discovery platform; Ferring Pharmaceuticals A/S). The assay employs a mouse anti‐gp130 monoclonal antibody as the capture reagent and a ruthenium‐tagged anti‐olamkicept F(ab')2 fragment as the detection reagent. Calibration standards were prepared in human serum, and the validated analytical range extended from 0.375 to 1440 μg/mL, with accuracy and precision meeting predefined acceptance criteria at all concentration levels. Assay validation included assessments of selectivity, dilution linearity, parallelism, intra‐ and inter‐assay precision, freeze–thaw stability, benchtop stability, and long‐term storage stability. No matrix interference was observed in serum from healthy volunteers. Samples below the lower limit of quantification were treated as zero for non‐compartmental analysis. This assay is consistent with the validated method previously used in the first‐in‐human Phase I study of olamkicept [10].
SAD PK parameters included area under the concentration‐time curve from dosing to infinity (AUCinf), area under the concentration‐time curve to last measurable concentration (AUClast), observed serum concentration at end of infusion (C eoi), baseline‐adjusted maximum observed concentration (C max; this was the same as the observed C max, since all participants were treatment‐naïve, and no measurable olamkicept concentrations were detected at baseline), time of maximum observed concentration (t max) measured from the start of infusion, terminal half‐life (t ½), mean residence time (MRT), total clearance (CL), and apparent volume of distribution at steady‐state (V ss). MAD PK parameters included area under concentration‐time curve from dosing up to time τ, where τ is the dosing interval (AUCτ), AUClast, observed accumulation index (R ac), C eio, C max, t max, t ½, MRT, CL, and V ss. Blood samples for the PK analysis were collected immediately before each infusion of investigational medicinal product on Day 1 of TP1 (SAD part) and TPs1–3 (MAD part), and 0.5, 2, 4, 8, 12, 24, 36, and 48 h after the start of infusion. Blood samples at 72 and 96 h after the start of the infusion were taken during TP1 in the SAD part, and TP1 and TP3 in the MAD part. Blood samples were also taken on Days 8 and 11 (SAD part TP1 and MAD part TP1 and TP3), as well as Days 15, 22, and 29 (SAD part) and Days 43, 50, and 57 (MAD part). PK analysis was conducted using Phoenix WinNonlin version 8.5 (Certara Inc., Radnor, PA, USA).
2.7. Secondary Immunogenicity Analysis
Testing for anti‐olamkicept antibodies was performed on Days 1, 15, and 57 in the MAD part. The analysis was performed using a validated electrochemiluminescence assay (Meso Scale Discovery) of a bridging model employing a tiered approach at Bioanalysis and Biomarkers, Ferring Pharmaceuticals A/S. Confirmed positive samples were subsequently analyzed for titer and cross‐reactivity to gp130.
2.8. Other Assessments
Demographics and medical history were recorded at screening.
2.9. Statistical Analysis
Data were reported using descriptive statistics. Data from participants in the placebo groups within each of the SAD and MAD parts of the trial were pooled separately. The full analysis set (FAS) comprised all randomized participants who received ≥ 1 dose of the investigational medicinal product. The description of exposure, compliance, and baseline characteristics (demographics, medical history, prior and concomitant medication, and physical examination) were based on the FAS. The per protocol (PP) analysis set comprised all participants in the FAS without major protocol deviations, analyzed by actual treatment received. The description of PK endpoints was based on the PP analysis set. The safety analysis set (SAS) comprised all treated participants, analyzed by actual treatment received. Safety descriptions were based on the SAS. No formal sample size calculations were performed.
3. Results
3.1. Participant Disposition
In total, 164 participants were screened for participation, 115 were considered screen failures and 49 were randomized to treatment (Table S2). Forty‐eight randomized participants were exposed to treatment. In the SAD part, one participant discontinued before treatment due to baseline failure (suspected hypothyroidism). In the MAD part, two participants discontinued treatment with placebo: one due to a TEAE (COVID‐19 infection) and one due to the participant requesting to withdraw from the trial. The FAS, PP, and SAS populations were identical and included all exposed participants.
3.2. Baseline Characteristics
Demographics and body measurements were similar between dose groups and trial parts, with mean age ranging from 30.8 to 36.0 years, and mean body mass index ranging from 23.4 to 26.7 kg/m2 (Table 1). Eighty‐three percent (40/48) of participants were White. No medical history reported by the participants was considered clinically relevant for their participation in the trial.
TABLE 1.
Baseline demographics (FAS).
| Olamkicept 1200 mg (N = 6) | Olamkicept 1800 mg (N = 6) | Olamkicept 2400 mg (N = 6) | Placebo (N = 6) | Total (N = 24) | |
|---|---|---|---|---|---|
| SAD part | |||||
| Age (years) | |||||
| Mean (SD) | 30.8 (8.1) | 36.0 (7.5) | 32.7 (7.4) | 35.3 (5.4) | 33.7 (7.0) |
| Median (min; max) | 33.5 (20.0; 41.0) | 39.5 (22.0; 41.0) | 34.0 (22.0; 41.0) | 35.0 (29.0; 42.0) | 34.0 (20.0; 42.0) |
| Baseline weight (kg) | |||||
| Mean (SD) | 85.2 (12.1) | 86.4 (10.8) | 79.5 (11.5) | 82.6 (10.0) | 83.4 (10.7) |
| Median (min; max) | 88.2 (69.7; 97.6) | 89.1 (67.5; 97.6) | 77.6 (67.4; 94.5) | 84.3 (63.7; 92.8) | 85.4 (63.7; 97.6) |
| Baseline BMI (kg/m2) | |||||
| Mean (SD) | 26.2 (3.5) | 26.7 (2.9) | 24.5 (2.1) | 25.4 (3.2) | 25.7 (2.9) |
| Median (min; max) | 26.6 (21.5; 29.8) | 27.7 (21.3; 29.3) | 24.2 (22.4; 27.4) | 25.1 (20.1; 29.4) | 25.6 (20.1; 29.8) |
| MAD part | |||||
| Age (years) | |||||
| Mean (SD) | 35.7 (7.5) | 33.5 (4.4) | 33.2 (4.7) | 33.5 (5.7) | 34.0 (5.4) |
| Median (min; max) | 36.0 (24.0; 44.0) | 34.0 (28.0; 39.0) | 31.0 (29.0; 40.0) | 33.5 (24.0; 40.0) | 34.0 (24.0; 44.0) |
| Baseline weight (kg) | |||||
| Mean (SD) | 75.3 (4.5) | 82.2 (10.8) | 81.7 (8.4) | 79.9 (10.0) | 79.8 (8.6) |
| Median (min; max) | 76.3 (69.7; 81.0) | 87.3 (64.7; 91.1) | 80.3 (71.8; 94.1) | 81.5 (63.5; 92.4) | 79.2 (63.5; 94.1) |
| Baseline BMI (kg/m2) | |||||
| Mean (SD) | 23.4 (2.0) | 25.0 (2.9) | 25.3 (2.0) | 25.6 (2.9) | 24.8 (2.5) |
| Median (min; max) | 23.6 (20.1; 25.9) | 25.7 (20.4; 28.4) | 25.6 (22.2; 27.8) | 26.4 (20.5; 28.0) | 25.1 (20.1; 28.4) |
Abbreviations: BMI, body mass index; FAS, full analysis set; MAD, multiple ascending dose; max, maximum; mg, milligrams; min, minimum; N, number; SAD, single ascending dose; SD, standard deviation.
3.3. Prior and Concomitant Medication
No prior medications were reported. Concomitant medication was reported for one participant in each of the 2400 mg olamkicept and placebo groups in the SAD part, and two participants in each of the olamkicept dose groups and one participant in the placebo group in the MAD part. The concomitant medications reported were classified under Anatomical Therapeutic Chemical Level One categories of anti‐infectives for systemic use, musculoskeletal system, and nervous system.
3.4. Exposure and Treatment Compliance
All participants in the SAD part received their scheduled single dose infusions of olamkicept or placebo. In the MAD part, 22 (91.7%), including 100% of olamkicept‐treated participants, received their scheduled infusions, and two (8.3%) in the placebo group did not complete all three infusions.
3.5. Safety
In total, four TEAEs were reported in the SAD part and 16 TEAEs were reported in the MAD part. TEAEs were non‐serious and affected a single participant in each of the four treatment groups in the SAD part (Table 2). In the MAD part, two participants in each of the olamkicept 1800 mg and placebo groups, and three participants in each of the olamkicept 1200 and 2400 mg groups experienced TEAEs; only toothache, nasopharyngitis, and headache were reported by more than one participant (Table S3). No treatment or dose‐related trends were observed across dose groups. One adverse drug reaction (ADR; diarrhea) and one serious TEAE (traumatic jaw fracture) were reported in the SAD part, and one TEAE leading to discontinuation (COVID‐19) was reported in the MAD part. No serious ADRs were reported. Except for the jaw fracture in the placebo group in the SAD part, all TEAEs were of mild or moderate intensity. No ADRs or TEAEs resulted in death.
TABLE 2.
Summary of adverse events (SAS).
| Olamkicept 1200 mg (N = 6) | Olamkicept 1800 mg (N = 6) | Olamkicept 2400 mg (N = 6) | Placebo (N = 6) | Total (N = 24) | |
|---|---|---|---|---|---|
| SAD part, n (%) [E] | |||||
| TEAE | 1 (16.7) [1] | 1 (16.7) [1] | 1 (16.7) [1] | 1 (16.7) [2] | 4 (16.7) [5] |
| ADR | 1 (16.7) [1] | 0 | 0 | 0 | 1 (4.2) [1] |
| Non‐drug related AE | 0 | 1 (16.7) [1] | 1 (16.7) [1] | 1 (16.7) [2] | 3 (12.5) [4] |
| AE leading to death | 0 | 0 | 0 | 0 | 0 |
| AE leading to discontinuation | 0 | 0 | 0 | 0 | 0 |
| Serious AE | 0 | 0 | 0 | 1 (16.7) [1] | 1 (4.2) [1] |
| Serious ADR | 0 | 0 | 0 | 0 | 0 |
| MAD part, n (%) [E] | |||||
| TEAE | 3 (50.0) [4] | 2 (33.3) [5] | 3 (50.0) [5] | 2 (33.3) [2] | 10 (41.7) [16] |
| ADR | 0 | 0 | 0 | 0 | 0 |
| Non‐drug related AE | 3 (50.0) [4] | 2 (33.3) [5] | 3 (50.0) [5] | 2 (33.3) [2] | 10 (41.7) [16] |
| AE leading to death | 0 | 0 | 0 | 0 | 0 |
| AE leading to discontinuation | 0 | 0 | 0 | 1 (16.7) [1] | 1 (4.2) [1] |
| Serious AE | 0 | 0 | 0 | 0 | 0 |
| Serious ADR | 0 | 0 | 0 | 0 | 0 |
Abbreviations: %, percentages of participants with event; ADR, adverse drug reaction; AE, adverse event; E, number of events; N, number of participants; n, number of participants with event; SAS, safety analysis set; TEAE, treatment‐emergent adverse event.
3.6. Clinical Laboratory Findings
No treatment‐ or dose‐related trends in clinical chemistry, hematology, hemostasis, urinalysis, vital signs, or electrocardiogram results were observed across dose groups. Abnormal results were sporadically reported, none of which were classified as clinically significant.
3.7. PK
Serum concentration profiles of olamkicept in the SAD part showed exposure during the full 28‐day TP (Figure 1). There was no evidence of accumulation in the MAD part (Figure 2). Mean t max, measured from the start of infusion until just after infusion completion, was 2.1 h across the SAD and MAD parts, and mean t 1/2 ranged from 5.2 to 5.8 days following a single IV infusion and 5.4 to 6.7 days following multiple IV infusions (Table 3). Exposure dose proportionally increased in both the SAD and MAD studies (Figures 3 and 4). The distribution and clearance of olamkicept was also similar across dose levels and regimens, with mean V ss ranging from 8.9 to 10.2 L and mean CL ranging from 2.3 to 2.6 L/day following single IV injections, and mean V ss ranging from 8.1 to 10.6 L and mean CL ranging from 2.3 to 2.5 L/day following multiple IV infusions (Table 3).
FIGURE 1.
Mean serum concentration–time profiles: SAD Part A Mean (± SD) serum concentration–time profiles of olamkicept following single ascending doses of 1200 mg, 1800 mg, and 2400 mg administered intravenously over 2 h to healthy male participants (N = 6 per dose). Profiles are displayed on a semi‐logarithmic scale to highlight the terminal elimination phase. Thin lines represent individual participant profiles; thick lines indicate mean ± SD. Olamkicept concentrations declined mono exponentially after infusion completion, consistent with linear pharmacokinetics across the tested dose range. SAD, single ascending dose; SD, standard deviation.
FIGURE 2.
Mean serum concentration–time profiles: MAD Part B Mean (±SD) serum concentration–time profiles of olamkicept following multiple ascending doses of 1200 mg, 1800 mg, and 2400 mg administered intravenously every 2 weeks (three doses in total) to healthy male participants (N = 6 per dose). Profiles are shown on a semi‐logarithmic scale. Vertical dashed lines indicate the timing of each administration (doses 1–3). Thin lines represent individual participant profiles; thick lines indicate mean ± SD. Comparable concentration–time curves across dosing cycles demonstrate minimal accumulation and consistent elimination kinetics. MAD, multiple ascending dose; SD, standard deviation.
TABLE 3.
Pharmacokinetics of olamkicept (PP analysis set).
| Olamkicept 1200 mg (N = 6) | Olamkicept 1800 mg (N = 6) | Olamkicept 2400 mg (N = 6) | |
|---|---|---|---|
| SAD part | |||
| AUCinf (day*μg/mL) | |||
| Mean (SD) | 522.1 (49.4) | 699.2 (55.0) | 1016.7 (105.8) |
| AUClast (day*μg/mL) | |||
| Mean (SD) | 516.2 (49.5) | 692.5 (53.7) | 1007.3 (106.4) |
| Ceoi (μg/mL) | |||
| Mean (SD) | 320.5 (17.6) | 418.8 (48.6) | 647.8 (107.3) |
| Cmax (μg/mL) | |||
| Mean (SD) | 340.5 (20.4) | 441.2 (52.1) | 687.7 (117.3) |
| T max (h) | |||
| Mean (SD) | 2.1 (0.12) | 2.1 (0.04) | 2.1 (0.04) |
| t 1/2 (day) | |||
| Mean (SD) | 5.8 (0.7) | 5.2 (0.4) | 5.4 (0.8) |
| MRT (day) | |||
| Mean (SD) | 4.0 (0.2) | 3.9 (0.2) | 3.7 (0.3) |
| CL (L/day) | |||
| Mean (SD) | 2.3 (0.2) | 2.6 (0.2) | 2.4 (0.3) |
| V ss (L) | |||
| Mean (SD) | 9.3 (0.8) | 10.2 (0.8) | 8.9 (1.5) |
| MAD part | |||
| AUCτ (day*μg/mL) | |||
| Mean (SD) | 495.2 (59.8) | 726.3 (114.1) | 1048.2 (151.9) |
| AUClast (day*μg/mL) | |||
| Mean (SD) | 470.89 (49.9) | 694.58 (115.0) | 954.39 (132.9) |
| R ac | |||
| Mean (SD) | 1.0 (0.1) | 1.0 (0.1) | 1.1 (0.1) |
| C eoi (μg/mL) | |||
| Mean (SD) | 297.6 (30.1) | 482.2 (51.2) | 696.7 (142.9) |
| C max (μg/mL) | |||
| Mean (SD) | 313.2 (33.4) | 512.0 (57.6) | 725.8 (134.2) |
| T max (h) | |||
| Mean (SD) | 2.1 (0.03) | 2.1 (0.03) | 2.1 (0.07) |
| t 1/2 (day) | |||
| Mean (SD) | 6.6 (0.8) | 6.7 (0.8) | 5.4 (0.7) |
| MRT (day) | |||
| Mean (SD) | 4.4 (0.3) | 3.9 (0.4) | 3.5 (0.3) |
| CL (L/day) | |||
| Mean (SD) | 2.5 (0.3) | 2.5 (0.4) | 2.3 (0.3) |
| V ss (L) | |||
| Mean (SD) | 10.6 (0.7) | 9.9 (2.1) | 8.1 (1.8) |
Abbreviations: AUCτ, area under the concentration–time curve from dosing up to time τ, where τ is the dosing interval; AUCinf, area under the concentration‐time curve from dosing to infinity; AUClast, area under the concentration‐time curve to last measurable concentration; C eio, observed serum concentration at end of infusion; CL, total clearance; C max, baseline‐adjusted maximum observed concentration (also referred to as maximum exposure); MRT, mean residence time; N, number of participants; n, number of participants with observations; PP, per protocol; R ac, observed accumulation index; SD, standard deviation; t ½, terminal half‐life; T max, time of maximum observed concentration; V ss, apparent volume of distribution at steady‐state.
FIGURE 3.
Dose proportionality of C max following SAD and MAD cohorts Relationship between olamkicept dose and observed C max values following single (SAD, panel a) and multiple (MAD, panel b) ascending dose administration. Gray circles represent individual participant values; black circles indicate geometric means ± 95% CIs. The orange line shows linear regression fits; corresponding equations and R 2 values are provided. C max increased approximately proportionally with dose under both SAD and MAD conditions, supporting linear pharmacokinetics. CI, confidence interval; C max, baseline‐adjusted maximum observed concentration (also referred to as maximum exposure); MAD, multiple ascending doses; SAD, single ascending doses.
FIGURE 4.
Dose proportionality of AUClast following SAD and MAD cohorts Relationship between olamkicept dose and AUClast values following single (SAD, panel a) and multiple (MAD, panel b) ascending dose administration. Gray circles represent individual participant values; black circles indicate geometric means ± 95% CIs. The orange line shows linear regression fits; corresponding equations and R 2 values are provided. AUClast increased linearly with dose, confirming dose proportional exposure across the studied range. AUClast, area under the concentration–time curve to last measurable concentration; CI, confidence interval; MAD, multiple ascending doses; SAD, single ascending doses.
3.8. Immunogenicity
Anti‐olamkicept antibodies were identified in five of 18 participants (27.8%) across all dose levels in the MAD part (Table S4). One participant in the olamkicept 2400 mg group had preexisting anti‐olamkicept antibodies before treatment, but he had a four‐fold increase in antibody levels after treatment (i.e., Day 57). In four participants (22.2%), anti‐olamkicept antibodies were only detected after treatment (Day 15 or 57). Antibody titers ranged from < 8 to 64, with the highest titer samples of 32 and 64 showing cross‐reactivity against gp130.
4. Discussion
This phase I trial examined the safety, PK, and immunogenicity of olamkicept 1200 mg, 1800 mg, and 2400 mg, either as single doses or as multiple doses infused every 2 weeks for 6 weeks. This extends the dose range compared with the previous phase I trial, which examined single (0.75–750 mg) or four multiple doses (75–600 mg; once weekly) of olamkicept in healthy men and women [10]. The higher doses of olamkicept administered in this trial demonstrated a positive safety profile that was consistent with the previous trial [10]. There were no events of gastrointestinal tract perforation or laboratory findings suggestive of myelotoxicity or hepatotoxicity, which have been reported with other IL‐6 or IL‐6R therapeutic antibodies [15]. A separate phase I, SAD trial has also been performed to assess the safety and PK of 1200 mg, 1800 mg, and 2400 mg of olamkicept in Japanese men [16].
Consistent with the previous phase I trial, there were no clear dose‐ or concentration‐related TEAEs, clinical laboratory results, vital signs, or physical examination findings [10]. There were no ADRs or TEAEs that resulted in death in either the current or previous phase I trials [10]. No infusion reactions were reported in the current trial; however, infusion reactions were reported by three of 84 (3.6%) participants treated with olamkicept in the previous phase I trial [10]. The safety findings from the current trial are also consistent with earlier phase II studies with lower doses of olamkicept of up to 600 mg every 2 weeks for the treatment of IBD [8, 11] and with the Japanese SAD part [16].
Olamkicept administered at up to 2400 mg every 2 weeks showed dose‐proportional increases in exposure, suggestive of linear PK, which is consistent with the phase I, first‐in‐human trial [10] and the phase I SAD part in Japanese men [16]. Also consistent with the previous trial [10], there was no evidence for the accumulation of olamkicept. Distribution and clearance were similar across dose groups.
In the current trial, treatment‐induced antibodies were detected in four out of 18 participants (22.2%). No dose‐dependency in anti‐olamkicept antibody frequencies or titers was observed. The presence of antibodies was not associated with any infusion reactions or other adverse events. The clinical impact of treatment‐induced antibodies remains unclear and warrants further investigation in larger, long‐term studies. Additionally, anti‐olamkicept antibodies were detected before drug exposure in one patient. Such pre‐existing antibodies may occur due to prior exposure to environmental antigens (e.g., microbial proteins or dietary components) that share structural similarities with olamkicept. The human‐derived domains of olamkicept may contain epitopes that cross‐react with naturally occurring antibodies. Other reasons for the occurrence of pre‐existing antibodies could be rheumatoid factors or anti‐hinge antibodies binding to conserved regions of therapeutic proteins [8]. They could also have been a false‐positive result, as the analytical method is designed to result in some false positives rather than false negatives.
The limitations of the current trial are typical for phase I investigations. This was a small trial in healthy volunteers focused on analyzing the safety and PK of olamkicept. The limited sample size may have restricted the ability to detect rare or less common adverse events and limited the statistical power to identify subtle dose‐related trends or immunogenicity signals. The follow‐up period may not have been sufficient to capture delayed adverse events, long‐term immunogenicity, or cumulative toxicity, especially relevant for a biologic intended for chronic use. The study was conducted exclusively in healthy male volunteers, so the findings may not fully extrapolate to the intended patient population (i.e., individuals with IBD, including women, older adults, and those with comorbidities). The immune status, disease‐related factors, and concomitant medications in patients may also influence both safety and PK. While the lack of ethnic and geographic diversity in the current trial may limit the generalizability of the findings to broader non‐European populations, a separate phase I trial has been performed with Japanese participants to address this [16]. Finally, as a phase I trial, no efficacy outcomes were included, so no conclusions can be drawn regarding clinical efficacy or optimal dosing for disease control in IBD. Therefore, further clinical studies are required to demonstrate the efficacy and safety of higher doses of olamkicept, up to 2400 mg every 2 weeks, in wider populations of patients with IBD.
In conclusion, this phase I trial in healthy men demonstrates that olamkicept, administered at doses up to 2400 mg every 2 weeks, is well tolerated and exhibits dose‐proportional PK without evidence of systemic accumulation. The incidence of anti‐drug antibodies suggested a benign immunogenicity profile, and no new safety signals were identified at these higher doses. Importantly, by selectively targeting IL‐6 trans signaling, olamkicept may avoid the adverse events associated with inhibition of classical IL‐6 pathways. However, as this study was conducted in a healthy population, further clinical trials in patients with IBD are essential to confirm the safety, immunogenicity, and therapeutic efficacy of higher olamkicept doses in the intended patient population.
Author Contributions
S.I., A.R., K.B., M.F., L.‐E.K, S.M., A.R., and P.P. wrote the manuscript; S.I., A.R., K.B., M.F., L.‐E.K, S.M., A.R., and P.P. designed the research; S.I. and K.B. performed the research; A.R., K.B., M.F., L.‐E.K, S.M., A.R., and P.P. analyzed the data.
Funding
This study was funded by Ferring Pharmaceuticals.
Conflicts of Interest
K.B., M.F., L.‐E.K., S.M., A.R. (Arjun Ravi) are employees of Ferring Pharmaceuticals. P.P. is employed by Ferring Pharmaceuticals, is a member of the Board of Directors of PharmaBiome, is CEO and shareholder of Shiroito Co. Ltd., and owns stocks of Takeda Pharmaceutical Co. Ltd.; All other authors declared no competing interests for this work.
Supporting information
Table S1: Full inclusion and exclusion criteria.
Table S2: Participant disposition.
Table S3: All AEs.
Table S4: Immunogenicity (PP analysis set).
Figure S1: (a) SAD; (b) MAD part design.
Acknowledgments
The authors acknowledge the contributions of the Ferring laboratory staff. Medical writing support, under the direction of the authors, was provided by Mike Lappin, PhD, Cristiana Miglio, PhD, and Nathaniel Grubbs, PhD, of IQVIA Medical Communications, funded by Ferring Pharmaceuticals, in accordance with Good Publication Practice guidelines.
Data Availability Statement
Information regarding the study is available from ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT06298032).
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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: Full inclusion and exclusion criteria.
Table S2: Participant disposition.
Table S3: All AEs.
Table S4: Immunogenicity (PP analysis set).
Figure S1: (a) SAD; (b) MAD part design.
Data Availability Statement
Information regarding the study is available from ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT06298032).