
==== Front
Clin Transl Sci
Clin Transl Sci
10.1111/(ISSN)1752-8062
CTS
Clinical and Translational Science
1752-8054
1752-8062
John Wiley and Sons Inc. Hoboken

10.1111/cts.13873
CTS13873
CTS-2024-0048
Article
Article
Randomized, placebo‐controlled study on the effects of intravenous GSK3858279 (anti‐CCL17) on a battery of evoked pain tests in healthy participants
Analgesic effects of GSK3858279 in healthy males
Boyle et al.
Boyle Yvonne 1 yboyle999@gmail.com

Hijma Hemme J. https://orcid.org/0000-0001-7298-8650
2 3
Rees Jamie https://orcid.org/0000-0001-9581-6229
4
Nijjar Jagtar https://orcid.org/0000-0003-4947-6299
5
Panoilia Eirini 5
Alvarez Yolanda https://orcid.org/0000-0001-6367-0165
4
Siederer Sarah https://orcid.org/0000-0001-6408-7393
5
Greening Emma 4
Emery Edward https://orcid.org/0000-0001-9723-8661
1
Abbott Banner Kathy https://orcid.org/0000-0003-1470-7368
4
Groeneveld Geert Jan https://orcid.org/0000-0002-4655-6667
2 3
1 GSK Cambridge UK
2 Centre for Human Drug Research Leiden The Netherlands
3 Leiden University Medical Centre Leiden The Netherlands
4 GSK Brentford UK
5 GSK Stevenage UK
* Correspondence
Yvonne Boyle, GSK, Cambridge, UK.
Email: yboyle999@gmail.com

09 9 2024
9 2024
17 9 10.1111/cts.v17.9 e1387317 5 2024
31 1 2024
02 6 2024
© 2024 GSK. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Abstract

C–C Motif Chemokine Ligand 17 (CCL17) is a chemokine that binds and signals through the G‐protein coupled CC‐chemokine receptor 4 and has been implicated in the development of inflammatory and arthritic pain. GSK3858279 is a high‐affinity, first‐in‐class, monoclonal antibody, binding specifically to CCL17 and inhibiting downstream signaling. In this phase I, randomized, single‐center, double‐blind, placebo‐controlled, three‐period, incomplete‐block crossover study (NCT04114656), the analgesic effects and safety of intravenous GSK3858279 were assessed in a battery of evoked acute pain assessments on healthy, adult (aged ≥18 years), male participants. Participants were randomized 1:1 to receive either one placebo (0.9% w/v NaCl) dose followed by two GSK3858279 doses (PAA treatment sequence), or one GSK3858279 dose followed by two placebo doses (APP treatment sequence). The co‐primary end points were ultraviolet B heat pain detection threshold (°C), cold pressor time to pain tolerance threshold (PTT, sec), and electrical PTT (mA, single stimulus). Twenty‐one participants were enrolled (PAA = 11; APP = 10). Mean age (standard deviation) was 29.3 (7.9) years for PAA, 31.1 (7.7) years for APP. No significant differences were observed in the analgesic effect between GSK3858279 and placebo for any end point. Exposure to GSK3858279 was similar between Period 1 (APP sequence), and Periods 2 and 3 (PAA sequence), with some GSK3858279 carry‐over. Changes in serum CCL17 levels were consistent with the expected GSK3858279 activity. All drug‐related adverse events were mild in intensity and caused no discontinuations. The absence of an efficacy signal in this acute pain model does not preclude efficacy in chronic pain states.

source-schema-version-number2.0
cover-dateSeptember 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:09.09.2024
Boyle Y , Hijma HJ , Rees J , et al. Randomized, placebo‐controlled study on the effects of intravenous GSK3858279 (anti‐CCL17) on a battery of evoked pain tests in healthy participants. Clin Transl Sci. 2024;17 :e13873. doi:10.1111/cts.13873

Yvonne Boyle, Hemme J. Hijma, Jamie Rees, Jagtar Nijjar, Emma Greening and Edward Emery: At time of study.
==== Body
pmcINTRODUCTION

C–C Motif Chemokine Ligand 17 (CCL17) is a chemokine produced by various cell types (including dendritic cells, macrophages, platelets, fibroblasts, endothelial cells, and keratinocytes) that binds and signals through the G‐protein coupled CC‐chemokine receptor 4 (CCR4), and has recently been implicated in the development of inflammatory and arthritic pain in preclinical models. 1 , 2 , 3 , 4 CCR4 is predominantly expressed on Type 2 T helper cells but is also present on other immune and non‐immune cell types. 1 , 4 In murine models, intraplantar injection of recombinant CCL17 resulted in pain in a CCR4‐dependent manner 1 while therapeutic dosing with an anti‐CCL17 surrogate monoclonal antibody (mAb) inhibited established inflammatory pain. 3 As the preclinical data are compelling, the role of CCL17 in modulating nociceptive responses in humans is being investigated; the use of experimental pain models may aid our understanding. Prior to the efficacy assessment of an analgesic in clinical trials with patients, human experimental models may be used to mimic certain aspects of a pain condition. In drug studies, these models can help to provide mechanistic information regarding the analgesic response. A combination of different experimental approaches may elucidate the different aspects of nociceptive processing and guide the early stages of drug development.

GSK3858279 is a high affinity, first‐in‐class, mAb, which binds specifically to CCL17. GSK3858279 inhibits the ability of CCL17 to activate CCR4, thereby preventing downstream consequences of CCR4 signaling. 1 The primary objective of this study was to elucidate the mechanistic basis for analgesic effects of intravenous (IV) GSK3858279 on acute pain in healthy human participants in a controlled, integrated battery of multimodal experimental evoked pain tests, including thermal, electrical, and mechanical pain. 5 This nociceptive test battery can be used to investigate the effects of analgesic compounds against several types of acute pain conditions; the models applied have been tested for predictive validity and reliability and can be used repeatedly and in short succession as part of early‐phase drug studies. 5

Secondary objectives were to evaluate the safety and tolerability of IV GSK3858279, and to explore the pharmacokinetics (PK) and target engagement of GSK3858279 following IV administration.

METHODS

Study design

This was a randomized, single‐center, double‐blind, placebo‐controlled, three‐period, two‐treatment, incomplete‐block crossover study (NCT04114656) (Figure 1). During each period of the study, participants received either GSK3858279 or placebo (0.9% w/v NaCl). Across three treatment periods, participants received either one dose of placebo followed by two doses of GSK3858279 (PAA treatment sequence), or one dose of GSK3858279 followed by two doses of placebo (APP treatment sequence) with an equal likelihood (1:1 ratio); the order was randomized and stratified by timing of dosing (morning or afternoon sessions). The randomization approach was purposely not shared in detail with the study team that was blinded, that is, it was only stated that the participants of each study period would receive both treatments in randomized order, with the option to receive two doses of GSK3858279 and one dose of placebo, or two doses of placebo and one dose of GSK3858279 with equal likelihood. A maximum of 30 participants were planned to be randomized into one of the two treatment arms using RAMOS NG, an internally validated software so that ~24 participants could complete all three periods of the study.

FIGURE 1 Study design. *ITT population: all randomized participants who received ≥1 dose of study treatment. † MITT population: all randomized participants who received ≥1 dose of study treatment and completed ≥1 round of nociceptive tests in ≥2 study periods. ITT, intent‐to‐treat; MITT, modified intent‐to‐treat; R, randomization; UVB, ultraviolet B; wks, weeks.

Following a protocol amendment, ~18 participants were planned to undergo the ultraviolet B (UVB) assessments on irradiated skin so that ~ 15 participants could complete the UVB assessments in all three periods.

Screening occurred ≤28 days prior to study procedures (≤42 days for the UVB screening assessment); each study period lasted 2 weeks within at least a 4‐week wash‐out period, starting from Day 1 of each study period. The study period was encapsulated within the wash‐out period so that there were only 4 weeks between doses. The final follow‐up visit was ~8 weeks after the last dose; participants were therefore on study for ~6 months.

The intent‐to‐treat (ITT) population included all randomized participants who received at least one dose of study treatment. The primary population (modified ITT [MITT]) included all randomized participants who received at least one dose of study treatment and completed at least one round of nociceptive tests in at least two study periods. The UVB‐ITT population included all randomized participants who received ≥1 dose of study treatment and completed ≥1 round of UVB heat pain detection tests on irradiated skin in ≥1 study period. The UVB‐MITT population included all randomized participants who received ≥1 dose of study treatment and completed ≥1 round of UVB heat pain detection tests on irradiated skin in ≥2 study periods.

The study protocol was reviewed and approved by an institutional review board, in accordance with the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and applicable country‐specific requirements. The study was performed in accordance with ICH GCP and all applicable participant privacy requirements, and principles outlined in the Declaration of Helsinki. Written informed consent was obtained from each participant prior to the performance of any study procedures. The protocol, any amendments, informed consent, and other information that required pre‐approval were reviewed and approved by an ethics committee/institutional review board (Stichting Beoordeling Ethiek Biomedisch Onderzoek, Netherlands).

Participants and procedures

Males aged 18–50 years with 50–100 kg body weight and body mass index (BMI) 18–30 kg/m2 who were overtly healthy (as determined by medical evaluation including medical history, physical examination, laboratory tests, vital signs, and cardiac monitoring) without any pain conditions or use of painkillers were eligible for inclusion in the study. Key exclusion criteria included the presence or significant history of disease or ongoing (chronic) pain at the time of enrollment.

At screening, UVB light was administered to determine eligibility for participation and to identify the individual dose that produced the first visually discernible erythema (minimal erythemic dose). 6

During the study periods, baseline values for pain tests were obtained by performing the battery of tests twice pre‐dose in the first study period; two nociceptive test measurements were performed at 1 and 3 h after dosing in each period. The battery of pain tests used has been thoroughly validated and is described elsewhere. 6 , 7 , 8 , 9 , 10

Blood samples were collected by venepuncture for analysis of total GSK3858279 serum concentrations, free CCL17 and total CCL17 (free CCL17 + drug‐CCL17 complex) serum concentrations, and GSK3858279 antibody formation and activity. Blood samples were collected at day 1 pre‐dose and on days 2, 8, and 15 prior to pain assessments. All blood samples were analyzed using validated analytical methods.

Study end points

The co‐primary end points were: UVB heat pain detection threshold (PDT, in°C), cold pressor time to pain tolerance threshold (cold pressor PTT, in sec), and electrical PTT (in mA) with a single stimulus. Exploratory end points included: serum PK concentrations and parameters; cold pressor PDT (in sec); single‐stimulus electrical PDT (in mA); repeated‐stimulus electrical PDT and PTT (both in mA); conditioned pain modulation (CPM) PDT and PTT (both in mA); pressure PDT and PTT (both in KPa); heat PDT (in°C) on normal skin; GSK3858279 antibody formation and neutralizing activity; and serum free and total CCL17 levels. CPM is a read‐out for modulation of the endogenous inhibitory pain pathway and is quantified as the difference between electrical pain thresholds (single stimulus) pre‐ and post‐cold pressor test.

Statistical analyses

A Bayesian modeling analysis was performed such that observed and mean model‐estimated parameters were given joint probability distribution, allowing for better estimation of clinically meaningful observations with a small sample size. 11 , 12 A sample size of 15 participants completing all three periods for the UVB heat pain detection end point would provide 90% probability of declaring a positive conclusion when the true ratio of GSK3858279 vs. placebo is 1.03. A sample size of 24 participants completing all three periods would provide ≥80% probability of declaring a positive conclusion for the cold pressor time to intolerable pain threshold and the electrical pain tolerance threshold when the true difference is 1.15; the assumed coefficient of variability for the end points used in these calculations was 3.7%, 25.6%, and 19.1%, respectively. A positive conclusion was to be declared if there was at least a 90% probability that the ratio of GSK3858279 vs. placebo was better than 1 (no difference) and a negative conclusion if there was less than 75% probability that the ratio of GSK3858279 vs. placebo was better than 1. The analysis area under the curve (AAUC) of the ratio to baseline was the primary summary measure. The nociceptive test results were log‐transformed to calculate the log change from the baseline result, which was used for the primary analysis, and back‐transformed to obtain the ratio to baseline result. The AAUC was calculated via the trapezoidal method and was normalized. Non‐compartmental analyses were performed to estimate PK parameters for total GSK3858279 (WinNonlin, version 8.0.0.3176).

An interim analysis was performed when the 12th UVB participant had completed his day 15 nociceptive tests. Interim futility was assessed by calculating the predictive probabilities of success (PPOS) for two end points that previously have shown to be sensitive to some drugs used in the treatment of neuropathic pain: cold pressor PTT and electrical stair PTT, using a Bayesian ratio to baseline analyses. PPOS was defined as the posterior probability of achieving the end‐of‐study success criteria if an additional 12 participants were recruited, given the results observed at the interim (and prior distribution). A threshold of 40% for the PPOS was chosen for each end point. Both end points failed to meet the 40% threshold and after a review of the data, the study was terminated early due to not meeting the pre‐specified futility decision criteria.

A post hoc analysis was performed in the UVB‐MITT population after study completion to confirm that heat hypersensitivity was induced during the study. This analysis compared differences in the pre‐dose heat PDT tests of UVB‐irradiated skin vs. normal skin.

RESULTS

Participant disposition and baseline characteristics

A total of 89 participants were screened and 21 were enrolled (Figure 2). All 21 participants were randomized to the PAA (n = 11) or APP (n = 10) treatment sequence in the safety and ITT populations; 16 participants were included in the MITT population; 16 participants were included in UVB‐ITT population and 13 participants in UVB‐MITT population. All participants were male, Caucasian, and recruited from a single center in The Netherlands. Mean age (standard deviation [SD]) was 29.3 (7.9) years for the group given the PAA sequence, and 31.1 (7.7) years for the group given the APP sequence; median BMI was 22.6 kg/m2 and 24.2 kg/m2, respectively.

FIGURE 2 Consort diagram. PAA: Placebo – GSK3858279 IV – GSK3858279 IV; APP: GSK3858279 IV – Placebo – Placebo. AE, adverse event; IV, intravenous; SAE, serious adverse event.

Co‐primary end points: experimental pain test results

UVB heat PDT

In each of the periods, the absolute mean (SD) PDT increased slightly on day 2 before decreasing across the remaining days for GSK3858279; there was no significant difference observed between GSK3858279 and placebo (Figure 3). For the Bayesian analysis, the ratio to baseline AAUC was 1.005 (95% credible interval [Cr I]: 0.980–1.030), for placebo and 0.998 (95% Cr I: 0.976–1.021) for GSK3858279 (Table S1, Figures S1 and S2). The GSK3858279 posterior ratio to placebo was 0.993 (95% Cr I: 0.968–1.020). There was a 29% posterior probability that GSK3858279 had a higher PDT compared with placebo (i.e., true ratio of GSK3858279 vs. placebo >1).

FIGURE 3 UVB heat pain detection: absolute mean score by period (UVB‐ITT population). The original unit for the UVB heat pain detection test was in Celsius. Period 1 (a), period 2 (b), period 3 (c). ITT, intent‐to‐treat; IV, intravenous; SD, standard deviation; UVB, ultraviolet B.

Cold pressor PTT

Across periods 1 and 2, the absolute mean score for GSK3858279 increased slightly while it remained constant or decreased for placebo, with no significant differences between the groups (Figure 4a,b). In period 3, the absolute mean score increased slightly for GSK3858279 and placebo, with no significant differences observed between the groups (Figure 4c). For period 3, in the placebo arm, one participant reported a daily mean ratio to baseline result of 1.98 and 2.51 on days 8 and 15, respectively, which was larger than the median results from those days (1.37 and 1.38, respectively). The ratio to baseline measurement was large for this participant due to their low baseline score; this anomaly did not affect the overall interpretation of the results. For the Bayesian analysis, the ratio to baseline AAUC was 1.05 (95% Cr I: 0.96–1.15) for placebo and 1.05 (95% Cr I: 0.97–1.14) for GSK3858279 (Table S1, Figures S1 and S3). The GSK3858279 posterior ratio to placebo was 1.00 (95% Cr I: 0.89–1.12). There was a 48% posterior probability that GSK3858279 increases PTT compared with placebo (i.e., true ratio of GSK3858279 vs. placebo >1).

FIGURE 4 Cold pressor time to intolerable pain: mean absolute score by period (ITT population). The original unit for the cold pressor time to intolerable pain test was in seconds. Period 1 (a), period 2 (b), period 3 (c). ITT, intent‐to‐treat; IV, intravenous; SD, standard deviation; UVB, ultraviolet B.

Electrical pain – single stimulus

Across the periods, the absolute mean PTT remained consistent for GSK3858279 and placebo, with the exception of a slight increase in PTT across period 2 for GSK3858279; no significant differences between the groups were observed (Figure 5). For the Bayesian analysis, the ratio to baseline AAUC was 1.09 (95% Cr I: 1.01–1.17) for placebo and 1.07 (95% Cr I: 1.00–1.14) for GSK3858279 (Table S1, Figures S1 and S4). The GSK3858279 posterior ratio to placebo was 0.98 (95% Cr I: 0.91–1.05). There was a 24% posterior probability that GSK3858279 increases PTT compared with placebo (i.e., true ratio of GSK3858279 vs. placebo >1).

FIGURE 5 Electrical pain tolerance threshold – single stimulus: absolute mean score by period (ITT population). The original unit for the electrical stair – single stimulus pain tolerance test was in milliamps. Period 1 (a), period 2 (b), period 3 (c). ITT, intent‐to‐treat; IV, intravenous; SD, standard deviation; UVB, ultraviolet B.

Safety

The rate of drug‐related adverse events (AEs) in each period was similar for placebo and GSK3858279 (Table 1; Table S3). No participants were withdrawn from the study due to AEs. There were no serious AEs (SAEs) or clinically significant safety findings. All drug‐related AEs were mild in intensity (Table 2).

TABLE 1 Overall summary of adverse events.

Period 1, n (%)	Placebo (N = 11)	GSK3858279 IV (N = 10)	Total (N = 21)	
Any AE a	4 (36)	6 (60)	10 (48)	
Any drug‐related AEs	3 (27)	2 (20)	5 (24)	
AEs leading to permanent discontinuation of study treatment/withdrawal from study	0	0	0	
Any SAE	0	0	0	
Period 2, n (%)	Placebo (N = 7)	GSK3858279 IV (N = 9)	Total (N = 16)	
Any AE a	5 (71)	4 (44)	9 (56)	
Any drug‐related AEs	1 (14)	1 (11)	2 (13)	
Adverse events leading to permanent discontinuation of study treatment/withdrawal from study	0	0	0	
Any SAE	0	0	0	
Period 3, n (%)	Placebo (N = 6)	GSK3858279 IV (N = 9)	Total (N = 15)	
Any AE a	2 (33)	4 (44)	6 (40)	
Any drug‐related AEs	2 (33)	2 (22)	4 (27)	
Adverse events leading to permanent discontinuation of study treatment/withdrawal from study	0	0	0	
Any SAE	0	0	0	
Abbreviations: AE, adverse event; IV, intravenous; SAE, serious adverse event.

a All reported AEs were mild in severity.

TABLE 2 All drug‐related adverse events by period.

System organ class preferred term, n (%)	Placebo (N = 11)	GSK3858279 IV (N = 10)	Total (N = 21)	
Period 1	
Participants with any event a	3 (27)	2 (20)	5 (24)	
Infections and infestations	
Any event	2 (18)	1 (10)	3 (14)	
Nasopharyngitis	0	1 (10)	1 (5)	
Rhinitis	1 (9)	0	1 (5)	
Upper respiratory tract infection	1 (9)	0	1 (5)	
Psychiatric disorders	
Any event	1 (9)	1 (10)	2 (10)	
Abnormal dreams	1 (9)	0	1 (5)	
Nightmare	0	1 (10)	1 (5)	
Gastrointestinal disorders	
Any event	1 (9)	0	1 (5)	
Abdominal distension	1 (9)	0	1 (5)	
General disorders and administration site conditions	
Any event	0	1 (10)	1 (5)	
Application site erythema	0	1 (10)	1 (5)	
Application site warmth	0	1 (10)	1 (5)	
Investigations	
Any event	0	1 (10)	1 (5)	
Urine output increased	0	1 (10)	1 (5)	
Metabolism and nutrition disorders	
Any event	1 (9)	0	1 (5)	
Decreased appetite	1 (9)	0	1 (5)	
Period 2	Placebo (N = 7)	GSK3858279 IV (N = 9)	Total (N = 16)	
Participants with any event a	1 (14)	1 (11)	2 (13)	
Gastrointestinal disorders	
Any event	1 (14)	1 (11)	2 (13)	
Abdominal pain upper	1 (14)	0	1 (6)	
Nausea	0	1 (11)	1 (6)	
Period 3	Placebo (N = 6)	GSK3858279 IV (N = 9)	Total (N = 15)	
Participants with any event a	2 (33)	2 (22)	4 (27)	
Nervous system disorders	
Any event	2 (33)	1 (11)	3 (20)	
Dizziness	1 (17)	0	1 (7)	
Presyncope	1 (17)	0	1 (7)	
Somnolence	0	1 (11)	1 (7)	
Cardiac disorders	
Any event	1 (17)	0	1 (7)	
Bradycardia	1 (17)	0	1 (7)	
General disorders and administration site conditions	
Any event	1 (17)	0	1 (7)	
Chills	1 (17)	0	1 (7)	
Musculoskeletal and connective tissue disorders	
Any event	0	1 (11)	1 (7)	
Myalgia	0	1 (11)	1 (7)	
Abbreviation: IV, intravenous.

a All reported AEs were mild in severity.

Exploratory analyses

Total GSK3858279 PK

The mean total GSK3858279 serum concentration–time profile in period 1 (treatment sequence APP) was similar to those in periods 2 and 3 (treatment sequence PAA). In period 2 (treatment sequence APP) after a wash‐out period of at least 4 weeks, pre‐dose GSK3858279 serum concentrations were quantifiable in the majority of participants. Similarly, for the PAA treatment sequence, quantifiable concentrations of GSK3858279 were reported in pre‐dose samples for period 3 following administration in period 2.

Systemic exposure to GSK3858279 (maximum observed drug concentration [C max], area under the curve from time zero to time of last quantifiable concentration [AUC0–t ], and area under the curve from time zero to 7 days post‐dose [AUC0–7]) was similar in period 1 for APP treatment sequence and in periods 2 and 3 for PAA treatment sequence.

Cold pressor time to PDT

For the Bayesian analysis, the posterior median ratios to baseline AAUC for the placebo and GSK3858279 groups were 0.99 (95% Cr I: 0.82–1.19) and 1.07 (Cr I: 0.90–1.27), respectively. The GSK3858279 posterior ratio to placebo was 1.08 (95% Cr I: 0.84–1.38). There was a 75% posterior probability that participants receiving GSK3858279 took longer to detect cold pressor pain in comparison to those receiving placebo.

Electrical PDT: single stimulus

For the Bayesian analysis, the posterior median ratios to baseline AAUC for the placebo and GSK3858279 groups were 1.22 (95% Cr I: 1.05–1.42) and 1.12 (Cr I: 0.98–1.30), respectively. The GSK3858279 posterior ratio to placebo was 0.92 (95% Cr I: 0.78–1.08). There was a 16% posterior probability that participants receiving GSK3858279 required higher mA to detect pain compared with those receiving placebo.

Electrical PTT: repeat stimulus

For the Bayesian analysis, the posterior median ratios to baseline AAUC for the placebo and GSK3858279 groups were 1.13 (95% Cr I: 1.06–1.21) and 1.08 (Cr I: 1.01–1.16), respectively. The GSK3858279 posterior ratio to placebo was 0.95 (95% Cr I: 0.87–1.04). There was a 14% posterior probability of GSK3858279 having a higher PTT in comparison to placebo.

Electrical PDT: repeat stimulus

For the Bayesian analysis, the posterior median ratios to baseline AAUC for the placebo and GSK3858279 groups were 1.26 (95% Cr I: 1.08–1.49) and 1.15 (Cr I: 1.00–1.33), respectively. The GSK3858279 posterior ratio to placebo was 0.91 (95% Cr I: 0.76–1.10). There was a 15% posterior probability that participants receiving GSK3858279 required higher mA to detect pain in comparison to those receiving a placebo.

CPM PDT

For the Bayesian analysis, the posterior median changes from baseline for the placebo and GSK3858279 groups were −0.72 (95% Cr I: 1.42–0.01) and −0.53 (Cr I: −1.23–0.20), respectively. The posterior difference was 0.19 (95% Cr I: −0.80–1.15). There was a 67% posterior probability that GSK3858279 improves the threshold for pain inhibition in comparison to placebo.

CPM PTT

For the Bayesian analysis, the posterior median changes from baseline for the placebo and GSK3858279 groups were −0.29 (95% Cr I: 0.68–0.10) and −0.04 (Cr I: −0.48–0.40), respectively. The posterior difference was 0.26 (95% Cr I: −0.27–0.78). There was an 85% posterior probability that GSK3858279 has an increased CPM response in comparison to placebo.

Heat PDT on normal skin; pressure PDT and pressure PTT

A review of summary statistics for these end points did not show signs of differences between the two treatments.

Immunogenicity assessment

The incidence of treatment‐induced anti‐drug antibodies (ADA) was 1/21 (5%) participants (Table S2). There was no observed impact on GSK3858279 safety or efficacy in this participant. Two participants were positive for ADA prior to dosing with GSK3858279 (preexisting ADA). Both were negative for ADA at subsequent post‐GSK3858279 administration time points (Table S2). These ADA responses are likely nonspecific and were not boosted following GSK3858279 administration.

Serum free CCL17

Based on observed free CCL17 serum concentrations, reductions from baseline in free CCL17 were achieved within a few hours after GSK3858279 administration and were maintained for up to 7 days post‐dose.

Serum total CCL17

Upon dosing with GSK3858279, the serum concentration of total CCL17 increased. This, along with observed reduction in free CCL17 described above, is consistent with the accumulation of mAb‐target complex with the soluble target. There was no appreciable difference in the concentration–time profiles of total CCL17 following the first administration of GSK3858279 in period 1 (treatment sequence APP) and period 2 (treatment sequence PAA). Due to the drug carry‐over concentrations from period 1 to period 2 (treatment sequence APP), total CCL17 concentrations appear to be higher following placebo administration in period 2 compared with period 3. Similarly, total CCL17 concentrations were higher in period 3 vs. period 2 for the PAA treatment sequence.

Confirmation of hyperalgesia

Post hoc analysis of pre‐dose heat PDT tests of UVB‐irradiated vs. normal skin demonstrated that UVB light indeed had induced local heat hyperalgesia (Figure S5).

DISCUSSION

In this study, administration of the anti‐CCL17 mAb GSK3858279 to healthy participants followed by testing for potential response to acute models of pain led to no acute (48 h) analgesic response vs. placebo in evoked pain assessments of heat PDT on UVB‐exposed skin, cold pressor tolerance, and electrical‐stimulation tolerance tests. Furthermore, GSK3858279 had no effects on pressure pain or CPM. These findings suggest that CCL17 does not modulate acute nociceptive thresholds in healthy volunteers. A post hoc analysis for the UVB‐MITT group confirmed that UVB irradiation had induced heat hyperalgesia. Therefore, the lack of acute analgesic effects of GSK3858279 may indicate that GSK3858279 does not affect acute, UVB‐induced inflammatory hyperalgesia in healthy participants. Overall, GSK3858279 was well tolerated with all drug‐related AEs being mild in intensity and led to a low incidence of AEs across all three study periods (≤22%). Exposure to GSK3858279 was similar across each of the three dosing periods.

There was a slightly higher exposure to GSK3858279 (AUC) in period 3 for the PAA sequence; however, this may be explained by drug carry‐over from period 2. GSK3858279 carry‐over from period 1 to period 2 was also observed in the APP sequence. An increase in total serum CCL17 was noticed after GSK3858279 dosing, consistent with the general case that binding of a mAb to a soluble target with rapid turnover results in a significant accumulation of mAb–target complex above the baseline levels of the target. 13 For the PAA sequence, higher total CCL17 concentrations were observed after the second GSK3858279 dose compared with the first. For the APP sequence, total CCL17 concentrations appeared to be higher following placebo administration in period 2 compared with period 3 due to the drug carry‐over concentrations from period 1 to period 2.

A strength of this study is the use of a comprehensive set of validated acute nociceptive pain tests. Human experimental pain models may aid in exploring drug effects on the pain system under controlled settings, but these models have limitations. 14 By performing multi‐model testing of acute pain, a differentiated and comprehensive view of various pain pathways and mechanisms can be evaluated, 15 and may provide mechanistic information to aid in decision‐making during a drug's development. It is important for future work to distinguish between acute and chronic effects, which have different timeframes, when analyzing the PK profile of a drug effect.

We assessed drug effects on multiple modalities of pain, including, but not limited to, inflammation (i.e., UVB‐induced hyperalgesia), tonic pain (i.e., cold pressor test), changes to peripheral pain processing (i.e., heat pain on unexposed skin), and changes to the endogenous inhibitory pain pathway (i.e., electrical stimuli). The UVB model was deemed particularly useful for this study, as it is sensitive to analgesic effects of agents such as nonsteroidal anti‐inflammatory drugs and anti‐tyrosine kinase A drugs. 8 , 16 While there was no evident effect of GSK3858279 on the pain tests, it was, as far as the authors are aware, the first study to use a comprehensive pain test battery in the assessment of a mAb.

Analgesic effects of drugs including NSAIDs are often tested using an acute dental pain model, which was not employed here. Although the acute dental pain model is a valuable experimental model for neurogenic inflammation, its use limits study design; crossover designs are not typically utilized with this model. The advantage of the battery of tests used in our study is they have been well‐validated under clinical trial conditions. 5 As this study was performed in healthy participants, pain that is driven by disease pathology, such as injury, localized inflammation, or chronic disease‐relevant pathology cannot be adequately captured. This is particularly relevant when assessing mechanisms that do not directly influence sensory neuron function but instead act via secondary cell types that are involved in disease pathogenesis. Thus, in this instance, a state of disease such as chronic pathology, is likely needed to show the efficacy of GSK3858279 as therapy. Another limitation of the pain models used in this study is the inability to replicate spontaneous pain, which is one of the main complaints from patients with chronic pain. 14 To address the slow rate of enrollment, an interim analysis was conducted to determine if the study should be continued. Based on results from the cold pressor and electrical pain (single stimulus) co‐primary end points, the study was stopped for futility.

For the cold pressor test, analysis of the results was hampered by an anomaly in baseline values for one participant; however, this did not affect the overall interpretation. The UVB data were more variable than expected based on previous experience with this model. 6 The other data were in line with expectations.

Due to the utilization of a Bayesian model and the required structure of the input dataset, participants with missing period 3 baseline data were not included in the Bayesian analyses, as the model requires non‐missing covariates, which included period baseline measurements. As a result, the primary analysis only included participants with non‐missing covariate data, meaning they would have had at least one pain test round in all three periods. In the MITT population, only one participant had data in two periods, while the remaining 15 had data in all three periods.

Only males were included in the study population; therefore, the findings are potentially not generalizable to females. It is conventional to exclude female participants in experimental crossover studies due to hormonal influences on pain 17 ; therefore, only male volunteers were recruited. Secondly, limited safety data were available as this was a phase I study, hence, female participants were excluded to remove the risk of a participant being of childbearing potential during the study.

CONCLUSIONS

No acute (48 h) analgesic response was reported for GSK3858279 in a battery of evoked pain assessments of healthy participants, providing evidence that CCL17 may not play a significant role in facilitating basal acute pain responses in humans. Overall, GSK3858279 was well tolerated with a low incidence of AEs. Evaluation in healthy participants may not adequately capture pain driven by disease pathology. Therefore, it is plausible that an effect of the drug might be seen in a chronic disease state, such as chronic inflammation, which was not investigated with this experimental paradigm.

AUTHOR CONTRIBUTIONS

All authors had access to the study data, took responsibility for the accuracy of the analysis, contributed to data interpretation, reviewed and contributed to the content of the manuscript, and had authority in the decision to submit the manuscript. Y.B., H.J.H., J.R., J.N., E.P., Y.A., S.S., E.G., E.E., K.A.B., and G.J.G. contributed to the writing of the manuscript and designed the research; H.J.H. and G.J.G. performed the research; Y.B., J.R., J.N., E.P., Y.A., S.S., E.G., E.E., and K.A.B. analyzed the data.

FUNDING INFORMATION

This study, including study design, data collection, analysis, and interpretation, and medical writing and submission support for the manuscript, was funded by GSK (study 209973).

CONFLICT OF INTEREST STATEMENT

YB – Former employee of and shareholder in GSK. HH – Former employee of the Centre for Human Drug Research which received funding from GSK to conduct this study. JR – Former employee of and current shareholder in GSK. JN – Former employee of and shareholder in GSK. EP – Employee of and shareholder in GSK. YA – Employee of and shareholder in GSK. SS – Employee of and shareholder in GSK. EG – Former employee of and shareholder in GSK. EE – Former employee of and shareholder in GSK. KAB – Employee of and shareholder in GSK. GJG – Employee of the Centre for Human Drug Research which received funding from GSK to conduct this study.

Supporting information

Data S1.

ACKNOWLEDGMENTS

Medical writing support, under the guidance of the authors, was provided by Fraser Shearer, PhD, of Ashfield MedComms, an Inizio company (Glasgow, UK), and was funded by GSK. GSK clinical science support at different stages of the study from Ed Cannons, Louise Cookson, Saima Muzaffar, Bethany Jordon, and Lizzie Lartey and the wider study team for support to complete this study especially during the challenges of the COVID‐19 pandemic.

DATA AVAILABILITY STATEMENT

Information on GSK's data sharing commitments and requesting access to anonymized individual participant data and associated documents can be found at www.clinicalstudydatarequest.com.
==== Refs
REFERENCES

1 Lee KM , Jarnicki A , Achuthan A , et al. CCL17 in inflammation and pain. J Immunol. 2020;205 (1 ):213‐222.32461237
2 Achuthan A , Cook AD , Lee MC , et al. Granulocyte macrophage colony‐stimulating factor induces CCL17 production via IRF4 to mediate inflammation. J Clin Invest. 2016;126 (9 ):3453‐3466.27525438
3 Cook AD , Lee MC , Saleh R , et al. TNF and granulocyte macrophage‐colony stimulating factor interdependence mediates inflammation via CCL17. JCI Insight. 2018;3 (6 ):e99249.29563337
4 Yoshie O , Matsushima K . CCR4 and its ligands: from bench to bedside. Int Immunol. 2015;27 (1 ):11‐20.25087232
5 van Amerongen G , Siebenga P , de Kam ML , Hay JL , Groeneveld GJ . Effect profile of paracetamol, Delta9‐THC and promethazine using an evoked pain test battery in healthy subjects. Eur J Pain. 2018;22 (7 ):1331‐1342.29635857
6 Siebenga PS , van Amerongen G , Klaassen ES , de Kam ML , Rissmann R , Groeneveld GJ . The ultraviolet B inflammation model: postinflammatory hyperpigmentation and validation of a reduced UVB exposure paradigm for inducing hyperalgesia in healthy subjects. Eur J Pain. 2019;23 (5 ):874‐883.30597682
7 Hijma HJ , Siebenga PS , de Kam ML , Groeneveld GJ . A phase 1, randomized, double‐blind, placebo‐controlled, crossover study to evaluate the pharmacodynamic effects of VX‐150, a highly selective NaV1.8 inhibitor, in healthy male adults. Pain Med. 2021;22 (8 ):1814‐1826.33543763
8 Okkerse P , van Amerongen G , de Kam ML , et al. The use of a battery of pain models to detect analgesic properties of compounds: a two‐part four‐way crossover study. Br J Clin Pharmacol. 2017;83 (5 ):976‐990.27862179
9 Hijma H , Koopmans I , Klaassen E , Doll RJ , Zuiker R , Groeneveld GJ . A crossover study evaluating the sex‐dependent and sensitizing effects of sleep deprivation using a nociceptive test battery in healthy subjects. Br J Clin Pharmacol. 2023;89 (1 ):361‐371.35997713
10 Siebenga PS , van Amerongen G , Okkerse P , et al. Reproducibility of a battery of human evoked pain models to detect pharmacological effects of analgesic drugs. Eur J Pain. 2019;23 (6 ):1129‐1140.30793411
11 van de Schoot R , Depaoli S , King R , et al. Bayesian statistics and modelling. Nat Rev Methods Primers. 2021;1 (1 ):1.
12 Yarnell CJ , Abrams D , Baldwin MR , et al. Clinical trials in critical care: can a Bayesian approach enhance clinical and scientific decision making? Lancet Respir Med. 2021;9 (2 ):207‐216.33227237
13 Davda JP , Hansen RJ . Properties of a general PK/PD model of antibody‐ligand interactions for therapeutic antibodies that bind to soluble endogenous targets. MAbs. 2010;2 (5 ):576‐588.20676036
14 Reddy KS , Naidu MU , Rani PU , Rao TR . Human experimental pain models: a review of standardized methods in drug development. J Res Med Sci. 2012;17 (6 ):587‐595.23626642
15 Olesen AE , Andresen T , Staahl C , Drewes AM . Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs. Pharmacol Rev. 2012;64 (3 ):722‐779.22722894
16 Loudon P , Siebenga P , Gorman D , et al. Demonstration of an anti‐hyperalgesic effect of a novel pan‐Trk inhibitor PF‐06273340 in a battery of human evoked pain models. Br J Clin Pharmacol. 2018;84 (2 ):301‐309.29178434
17 Athnaiel O , Cantillo S , Paredes S , Knezevic NN . The role of sex hormones in pain‐related conditions. Int J Mol Sci. 2023;24 (3 ):1866.36768188
