Abstract
Aim
There is an unmet need for more effective therapies in inflammatory bowel disease (IBD). A single drug that blocks multiple distinct pathogenic pathways may offer therapeutic benefit superior to current monotherapies. PF‐07261271, a bispecific antibody targeting both the p40 subunit of interleukin‐12/23 and tumour necrosis factor‐like cytokine 1A (TL1A), is being investigated as a potential new IBD therapy. This study evaluates the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PF‐07261271 in healthy participants.
Methods
This phase 1, randomized, double‐blind, placebo‐controlled study assessed single ascending doses (SAD; intravenous 30–1000 mg) and multiple doses (MD; subcutaneous 300 mg once every 4 weeks) of PF‐07261271 in healthy adults. Safety, PK, immunogenicity and exploratory PD serum biomarkers (total soluble TL1A [sTL1A] and p40) were evaluated.
Results
Thirty‐five participants were enrolled (Part A: SAD, N = 27; Part B: MD, N = 8). PF‐07261271 was generally safe and well tolerated; all treatment‐emergent adverse events were mild/moderate. Following peak serum concentration, there was a multi‐phase decline with a trend towards increased terminal half‐life at the higher doses. For the MD cohort, the estimated bioavailability of PF‐07261271 administered subcutaneously was 48%. Dose‐dependent increases from baseline in serum total sTL1A and p40 levels were observed in participants receiving PF‐07261271, demonstrating target engagement. There was no apparent impact of anti‐drug antibodies on safety, PK or PD parameters.
Conclusion
PF‐07261271 demonstrated p40 and TL1A target engagement and a favourable safety profile. Further studies are warranted to evaluate its safety and efficacy in patients with IBD.
ClinicalTrials.gov: NCT05536440.
Keywords: bispecific antibody, inflammatory bowel disease, p40, TL1A
What is already known about this subject
More effective treatments are needed for inflammatory bowel disease (IBD).
Interleukin‐12/23 subunit p40 (p40) and tumour necrosis factor‐like cytokine 1A (TL1A) have well‐recognized roles in IBD pathogenesis.
Neutralizing p40 or TL1A independently with monospecific antibodies has shown clinical efficacy in patients with IBD.
What this study adds
PF‐07261271, a p40xTL1A bispecific antibody, demonstrated p40 and TL1A target engagement and a favourable safety profile in healthy participants.
The study supports further investigation of PF‐07261271 in inflammatory diseases, including IBD, where PF‐07261271 is expected to provide enhanced inhibition of multiple pathways driving disease.
1. INTRODUCTION
Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a chronic inflammatory disorder of the gastrointestinal (GI) tract, characterized by immune dysregulation and a complex interplay of inflammatory pathways. 1 Current treatments for IBD primarily include broad or targeted immunosuppressive agents that aim to dampen pathogenic immune activation in the GI tract and induce remission. 2 However, a large proportion of patients receiving these therapies do not achieve lasting remission, 3 highlighting a critical need for more effective, innovative treatments to achieve favourable efficacy outcomes. These limitations may be addressed by simultaneously targeting multiple disease mechanisms, potentially increasing efficacy while maintaining safety. 4 , 5 As such, a bispecific antibody that inhibits two distinct pathological targets may present a compelling alternative to available therapies. 6 , 7 , 8 , 9
The shared p40 subunit of interleukin (IL)‐12 and IL‐23 and tumour necrosis factor‐like cytokine 1A (TL1A) are two clinically validated therapeutic targets in IBD, 10 , 11 , 12 , 13 , 14 , 15 playing critical roles in disease pathogenesis. 16 , 17 IL‐12 is essential for the differentiation and activation of T helper (Th)1 cells, while IL‐23 reinforces Th17 cell activation, both of which are key drivers of inflammation in IBD. 16 TL1A, through binding and activation of death receptor 3 (DR3), has been shown to amplify inflammatory and fibrotic signalling in IBD. 17 , 18 , 19 Monospecific inhibition of p40 or TL1A with neutralizing monoclonal antibodies in separate clinical studies has demonstrated clinical efficacy and reduction of inflammatory markers in patients with IBD. This includes ustekinumab, a monoclonal antibody targeting p40, 14 , 15 and the TL1A‐targeting antibodies afimkibart (previously PF‐06480605/RO7790121), tulisokibart and duvakitug. 10 , 11 , 12 , 13 , 20 , 21 To date, no approved therapies are available that inhibit both p40 and TL1A simultaneously. 22
PF‐07261271 (now RO7837195) is a novel recombinant fully human bispecific immunoglobulin G1 antibody designed to simultaneously target both p40 and TL1A, and is currently being investigated for the treatment of moderate to severe IBD. By combining neutralizing high‐affinity binding domains against both p40 and TL1A within a single antibody molecule, PF‐07261271 aims to maximize suppression of distinct and overlapping inflammatory pathways driving IBD for enhanced efficacy.
This study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses (SAD) and multiple doses (MD) of PF‐07261271 in healthy participants.
2. METHODS
2.1. Study design
This phase 1, randomized, double‐blind, placebo‐controlled study (NCT05536440) was designed to assess the safety, tolerability, PK and PD of PF‐07261271 in healthy adults. The study consisted of two parts. Part A comprised the SAD cohorts that evaluated four single doses of PF‐07261271 (30 mg, 100 mg, 300 mg and 1000 mg) and placebo administered intravenously (IV; Figure 1). An additional dose of 1000 mg PF‐07261271 and placebo was evaluated in participants of Japanese origin (required to have four Japanese biological grandparents born in Japan). Part B comprised the MD cohort and evaluated 300 mg subcutaneous (SC) doses of PF‐07261271 or placebo administered every 4 weeks for a total of two doses. For IV dosing in the SAD cohorts, study intervention was administered as an IV infusion over approximately 60 min, with infusion volumes ranging from 50 mL to 130 mL. SC injections in the MD cohort were administered in the abdomen, thigh or back of the arms, with an injection volume of 3 mL.
FIGURE 1.
Participant schema and cohort design. IV, intravenous; JPN, Japanese; MD, multiple doses; N, number of participants assessed; Q4W, every 4 weeks; SAD, single ascending doses; SC, subcutaneous.
2.2. Study participants
Participants were healthy adults aged 18–65 years (or the minimum age of consent in accordance with local regulations) at screening, with a body mass index (BMI) of 17.5–30.5 kg/m2 and a total body weight exceeding 50 kg. Exclusion criteria included: history of clinically significant disease and other medical or psychiatric conditions, use of prohibited concomitant medications, recent exposure to live or attenuated vaccines, recent administration with an investigational product, abnormal blood pressure and clinical laboratory abnormalities. Full exclusion criteria are available in the Supplementary Methods.
This study was conducted in accordance with the Declaration of Helsinki, International Council of Harmonisation Good Clinical Practice guidelines and all applicable laws and regulations, including privacy laws. The protocol, amendments, informed consent forms, investigator brochures and other relevant documents received Institutional Review Board approval from Advarra (Pro00065890) prior to study initiation. At each investigational site, investigators ensured informed consent was obtained prior to enrolment.
2.3. Safety and tolerability
Safety assessments included physical examinations, vital signs, 12‐lead electrocardiograms (ECGs) and clinical laboratory tests. The incidence and severity of treatment‐emergent adverse events (TEAEs) and serious adverse events (SAEs) were monitored along with infusion/injection site reactions.
2.4. Pharmacokinetics
Serum concentrations of PF‐07261271 were assessed via blood samples collected throughout the study period. Sample collection and handling followed procedures detailed in the laboratory manual. Samples were collected at the pre‐specified time points listed below, and collection was stopped once the drug concentration was below the lower limit of quantification (LLOQ). For the SAD cohorts, PK blood samples were collected on day 1 between 2 h and 5 min before the start of infusion, at the end of infusion and at 2, 4, 8 and 12 h after the start of infusion. PK blood samples were also collected on days 2, 3, 5, 8, 15, 32, 46, 61, 91, 181, 211, 241, 271, 301, 331, 361 and 451. For the MD cohort, PK blood samples were collected between 2 h and 5 min pre‐administration and 12 h post‐administration on days 1 and 29, as well as on days 3, 5, 8, 15, 31, 36, 51, 66, 81, 111, 171, 201, 231, 261, 291, 321, 351, 381 and 471.
Concentrations of PF‐07261271 were determined by electrochemiluminescent (ECL) ligand‐binding assay using Meso Scale Discovery (MSD) technology. In this method, biotinylated monoclonal antibody (Mu Anti‐[p40 mAb]‐Biotin) was bound to a washed and blocked streptavidin‐coated MSD plate. Calibration standards, quality controls and samples were diluted 1:80 and incubated on the plate. The plate was washed, and PF‐07261271 was detected using ruthenylated monoclonal antibody (Mu Anti‐[TL1A mAb]‐Ru), tripropylamine read buffer and the MSD imager. This method was fully validated according to current industry and regulatory guidelines. Method performance with respect to precision and accuracy, selectivity, specificity, dilutional linearity, hook effect and stability was evaluated. The assay calibration curve range was 5.0 ng/mL to 5200 ng/mL with an LLOQ of 10 ng/mL.
For the SAD cohorts, PK parameters assessed included: area under the serum concentration–time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast), AUC from time zero extrapolated to infinite time (AUCinf), maximum serum concentration during the dosing interval (Cmax), time to reach Cmax post‐IV infusion or SC administration (Tmax), terminal half‐life (t½), total clearance of drug from serum (CL), volume of distribution for extravascular dosing (Vz) and steady‐state volume of distribution (Vss). For the MD cohort, PK parameters assessed included: AUC at steady state over the dosing interval (AUCtau), Cmax, Tmax, t½ and estimated bioavailability (F), assessed using AUCtau after the first SC dose on day 1 and AUC from time zero to 672 h post‐dose from the SAD cohorts at the same dose level.
2.5. Immunogenicity
Immunogenicity assessments comprised the incidence of the development of anti‐drug antibodies (ADA) and neutralizing antibodies (NAb) against PF‐07261271 and were conducted using blood samples collected and analysed using validated methods. Samples were collected at the pre‐specified time points listed below, and collection was stopped once the drug concentration was below the LLOQ. In the SAD cohorts, immunogenicity samples were collected on day 1 between 2 h and 5 min pre‐administration, and on days 8, 15, 32, 46, 61, 91, 181, 211, 241, 271, 301, 331, 361 and 451. In the MD cohort, immunogenicity samples were collected between 2 h and 5 min pre‐administration on days 1 and 29, and on days 8, 15, 51, 66, 81, 111, 171, 201, 231, 261, 291, 321, 351, 381 and 471.
Samples were analysed using a tiered approach consisting of screening, confirmation and determination of titre. The presence of ADA was detected by a quasi‐quantitative bridging ECL immunoassay using MSD technology. Murine monoclonal antibodies were used as positive controls (PC), and pooled normal human serum was used as a negative assay control (NC). A sample pre‐treatment to remove the endogenous target was applied to serum samples, PC and NC. This method was fully validated according to current industry and regulatory guidelines. Method performance with respect to precision, selectivity, specificity, prozone effect, plate homogeneity, stability and robustness was evaluated. This ADA assay was shown to be both sensitive (1.28 ng/mL anti‐p40 and 0.790 ng/mL anti‐TL1A) and drug‐tolerant (100 ng/mL anti‐PF‐07261271 PC antibody was detected in the presence of up to 500 μg/mL, which was the highest PF‐07261271 concentration assessed) based on murine monoclonal antibody PCs and the assay cut point for patients with IBD.
Positive ADA samples were further characterized for neutralizing capability using a qualitative competitive ligand‐binding ECL immunoassay method utilizing MSD Multiplex technology. Sample pre‐treatment using SPEAD (solid‐phase extraction with acid dissociation) was applied to serum samples, PC and NC. This method was fully validated according to current industry and regulatory guidelines. Method performance with respect to precision, selectivity, specificity, prozone effect, plate homogeneity, stability and robustness was evaluated. This NAb assay was shown to be both sensitive (79.1 ng/mL p40 and 236 ng/mL TL1A) and drug‐tolerant (1000 ng/mL of both anti‐p40 and anti‐TL1A PCs were detected in the presence of 300 μg/mL and 150 μg/mL PF‐07261271, respectively) based on murine monoclonal antibody PCs and the assay cut point for combined normal and IBD subjects.
2.6. Biomarkers
Blood samples were collected to assess the change from baseline in blood levels of total serum soluble TL1A (sTL1A) and p40 after dosing as exploratory PD biomarkers. Samples were collected at the pre‐specified time points listed below, and collection was stopped once the drug concentration was below the LLOQ. For the SAD cohorts, biomarker blood samples were collected on day 1 between 2 h and 5 min before the start of infusion, at the end of infusion and at 12 h post‐administration. Biomarker blood samples were also collected on days 2, 3, 5, 8, 15, 32, 46, 61, 91, 181, 211, 241, 271, 301, 331, 361 and 451. For the MD cohort, biomarker blood samples were collected between 2 h and 5 min pre‐administration and 12 h post‐administration on days 1 and 29, as well as on days 2, 3, 5, 8, 15, 30, 31, 36, 51, 66, 81, 111, 171, 201, 231, 261, 291, 321, 351, 381 and 471.
An immunoaffinity‐liquid chromatography‐high resolution tandem mass spectrometry assay was developed to evaluate the effect of PF‐07261271 on total serum target levels of p40 and TL1A as exploratory biomarkers. The assay was fully validated for its context of use. Assay performance with respect to accuracy, precision, linearity, selectivity, specificity, carryover, matrix effect, dilution integrity and stability was evaluated. The calibration standard responses were linear across the assay range of quantification (LLOQ to upper limit of quantification [ULOQ]) from 37.5 to 18 800 pg/mL for total p40 and 50.0 to 25 000 pg/mL for total TL1A. A weighted quadratic least squares regression was used to fit the curve. Samples above the ULOQ were diluted, and those below the LLOQ were reported as such. No interference by 900 μg/mL of PF‐07261271 was observed for each analyte at quality control‐low and quality control‐high, which established that the assay reliably measured total (drug‐bound and unbound) p40 and TL1A.
2.7. Statistical analyses
No formal statistical hypotheses were tested. Analysis sets included: the safety set (all randomized participants who received at least one dose of study treatment, analysed according to the intervention received); the PK analysis set (all randomized participants who received at least one dose of PF‐07261271 with at least one reported serum concentration); the PD analysis set (all randomized participants who received at least one dose of PF‐07261271 with baseline and at least one post‐dose assessment). Safety, biomarker, immunogenicity and serum concentration–time data were summarized descriptively. PK parameters were calculated from actual sample collection times using an internally validated application system open non‐compartmental analysis (openNCA, version 2.7.8).
2.8. Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in https://www.guidetopharmacology.org, and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24. 23
3. RESULTS
3.1. Demographics and disposition
In total, 35 participants were enrolled and randomized in this study (Part A, SAD cohorts, N = 27; Part B, MD cohort, N = 8); a participant schema is shown in Figure 1. All participants in the SAD cohorts received either PF‐07261271 or placebo and completed the study. In the MD cohort, one participant discontinued due to a non‐serious TEAE of ventricular extrasystoles after a single dose of PF‐07261271, which was not considered treatment related by the investigator. Participant demographics and baseline characteristics for each cohort are shown in Table 1. For both the SAD and MD cohorts, respectively, participants were mostly male (74.1% and 62.5%), White (59.3% and 87.5%) and not Hispanic or Latino (81.5% and 87.5%). In the SAD and MD cohorts, respectively, the mean age for participants was 40.5 (standard deviation [SD] 11.1) and 43.4 (SD 14.8) years, and the mean BMI was 25.0 (SD 3.0) and 25.3 (SD 3.1) kg/m2.
TABLE 1.
Summary of participant demographics and baseline characteristics for the SAD and MD cohorts (safety set).
| SAD cohorts (IV single dose) | MD cohort (SC Q4W) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Characteristic | Placebo (N = 8) | PF‐07261271 30 mg (N = 2) | PF‐07261271 100 mg (N = 2) | PF‐07261271 300 mg (N = 4) | PF‐07261271 1000 mg (N = 6) | Placebo JPN (N = 1) | PF‐07261271 1000 mg JPN (N = 4) | Placebo (N = 2) | PF‐07261271 300 mg (N = 6) |
|
Age (years), mean (SD) |
38.0 (11.8) |
26.5 (6.4) |
31.0 (1.4) |
40.3 (11.8) |
44.5 (9.4) |
46.0 (‐) |
50.0 (8.3) |
44.5 (23.3) |
43.0 (14.0) |
| Female, n (%) |
3 (37.5) |
1 (50.0) |
0 |
1 (25.0) |
1 (16.7) |
0 |
1 (25.0) |
1 (50.0) |
2 (33.3) |
| Race, n (%) | |||||||||
| White |
6 (75.0) |
2 (100.0) |
1 (50.0) |
4 (100.0) |
3 (50.0) |
0 | 0 |
1 (50.0) |
6 (100.0) |
| Black or African American |
2 (25.0) |
0 |
1 (50.0) |
0 |
2 (33.3) |
0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 |
1 (16.7) |
1 (100.0) |
4 (100.0) |
0 | 0 |
| Multiracial | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
1 (50.0) |
0 |
| Ethnicity, n (%) | |||||||||
| Hispanic or Latino |
2 (25.0) |
0 |
1 (50.0) |
0 |
2 (33.3) |
0 | 0 | 0 |
1 (16.7) |
| Not Hispanic or Latino |
6 (75.0) |
2 (100.0) |
1 (50.0) |
4 (100.0) |
4 (66.7) |
1 (100.0) |
4 (100.0) |
2 (100.0) |
5 (83.3) |
|
Weight (kg), mean (SD) |
75.7 (14.5) |
76.4 (28.0) |
71.9 (11.8) |
72.6 (14.9) |
86.2 (17.9) |
65.5 (‐) |
72.4 (15.4) |
77.7 (27.3) |
77.6 (11.7) |
| BMI (kg/m2), mean (SD) | 25.4 (2.9) | 24.6 (6.3) | 23.9 (2.1) | 22.5 (2.6) | 27.0 (1.9) | 22.6 (‐) | 24.8 (3.1) | 24.9 (5.8) | 25.4 (2.6) |
Note: “‐“ indicates that a value could not be calculated.
Abbreviations: BMI, body mass index; IV, intravenous; JPN, Japanese; MD, multiple doses; N, number of participants; n, number of participants in group; Q4W, every 4 weeks; SAD, single ascending doses; SC, subcutaneous; SD, standard deviation.
3.2. Safety and tolerability
In the SAD cohorts, 23 TEAEs were reported in 12/27 (44.4%) participants; six TEAEs were considered treatment related by the investigator (reported in one participant receiving placebo, one participant receiving 300 mg PF‐07261271 and one participant receiving 1000 mg PF‐07261271; Table 2). In the MD cohort, 10 TEAEs were reported in 7/8 (87.5%) participants; five TEAEs were considered treatment related (one participant receiving placebo and four participants receiving PF‐07261271). No SAEs, severe TEAEs or TEAEs leading to death were reported in any cohorts (Table 2). No treatment‐related TEAEs were associated with treatment discontinuation (Table 2).
TABLE 2.
Summary of TEAEs and SAEs of participants in the SAD and MD cohorts (safety set).
| SAD cohorts (IV single dose) | MD cohort (SC Q4W) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| n (%) | Placebo (N = 8) | PF‐07261271 30 mg (N = 2) | PF‐07261271 100 mg (N = 2) | PF‐07261271 300 mg (N = 4) | PF‐07261271 1000 mg (N = 6) | Placebo JPN (N = 1) | PF‐07261271 1000 mg JPN (N = 4) | Placebo (N = 2) | PF‐07261271 300 mg (N = 6) |
| TEAEs | 4 (50.0) | 1 (50.0) | 1 (50.0) | 3 (75.0) | 2 (33.3) | 0 | 1 (25.0) | 2 (100.0) | 5 (83.3) |
| Treatment related | 1 (12.5) | 0 | 0 | 1 (25.0) | 1 (16.7) | 0 | 0 | 1 (50.0) | 4 (66.7) |
| Treatment‐emergent SAE | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Severe TEAE | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| TEAEs leading to death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| TEAEs leading to discontinuation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (16.7) a |
| Treatment related | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| TEAEs leading to dose interruptions | 0 | 0 | 0 | 1 (25.0) b | 1 (16.7) b | 0 | 0 | 0 | 1 (16.7) c |
| Treatment related | 0 | 0 | 0 | 1 (25.0) b | 1 (16.7) b | 0 | 0 | 0 | 0 |
Abbreviations: COVID‐19, coronavirus disease 2019; IV, intravenous; JPN, Japanese; MD, multiple doses; N, number of participants; n, number of participants in group; Q4W, every 4 weeks; SAD, single ascending doses; SAE, serious adverse event; SC, subcutaneous; TEAE, treatment‐emergent adverse event.
One participant permanently discontinued the study intervention and study due to a TEAE of ventricular extrasystoles, which was not considered as treatment related by the investigator and the exact cause of event could not be determined.
One participant in the 1000 mg and one participant in the 300 mg SAD cohorts experienced dose interruption due to TEAEs of nausea and vomiting and hot flush, respectively, which were considered as treatment related by the investigator.
One participant in the MD cohort experienced dose interruption due to a TEAE of COVID‐19, which was not considered as treatment related by the investigator.
In the SAD cohorts, the most frequently reported TEAE was headache (n = 3 [11.1%], including n = 2 in the placebo group and n = 1 in the PF‐07261271 30 mg IV single dose group). No infusion‐related reactions were reported in the SAD cohorts. In the MD cohort, the most frequently reported TEAE was injection site reaction (n = 5 [62.5%], including n = 1 in the placebo group and n = 4 in the PF‐07261271 300 mg SC group); all events in participants receiving PF‐07261271 resolved within a day without treatment, with no potentially immunogenic response of clinical concern. All TEAEs in both sets of cohorts were mild or moderate in severity, and all participants with treatment‐related events continued in the study. No clinically significant trends were observed in vital signs, ECGs or clinical laboratory evaluations.
3.3. Pharmacokinetics
In the non‐Japanese SAD cohorts, PK evaluations of PF‐07261271 demonstrated a multi‐phasic decline in serum concentrations following Cmax, with a trend towards increased t½ at the higher doses, potentially due to target‐mediated drug disposition observed at the low doses (Figure 2A). AUClast, AUCinf and Cmax increased with ascending doses of PF‐07261271 (Table 3). In particular, AUCinf increased more than dose proportionally from 30 mg to 1000 mg, while Cmax increased more than dose proportionally from 30 mg to 300 mg and less than dose proportionally from 300 mg to 1000 mg. Individual Tmax values ranged between 1 and 13 h at lower doses (30 mg and 100 mg cohorts); in the 300 mg and 1000 mg cohorts, median Tmax ranged from 2 to 3 h (Table 3). Individual t½ values ranged between 158 and 328 h (~7 to 14 days) for the 30 mg and 100 mg cohorts, and arithmetic mean values ranged between 331 and 1533 h (~14 to 64 days) for the 300 mg and 1000 mg cohorts (Table 3). Geometric mean CL values decreased with increasing doses of PF‐07261271; Vss was similar across 30–300 mg cohorts but increased for the 1000 mg cohort (Table 3).
FIGURE 2.
Median serum PF‐07261271 concentration–time profiles (semi‐logarithmic scale) for the A) SAD cohorts and B) MD cohort (PK analysis set). LLOQ was 10.0 ng/mL. IV, intravenous; JPN, Japanese; LLOQ, lower limit of quantitation; MD, multiple doses; PK, pharmacokinetics; SAD, single ascending doses; SC, subcutaneous.
TABLE 3.
Descriptive summary of PF‐07261271 PK parameters for the SAD and MD cohorts (PK analysis set).
| SAD cohorts (IV single dose) | MD cohort (SC Q4W) | ||||||
|---|---|---|---|---|---|---|---|
| Parameter (units) a | 30 mg (N = 2) | 100 mg (N = 2) | 300 mg (N = 4) | 1000 mg (N = 6) | 1000 mg JPN (N = 4) | 300 mg (N = 6) day 1 | 300 mg (N = 6) day 29 |
| N2, N3 | 2, 2 | 2, 2 | 4, 3 | 6, 6 | 4, 4 | 6, 0 | 5, 5 |
| AUCtau (μg.hr/mL) | ‐ | ‐ | ‐ | ‐ | ‐ | 17 600 (27) | 27 900 (22) |
| AUClast (μg.hr/mL) | 3740, 4200 | 16 300, 20 000 | 65 600 (35) | 324 100 (18) | 345 000 (28) | ‐ | ‐ |
| AUCinf (μg.hr/mL) | 3740, 4530 | 16 600, 21 300 | 61 010 (36) | 332 600 (18) | 368 100 (28) | ‐ | ‐ |
| Cmax (μg/mL) | 10.4, 10.5 | 46.9, 50.0 | 143.3 (21) | 372.8 (17) | 313.9 (31) | 34.1 (28) | 49.6 (28) |
| Rac | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | 1.5 (9) |
| Rac,Cmax | ‐ | ‐ | ‐ | ‐ | ‐ | ‐ | 1.4 (25) |
| Tmax (hr) | 2.0–2.0 | 1.1–13.2 | 2.1 (1.0, 4.0) | 3.1 (1.0, 5.5) | 5.3 (2.2, 48.0) | 253.0 (48.0, 338.0) | 170.0 (48.0, 172.0) |
| t½ (hr) | 158, 328 | 297, 299 | 330.7 ± 193.3 | 1533 ± 324.4 | 1529 ± 1018.5 | ‐ | 1150 ± 856.4 |
| CL (L/hr) | 0.00663, 0.00802 | 0.00469, 0.00604 | 0.004920 (36) | 0.003007 (18) | 0.002715 (28) | ‐ | ‐ |
| Vss (L) | 3.9, 4.1 | 2.8, 3.9 | 3.4 (9) | 6.0 (14) | 6.0 (37) | ‐ | ‐ |
Note: “‐” indicates no data available.
Abbreviations: AUC, area under the serum concentration–time curve; AUCinf, AUC from time zero extrapolated to infinite time; AUClast, AUC from time zero to the time of the last quantifiable concentration; AUCtau, AUC from time zero to time tau; CL, clearance of drug from serum; Cmax, maximum serum concentration during the dosing interval; CV%, coefficient of variation; hr, hour; IV, intravenous; JPN, Japanese; max, maximum; MD, multiple doses; min, minimum; N, number of participants; N2, number of participants with contributing data for AUClast, Cmax, Tmax, AUCtau, Rac and Rac,Cmax; N3, number of participants with contributing data for AUCinf, CL, Vss and t½; PK, pharmacokinetics; Q4W, every 4 weeks; Rac, accumulation ratio; Rac,Cmax, accumulation ratio of Cmax; SAD, single ascending doses; SC, subcutaneous; SD, standard deviation; t½, terminal half‐life; Tmax, time to reach Cmax; Vss, steady‐state volume of distribution.
Parameters, except Tmax and t½, are presented as geometric mean (CV%), excluding 30 mg and 100 mg groups, for which individual values are reported due to <3 measurements per cohort being available. Data are presented as median (min, max) for Tmax and arithmetic mean ± SD for t½.
In Japanese participants, PK parameters were generally similar to those observed in non‐Japanese participants at the same dose (Table 3). Mean t½ values for both non‐Japanese and Japanese participants were also similar: 1533 and 1529 h (~64 days each), respectively. These findings suggest no ethnic differences in the PK of PF‐07261271.
For the MD cohort, serum exposure (Cmax and AUCtau) was higher on day 29 (post‐dose 2) than on day 1 (post‐dose 1), with geometric mean accumulation ratios after the second dose of 1.4 and 1.5 for Cmax and AUCtau, respectively (Table 3). Generally, Tmax was achieved faster after the second dose on day 29 than following the first dose on day 1 (medians of 170 and 253 h, respectively); mean t½ on day 29 was approximately 48 days (Table 3). Geometric mean Vz/F was 12.1 L, and estimated F for the SC dose was approximately 48% relative to the 300 mg IV dose.
3.4. Immunogenicity, pharmacodynamics and biomarkers
All participants in both the SAD and MD cohorts who received at least one dose of PF‐07261271 developed ADAs that persisted to their last available sample (Table 4); median time to the first ADA response ranged from 23.0 to 54.5 days. A total of 83.3% of participants had NAb in both the SAD and MD cohorts; median time to the first NAb response ranged from 52.5 to 178.0 days.
TABLE 4.
Proportion of participants receiving PF‐07261271 with positive ADA or NAb responses in the SAD and MD cohorts (PK analysis set).
| SAD cohorts (IV single dose) | MD cohort (SC Q4W) | |||||
|---|---|---|---|---|---|---|
| 30 mg (N = 2) | 100 mg (N = 2) | 300 mg (N = 4) | 1000 mg (N = 6) | 1000 mg JPN (N = 4) | 300 mg (N = 6) | |
| ADA incidence, n (%) | 2 (100.0) | 2 (100.0) | 4 (100.0) |
6 (100.0) |
4 (100.0) |
6 (100.0) |
| NAb incidence, n (%) | 2 (100.0) | 2 (100.0) | 4 (100.0) |
5 (83.3) |
2 (50.0) |
5 (83.3) |
Abbreviations: ADA, anti‐drug antibodies; IV, intravenous; JPN, Japanese; MD, multiple doses; N, number of participants; n, number of participants in group; NAb, neutralizing antibodies; PK, pharmacokinetics; Q4W, every 4 weeks; SAD, single ascending doses; SC, subcutaneous.
Median serum total sTL1A and p40 concentration–time profiles showed dose‐dependent increases from baseline in participants receiving PF‐07261271 in both the SAD and MD cohorts, demonstrating TL1A and p40 target engagement at all doses tested (Figure 3). Peak sTL1A levels were generally observed between days 15–61 post‐dose in the SAD cohorts and around day 81 for the MD cohort (Figure 3). After reaching peak levels, the total sTL1A target levels decreased for all doses and returned to baseline levels for doses ≤300 mg. Peak total p40 levels were generally reached between days 15–61 post‐dose for the SAD cohorts and around day 81 for the MD cohort (Figure 3). There were no changes observed in the median serum total sTL1A and p40 levels following placebo dosing.
FIGURE 3.
Median serum A) total sTL1A and B) p40 concentration–time profiles (semi‐logarithmic scale) for the SAD cohorts and MD cohort (PD analysis set). The LLOQ was 50.0 pg/mL for sTL1A and 37.5 pg/mL for p40. IV, intravenous; JPN, Japanese; LLOQ, lower limit of quantitation; MD, multiple doses; PD, pharmacodynamics; SAD, single ascending doses; SC, subcutaneous; sTL1A, soluble tumour necrosis factor‐like cytokine 1A.
4. DISCUSSION
In this first‐in‐human study, the safety, tolerability, PK and PD of single and multiple doses of PF‐07261271 compared with placebo in healthy participants were evaluated. Both single and multiple doses of PF‐07261271 were well tolerated. All reported TEAEs were mild or moderate with no SAEs or deaths reported. These findings are consistent with clinical safety data reported for therapies that independently target p40 or TL1A pathways, 10 , 11 , 20 , 21 suggesting a similar safety profile for PF‐07261271 compared with either monotherapy.
PK analysis revealed a multi‐phasic decline in serum PF‐07261271 concentrations following Cmax, with a trend towards increased t½ at higher doses. The estimated bioavailability following SC injection was approximately 48% of matched IV administration, and median Tmax for the 300 mg SC dose was 253 h (~11 days) after the first dose on day 1 and 170 h (~7 days) after the second dose on day 29. The relatively long Tmax for PF‐07261271 is due to slow lymphatic absorption resulting from limited flow rate and is consistent with the Tmax of other approved biologics, with values ranging from 2 to 14 days. 24 Collectively, these PK findings support SC dosing as a viable route of administration. It should be noted that due to <3 participants in the 30 mg and 100 mg cohorts, the relationship between serum PK parameters and dose could not be fully assessed. The serum PK results were similar between Japanese and non‐Japanese participants at the 1000 mg IV dose, suggesting no meaningful ethnic differences in PF‐07261271 PK.
Another key finding of this study was the target engagement of PF‐07261271, demonstrated by dose‐dependent increases in total serum sTL1A and p40 levels, following PF‐07261271 administration compared with placebo. By engaging both TL1A and p40 targets and maximizing therapeutic coverage of both of their signalling pathways, PF‐07261271 aims to provide a dual targeting approach for treating IBD with a single molecule. This approach has the potential to better address the limitations of current IBD monotherapies, drive superior rates of remission and break the observed therapeutic ceiling. 20 , 25 , 26 These PK and target engagement data were helpful in informing the PK/PD model used in phase 2 dose design and support further evaluation of PF‐07261271 in IBD and other inflammatory conditions.
All participants who received at least one dose of PF‐07261271 developed ADAs, and 83.3% developed NAb following single and multiple doses. Despite high immunogenicity, there was no apparent impact of immunogenicity on PK, PD biomarker responses or safety. No participants had a potentially immunogenic response of clinical concern. It should be noted that owing to the small sample size, high variability and 100% ADA incidence, additional data are needed before making definitive conclusions on immunogenicity impact. In the phase 1, 2a and 2b trials of afimkibart, which also targets TL1A, the incidence of ADAs and NAb ranged from 50% to 100% and 8% to 35%, respectively, with no apparent impact of ADA and NAb status on efficacy, PK or PD seen at the clinically relevant doses. 11 , 12 , 27
As is typical of first‐in‐human studies, the limitations of this study include the small participant population assessed and their limited demographic variability. Additionally, only healthy participants were evaluated in this phase 1 study, and, as such, findings may differ in patients with IBD, and inferences to larger or different disease populations are limited.
5. CONCLUSIONS
In this first‐in‐human phase 1 study of healthy participants, PF‐07261271 was generally safe and well tolerated and demonstrated both p40 and TL1A target engagement, with no apparent impact of immunogenicity on PK, PD biomarker responses or safety. Future clinical studies evaluating the safety and efficacy of PF‐07261271 in IBD and other relevant disease populations are warranted.
AUTHOR CONTRIBUTIONS
Srividya Neelakantan, Christopher Banfield, Kenneth Hung, Vivek Pradhan, Elena Peeva, Michael S. Vincent and Valerie M. Clerin contributed to the design or conception of the study. Srividya Neelakantan and Yuxi Zhao contributed to the acquisition or analysis of data. All authors contributed to the interpretation of data, drafted or critically reviewed the manuscript for important intellectual content, and approved the final submitted version.
CONFLICT OF INTEREST STATEMENT
SN, AS, YZ, GL, EP, MSV and VMC are employees of Pfizer Inc. CB and KH were employees of Pfizer Inc at the time of the study. VP, DPR and BGJ are employees and shareholders of Pfizer Inc.
Supporting information
Data S1. Supporting Information.
ACKNOWLEDGEMENTS
This study was sponsored by Pfizer Inc. The authors would like to acknowledge Allan McPhee, Nancy Raha and Lindsay King for their contributions to the assay validation and analysis of clinical samples, and Carolyn Soglia for study management. Medical writing support, under the guidance of the authors, was provided by Wynand van Losenoord, MSc, and Amy Churchlow, MSc, employees from the Publications and Medical Affairs Division of Omnicom Health Medical Communications and was funded by Pfizer, New York, NY, USA in accordance with Good Publication Practice 2022 guidelines (Ann Intern Med 2022; 175:1298‐1304). During the preparation of this work, the authors used Pfizer's generative artificial intelligence tool MAIA to assist with writing the manuscript first draft. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
Neelakantan S, Banfield C, Hung K, et al. A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of PF‐07261271 in healthy participants. Br J Clin Pharmacol. 2026;92(10):3413‐3423. doi: 10.1002/bcp.70602
Christopher Banfield and Kenneth Hung, Affiliation at the time the study was conducted.
The authors confirm that the Principal Investigator for this paper is Joel Neutel and that he had direct clinical responsibility for patients.
Funding Information This study was sponsored by Pfizer Inc.
DATA AVAILABILITY STATEMENT
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.
REFERENCES
- 1. Alghamdi KS, Kassar RH, Farrash WF, et al. Key disease‐related genes and immune cell infiltration landscape in inflammatory bowel disease: a bioinformatics investigation. Int J Mol Sci. 2024;25(17):9751. doi: 10.3390/ijms25179751 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Cai Z, Wang S, Li J. Treatment of inflammatory bowel disease: a comprehensive review. Front Med (Lausanne). 2021;8:765474. doi: 10.3389/fmed.2021.765474 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Peyrin‐Biroulet L, Lemann M. Review article: remission rates achievable by current therapies for inflammatory bowel disease. Aliment Pharmacol Ther. 2011;33(8):870‐879. doi: 10.1111/j.1365-2036.2011.04599.x [DOI] [PubMed] [Google Scholar]
- 4. Renna S, Cottone M, Orlando A. Optimization of the treatment with immunosuppressants and biologics in inflammatory bowel disease. World J Gastroenterol. 2014;20(29):9675‐9690. doi: 10.3748/wjg.v20.i29.9675 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Targownik LE, Benchimol EI, Bernstein CN, et al. Combined biologic and immunomodulatory therapy is superior to monotherapy for decreasing the risk of inflammatory bowel disease‐related complications. J Crohns Colitis. 2020;14(10):1354‐1363. doi: 10.1093/ecco-jcc/jjaa050 [DOI] [PubMed] [Google Scholar]
- 6. Caron B, Netter P, Danese S, Peyrin‐Biroulet L. Bispecific antibodies for the treatment in inflammatory bowel disease: an avenue worth exploring? Expert Opin Biol Ther. 2022;22(8):951‐953. doi: 10.1080/14712598.2022.1985999 [DOI] [PubMed] [Google Scholar]
- 7. Jairath V, Danese S, D'Haens G, et al. OP31 phase 1b study of SOR102, a novel, orally delivered bispecific anti‐TNF/anti‐IL‐23 domain antibody in patients with mild to severe ulcerative colitis. J Crohns Colitis. 2025;19(Supplement):i62‐i63. doi: 10.1093/ecco-jcc/jjae190.0031 [DOI] [Google Scholar]
- 8. Ran H, Huang J, Zhang X, et al. Engineering and development of a novel bispecific antibody targeting both TL1A and α4β7 for the treatment of IBD. J Crohns Colitis. 2025;19: I1618. doi: 10.1093/ecco-jcc/jjae190.1022 [DOI] [Google Scholar]
- 9. Wang J, Kang G, Lu H, et al. Novel bispecific nanobody mitigates experimental intestinal inflammation in mice by targeting TNF‐α and IL‐23p19 bioactivities. Clin Transl Med. 2024;14(3):e1636. doi: 10.1002/ctm2.1636 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Reinisch W, Stepek D, Kempinski R, et al. OP41 Duvakitug (TEV‐48574), an anti‐TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active ulcerative colitis: results from a phase 2b, randomised, double‐blind, placebo‐controlled, dose‐ranging, basket trial (RELIEVE UCCD). J Crohns Colitis. 2025;19(Supplement):i79‐i80. doi: 10.1093/ecco-jcc/jjae190.0039B [DOI] [Google Scholar]
- 11. Danese S, Klopocka M, Scherl EJ, et al. Anti‐TL1A antibody PF‐06480605 safety and efficacy for ulcerative colitis: a phase 2a single‐arm study. Clin Gastroenterol Hepatol. 2021;19(11):2324‐2332.e6. doi: 10.1016/j.cgh.2021.06.011 [DOI] [PubMed] [Google Scholar]
- 12. Danese S, Allegretti JR, Schreiber S, et al. Anti‐TL1A antibody, afimkibart, in moderately‐to‐severely active ulcerative colitis (TUSCANY‐2): a multicentre, double‐blind, treat‐through, multi‐dose, randomised, placebo‐controlled, phase 2b trial. Lancet Gastroenterol Hepatol. 2025;10(10):882‐895. doi: 10.1016/S2468-1253(25)00129-3 [DOI] [PubMed] [Google Scholar]
- 13. Jairath V, Kierkus J, Duvall GA, et al. OP40 Duvakitug (TEV‐48574), an anti‐TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active Crohn’s disease: results from a phase 2b, randomised, double‐blind, placebo‐controlled dose‐ranging, basket trial (RELIEVE UCCD). J Crohns Colitis. 2025;19(Supplement):i77‐i78. doi: 10.1093/ecco-jcc/jjae190.0039A [DOI] [Google Scholar]
- 14. Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381(13):1201‐1214. doi: 10.1056/NEJMoa1900750 [DOI] [PubMed] [Google Scholar]
- 15. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2016;375(20):1946‐1960. doi: 10.1056/NEJMoa1602773 [DOI] [PubMed] [Google Scholar]
- 16. Jefremow A, Neurath MF. All are equal, some are more equal: targeting IL 12 and 23 in IBD ‐ a clinical perspective. Immunotargets Ther. 2020;9:289‐297. doi: 10.2147/ITT.S282466 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Schweckendiek D, Rogler G. Antibodies targeting the tumor necrosis factor‐like ligand 1A in inflammatory bowel disease: a new kid on the (biologics) block? Digestion. 2024;105(6):411‐418. doi: 10.1159/000540421 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Valatas V, Kolios G, Bamias G. TL1A (TNFSF15) and DR3 (TNFRSF25): a co‐stimulatory system of cytokines with diverse functions in gut mucosal immunity. Front Immunol. 2019;10:583. doi: 10.3389/fimmu.2019.00583 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Shih DQ, Zheng L, Zhang X, et al. Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal Immunol. 2014;7(6):1492‐1503. doi: 10.1038/mi.2014.37 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Hassan‐Zahraee M, Ye Z, Xi L, et al. Antitumor necrosis factor‐like ligand 1A therapy targets tissue inflammation and fibrosis pathways and reduces gut pathobionts in ulcerative colitis. Inflamm Bowel Dis. 2022;28(3):434‐446. doi: 10.1093/ibd/izab193 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Sands BE, Feagan BG, Peyrin‐Biroulet L, et al. Phase 2 trial of anti‐TL1A monoclonal antibody tulisokibart for ulcerative colitis. N Engl J Med. 2024;391(12):1119‐1129. doi: 10.1056/NEJMoa2314076 [DOI] [PubMed] [Google Scholar]
- 22. Purnak T, Ertan A. Optimal management of patients with moderate‐to‐severe inflammatory bowel disease. J Clin Med. 2024;13(23):7026. doi: 10.3390/jcm13237026 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Alexander SPH, Fabbro D, Kelly E, et al. The concise guide to PHARMACOLOGY 2023/24: catalytic receptors. Br J Pharmacol. 2023;180(Suppl 2):S241‐S288. doi: 10.1111/bph.16180 [DOI] [PubMed] [Google Scholar]
- 24. Zhao L, Ren TH, Wang DD. Clinical pharmacology considerations in biologics development. Acta Pharmacol Sin. 2012;33(11):1339‐1347. doi: 10.1038/aps.2012.51 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Nakase H, Sato N, Mizuno N, Ikawa Y. The influence of cytokines on the complex pathology of ulcerative colitis. Autoimmun Rev. 2022;21(3):103017. doi: 10.1016/j.autrev.2021.103017 [DOI] [PubMed] [Google Scholar]
- 26. Raine T, Danese S. Breaking through the therapeutic ceiling: what will it take? Gastroenterology. 2022;162(5):1507‐1511. doi: 10.1053/j.gastro.2021.09.078 [DOI] [PubMed] [Google Scholar]
- 27. Banfield C, Rudin D, Bhattacharya I, et al. First‐in‐human, randomized dose‐escalation study of the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of PF‐06480605 in healthy subjects. Br J Clin Pharmacol. 2020;86(4):812‐824. doi: 10.1111/bcp.14187 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting Information.
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.