Article Text

Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials
  1. Matthew A Brown1,2,
  2. Martin Rudwaleit3,
  3. Floris A van Gaalen4,
  4. Nigil Haroon5,
  5. Lianne S Gensler6,
  6. Carmen Fleurinck7,
  7. Alexander Marten8,
  8. Ute Massow8,
  9. Natasha de Peyrecave7,
  10. Thomas Vaux9,
  11. Katy White9,
  12. Atul Deodhar10,
  13. Irene van der Horst-Bruinsma11
  1. 1Genomics England, London, UK
  2. 2Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, UK
  3. 3Klinikum Bielefeld, University of Bielefeld, Bielefeld, Germany
  4. 4Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  5. 5University Health Network, Schroeder Arthritis Institute, Department of Medicine/Rheumatology, University of Toronto, Toronto, Ontario, Canada
  6. 6Department of Medicine/Rheumatology, University of California, San Francisco, California, USA
  7. 7UCB Pharma, Brussels, Belgium
  8. 8UCB Pharma, Monheim am Rhein, Germany
  9. 9UCB Pharma, Slough, UK
  10. 10Division of Arthritis and Rheumatic Diseases, Oregon Health and Science University, Portland, Oregon, USA
  11. 11Department of Rheumatology, Radboud University Medical Centre, Nijmegen, The Netherlands
  1. Correspondence to Professor Matthew A Brown, Genomics England, London, UK; matt.brown{at}genomicsengland.co.uk

Abstract

Objectives Acute anterior uveitis (‘uveitis’) is a common axial spondyloarthritis (axSpA) extramusculoskeletal manifestation. Interleukin (IL)-17 is implicated in its pathogenesis, however, there is conflicting evidence for IL-17A inhibition in uveitis management. We report pooled analyses of uveitis incidence in patients receiving bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, from phase 2b/3 trials.

Methods Data were pooled for patients receiving BKZ 160 mg or placebo in the double-blind treatment period of the phase 3 BE MOBILE 1 (NCT03928704; non-radiographic axSpA) and BE MOBILE 2 (NCT03928743; radiographic axSpA) trials. Data were separately pooled for patients treated with at least one BKZ dose in the BE MOBILE trials and their ongoing open-label extension (OLE; NCT04436640), and the phase 2b BE AGILE trial (NCT02963506; radiographic axSpA) and its ongoing OLE (NCT03355573). Uveitis rates and exposure-adjusted incidence rates (EAIR)/100 patient-years (PYs) are reported.

Results In the BE MOBILE 1 and 2 double-blind treatment period, 0.6% (2/349) of patients receiving BKZ experienced uveitis vs 4.6% (11/237) receiving placebo (nominal p=0.001; EAIR (95% CI): 1.8/100 PYs (0.2 to 6.7) vs 15.4/100 PYs (95% CI 7.7 to 27.5)). In patients with history of uveitis, EAIR was lower in patients receiving BKZ (6.2/100 PYs (95% CI 0.2 to 34.8); 1.9%) vs placebo (70.4/100 PYs (95% CI 32.2 to 133.7); 20.0%; nominal p=0.004). In the phase 2b/3 pool (N=848; BKZ exposure: 2034.4 PYs), EAIR remained low (1.2/100 PYs (95% CI 0.8 to 1.8)).

Conclusions Bimekizumab, a dual-IL-17A/F inhibitor, may confer protective effects for uveitis in patients with axSpA.

  • Uveitis
  • Uveitis, Anterior
  • Axial Spondyloarthritis
  • Interleukin-17

Data availability statement

Data are available on reasonable request. Underlying data from this manuscript may be requested by qualified researchers six months after product approval in the USA and/or Europe, or global development is discontinued, and 18 months after study completion. Investigators may request access to anonymised individual patient-level data and redacted trial documents which may include: analysis-ready datasets, trial protocols, annotated case report forms, statistical analysis plans, dataset specifications and clinical study reports. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password-protected portal.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Acute anterior uveitis (AAU; ‘uveitis’) is the most common extramusculoskeletal manifestation among patients with axial spondyloarthritis (axSpA), and significantly impacts health-related quality of life, posing a substantial burden for patients.

  • Monoclonal antibodies against tumour necrosis factor are currently recommended in patients with axSpA and a history of recurrent AAU.

  • Interleukin (IL)-17 has been implicated in the pathogenesis of AAU, however, clinical data on the effectiveness of IL-17A inhibition (IL-17Ai) alone in uveitis prevention are conflicting.

  • Bimekizumab (BKZ) is a humanised monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, which has demonstrated long-term efficacy and a positive benefit–risk profile across the full disease spectrum of axSpA.

WHAT THIS STUDY ADDS

  • During the double-blind treatment period of the phase 3 BE MOBILE trials, the incidence rate of uveitis was lower to Week 16 in patients randomised to BKZ compared with patients randomised to placebo.

  • In a large pool of phase 2b/3 trial data, the incidence rate of uveitis with BKZ over a long duration remained low, suggesting BKZ may be an appropriate treatment option for patients with axSpA and uveitis.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • This is the first analysis to examine the effect of BKZ on uveitis in patients with axSpA and suggests that BKZ, a dual-IL-17A/F inhibitor, may confer protective effects for AAU in patients with axSpA.

Introduction

Uveitis, specifically acute anterior uveitis (AAU), is the most common extramusculoskeletal manifestation among patients with axial spondyloarthritis (axSpA), which poses a substantial burden for patients and significantly affects physical and social functioning.1 2 Estimates indicate that AAU prevalence is between 20%–50% in patients with radiographic (r)-axSpA (ie, ankylosing spondylitis (AS))3 and approximately 12%–16% in patients with non-radiographic (nr)-axSpA.4–8 Factors associated with AAU in patients with spondyloarthritis (SpA) include HLA-B27 positivity, older age, smoking, delayed diagnosis and longer disease duration.9 10

The pathobiology of AAU associated with SpA remains complex. Both tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-17 have been implicated in AAU pathogenesis and are potential therapeutic targets.11 Other mediators have also been implicated in AAU in SpA, including IL-6, IL-10, IL-15, IL-18, IL-22, IL-23 and granulocyte-macrophage colony-stimulating factor, as well as several other chemokines and matrix metalloproteinases.12–14 Single-nucleotide polymorphisms in IL23R are associated with AAU, which is significant given early evidence that IL-17 is a potential therapeutic target for axSpA arose from associations of IL23R with the disease, as it plays a role in the regulation of T helper 17 and other IL-17 producing cells.5 15 16

Monoclonal antibodies (MAbs) against TNF (TNF inhibitors (TNFi)), such as infliximab, adalimumab, certolizumab pegol and golimumab, have demonstrated effectiveness in reducing recurrent AAU in patients with axSpA, although evidence is mixed for the fusion protein etanercept.17–24 As such, the Assessment of SpondyloArthritis International Societ-European Alliance of Associations for Rheumatology recommendations for the management of axSpA suggest MAbs against TNF in patients with active axSpA and recurrent AAU.25 Yet, while MAbs against TNF can reduce AAU rates for many patients, some patients continue to experience recurrence as outlined above, and there remains a need for another treatment option which both elicits high levels of clinical response and prevents AAU.26

While IL-17 has also been recognised as a potential driver of AAU pathogenesis, clinical data on the effectiveness of IL-17A inhibition (IL-17Ai) alone are conflicting.27–30 Indeed, as outlined in the 2019 American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network recommendations, the impact of the IL-17Ais secukinumab and ixekizumab on uveitis is not well defined with conflicting data reported.31 While intravenous secukinumab has previously been shown to be effective in a phase 2 trial in patients with chronic non-infectious uveitis, subcutaneous secukinumab subsequently failed to demonstrate efficacy in three separate randomised, controlled phase 3 clinical trials.27 28 In addition to these trials, separate national observational cohort studies of patients with SpA and r-axSpA (AS) have found that treatment with secukinumab is associated with a higher risk of AAU compared with some TNFis in clinical practice.29 30 On the contrary, recent long-term data of ixekizumab in patients with axSpA have suggested more promise for IL-17Ai in AAU.32

Bimekizumab (BKZ) is a humanised monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A. As with IL-17A, IL-17F is also implicated in AAU pathogenesis,12 and investigation of the effectiveness of dual IL-17A/Fi in AAU is warranted. To date, BKZ has demonstrated long-term efficacy and a positive benefit–risk profile across the full disease spectrum of axSpA.33 34 Here, we present pooled analyses of the incidence of uveitis in patients treated with BKZ in the phase 3 BE MOBILE 1 and BE MOBILE 2 trials, the phase 2b BE AGILE trial and their open-label extensions (OLE).

Methods

Study design and patients

The study designs and inclusion and exclusion criteria for the phase 3 BE MOBILE trials have been described previously.34 Briefly, BE MOBILE 1 (NCT03928704; active nr-axSpA) and BE MOBILE 2 (NCT03928743; active r-axSpA) comprised a 16-week double-blind treatment period, during which patients were randomised 1:1 (in BE MOBILE 1) and 2:1 (in BE MOBILE 2) to receive subcutaneous BKZ 160 mg or placebo every 4 weeks (Q4W). This was followed by a 36-week maintenance period, during which all patients received BKZ 160 mg Q4W. Patients were permitted to have a history of uveitis but could not have had an active episode within six weeks of the baseline visit. On entry to the ongoing BE MOVING OLE (NCT04436640; data cut-off 4 July 2022 for this analysis) at Week 52, all patients remained on BKZ 160 mg Q4W for up to two years.

The study design, inclusion and exclusion criteria for the phase 2b BE AGILE trial and its OLE have also been described previously.33 35 Briefly, BE AGILE (NCT02963506; active r-axSpA) comprised a 12-week double-blind, dose-ranging period followed by a 36-week randomised period (BKZ 160 mg or 320 mg Q4W). On entry to the BE AGILE OLE (NCT03355573; data cut-off 4 July 2022 for this analysis) at Week 48, all patients received BKZ 160 mg Q4W for up to four years.

Statistical analysis

Uveitis events were identified during the trials using the preferred terms ‘autoimmune uveitis’, ‘iridocyclitis’, ‘iritis’ and ‘uveitis’, coded according to the Medical Dictionary for Regulatory Activities (MedDRA) v.19.0; note that ‘acute anterior uveitis’ was not a specific preferred term available in MedDRA v.19.0. For simplicity, the blanket term ‘uveitis’ is used to cover all of these preferred terms throughout the Results section. In addition, a dedicated page on extramusculoskeletal manifestations was completed to inform whether a history of uveitis was present and whether the diagnosis was confirmed by an ophthalmologist.

Data were separately pooled for patients randomised to BKZ 160 mg or placebo in the 16-week double-blind treatment period of BE MOBILE 1 and 2, and pooled for all patients who received at least one dose of BKZ 160 mg Q4W in the phase 2b and 3 trials described above (online supplemental figure S1). New uveitis events and recurrent events were analysed and presented by patients with or without a history of uveitis.

Supplemental material

Occurrence of uveitis events is reported as exposure-adjusted incidence rates (EAIRs) and exposure-adjusted event rates (EAERs) per 100 patient-years (PYs). EAIR is the number of patients with at least one event per 100 PYs, and EAER is the total number of events per 100 PYs. Baseline demographics and characteristics of patients are also presented by patients who experienced a uveitis event or did not experience a uveitis event during the trials. As the incidence of uveitis was not included in the hierarchical statistical plan of the trials, reported p values are nominal. P values are based on the Cochran-Mantel-Haenszel test for general association.

Patient and public involvement

While patients with axSpA were consulted during development of the BKZ in axSpA clinical trial programme to understand treatment needs and recommend ways to facilitate trial participation while minimising burden of trial visits, there was no specific patient involvement in the analyses presented here. Trial participants were recruited by the trial sites and provided written consent to participate.

Results

Patient disposition, demographics and baseline characteristics

Overall, 349 patients were randomised to BKZ 160 mg and 237 patients were randomised to placebo in the double-blind treatment period of BE MOBILE 1 and 2. In the overall phase 2b/3 trial pool, 848 patients received at least one dose of BKZ 160 mg.

The patient demographics and baseline characteristics of the trial populations are shown in table 1. Due to the study designs of the trials and the 2:1 randomisation ratio in BE MOBILE 2 (r-axSpA), a higher proportion of patients treated with BKZ (63.3%) had r-axSpA than placebo (46.8%). In the pooled BE MOBILE phase 3 trials, patients treated with placebo had a slightly higher rate of history of uveitis (19.0%) compared with patients treated with BKZ (14.9%). Patients treated with BKZ also had a longer duration since first onset of axSpA symptoms (12.4 years) compared with placebo (10.3 years).

Table 1

Patient demographics and baseline characteristics

In patients with a history of uveitis in the total phase 2b/3 trial pool, of those with recorded dates at baseline, the mean (SD) time since first diagnosis of uveitis was 9.2 years (8.8; n=115) and mean (SD) time since the resolution of the last uveitis event was 3.9 years (6.5; n=107). In patients with a history of uveitis who also had a uveitis event during the phase 2b/3 trials, of those with recorded dates at baseline, the mean (SD) time since first diagnosis of uveitis was 9.0 years (10.8; n=14) and mean (SD) time since the resolution of the last uveitis event was 4.3 years (8.0; n=14).

Incidence of uveitis

BE MOBILE 1 and 2: pooled and individual phase 3 double-blind treatment periods (Weeks 0–16)

In the pooled phase 3 analysis of the 16-week double-blind treatment period of the BE MOBILE trials, the proportion of patients experiencing uveitis events was lower in patients treated with BKZ (0.6% (2/349)) compared with patients receiving placebo (4.6% (11/237)); EAIR (95% CI) was 1.8/100 PYs (0.2 to 6.7) in patients receiving BKZ, and 15.4/100 PYs (95% CI 7.7 to 27.5) in those receiving placebo (nominal p=0.001) (figure 1A). 13 uveitis events in total occurred in 11 patients randomised to placebo (EAER: 17.8/100 PYs); of the 11 patients, nine (3.8%) experienced one event and two (0.8%) patients experienced two events in total. Three uveitis events occurred in two patients randomised to BKZ (EAER: 2.8/100 PYs); one (0.3%) patient experienced one event and the other patient (0.3%) experienced two events.

Figure 1

EAIRs of uveitis in the double-blind treatment period (Weeks 0–16) of BE MOBILE 1 and 2 in all patients (A) and split by history of uveitis (B). Data are presented as EAIR/100 PYs (95% CI); n/N is the number of patients who had at least one uveitis event/total number of patients. BKZ, bimekizumab; EAIR: exposure-adjusted incidence rate; PYs, patient-years; Q4W, every 4 weeks.

In patients with a history of uveitis, uveitis occurred in 1.9% (1/52) of patients randomised to BKZ, compared with 20.0% (9/45) randomised to placebo (nominal p=0.004). The incidence rate of uveitis in these patients with a history of uveitis was lower in those treated with BKZ (EAIR: 6.2/100 PYs (95% CI 0.2 to 34.8)) than placebo (70.4/100 PYs (95% CI 32.2 to 133.7); figure 1B). One event occurred in the one patient randomised to BKZ (EAER: 6.1/100 PYs) and in total 11 events occurred in the nine patients randomised to placebo (EAER: 78.8/100 PYs). Of these nine patients randomised to placebo, seven (15.6%) experienced one event, while two (4.4%) patients experienced two. In patients without a history of uveitis, uveitis events occurred in 0.3% (1/297) of patients randomised to BKZ during the double-blind treatment period, compared with 1.0% (2/192) of patients randomised to placebo (nominal p=0.330). Accordingly, the EAIR of uveitis in these patients treated with BKZ was lower than placebo (BKZ: 1.1/100 PYs (95% CI 0.0 to 6.0); placebo: 3.4/100 PYs (95% CI 0.4 to 12.3); figure 1B). In total two events occurred in the one patient randomised to BKZ (EAER: 2.2/100 PYs) and each of the two patients randomised to placebo experienced only one event (EAER: 3.4/100 PYs).

Separately, during the double-blind treatment period of BE MOBILE 1, 1.6% (2/128) of patients treated with BKZ had a uveitis event, compared with 4.8% (6/126) receiving placebo (nominal p=0.145; figure 2). In the double-blind treatment period of BE MOBILE 2, no patients treated with BKZ (0/221) had a uveitis event, while 4.5% (5/111) of patients receiving placebo did (nominal p=0.002; figure 2).

Figure 2

Incidence of uveitis in the double-blind treatment period (Weeks 0–16) of BE MOBILE 1 and 2. BKZ, bimekizumab; nr-axSpA, non-radiographic axial spondyloarthritis; Q4W, every 4 weeks; r-axSpA, radiographic axial spondyloarthritis.

Of patients randomised to BKZ, during the 16-week double-blind treatment period, none discontinued treatment due to uveitis; two patients randomised to placebo discontinued the trial due to uveitis, both in BE MOBILE 1.

Pooled phase 2b/3

In the pooled phase 2b/3 trial data, total BKZ exposure was 2034.4 PYs (N=848). Overall, 2.9% (25/848) of patients had a uveitis event; in these patients, a total of 34 uveitis events occurred (EAER: 1.7/100 PYs); 20 (2.4%) patients experienced one event, three (0.4%) patients experienced two events and two (0.2%) patients experienced three or more events. The EAIR (95% CI) of uveitis in patients treated with BKZ was 1.2/100 PYs (0.8 to 1.8) (figure 3A).

Figure 3

EAIRs of uveitis in the phase 2b/3 trial data pool in all patients (A) and split by history of uveitis (B). Data are presented as EAIR/100 PYs (95% CI); n/N is the number of patients who had at least one uveitis event/total number of patients. BKZ, bimekizumab; EAIR: exposure-adjusted incidence rate; PYs, patient-years; Q4W, every 4 weeks.

The EAIR (95% CI) in patients without a history of uveitis (0.6/100 PYs (0.3 to 1.2)) was lower compared with those with a history of uveitis (4.6/100 PYs (95% CI 2.5 to 7.7)) (figure 3B). Uveitis occurred in 10.8% (14/130) of patients with a history of uveitis, with a total of 17 events occurring in these 14 patients (EAER: 5.3/100 PYs). Of these 14 patients with a history of uveitis, 12 (9.2%) patients only experienced one event, one (0.8%) patient experienced two events and one (0.8%) patient experienced three events in total. Only 1.5% (11/718) of patients without a history of uveitis had an event. In total, 17 events occurred in these patients (EAER: 1.0/100 PYs); eight (1.1%) patients experienced one event, two (0.3%) patients experienced two events and one (0.1%) patient had five.

All uveitis events were mild or moderate and only one led to permanent discontinuation of BKZ. This event was AAU with an onset of 209 days after the first treatment administration. The event was intermittent, of mild intensity and resulted in BKZ being withdrawn; the event was resolved with concomitant medication.

Characteristics associated with uveitis

The baseline demographics and characteristics are presented by patients who had at least one uveitis event in the phase 2b/3 trials and patients who did not have a uveitis event in table 2. It is worth noting the imbalance in the number of patients who had uveitis (n=25) compared with those who did not (n=823).

Table 2

Patient demographics and baseline characteristics split by patients with and without a uveitis event in the pooled phase 2b/3 trials

Most markedly, in comparison with patients who did not have uveitis during the phase 2b/3 trials, a higher proportion of patients who experienced uveitis had a history of uveitis (56.0% (14/25) vs 14.1% (116/823)). Additionally, a higher proportion of patients who had uveitis events during the trials were female (36.0% (9/25) vs 28.3% (233/823)); HLA-B27 positive (92.0% (23/25) vs 84.3% (694/823)); had r-axSpA (84.0% (21/25) vs 70.8% (583/823)); had a longer time since first axSpA symptoms to trial baseline (15.5 vs 12.3 years); had prior TNFi exposure (20.0% vs 12.5%) and had higher high-sensitivity C reactive protein (hs-CRP; geometric mean (geometric coefficient of variation, CV): 9.4 mg/L (239.4%) vs 7.1 mg/L (238.1%)).

Time to first uveitis event

To explore the relationship between time on BKZ treatment and incidence of uveitis, a Kaplan-Meier analysis of time to first uveitis event in patients receiving BKZ in the phase three trial and phase 2b/3 trial pools up to Week 96 is presented in figure 4. These analyses suggest that there is no trend in time from the first BKZ administration and the first incidence of uveitis.

Figure 4

Kaplan-Meier estimates for time to first uveitis event in patients receiving BKZ in the phase 3 and phase 2b/3 trial pools. Includes all patients who received BKZ 160 mg Q4W. Time to first occurrence of uveitis (weeks) was calculated as (date of first onset of uveitis—date of first BKZ administration+1)/7. BKZ, bimekizumab; Q4W, every 4 weeks.

Discussion

AAU is the most common extramusculoskeletal manifestation of axSpA1 and represents a significant burden on the quality of life of patients, potentially leading to complications such as formation of synechiae, glaucoma, cataracts and even blindness.2 36–38 Management of AAU in axSpA is, therefore, an integral part of management of the disease itself.

This is the first comprehensive overview of uveitis incidence in patients with both nr-axSpA and r-axSpA treated with BKZ, which selectively inhibits IL-17F in addition to IL-17A. We show that the proportion of patients experiencing uveitis in the BE MOBILE phase 3 trials was lower to Week 16 in patients with axSpA treated with BKZ compared with placebo (0.6% vs 4.6%; nominal p=0.001). The difference in incidence of uveitis to Week 16 between patients receiving BKZ and placebo varied based on their history of uveitis. Among patients with a history of uveitis, BKZ greatly lowered the uveitis rate (1.9%) compared with placebo (20.0%; difference: 18.1%; nominal p=0.004) to Week 16. For patients without a history of uveitis, the rate of uveitis in patients receiving BKZ was numerically lower than those receiving placebo, however, with a smaller difference between the groups (BKZ: 0.3%; placebo: 1.0%; difference: 0.7%; nominal p=0.330). The higher overall rates of uveitis in patients with a history of uveitis are expected given the increased risk of recurrence in these patients. This is supported by analyses here showing higher rates of history of uveitis in patients who had a uveitis event during the trials. However, BKZ treatment resulted in greatly reduced uveitis rates in this high-risk group. The smaller difference in patients without a history of uveitis aligns with previous studies, where it is more challenging to detect a treatment’s efficacy in reducing AAU rates in these patients. In the RAPID-axSpA trial of certolizumab pegol in patients with axSpA, to Week 24 no patients without a history of uveitis receiving certolizumab pegol or placebo had a uveitis event.17

Over the longer term, in the large phase 2b/3 trial pool spanning 2034.4 PYs and 848 patients with active axSpA treated with BKZ, EAIR remained low (1.2/100 PYs). The low rate of uveitis observed with BKZ treatment in this phase 2b/3 trial pool is consistent with the previously reported three-year results from the phase 2b BE AGILE trial, in which the EAIR was 0.7/100 PYs.33 As a reference, the EAIR of 1.2/100 PYs observed here is also low compared with rates in the placebo arms of other longer-term randomised controlled clinical trials. For instance, in a 52-week placebo-controlled trial of certolizumab pegol in nr-axSpA, an EAIR of 7.2/100 PYs was observed in patients receiving placebo (15.8% of patients had a history of AAU).39 In a pooled analysis of four placebo-controlled etanercept trials in r-axSpA (AS), patients receiving placebo (exposure of 83.0 PYs) had an EAIR of 19.3/100 PYs (21.7% of patients had a history of AAU).19

In patients with a history of uveitis, the incidence of uveitis with BKZ treatment also remained low, at 4.6/100 PYs. Comparing this with previous uveitis rates observed in this patient group with TNFi treatment, in a two-year phase 4 trial in patients with axSpA and a history of recurrent AAU, treatment with certolizumab pegol resulted in an AAU incidence of 17.7/100 PYs.22 In the RHAPSODY trial of adalimumab in patients with r-axSpA (AS), the rate of anterior uveitis (AU) in patients with a history following adalimumab treatment was 28.9/100 PYs.24 However, caution should be taken when directly comparing across separate trials, where differences in study design and patient populations may impact the results.

At baseline in the pooled phase 3 studies, a higher proportion of patients treated with BKZ had r-axSpA and a longer duration since first onset of symptoms than patients receiving placebo, which is of note given both these factors are associated with higher AAU incidence and could, therefore, provide additional robustness to the low incidence seen with BKZ treatment.7 10 However, on the contrary, a higher proportion of patients receiving placebo had a history of uveitis vs BKZ. Indeed, an additional analysis was presented to further explore the association of baseline characteristics and demographics with uveitis. This analysis indicated differences in some demographics and baseline characteristics in patients who had uveitis during the trials compared with patients who did not; a higher proportion of patients were females, had a history of uveitis, HLA-B27 positivity, r-axSpA, longer disease duration, prior TNFi exposure and higher baseline hs-CRP. This is in line with previous observations that have identified longer disease duration and HLA-B27 positivity as factors associated with AAU; additional factors previously associated with AAU identified in other studies include older age, smoking history and history of inflammatory bowel disease.10 40 41 It was observed here that a slightly higher proportion of patients with uveitis were female than those without uveitis, which is not expected based on previous studies. However, this difference was not marked, and it should be noted that only 25 patients treated with BKZ experienced uveitis in the phase 2b/3 trials, compared with 823 who did not, thus the overall differences observed in this study should be interpreted with caution.

Current guidelines recommend MAbs against TNF for the prevention of recurrent AAU in patients with axSpA, following accumulation of substantial evidence demonstrating reduced AAU rates with TNFi treatment, as described earlier.25 While there is substantial data supporting the role of TNFi in the management of AAU, the effectiveness of IL-17Ai in AAU is less clear, and there is limited evidence available. In three-year data from the COAST programme of ixekizumab in patients with axSpA (total exposure: 2097.7 PYs), incidence of uveitis was 2.8/100 PYs in all patients; in patients with a history of uveitis (18.6%), the incidence was 10.7/100 PYs.32 In a phase 2 trial in 16 patients with chronic non-infectious uveitis, secukinumab 10 mg/kg administered intravenously demonstrated safety and efficacy, with improvements in visual acuity and reductions in ocular inflammation; 13 patients showed improvement in ocular inflammation at Week 8, and two patients had no change in ocular inflammation.28 However, subcutaneous secukinumab (150 mg and 300 mg) subsequently failed to demonstrate efficacy in three separate phase 3 clinical trials in non-infectious uveitis; in the trials, two of which were terminated early due to lack of efficacy, there were no statistically significant differences in the recurrence of non-infectious uveitis between the secukinumab and placebo groups.27 Given intravenous secukinumab demonstrated efficacy while subcutaneous secukinumab did not, it could be hypothesised that tissue penetration may have contributed to these findings. Further to these trials, in a national observational cohort study in patients with SpA in Sweden, treatment with the IL-17Ai secukinumab was found to be less effective for AU than treatment with TNFis.30 In another retrospective national cohort study of patients with r-axSpA (AS), compared with adalimumab, secukinumab treatment was associated with a higher risk of new-onset AAU.29

Here, this pooled analysis evaluated the impact of dual IL-17A/Fi with BKZ on uveitis in patients with axSpA. Increased serum levels of IL-17A have been found in patients with AAU compared with healthy controls, particularly in active uveitis.42 Fluorescence-activated cell sorting has also demonstrated that patients with AAU have a statistically significant increase in both IL-17A and IL-17F, produced by CD8+ cells.12 These data suggest that both IL-17A and IL-17F are important targets in AAU. Moreover, IL-17A and IL-17F share overlapping biology but are differentially regulated at the tissue level and can independently contribute to maintaining inflammation.43 Preclinical studies have indicated that dual inhibition of both IL-17A and IL-17F may lead to more effective suppression of inflammation compared with IL-17A-specific inhibition.43–45 Interestingly, in a preclinical mouse model of uveitis, loss of IL-17A in autopathogenic T helper 17 cells has been shown to not reduce their pathogenicity, and instead enhances expression of other cytokines such as IL-17F.46 Clinical data presented in this pooled analysis suggest that dual inhibition of both IL-17A and IL-17F with BKZ may be effective for the prevention of axSpA-related AAU. In addition, in a pool of one phase 2 and two separate phase 3 studies and their OLEs of BKZ in patients with psoriatic arthritis (N=1407; BKZ exposure: 2590.8 PYs) no patients had uveitis as of a July 2022 data-cut,47 although it should be acknowledged that incidence of AAU is lower in psoriatic arthritis compared with axSpA.48 Further elucidation of the potential role of IL-17F in the pathobiology of AAU as well as evidence of BKZ in real-world clinical settings are warranted to further substantiate these observations.

The analyses presented here were performed on a large patient population, pooled from phase 2b/3 trials, with an overall long-term exposure to treatment (2034.4 PYs). The analyses also had a placebo comparison up to Week 16, something which was not presented in pooled analyses of uveitis incidence from phase 3 axSpA trials in secukinumab.49 There are some limitations, however, that should be noted. For example, uveitis reporting in the trials was based on spontaneous reporting of adverse events, rather than an analysis based on a focused endpoint, and not every event was assessed by an ophthalmologist. Caution should also be taken when interpreting the results from the double-blind treatment period of the phase 3 BE MOBILE trials, provided the low overall number of patients with AAU and relatively short duration of this treatment period. Indeed, there is a lack of a long-term placebo comparison beyond 16 weeks, although this is of course constrained by ethical considerations. Further, regarding data on recurrence of uveitis, no requirement for separation between events was applied to consider them separate events; it may, therefore, be possible that some recurrences were part of the same event.

Overall, in this analysis exploring the effect of dual IL-17A/Fi on uveitis in patients with axSpA, the incidence rate of uveitis was lower to Week 16 in patients with axSpA randomised to BKZ 160 mg Q4W vs placebo in the double-blind treatment period of the phase 3 BE MOBILE trials. In a large pool of phase 2b/3 trial data, the EAIR with BKZ over a long duration, 2034.4 PYs, remained low at 1.2/100 PYs. These data suggest that BKZ, a dual-IL-17A/F inhibitor, may confer protective effects for uveitis in patients with axSpA.

Data availability statement

Data are available on reasonable request. Underlying data from this manuscript may be requested by qualified researchers six months after product approval in the USA and/or Europe, or global development is discontinued, and 18 months after study completion. Investigators may request access to anonymised individual patient-level data and redacted trial documents which may include: analysis-ready datasets, trial protocols, annotated case report forms, statistical analysis plans, dataset specifications and clinical study reports. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password-protected portal.

Ethics statements

Patient consent for publication

Ethics approval

These trials were conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Guidance for Good Clinical Practice. Independent institutional review board approvals were obtained, and all patients provided written informed consent in accordance with local requirements.

Acknowledgments

The authors thank the patients and their caregivers in addition to all the investigators and their teams who contributed to these studies. The authors also acknowledge Celia Menckeberg, PhD, UCB Pharma, Breda, The Netherlands for publication coordination and editorial assistance, and Patrick Cox, BSc, Costello Medical, London, UK and Joseph Smith, PhD, Cambridge, UK for medical writing and editorial assistance. These studies were funded by UCB Pharma. This work was originally presented at EULAR 2024 (Milan, Italy), and has been presented at ACR 2023 (San Diego, CA, USA), CRA & AHPA 2024 (Winnipeg, MB, Canada), BSR 2024 (Liverpool, UK) and NZRA/ARA 2024 (Christchurch, New Zealand).

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • MAB and MR are joint first authors.

  • Handling editor Josef S Smolen

  • MAB and MR contributed equally.

  • Contributors Substantial contributions to study conception and design: MAB, MR, FAvG, NH, LSG, CF, AM, UM, NdP, TV, KW, AD, IvdH-B; substantial contributions to analysis and interpretation of the data: MAB, MR, FAvG, NH, LSG, CF, AM, UM, NdP, TV, KW, AD, IvdH-B; drafting the article or reviewing it critically for important intellectual content: MAB, MR, FAvG, NH, LSG, CF, AM, UM, NdP, TV, KW, AD, IvdH-B; final approval of the version of the article to be published: MAB, MR, FAvG, NH, LSG, CF, AM, UM, NdP, TV, KW, AD, IvdH-B. Guarantor: MAB.

  • Funding This article was based on the original studies BE MOBILE 1 (NCT03928704), BE MOBILE 2 (NCT03928743), BE MOVING (NCT04436640), BE AGILE (NCT02963506), and the BE AGILE OLE (NCT03355573) which were sponsored by UCB Pharma. Support for third-party writing assistance for this article, provided by Patrick Cox, BSc, Costello Medical, London, UK, was funded by UCB Pharma in accordance with Good Publication Practice 2022 guidelines (https://www.ismpp.org/gpp-2022).

  • Competing interests MAB: Grant/research support from UCB Pharma; consultant for Clementia, Grey Wolf Therapeutics, Incyte, Ipsen, Pfizer, Regeneron and Xinthera; speaker for Novartis and Pfizer; payment for expert testimony from Ipsen; participation on a Data Safety Monitoring Board or Advisory Board for Incyte, Ipsen and Regeneron. MR: Speakers bureau from AbbVie, Boehringer Ingelheim, Chugai, Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma; consultant of AbbVie, Eli Lilly, Novartis and UCB Pharma. FAvG: Grants from Jacobus Stichting, Novartis, Stichting ASAS, Stichting Vrienden van Sole Mio and UCB Pharma; consultant for AbbVie, ASAS, BMS, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma. NH: Consultant for AbbVie, Eli Lilly, Janssen, Novartis and UCB Pharma. LSG: Consultant for Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma; grant/research support from Novartis and UCB Pharma paid to institution; participation on a Data Safety Monitoring Board or Advisory Board for Acelyrin; member of the Spondylitis Association of America Medical Scientific Advisory Board and ASAS Executive Committee. CF, KW: Employee and shareholder of UCB Pharma. AM, UM, TV, NdP: Employees of UCB Pharma. AD: Speaker for Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma; consultant for BMS, Eli Lilly, Janssen, MoonLake, Novartis, Pfizer and UCB Pharma; grant/research support from BMS, Celgene, Eli Lilly, Janssen, MoonLake, Novartis, Pfizer and UCB Pharma; support for attending meetings and/or travel from Eli Lilly; participation on a Data Safety Monitoring Board or Advisory Board for BMS, Eli Lilly, Janssen, MoonLake, Novartis, Pfizer and UCB Pharma; member of the steering committee of GRAPPA. IvdH-B: Consultant for AbbVie, Eli Lilly, MSD, Novartis and UCB Pharma; unrestricted grants received for investigator-initiated studies from AbbVie, MSD, Pfizer and UCB Pharma; fees received for Lectures from AbbVie, BMS, MSD and Pfizer.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.