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Expert Review of Clinical Immunology Volume 17, 2021 - Issue 10
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Drug Profile

Ixekizumab: an IL-17A inhibitor for the treatment of axial Spondylarthritis

Stephanie R Harrisona NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals Trust, Leeds, UK;b Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UKORCID Iconhttps://orcid.org/0000-0002-7465-2621View further author information
ORCID Icon &
Helena Marzo-Ortegaa NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals Trust, Leeds, UK;b Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UKCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0002-9683-3407View further author information
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Pages 1059-1071 | Received 03 Jun 2021, Accepted 17 Aug 2021, Published online: 26 Aug 2021

ABSTRACT

Introduction

Axial spondyloarthritis (axSpA) is an inflammatory arthritis which affects primarily the entheses of the spine and sacroiliac joints with peripheral joint synovitis and extra-articular manifestations. In 2017, the first IL-17A inhibitor (IL-17Ai) secukinumab was approved for the treatment of radiographic axSpA not responding adequately to conventional therapies, and this was followed in 2019 by a second IL-17Ai, ixekizumab. These agents represent the first alternative class of biological treatments after the TNF inhibitor which dominated the therapeutic landscape of axSpA for over a decade.

Areas covered

This review discusses the role of IL-17Ais in the treatment in axSpA focusing on the newest IL-17Ai ixekizumab. It provides a detailed overview of the drug pharmacodynamic, pharmacokinetics, and clinical trial data, including areas of future research needed in the post-marketing era.

Expert opinion

Early trials of ixekizumab for axSpA have shown encouraging results and an acceptable safety profile. Future phase IV trials should focus on direct head-to-head comparisons between ixekizumab and other biologic drugs, and stratify patients according to important disease characteristics known to affect treatment response including sex, HLA-B27 status, presence of MRI bone marrow edema at baseline, disease duration and any extra-articular manifestations.

1. Introduction

Axial spondyloarthritis (axSpA) is an inflammatory disease primarily affecting the axial skeleton (sacroiliac and spinal joints) and entheses, which can be associated with peripheral arthritis and extra-articular manifestations (EAMs) including uveitis, inflammatory bowel disease (IBD), and psoriasis [Citation1,Citation2]. Unlike other inflammatory arthritis, which more frequently affect females ages 50–60 years [Citation2–5], axSpA typically starts before the age of 45 years with a male preponderance particularly in the case of radiographic axSpA (r-axSpA). As a result, axSpA has a significant impact on work productivity and quality of life [Citation3–5]. Moreover, as patients are younger, the need for aggressive control of disease is paramount, since the potential for and impact of irreversible joint damage can be very significant.

There are no diagnostic criteria for axSpA. Historical classification criteria such as the New York Criteria weighted heavily on the presence of new bone formation at the sacroiliac/vertebral joints as identified on plain radiography [Citation6,Citation7]. However, the introduction of magnetic resonance imaging (MRI) clearly demonstrated that inflammation in the sacroiliac joints, and occasionally the spine may precede permanent bony changes by decades in some cases, allowing for an earlier identification of disease independently of radiographic findings [Citation8]. New terminology was therefore introduced to distinguish between those cases that can be identified by the presence of sacroiliitis on plain radiographs (r-axSpA), traditionally known as ankylosing spondylitis (AS) and those that cannot [non-radiographic axSpA (nr-axSpA)], but may otherwise be identifiable by MRI and other clinical criteria, including human leucocyte antigen (HLA)-B27 [Citation9,Citation10]. This nomenclature can cause confusion amongst specialists and non-specialists alike. Nevertheless, whilst the terms are conceptually different, nr-axSpA and r-axSpA should be considered a continuum of the same disease rather than distinct disease entities. As familiarity with this classification criteria increases, clinical and immunobiological differences between the two are increasingly described; for example females and HLA-B27 negative individuals may be less likely to present with, or progress to, r-axSpA, yet nevertheless report significant symptoms and comparable disease burden [Citation9]. These differences may be important for understanding the onset, pattern, progression of disease and response to treatment.

2. The role of interleukin-17 in axSpA

The interleukin-17 (IL-17) signaling pathway includes five receptors (IL-17 receptors A to E) which combine at the cell surface as heterodimers/ homodimers capable of bindings one or more of the six known IL-17 cytokines (IL-17A to IL-17 F), forming an essential part of the physiological response to extracellular bacteria and fungi at the mucosal surfaces, skin, and gastrointestinal tract [Citation11]. Individually, these cytokines exert only modest effects on the immune system, however working synergistically with TNF, IL-1β, IFNγ, GM-CSF they become powerful mediators of inflammatory responses [Citation11]. IL-17 cytokines are expressed by a number of immune cells including Th17+ CD4 T cells, NK cells, NKT cells, Tγd cells, CD8+ lymphocytes, and innate lymphoid cells (ILC)3 cells, which are activated mainly at sites of inflammation and mechanical stress including the intestinal tract, joints and entheses [Citation11]. These areas are more frequently implicated in axSpA compared with other inflammatory arthritides such as rheumatoid arthritis (RA). The most clinically relevant of the IL-17 cytokines are IL-17A, and to a lesser extent IL-17F which bind to IL-17 receptors on CD4+ Th17 cells, activating the downstream intracellular STAT3 and ROR-c pathways in an IL-6 and TGFβ-dependent fashion respectively [Citation12].

Various in-vitro, animal and in-vivo studies of blood samples from patients with a number of chronic inflammatory and immune-mediated diseases including asthma, multiple sclerosis [Citation13], and seronegative arthritis’ and related diseases including Crohn’s disease, posterior uveitis, RA, skin psoriasis (PsO), psoriatic arthritis (PsA), or axSpA [Citation14–17] have shown dysregulation of the IL-17 axis. However trials of IL-17 inhibitors (IL-17i) have only demonstrated clinical benefit in PsO, PsA, and axSpA [Citation18–26]. The strongest genetic association for both these diseases is human leucocyte antigen (HLA)-B27, located in the major histocompatibility complex (MHC) class I region. Although the exact role of HLA-B27 in the pathogenesis of axSpA remains unclear, intriguingly, HLA-B27 is closely associated with areas of the genome important in IL-17 signaling, and several SNPs in IL-17 signaling are implicated in axSpA [Citation27–30]. Misfolding of HLA-B27 activates the unfolded protein response leading to Th17 activation and IL-23 production in rat models [Citation31], and abnormal HLA-B27 homodimers may bind KIR3DL2 on NK cells/ CD4 + T cells inducing survival, proliferation and IL-17 production [Citation32]. Circulating Th17 cells and IL-23/IL-17A are decreased in the peripheral blood and synovial fluid samples from axSpA patients, and in mouse models of axSpA the IL-23/17 axis is active at sites on entheseal inflammation [Citation30,Citation33–40]. New bone formation occurs concurrently with bony erosions in axSpA, and although the pathogenic mechanisms remain unclear, there is accumulating evidence that IL-17A may play an important role in these processes, though studies are conflicting [Citation41–49]. Finally, IL-17 dysregulation is implicated in the pathophysiology of various extra-articular manifestations of axSpA including IBD, uveitis and the immunomodulation of pain signaling pathways [Citation12].

3. Overview of the treatment of axSpA

3.1. Non-pharmacological treatment and non-steroidal anti-inflammatory drugs

Whilst subtle differences exist in treatment guidelines for axSpA between countries and health economies, expert clinical consensus is that first-line treatment should consist of non-pharmacological measures (e.g. exercise programmes, physiotherapy, occupational therapy and podiatry) and non-steroidal anti-inflammatory drugs (NSAIDs) [Citation50–53]. These may be enough for some individuals; however a significant proportion will go on to require biological disease-modifying drugs (bDMARDs).

3.2. Tumor necrosis factor inhibitors

Tumor necrosis factor alpha inhibitors (TNFis) are the first-line bDMARDs recommended by the American College of Rheumatology (ACR), the Assessment of Ankylosing Spondylitis and European League Against Rheumatism group (ASAS/EULAR) and the National Institute of Health Research (NICE), and have demonstrated superiority to placebo in both r-axSpA and nr-axSpA [Citation51–53]. Currently there are 5 TNFi licensed in axSpA, including a chimeric IgG anti-human monoclonal, infliximab (Remicade®); 2 fully human monoclonal antibodies (mAb) adalimumab (Humira®) and golimumab (Simponi®), a PEGylated Fab fragment, certolizumab (Cimzia®) and a TNFR2 dimeric fusion protein with an IgG1 Fc, etanercept (Enbrel®) [Citation54–60].

In addition, several biosimilar agents to three of these TNFi (adalimumab, etanercept and infliximab) have become available in recent years. Although there are few studies comparing the efficacy of bio-originators with their biosimilars in axSpA; data from trials performed in other disease areas have demonstrated non-inferiority [Citation61–63], and with no other data to suggest one TNFi is superior to another, choice of TNFi used is largely dictated by costs (strongly favoring biosimilars) [Citation60,Citation64], patient preference (longer dosing interval, option for self-administration, etc.), and local availability.

However an estimated 30–40% of patients with axSpA develop either primary non-response, secondary non-response and/or adverse events (AE) [Citation65–67]. Provided there are no contraindications, most cases have traditionally been offered a second TNFi. However emerging data suggest that primary non-response to a first TNFi may be associated with higher likelihood of second TNFi failure, suggesting a different immune pathway may be driving the disease in some of these patients [Citation68–70].

3.3. IL-17A inhibitors for axial spondyloarthritis

IL-17Ais secukinumab (Cosentyx®) and ixekizumab (Taltz®) are the only alternative biologics to TNFis currently licensed in axSpA. Secukinumab received FDA approval for both r-axSpA and nr-axSpA in 2016/ 2020 respectively, followed at a later date by ixekizumab (r-axSpA 2019; nr-axSpA 2020) [Citation71,Citation72]. Similarly, both drugs have been approved by the European Medicines Agency (EMA) [secukinumab (r-axSpA 2015; nr-axSpA 2020) and ixekizumab (r-axSpA 2020; nr-axSpA 2020)] [Citation73,Citation74]. The ACR recommends considering both secukinumab and ixekizumab for r-axSpA and nr-axSpA with primary non-response to TNFis [Citation53]. NICE recently reviewed their recommendations on the use of IL-17Ais for nr-axSpA, supporting the use of secukinumab and ixekizumab for both r- and nr-axSpA who have failed, or cannot tolerate, a TNFi [Citation75,Citation76].

The reminder of this review will focus on ixekizumab, first outlining the drug pharmacokinetics and pharmacodynamics, then moving to an in-depth discussion of the clinical trial evidence supporting its role for the treatment of axSpA, including important AEs, limitations and areas which require further research moving forward to better characterize the role of ixekizumab in real-world clinical practice.

4. Introduction to ixekizumab

4.1. Pharmokinetics and pharmacodynamics

Ixekizumab is a humanized IgG4 monoclonal antibody against IL-17A which prevents IL-17A from interacting with its receptor [Citation77,Citation78]. Developed by Eli Lilly, the protein molecular backbone comprises two pairs of identical light and heavy amino acid chains (219 and 445 amino-acid in length respectively), weighing 146,158 Da [Citation78,Citation79]. Detailed pharmacokinetic data are available from the first trials in man of ixekizumab, which were for the treatment of plaque PsO [Citation79], and are consistent with subsequent pharmacokinetic studies specifically in r-axSpA and nr-axSpA [Citation80]. With administration via subcutaneous injection (initial loading dose 160 mg, then 80 mg every 2 weeks for 12 weeks, then 80 mg 4 weekly thereafter), drug was detected in the serum 4 days post dose, reaching steady peak serum concentrations of 9.3±5.3 mcl/mL by week 8, and 3.5± 2.5mcg/mL by week 10 if using a 4-weekly administration interval. Volume of distribution (geometric mean CV, %) was 7.11 L, or 29%. Although elimination is poorly characterized, it is expected to be degraded into small peptides/amino acids akin to endogenous IgG, and has a half-life of 13 days, with clearance and volume of distribution increasing proportionally with the subject’s weight. No pharmacokinetic interactions were detected with co-administration of oral corticosteroids, NSAIDs, methotrexate or sulfasalazine, or following prior exposure to adalimumab or methotrexate. Similarly, no significant interactions are reported with other commonly prescribed drugs dependent on the cytochrome p450 enzyme system in the liver for clearance, including caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), or midazolam (CYP3A substrate) [Citation79].

Ixekizumab has been studied in the over 65s and children aged 6–18 years in human studies which suggest the drug can be safely administered at age-appropriate doses with no significant differences in drug clearance. Studies in cynomolgus monkey revealed no demonstrable impact of reproductive organs, menstrual cycle length or sperm count though fertility was not evaluated specifically, nor pregnancy or lactation. The manufacturer therefore advises that females should be using reliable contraception whilst on treatment, avoid taking ixekizumab pregnancy and lactation and allow a minimum 10 week washout period between last drug dose and conception [Citation79,Citation81]. No specific advice is given with regards to discontinuing treatment in male patients attempting to conceive with their partner. Finally, no specific case reports of teratogenic effects have yet been published in patients who have conceived without interruption of treatment [Citation79].

5. Clinical efficacy

5.1. Ixekizumab in radiographic and non-radiographic axSpA

Phase I and II trials of ixekizumab were first conducted in plaque PsO and RA, though subsequent phase III trials and their open label extensions found clinical efficacy in PsO and PsA [Citation20–25]. IL-17Ai had first shown efficacy in r-axSpA in phase III trials of with secukinumab [Citation82–85]. A number of trials for other IL-17Ais in r-axSpA and nr-axSpA have since been undertaken, including ixekizumab [Citation86–88], bimekizumab [Citation89–93], and brodalumab [Citation94]; however, to date only data from phase III trials of ixekizumab and secukinumab have been published [Citation82,Citation86–88]. The results of all completed phase III trials of secukinumab and ixekizumab in r-axSpA and nr-axSpA are summarized in .

Table 1. Summary of Phase III trials in IL-17Ais in axSpA

Three multi-center double-blind randomized controlled phase III trials were conducted for ixekizumab in axSpA; COAST-V, COAST-W and COAST-X. COAST-V looked at the efficacy and safety of ixekizumab in adult patients with r-axSpA who had failed/ were intolerant of ≥2NSAIDs and were naïve to biologics [Citation87]. Patients assigned to ixekizumab treatment were randomly assigned in a 1:1 ratio to either subcutaneous (SC) ixekizumab 160 mg starting dose followed by 80 mg every 2 weeks (Q2W) or 4 weeks (Q4W). Placebo and an adalimumab treated groups were also included although the study was not powered to directly compare ixekizumab and adalimumab [Citation87]. At week 16, ASAS40 response was achieved by 52% (n = 43/83) and 48% (n = 39/81) in the Q2W and Q4W groups compared with 18% (n = 16/87) of placebo (p < 0.001). A significant but numerically smaller number of adalimumab treated patients also achieved ASAS40 response compared with placebo (36%, n = 32/90, p = 0.0053). COAST-W compared ixekizumab versus placebo in r-axSpA patients who had failed no more than 1 or 2 prior TNFis [Citation88]. Ixekizumab was superior to placebo in both the Q2W and Q4W groups, although numerically fewer patients achieved ASAS40 response criteria at week 16 compared with the TNFi naïve group [Q2W 30.6% (n = 30/98), Q4W 25.4% (n = 29/114), placebo 12.5% (n = 13/104)]. Of note, this trial did not stratify patients according to reason for TNFis failure (PNR, SNR or AE), although patients were stratified according to number of prior TNFis (1 versus 2). The third phase III trial of ixekizumab, COAST-X, included nr-axSpA patients only [Citation86]. Comparable efficacy (as assessed by ASAS40) was reported with both Q2W and Q4W dosing of ixekizumab in nr-axSpA compared with placebo at 16 weeks [Q4W 35% (n = 34/96), Q2W 40% (n = 41/102), placebo 19% (n = 20/105)]. All three COAST trials included a number of secondary outcomes including ASAS20, BASDAI50, absolute change in BASDAI, ASDAS-CRP remission, ASDAS-CRP low disease activity, absolute change in ASDAS-CRP, absolute change in BASFI, absolute change in CRP, MRI SPARCC spine, MRI SPARCC SIJ, SF-36 PCS, and ASAS-HI). Note that some of the secondary endpoints did vary slightly between individual COAST trials, as summarized in . Nevertheless all secondary endpoints were met.

More recently the interim results of COAST-Y an extension period including a double-blind placebo-controlled randomized withdrawal, were published, with data up to week 64 currently available [Citation99]. Patients who did not achieve remission in the lead in period continued ixekizumab beyond 24 w (group A; group A1 = Q2W, group A2 = Q4W) whereas those who achieved sustained remission (group B) in the lead in period (0–24 weeks) were randomized 2:1 to either continue ixekizumab Q2W (group B1), Q4W (group B2) or placebo (group B3) beyond week 24 (24–64 wk). Patients who flared following withdrawal of treatment were permitted to restart ixekizumab (REP). In group A1 234/255 and group A2 312/318 patients completed the study to w64, with no flares. In group B1, 42/48 patients completed the study up to 64 w, of which 5 flared and in group B2, 45/54 patients completed the study to 64 w and 6 patients flared. On the other hand, in B3, of the 32/53 patients completed the study to 64 w and 19 flared. The 30 patients in total who flared were then entered into the REP. This included six patients retreated with ixekizumab Q2W, five retreated with ixekizumab Q4W, nine patients retreated with placebo Q2W and ten retreated with placebo Q4W. There were no treatment flares in any group except for on patients on placebo Q2W. Data beyond 64 weeks are still being collected and have yet to be published.

6. Safety and tolerability of ixekizumab and other IL-17A inhibitors

For detailed safety data from all trials of IL-17Ai readers are directed to existing comprehensive reviews [Citation100–102]. Although the majority of existing safety data come from patients with PsO, results from studies for axSpA are comparable. Briefly, common adverse events include infections (upper and lower respiratory tract), injection site reactions, and headaches; less common adverse events include hypersensitivity/ allergic reactions, malignancies, depression, suicidal behaviour/ deliberate self-harm, cytopenias, major adverse cardiovascular events, vascular death, non-fatal myocardial infarction, non-fatal stroke, iritis and iridocyclitis [Citation103]. Of particular interest to the population of axSpA is the apparent increased risk of new-onset and flare of IBD in patients taking IL-17A is reported in some studies, including trials of IL-17Ais for IBD [Citation104], as IBD is a known EAMs of axSpA [Citation2]. On the other hand, the most recent and largest meta-analyses of incidence of flare and new IBD in PsO, PsO, AS and RA suggests no increased incidence of IBD in worst or best case scenario [Citation105,Citation106]. Furthermore the COAST trials, which allowed the inclusion of patients with known IBD that had been inactive for at least 6 months, did not report increased incidence of flare of IBD. Nevertheless, many trials do not clearly define IBD or specify this as an outcome of interest, possibly leading to under-reporting and misrepresentation of the true risk, and therefore known IBD remains a relative contraindication to ixekizumab and secukinumab therapy.

7. Limitations in existing research

Accumulating evidence of the efficacy of IL-17Ais is causing a shift in the treatment paradigms in axSpA, with the ACR issuing recommendations for the use of IL-17Ais in the r- and nr-axSpA population with primary non-response to a TNFi [Citation53] the same as NICE guidance [Citation75,Citation76]. These decisions are overall, significantly impacted by economic considerations, since taken together the available data suggest that efficacy of IL-17Ai to date are at least comparable to that of TNFi in the bDMARD population.

There are many relevant questions that remain unanswered. For example, differences in the patient demographics (notably, for gender, disease durations and HLA-B27 status) exist between trials of IL-17Ais in r-axSpA and nr-axSpA () [Citation107,Citation108]. In particular, no stratification according to sex has been considered in any phase III trials in axSpA despite evidence from real world studies suggesting treatment response in females is lower, as is drug survival with females seeing a higher number of drug switches [Citation108]. It is also interesting that comparable efficacy is demonstrated in r-axSpA and nr-axSpA, particularly as in the later there may be no objective evidence of inflammation (i.e. normal CRP and/or MRI) and exploring why this apparent paradox may exist should be an area of future study. In addition, future longitudinal data on the potential impact of IL-17Ais on radiographic progression would be of interest, although such studies are likely to be difficult for several reasons, including the slow rate of progression to radiographic disease and the fact that obtaining a suitable control group may be challenging [Citation9]. Finally, the outcome measures used in IL-17Ai trials are either entirely or largely dependent on patient reported outcome measures and visual analogue scores for function/ pain [Citation109]. These are influenced by a whole host of factors that are not necessarily disease-related. However, the COAST and PREVENT studies did use ASAS40 as the primary endpoint rather than ASAS20, to try and improve the robustness of their outcome measures ().

Although the COAST-Y trials recently reported longitudinal follow up data for Ixekizumab beyond 1 year [Citation99], there remains significant need for larger, real-world data sets in order to understand the development of secondary non-response are needed. Laboratory investigations in axSpA such as CRP are nonspecific and frequently CRP is normal at the time of phlebotomy despite increasing symptoms and evidence of disease progression on imaging [Citation110–112]. A more objective measure would be MRI, which has shown to better correlate with clinical outcomes and progression, and is a noninvasive imaging modality with no risk of radiation exposure [Citation110]. Finally, the majority of clinical trials do not include large numbers of patients from non-Caucasian ethnic groups. The lack of data on the treatment of axSpA in minority ethnic groups is a longstanding problem and future trials must include these underrepresented groups, particularly as different genetics, biology and socioeconomic factors may produce different efficacy, side effects and pharmacodynamics. To this end, there are already trials for ixekizumab in the Chinese population with axSpA [Citation113]. These and other similar studies in underrepresented patient groups will be essential moving forward, ensuring equality and equity of access to effective treatments for all patients with axSpA at global level.

8. Expert opinion

In little over a decade, treatment options in axSpA have increased significantly with multiple biologic drugs now available. The key challenge however remains how to personalize treatment and crucial to this is the development of biomarkers (clinical, laboratory, or imaging) so that the right drug is given to each patient, first time. Ixekizumab has shown promising early results, however to clearly delineate its place in the treatment algorithm of axSpA precision medicine trials and head-to-head drug comparison studies are warranted. These would benefit clinicians, patients, drugs companies, and policy-makers alike by maximizing clinical efficacy, minimizing drug switching and risks of non-response or adverse events, and enabling pharmaceutical companies to expand the drug license.

Biomarker development is challenging in any disease, and axSpA has been no different, with no proposed serum biomarkers progressing beyond the pilot/discovery phase. Perhaps one reason for this is the approach taken thus far to study each candidate biomarker in isolation, in relatively small heterogeneous under-powered cohorts that would therefore be unlikely to detect small but important differences that could have biomarker potential in real world practice [Citation114–117]. Moving forward, studies in axSpA should focus on combinations of biomarkers and construction of predictive algorithms; a tried and tested approach that has shown efficacy in other diseases including breast cancer and systemic lupus erythematosus [Citation118,Citation119].

Another area for development is head-to-head drug trials for different biological drugs, comparing drugs both within and between classes. The COAST-V trial is the only trial of IL-17Ai to include an active reference arm, and this showed numerical greater proportion of patients responding to IL-17Ais as the first-line bDMARD compared with adalimumab, however the trial was not powered to detect statistical significance of potential superiority of ixekizumab versus adalimumab [Citation87]. If these findings were reproduced in adequately powered trials, this would be potentially paradigm changing for axSpA. Future phase-IV clinical trials should also seek to stratify patients according to predefined characteristics that are already known to influence responsiveness to bDMARDs such as previous primary or secondary non-response to another biologic drug, sex, CRP, and baseline MRI.

9. Conclusion

IL-17Ai provide the first alternative class of biologic drugs to TNFi for axSpA. Clinical trials of ixekizumab, the latest IL-17Ai to come to the market, have shown promising early results for the treatment of both r- and nr-axSpA, with good efficacy and acceptable safety profile. Real life data are now needed to confirm the long-term efficacy and safety of these drugs, and potential differentiators with TNFi. Future research should explore the need for biomarkers of response to individualize the treatment prescription of ixekizumab and other biologics in a safe and effective manner in axSpA.

Article highlights

  • IL-17A inhibitors are currently the only alternative class of biologic drugs for patients with axial spondyloarthritis who do not respond to, or do not tolerate TNF inhibitors.

  • Ixekizumab recently became the second IL-17A inhibitor to receive approval from NICE and the FDA for the treatment of radiographic and non-radiographic axial spondyloarthritis.

  • Ixekizumab has an acceptable side effect profile which is comparable to other IL-17A inhibitors.

  • Moving forward, head-to-head studies in real-world clinical practice and biomarkers to personalize treatment choices would help to further improve outcomes for patients treated with IL-17A inhibitors and other biological drugs.

Declaration of interest

SR Harrison has been paid to give a talk to Eli Lilly and received a small personal award to attend a conference from Eli Lilly. H Marzo-Ortega has received research grants from Janssen, Novartis and UCB as well as honoraria/speaker fees from ABvie, Eli-Lilly, Janssen, Novartis, Pfizer, Takeda, and UCB. The author(s) have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Acknowledgments

H Marzo-Ortega is supported by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (LBRC). The views expressed are those of the authors and not necessarily those of the (UK) National Health Service (NHS), the NIHR, or the (UK) Department of Health.

Additional information

Funding

This paper is not funded.

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