Biologics Targeting Interleukin-17

Introduction: Targeting the IL-23/IL-17 Pathway

An increased understanding of the immunologic pathways involved in AS has identified a number of promising therapeutic targets, such as tumor necrosis factor-α (TNF-α) and IL-17 inflammatory pathways. TNF-α is quite pleiotropic with broad involvement in many immune-mediated diseases with impact on both innate and adaptive immunity. Anti-TNF therapy impairs the body’s ability to mount protective responses against intracellular bacteria (such as Mycobacterium Tuberculosis) and other granulomatous infections. The selectivity of a treatment and the type of its target can have important implications for efficacy and safety. The fact that a considerable proportion of patients with axial spondyloarthritis (axSpA) do not respond adequately to tumor necrosis factor inhibitors (TNFis) or they may have contraindications, such as demyelinating diseases, support a need for other targeted therapies.

Genome wide association studies had identified a significant association of ankylosing spondylitis (AS) with various polymorphisms in the IL-23 receptor (IL-23R) gene has generated interest in the IL17/23 pathway as a potential therapeutic target for AS. Layered on this background, presence of increased numbers of Th17, Th22 and γδ T cells in the peripheral blood and increased level of IL-17 and IL-23 in the serum and synovial tissue demonstrated in studies of human blood cells and joint tissues, provided further early evidence in support of a central role for the IL-23/IL-17 pathway in axSpA. IL-17A can be produced by a range of different cell types as part of both the adaptive and innate immune responses (Figure 16-1). These include, besides Th17 cells, neutrophils, macrophages, mast cells, cytotoxic T cells and Group 3 innate lymphoid cells. Recent findings suggest that the contribution of IL-23/IL-17 signaling pathways possibly differs in male and female AS patients, and that IL-17 and IL-22 secreting-type 3 innate lymphoid cells are increased in AS patients.

The IL-17 family consists of six members (IL-17A–F), and IL-17A has a central role in spondyloarthritis (SpA). Inhibition of IL-17A represents a novel therapeutic approach in the management of AS/axSpA, psoriatic arthritis (PsA) and psoriasis. Secukinumab, a recombinant fully human IgG1κ monoclonal antibody which selectively targets human IL-17A and inhibits its interaction with its receptors, thus blocking the release of proinflammatory cytokines, chemokines and mediators of tissue damage. Ixekizumab, a humanized IgG4 monoclonal antibody also specifically targets and neutralizes the cytokine IL-17A. As discussed later in this module in more detail, both agents have been shown to be safe and effective in the treatment of patients with AS and non-radiographic axial spondyloarthritis (nr-axSpA) in phase 3 trials. This has resulted in their approval both in the United States (US) and Europe for such treatment of adult patients with active disease.

IL-23 is an essential upstream regulator of Th17 cells, which are the primary source of IL-17 production. However, inhibition of IL-23 produce qualitatively and quantitatively different therapeutic responses from the inhibition of IL-17A. Targeting IL-23 has shown no efficacy in axSpA, demonstrated similar efficacy to IL-17is in psoriatic arthritis (PsA) and revealed somewhat better efficacy than IL-17is in one trial of patients with psoriasis, but not so in another such trial. Moreover, anti-IL23 therapy has been found to be effective in the treatment of inflammatory bowel disease (IBD), while two different IL-17is have been demonstrated to worsen Crohn’s Disease (CD).

These findings suggest that blocking the IL23/17 axis at distinct levels lead to differing effects, with variable hierarchies in different tissues. The discrepancy between the efficacy of inhibitors of IL23 and IL-17 in axSpA point to a key role for IL-23 independent IL-17 production in driving enthesitis, osteitis and/or synovitis, while IL-23 driven IL-17 release may still be important in the induction phase of the disease, as well as in in the initiation of enthesitis. On the other hand, good efficacy obtained both with IL-23 and IL-17 blockade in the treatment of psoriasis indicate, IL-23 driven IL-17 release plays a key role in its pathogenesis because ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab and tildrakizumab were highly efficacious and generally well-tolerated when used as treatments for moderate to severe plaque psoriasis.

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Efficacy of IL-17 Inhibitors in AS

Secukinumab (Cosentyx)

Secukinumab is a recombinant, high-affinity, fully human immunoglobulin 1/ kappa monoclonal antibody that selectively binds to and neutralizes IL-17A. It is the first IL-17A inhibitor approved for the treatment of signs and symptoms of adult patients with active AS, both by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). It has recently been approved also for the treatment of active nr-axSpA with objective signs of inflammation. The current recommended dosage of secukinumab for AS is 150 mg every 4 weeks in US (monthly in EU), with or without a loading dose of 150 mg at Weeks 0, 1, 2, 3 and 4 (Figure 16-2). Based on clinical response, the dose can be increased to 300 mg in the US. As per the package insert, consideration should be given to discontinuing treatment in patients who have shown no response within 16 weeks of treatment. Some patients with an initial partial response may subsequently improve with continued treatment beyond 16 weeks.

The efficacy and subsequent approvals of secukinumab were based on four randomized, double-blind and placebo-controlled phase 3 trials:

• MEASURE 1, a 2-year study with a 3-year extension
• MEASURE 2, a 5-year study
• MEASURE 3, a 3-year study
• MEASURE 4, a 2-year-study.

The data provided by the pivotal MEASURE 1 and MEASURE 2 trials involving 590 adults with active AS fulfilling the modified New York criteria. Patients with total spinal ankylosis were excluded. The active disease was defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥4 and spinal pain score of ≥4 cm on a 10-cm visual analog scale, despite treatment with maximum tolerated doses of nonsteroidal anti-inflammatory drugs (NSAIDs). Patients who previously used no more than one anti-TNF agent were allowed to participate if they were intolerant or had an inadequate response (anti-TNF–IR). The efficacy of subcutaneous (SC) doses of 75 and 150 mg secukinumab given every 4 weeks was compared with placebo.

MEASURE 3 the efficacy of intravenous (IV) doses of 150 and 300 given every 4 weeks was tested against placebo; and in MEASURE 4 the efficacy of 150 mg secukinumab given SC every 4 weeks with or without a loading dose was evaluated relative to placebo. In MEASURE 1 and MEASURE 3, patients received a 10 mg/kg IV loading dose of secukinumab at Week 0, 2 and 4, followed by SC injections every 4 weeks, starting at Week 8. In MEASURE 2 and MEASURE 4, maintenance dosing was preceded by 4 weekly and 3 weekly SC loading doses of 150 mg secukinumab, respectively.

In all the trials, patients in the placebo group were treated according to the same IV or SC dosing schedule. In MEASURE 1, 2 and 3, placebo-receiving patients were re-randomized into one of the active treatment arms at Week 16; in MEASURE 4, all placebo patients were switched to SC secukinumab 150 mg every 4 weeks at Week 16. Assessment of Spondyloarthritis International Society criteria for 20% improvement (ASAS20) response rate at Week 16 was the primary endpoint in all the trials, whereas Assessment of Spondyloarthritis International Society criteria for 40% improvement (ASAS40), ASAS 5/6, ASAS partial remission response rates and change from baseline in the high-sensitivity C-reactive protein (CRP) level, total BASDAI score, the summary score for the physical component in version 2 of SF-36 and the score on the AS quality of life at Week 16 were the secondary endpoints, but not all were included in each trial (Table 16-1). Across all the MEASURE trials, the mean age ranged from 40 to 45 years, with 22%-39% having been exposed to previous anti-TNF therapy.

In MEASURE 1, 2 and 3, a significantly higher proportion of patients receiving secukinumab 150 mg than those receiving placebo achieved the primary endpoint (ASAS20) and all the other endpoints at Week 16 with the exception of ASAS partial remission rates in MEASURE 2 and 3 (Table 16-1 and Figure 16-3).

The same was true also for health-related quality of life, functional impairment, spinal mobility, fatigue and work productivity scores at Week 16 in MEASURE 1. Except for the secukinumab 75-mg arm in MEASURE 2, primary outcome endpoints, as well as most of the secondary endpoints were achieved with different dose regimens assessed in MEASURE 1, 2 and 3 studies, without a notable difference. In MEASURE 4, secukinumab given in the approved dose of 150 mg every 4 weeks (with or without a loading dose) failed to demonstrate any superior efficacy to placebo, for the primary endpoint, or any of the secondary endpoints, probably due to unexpectedly high placebo responses (Table 16-1). Efficacy was demonstrated both in TNFi–naïve patients, and those intolerant to or refractory to TNFis (TNF-IR) (Figure 16-4). The response was quite rapid in both groups of patients. Improvements with secukinumab 300 mg were numerically higher compared with the 150-mg dose for some higher hurdle endpoints and in TNF-IR patients.

In MEASURE 1 to 4, secukinumab provided sustained improvements as measured by ASAS20 and ASAS40 responses in patients with active AS through Year 1, Year 2, Year 3, Year 4 and Year 5. These effects were sustained through 5 years in patients who were originally randomized to secukinumab 150 mg and were 77.6% and 64.5%, for ASAS20 and ASAS40, respectively, in the 5-year extension study of MEASURE 1 (Figure 16-5). The corresponding figures in the 5-year extension study of MEASURE 2 were 67% and 50%, respectively (Figure 16-6). These responses were maintained both in the anti-TNF–naïve and anti-TNF–IR groups, though with better results in the former. Improved patient reported outcomes in health-related quality of life, functional impairment and fatigue, as well as spinal mobility scores were also maintained through 5 years. In MEASURE 1 and MEASURE 2, about 49% to 54% of the patients on secukinumab 75 mg had their dose escalated after 140 to 156 weeks, based on the judgement of the treating physician, which resulted in improvements in clinical outcomes. A recent meta-analysis estimated a comparable one year drug survival for secukinumab (77%) and TNFis (63%-76%).

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Ixekizumab (Taltz)

Ixekizumab is a humanized IgG4 variant/kappa monoclonal antibody that binds with high affinity and specificity to IL-17A. It is indicated for the treatment of adult patients with active AS. The recommended dose, both in the US and in Europe, is 160 mg by SC injection (two 80 mg injections) at Week 0, followed by 80 mg every 4 weeks (Table 16-2). Consideration should be given to discontinuing treatment in patients who have shown no response after 16 to 20 weeks of treatment. Some patients with initially partial response may subsequently improve with continued treatment beyond 20 weeks.

The approval of ixekizumab for the AS indication was based on the positive results of two phase 3 randomized, double-blind, placebo-controlled trials, COAST-V and COAST-W, which examined the efficacy and safety of the drug in adult patients with active AS. COAST-V included biologic naïve patients with active disease who failed at least two NSAIDs or had intolerance to NSAIDs, whereas COAST-X involved patients who had prior inadequate response or intolerance to one or two TNFis. Ixekizumab showed efficacy in treating signs and symptoms of the disease in both patient populations.

In COAST-V, 341 eligible patients were randomized (in a 1:1:1:1 ratio) to receive placebo or ixekizumab 80 mg every 2 weeks or ixekizumab 80 mg every 4 weeks or adalimumab 40 mg every 2 weeks. Patients randomized to ixekizumab arms were assigned in a 1:1 ratio to receive an initial dose of 80 or 160 mg ixekizumab at Week 0. The COAST-W study had a very similar design, except that it lacked an active control group of adalimumab, so the eligible 316 patients were randomized into one of the other three study arms; placebo, ixekizumab 80 mg every 2 weeks or ixekizumab 80 mg every 4 weeks. Both pivotal studies had the same primary endpoint of ASAS40 at Week 16, and it was 37% in the adalimumab arm in COAST-V, 52% in the 80 mg every 2 weeks arm, 48% in the ixekizumab 80 mg every 4 weeks arm and 17% in the placebo group (P<0.001) (Figure 16-7). The ASAS40 responses in COAST-W, were 31% and 25% in the two ixekizumab arms and 13% in the placebo arm (P=0.003 and P=0.017, respectively (Figure 16-7).

The secondary endpoints in both studies were very similar and included objective measures of disease activity, patient-reported outcomes and magnetic resonance imaging (MRI) of the sacroiliac joints (only in COAST-V) and spine. Both ixekizumab treatment arms in both studies met all the secondary endpoints and demonstrated significant improvements in disease activity, physical function, objective markers of inflammation, quality of life, health status and overall function and work productivity. The clinical improvement was rapid, with statistically significant differences reported as early as Week 1. All positive effects were sustained up to 52 weeks both in bDMARD-naive and TNF inhibitor-experienced patients (Figure 16-8).

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Efficacy of IL-17 Inhibitors in nr-axSpA

Secukinumab and ixekizumab are approved in the US and Europe for the treatment of active nr-axSpA with objective signs of inflammation as indicated by elevated CRP and/or MRI evidence in adult patients who have responded inadequately to NSAIDs. The recommended dose for secukinumab for the treatment of nr-axSpA in the US is the same dose as for AS, 150 mg every 4 weeks (every 4 weeks) (monthly in EU), with or without a loading dose of 150 mg at Weeks 0, 1, 2, 3 and 4 (Figure 16-2) Based on clinical response, the dose can be increased to 300 mg in US. The recommended dose for ixekizumab for the treatment of nr-axSpA in the US is 80 mg by SC injection every 4 weeks (Table 16-2); whereas it is the same dose as for AS in Europe, 160 mg (two 80 mg injections) by injection at Week 0, followed by 80 mg every 4 weeks.

Secukinumab

PREVENT is an ongoing 2-year randomized, double-blind, placebo-controlled phase 3 trial (with a 2-year extension phase) to investigate the efficacy and safety in patients with active nr-axSpA. The study enrolled 555 adult patients with active nr-axSpA (with onset before 45 years of age, spinal pain rated as ≥40/100 on a visual analog scale and BASDAI index ≥4 and who had been taking at least two different NSAIDs at the highest dose up to 4 weeks prior to study start. Patients may have previously taken a TNFi (not more than one) but had an inadequate response. Of the 555 patients, male and female, enrolled in the study, 501 (90%) were biologic naive. Patients were allocated to one of three treatment groups: secukinumab 150 mg SC with loading dose (150 mg SC weekly for 4 weeks, then maintenance with 150 mg every 4 weeks); secukinumab 150 mg no loading dose (150 mg SC monthly), or placebo (SC weekly for 4 weeks, followed by maintenance every 4 weeks).

The primary endpoints were the proportion of patients achieving an ASAS40 response at Weeks 16 and 52. The study achieved ASAS40 response at Week 16, the primary endpoints for the treatment arm with loading and the ASAS40 response at Week 52, the primary endpoint for the treatment arm without loading, per EU and US regulatory requirements, respectively. Secukinumab ASAS40 responses were significantly greater vs placebo at Week 16 (41.5% vs 29.2%, P<0.05) and at Week 52 (39.8% vs 19.9%, P<0.05) (Figure 16-9). Secukinumab also demonstrated significant improvement in secondary endpoints including BASDAI, ASDAS with CRP score (ASDAS-CRP). disease activity, physical function, quality of life and objective signs of inflammation, irrespective of their prior anti-TNF exposure status.

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Ixekizumab

The pivotal trial of ixekizumab for nr-axSpA (COAST-X) included 303 patients with active nr-axSpA who were randomly assigned (1:1:1) to receive SC 80 mg ixekizumab every 4 weeks or every 2 weeks, vs placebo. Patients previously exposed to biologic treatments were excluded. This study, also, had two primary endpoints, ASAS40 response at Weeks 16 and 52, to meet the disparate demands of regulatory authorities in the EU and US, respectively. Compared with placebo, patients receiving either dose of ixekizumab achieved ASAS40 response at significantly higher rates, both at Week 16 (every 4 weeks arm: 35%; every 2 weeks arm: 40%; vs placebo arm: 19%) and at Week 52 (30%, 31% and 13%, respectively) (Figure 16-10). Ixekizumab was also superior to placebo, in improving self-reported functioning and health in these patients.

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Efficacy on Imaging Findings

In MEASURE 1, among the AS patients who were TNFi-naïve, significant improvements were observed, relative to placebo, in MRI measured inflammation scores in the sacroiliac joints at Week 16, both with 75- and 150-mg secukinumab doses, with mean improvements from baseline of 59%, 63% and 7%, respectively. Mean reductions from baseline to Week 16 in MRI scores for spinal activity and Berlin spine scores were also greater in patients receiving secukinumab than those receiving placebo (Figure 16-11); but the differences were not significant for the 150-mg dose. The positive effect on MRI outcomes were sustained through Week 52 (Figure 16-11) and Week 208.

Ixekizumab, also, significantly reduced SpA Research Consortium of Canada (SPARCC) MRI assessed inflammation scores in the sacroiliac joints and spine in biologic naïve patients and even in the spine of TNFi-intolerant or inadequate responder AS patients (Figure 16-12).

Improvements in MRI scores in the sacroiliac joints were also observed in nr-axSpA trials of secukinumab and ixekizumab. Secukinumab 150 mg with or without loading dose significantly reduced sacroiliac joint edema score on MRI in patients vs placebo (-1.68 and -1.03 vs -0.39; both P<0.0001). The effect of both secukinumab doses, was sustained through Week 52 (Figure 16-9). In the nr-axSpA study of ixekizumab significant treatment effect on MRI assessed inflammation of the sacroiliac joints was also noted, both at Week 16 and Week 52 (Figure 16-13).

Prevention of structural damage is a very important long-term treatment goal in AS and yet it remains controversial whether the reduction in MRI assessed inflammation directly inhibits osteoproliferation. Secukinumab, demonstrated a low rate of structural radiographic progression in patients included in MEASURE 1, which was sustained through 4 years. Approximately 80% of patients randomized to secukinumab showed no radiographic progression (modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) change from baseline <2) at Week 104 and at Week 208 (Figure 16-14). Among patients who were originally randomized to 150-mg arm, change from baseline in mSASSS over 2 years was 0.5±1.69 and 1.2±3.91 over 4 years (Figure 16-15).

A comparative analysis of the radiographic images of the participants of MEASURE-1 with those of from an earlier study involving biologic-naive patients treated with NSAIDs revealed numerically more favorable (but statistically not significant) results with secukinumab relative to NSAID treatment regarding the proportion of patients with no progression (mSASSS change from baseline ≤0), which were 60.7% vs 52.2%, respectively and change in mSASSS from baseline to year 2, which were 0.55±0.139 vs 0.89±0.216, respectively. However, such comparisons between different studies using different designs and populations should be interpreted cautiously because they are susceptible to bias which may lead to over- or underestimation of the results. The SURPASS trial, the first head-to-head, phase 3b, randomized study compared the effects of secukinumab and adalimumab biosimilar on spinal radiographic progression, and found no difference between the two treatment groups.

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Safety and Tolerability

Secukinumab and ixekizumab have demonstrated an acceptable safety profile in pivotal phase 3 trials of AS, both in the placebo-controlled and the entire safety period spanning at least 52 weeks. This is consistent with multiple phase 2 and 3 trials of these agents for other indications. Two recent publications, each based on a pooled analysis of 21 trials of psoriasis, PsA and axSpA, provided long-term safety data up to 5 years for secukinumab and ixekizumab, which were in line with their known safety profile of these IL-17 blocking agents without any discernible pattern across indications.

In the first 16 weeks of the MEASURE 1 to 4 trials, treatment-emergent adverse events occurred in 45% to 68% of secukinumab recipients vs in 44% to 55% of placebo recipients. The corresponding figures in the COAST-V and COAST-W trials were 43% to 63% among ixekizumab recipients vs 40% to 49% in their placebo comparators (Table 16-3). Serious adverse events (SAEs) occurred in similar rates between the secukinumab and placebo receiving patients (1%-6% vs 1%-4%) and between the ixekizumab or placebo receiving patients (1%-3% vs 0%-5%) in the same period. For those receiving secukinumab vs placebo in MEASURE 1 and 2, the incidence of infection, nasopharyngitis, and candida infections were 30.7% vs 17.9%, 11.4% vs 6.1% and 0.5% vs 0%, respectively. The corresponding figures in COAST-V were 20% vs 15%, 7% vs 6. 7% and 0.5% vs 0%, with ixekizumab vs placebo. A recent meta-analysis based on the data from these six phase 3 trials, indicated a significantly increased risk with IL-17is for treatment emergent adverse events (risk ratio, RR:1.11, 95% CI 1.01 to 1.22) and for non-severe infections (RR:1.82, 95% CI 1.40 to 2.37); but not for death, discontinuation due to adverse events, or SAEs.

A very comprehensive analysis of the long-term pooled safety and tolerability data (n=7,355; mean exposure=16,226.9 patient-years [PY]) for secukinumab across different indications (up to 5 years of treatment in psoriasis and PsA; up to 4 years in AS) revealed a favorable safety profile also in the long-term for all approved indications. Discontinuations due to AE and death rates were low across indications (6.4%-7.3% and 0.2%-0.8%, respectively). Secukinumab was associated with a generally low frequency of adverse events (AEs). The exposure adjusted incidence ratios (EAIRs) of any adverse event over the assessment period was 140 for AS, 147 for PsA and 204 for psoriasis per 100 patient-years (PY). No discernible pattern was noted regarding SAEs across the treatment groups in all indications (Table 16-4).

The most frequent AE was viral upper respiratory tract infection, with the highest exposure adjusted incidence ratio (EAIR) observed in psoriatic patients (21 per 100 PY), possibly due to the use of higher secukinumab doses for this indication (Table 16-5). EAIRs of serious infections, as well as of major adverse cardiac events (MACE), neutropenia, and malignancy, were similarly low in three disease populations. EAIRs of candida infections, IBD, and uveitis were also low overall, those for candida infections trending to be higher among patients with psoriasis, while those for the remaining seemed to be greater in axSpA patients (Table 16-5).

These findings were consistent with previous reports and detected no new safety signals. This analysis was accompanied by data from post-marketing safety surveillance, which also revealed low EAIRs for neutropenia (≥1/1000 to <1/100) and IBD (0.2) per 100 PY. No case of active TB was reported. Data on a year-by-year basis for any AE, any SAE, serious infections, candida infection, IBD and major adverse cardiac events (MACE) showed no increase with secukinumab treatment over time across studies within each indication. A recent analysis assessed the outcomes of pregnancies from this safety cohort and did not find any evidence for increased rates of adverse pregnancy outcomes with secukinumab. Secukinumab carry an FDA class B pregnancy risk, suggesting that although no risk is apparent from animal studies, there are no controlled studies of pregnant women receiving this biologic agent.

A similar large analysis of the long-term safety and tolerability of ixekizumab in 8,228 patients with psoriasis, PsA and axSpA, with an ixekizumab exposure of 20,895.9 PY, has been reported. The most common treatment-emergent adverse events (TEAEs) were nasopharyngitis (14.4%-25.7%), upper respiratory tract infection (10.5%-15.6%) and injection-site reactions (15.1%-18.5%) (Table 16-6 and Table 16-7). The most reported TEAEs of special interest were infections (10.5%-15.6%). Incidence rates (IR) for serious infections were 1.3 per 100 PY for all indications, while IR for candida infections ranged from 1.6 to 2 per 100 PY across indications. IRs of IBD, MACE, malignancy were lower than 1 per 100 PY across all disease groups. Iritis and iridocyclitis were apparently more frequently observed among axSpA patients (Table 16-7).

The untoward effects did not change over the time; the most common TEAEs were observed most frequently within the first year of ixekizumab therapy with the IRs decreasing over time and exposure, including that of injection site reactions. Neutralizing anti-drug antibodies were detected in 1% to 8% of the patients. Oral and esophageal candida infections were mainly the most frequent opportunistic infections, without any report of deep organ or bloodstream candidiasis. Overall, annual tuberculosis (TB) testing identified 128 patients with latent TB infections in the whole study population, with no cases of with reactivation. The findings were consistent with previously published reports and did not show any new safety signals.

It is not unexpected to see an increase in infection risk in patients treated with IL-17, since IL17A is involved in mucocutaneous defense and also plays a role in the defense against extracellular pathogens.

Therefore, caution should be exercised when considering the use of IL-17 blocking agents in patients with a chronic infection or a history of recurrent infection. If a serious infection develops, they should be discontinued until the infection resolves. Live vaccine should not be given while patients are taking IL-17 targeting therapies. A recent systematic review of the published trials of psoriasis and PsA found relatively high rates of mucocutaneous candidiasis: 4.0% for brodalumab, 1.7% for secukinumab and 3.3% for ixekizumab, 0.3% for placebo. The authors suggested to monitor patients undergoing such treatment for fungal infection and treat them as necessary. The seemingly greater rates than those observed among AS patients may be due to the use of higher doses of the anti-IL-17 agents in psoriasis patients than AS patients.

Despite the effect of IL-17 and IL-23 in preclinical studies on the defense mechanism against the infection by M Tuberculosis, the cumulative data across multiple trials of IL-17is did not show an increase in the risk of active TB, neither in patients with a history of active TB nor in those with latent tuberculosis infection (LTBI). Nevertheless, as per current guidelines, IL-17 inhibitors should not be given to patients with active TB, and prophylactic treatment should be initiated in patients with LTBI before starting these agents. Regular evaluation of patients for signs and symptoms of active TB is warranted if they are under treatment with anti-IL-17 therapies.

Occurrence of IBD as an adverse event is of special interest for IL-17 targeting therapies. New-onset IBD cases and exacerbations, in some cases serious, have been observed during clinical trials of both secukinumab and ixekizumab in patients with plaque psoriasis, PsA, AS and nr-axSpA. Among the 571 patients exposed to secukinumab treatment for 52 weeks, there were eight cases of IBD during the entire treatment period. Five of them had Crohn’s Disease (CD), of which three patients had a previous medical history of this disease and three had ulcerative colitis (UC). The exposure-adjusted rate of 0.7 per 100 PY is comparable with that in patients with AS treated with anti-TNF inhibitors.

Moreover, a phase 2 proof of concept study with secukinumab in active CD was terminated due to a lack of clinical benefit and not due to safety reasons. A recent meta-analysis involving 38 RCTs and 16,690 patients treated with IL‐17 inhibitors identified twelve cases of new onset IBD in five studies, whereas no cases were reported with placebo. The difference was not significant. It is still advised to be vigilant for signs and symptoms of IBD, while following patients who are treated with IL-17is and caution should be exercised when prescribing IL-17 blocking agents to patients with IBD.

Other adverse events of interest pre-specified for IL-17is include neutropenia (which are generally rare, usually grade 1 or 2 in severity and have no apparent temporal relationship to infections), MACE, uveitis and malignancy. EAIR of MACE for the 52 week treatment period of secukinumab and ixekizumab are ≤0.4 per 100 PY, which is consistent with incidence rates reported in psoriasis and PsA. The incidence of uveitis in patients with active AS is not increased with IL-17 blocking agents. A pooled analysis of participants of MEASURE 1-3 (N=794) estimated the EAIR for uveitis at 1.4 per 100 PY over the entire treatment period. The EAIR for uveitis using the post-marketing data of all approved indications in the same study was calculated to be 0.03 per 100 PY. In the recently published pooled analysis of secukinumab calculated the EAIR for uveitis at 1.4 per 100 PY, whereas the pooled analysis of ixekizumab estimated an IR of 3.5 for anterior uveitis in AS patients.

The available published data from clinical trials of patients with psoriasis suggest the risk for malignancy under treatment with IL-17is is comparable to that seen in the general population and in a psoriatic population, and maybe even less than in the latter. However, no firm conclusion can be drawn on this without further data. In this context, it may be interesting to mention two cases with a history of lymphoproliferative disease and one case with a history of an in-situ bladder carcinoma, all of whom were treated with IL-17is successfully, without any recurrence or worsening of their malignancy.

Since secukinumab and ixekizumab both are monoclonal antibodies, they have the potential for immunogenicity. A study analyzing available samples from 1,414 patients with PsA and 1164 patients with AS exposed to secukinumab for up to 52 weeks found treatment-emergent antidrug antibodies in <1% of patients, all antibodies were of non-neutralizing type. Among patients taking ixekizumab treatment, 9% develop anti-drug antibodies during the 12-week treatment period. The prevalence increases to 22% over a treatment period of 60 weeks. Antibodies at high titers may decrease clinical response. Approximately, 2% of patients receiving ixekizumab at the recommended dosing regimen develop neutralizing antibodies associated with low drug concentrations and reduced efficacy. An in vitro study demonstrated a significantly lower immunogenicity potential for secukinumab in a direct comparison with ixekizumab. The higher prevalence of anti-drug antibodies among patients treated with ixekizumab than with secukinumab may be related to the higher occurrence of injection site reactions with ixekizumab (15.1% vs 0.6%, in psoriatic patients).

In conclusion, targeting the IL-23/IL-17 pathway appears to be a safe and effective strategy for treatment of AS/axSpA patients.

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IL-17 Inhibitors in the Guidelines

Based on the data from the registration trials of secukinumab and ixekizumab, latest version of the ACR/SAA/SPARTAN guidelines recommend treatment with secukinumab or ixekizumab in adult with AS or nr-axSpA, who have active disease provided that they have failed previous NSAID therapies. However, they recommend treatment with TNFi over treatment with secukinumab or ixekizumab in biologic-naïve patients. But the level of this recommendation was graded as “very low” and was based “on greater experience with TNFi and familiarity with their long‐term safety and toxicity.” Moreover, TNFi treatment was also recommended over treatment with IL-17is in secondary non-responders to the first anti-TNF therapy, although the level of evidence was again graded as very low.

Similarly, the panel recommended treatment with secukinumab or ixekizumab over tofacitinib if treatment with TNFi is not an option, except for patients who have coexisting UC because tofacitinib is an approved treatment for UC. It is also pointed out that IL-17is have been associated with the new onset, or exacerbation, of IBD. American College of Rheumatology (ACR) guidelines favor treatment with secukinumab or ixekizumab over other therapies in patients with specific contraindications for TNFi treatment such as congestive heart failure or demyelinating disease. Secukinumab or ixekizumab are recommended over other treatments also in patients who have shown primary non-response to first TNFi or who have failed second anti-TNF agent.

The 2022 ASAS/EULAR guidelines are broadly in alignment with the ACR recommendations; however, they do not prioritize TNFis over IL-17is or JAKis, merely noting that current practice is to start with either a TNFi or a IL-17i, reflecting the longer experience and greater evidence base for these agents. The guidelines also recommend to consider switching to another bDMARD (TNFi or IL-17i) or a Janus kinase inhibitor (JAKi) if initial tsDMARD or bDMARD therapy fails, to avoid the use of IL-17i therapy in patients with active IBD and to give preference to an IL-17i in patients with significant psoriasis because of superior skin outcomes.

The efficacy achieved with secukinumab or ixekizumab in AS appears to be comparable with results reported in phase 3 clinical trials of TNFis in mostly biologic-naïve patients However, no head-to-head trials have been undertaken and indirect comparisons should always be interpreted with caution. The COAST-V trial of ixekizumab had an adalimumab arm, and both agents showed a significantly greater ASAS20 and ASAS40 responses at Week 16 than with placebo (Figure 16-8). But the study was not designed to test the non-inferiority or superiority of ixekizumab to adalimumab. The above mentioned SURPASS trial found equivalent clinical efficacy data for secukinumab vs adalimumab biosimilar, although collected as secondary endpoints.

It is clear that secukinumab and ixekizumab offer a therapeutic alternative to anti-TNF agents, which were previously the only available biologic therapies for AS. This partly fulfills an unmet need for more treatment options particularly for patients who become unresponsive to and/or cannot tolerate currently approved medications. They are the first biologic class after TNFi to be approved for use in patients with active AS. Further clinical studies may help in identifying specific patient populations that may be suitable for first-line systemic treatment with IL-17i or TNFi.

Other IL-17 Inhibitors

Netakimab which is a humanized IgG1κ type monoclonal antibody against IL-17A; brodalumab, a fully human igG2 monoclonal antibody against IL-17 receptor subunit; and bimekizumab which is a humanized monoclonal IgG1 antibody and a dual inhibitor of IL-17A and IL-17F, are in late stage of their development for AS/axSpA. A phase 2B dose ranging study of bimekizumab showed promising results with ASAS40 responses at Week 12 (29.5% to 46.7% vs 13.3% for placebo; P<0.05 for all comparisons). A recent randomized, multicentre, placebo-controlled phase 3 study of brodalumab conducted at 48 sites in Japan, Korea and Taiwan showed that this IL-17i is also a potential therapeutic option for patients with axSpA.

IL-23 Targeting Therapies

IL-23 is believed to be an upstream regulator of the production of IL-17, therefore targeting IL-23 as treatment strategy in axSpA has been tested with ustekinumab and risankizumab, but showed no success. No studies have been conducted with other IL-23 blockers.

Ustekinumab (Stelara)

Ustekinumab, an antibody to the p40 protein subunit shared by IL12 and IL23 has been shown to be a well-tolerated and effective therapy for psoriasis, PsA, CD and UC. However, it failed to meet the primary endpoint (ASAS40 at Week 24) and major secondary endpoints in a placebo-controlled phase 3 study involving 346 patients with active AS. Subsequently, two linked phase 3 studies, one involving patients with AS and the other involving patients with nr-axSpA were prematurely terminated as had been preplanned. For all three studies, neither of the 45- and 90-mg doses of ustekinumab demonstrated clinically meaningful improvement over placebo on key efficacy end points. An earlier open-label trial had yielded positive results in patients with active AS. A post-hoc subgroup analysis of the data from two randomized placebo-controlled trials of ustekinumab in patients with PsA (PSUMMIT-1&2), noted significant improvements in axial signs and symptoms in those with baseline peripheral arthritis and physician-reported spondylitis through Week 24.

Risankizumab (Skyrizi)

Risankizumab is a humanized IgG1 monoclonal antibody directed against subunit p19 of IL-23 protein. It is indicated for the treatment of psoriasis. Risankizumab failed to show efficacy in a phase 2 trial of AS involving a total of 159 patients. At Week 12, ASAS20 response was attained in 25.5%, 20.5% and 15.0% in the risankizumab 18 mg, 90 mg and 180 mg groups, respectively, compared with 18% in the placebo group.

Guselkumab (Tremfya)

Guselkumab is a human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody that selectively binds to the p19 subunit of IL-23. Its efficacy has not been assessed in AS.

Other

No study has been conducted in AS with any of the other IL-23 inhibitors. A phase 2a study to evaluate the efficacy and safety of tildrakizumab (NCT02980705) in patients with active AS or nr-axSpA was terminated by the study sponsor.

Concluding Remarks

NSAIDs are the cornerstone of pharmacologic therapy in AS and nr-axSpA. For the patients who have active disease despite an optimal NSAID therapy or who are intolerant to NSAIDs, TNFis were the only treatment option until the approval of secukinumab and ixekizumab for the treatment of AS and nr-axSpA. Although there are no head-to-head trials between the two class of biologics, available evidence suggests that both secukinumab and ixekizumab seem to have a comparable efficacy and safety in axSpA to anti-TNF therapy. However, current treatment guidelines suggest to use TNFis as the next step therapy after NSAIDs. This recommendation is made on the basis of longer experience with TNFis than IL-17is, although there is no evidence in support of superiority of TNFis over IL-17is.

Cumulated data to date suggest that TNFis and IL-17is may have a different safety profile, which may be important for making optimal choices when starting biologics for individual patients. It remains to be seen whether the effect of these two drugs differ on new bone formation. The ongoing SURPASS study will provide comparative data for the efficacy and safety of these two types of biologics in the treatment of AS, although these data will be collected as secondary endpoints. Future controlled studies, like the SURPASS study, are expected to bring new insights on the efficacy and safety of anti-IL-17 agents which will help to define the role of different types of biologics for an optimal treatment strategy in AS. With the introduction of JAK inhibitors into the clinical practice in the near future, it will be even more important to answer the critical question whether patients respond differently to different types of drugs and whether it will be possible to identify patients who are more likely to respond to a specific class of drugs.