(1)
VA Portland Health Care System, Oregon Health & Science University, Portland, Oregon, USA
As shown in Fig. 5.1a–e, there are multiple points where the interleukin 17 (IL-17)/Th17 pathway can be blocked for therapy of inflammatory diseases. These include targeting cytokines that promote Th17 cells, targeting IL-17 cytokines, targeting IL-17Rs, targeting Th17 master transcription factor RAR-related orphan receptor gamma t (RORγt), and blocking IL-17 cytokine signaling. Currently clinically available agents and those in late-phase development blocking IL-17 pathway are almost exclusively monoclonal antibodies. Small molecules blocking RORγt activity appear to be promising, and several molecules are in early-phase trials. RNAi offers precise blockade of the target but delivery of efficient quantity for therapeutic purpose is a challenge. More research on this aspect is required before it can be tested clinically.
Figure 5.1
(a) Agents blocking Th17 cell upper stream cytokines. IL-6, TNF, and IL-1 are all shown to involve Th17 cell differentiation. In particular, IL-6 has been shown to be an essential inflammatory cytokine in initiation of Th17 cell differentiation. Biological agents blocking TNF, IL-6, or IL-1 are efficacious therapeutics and may suppress Th17 cells in vivo. Monoclonal antibodies to the IL-12/IL-23 shared subunit, p40 (ustekinumab), and to IL-23-specific subunit, p19 (tildrakizumab and guselkumab), have been developed and demonstrated highly efficacious in treating inflammatory diseases which are mediated by IL-17/Th17 pathway. (b) Agents blocking IL-17 cytokine activities. Secukinumab and ixekizumab are two monoclonal antibodies to IL-17A, which have been approved for treating inflammatory diseases and are highly efficacious for psoriasis. They may also interfere with IL-17A/F activity. An IL-17A and IL-17F bispecific antibody, bimekizumab, is under early-phase clinical investigation. A soluble IL-17R fused with IgG Fc can be developed as a therapeutic agent to block IL-17 binging to the receptors. (c) Inhibitors blocking IL-17 signaling. Brodalumab is a human monoclonal antibody to IL-17RA, which is effective for psoriasis and psoriatic arthritis (see Fig. 5.2b). Since IL-17RA is a common receptor for IL-17A, IL-17F, IL-17E (IL-25), and IL-17C, the effect of brodalumab may be broad and undesired outcome may be expected. Agents blocking Act1 may also have broad suppressive effect. (d) Small molecule drugs blocking RORγ activity. (A) Several small molecules have been identified to block RORγ/RORγt activity. Three such small molecule drugs are in Phase I clinical studies. (b) Digoxin is a prototype small molecule that is able to inhibit RORγt activity and suppress Th17 development. Schematic representation of ligand-binding domain of RORγt (dark blue) bound with digoxin. Bound digoxin is depicted with carbon atoms in cyan and oxygen atoms in red (Reproduced with permission from © The American Society for Biochemistry and Molecular Biology. All rights reserved. Fujita-Sato et al. [1]). (e) Small interference RNA suppressing RORγt. Schematic graph shows shRNA to RORγt is delivered by CD4 aptamer into Th17 cell. (a) An RNA aptamer specific for CD4 is linked with RORγt shRNA to form a chimeric molecule. In the cytoplasm, RORγt antisense is released and binds to and degrades RORγt mRNA to prevent the protein translation. (b) Predicted secondary structure of CD4 aptamer and RORγt shRNA chimera (Reproduced with permission from © Elsevier. All rights reserved. Song et al. [2]). IL interleukin, RAR related orphan receptor gamma t RORγt, TNF tumor necrosis factor
5.1 Targeting Upper Stream Cytokines
5.1.1 Impact on IL-17/Th17 Cells by Blocking Interleukin 6 and Tumor Necrosis Factor Signaling
Several inflammatory cytokines including IL-6, IL-1, and tumor necrosis factor (TNF) are indicated to induce Th17 cell differentiation in in vitro experiments. Blocking these cytokine activities has been in practice for treating inflammatory diseases before the identification of Th17 cells. In theory, blocking TNF, IL-1, and IL-6 treatment will have a negative effect on Th17 cell development. Indeed, clinical observations suggest that inhibition of IL-6 signaling and blocking TNF activity has an impact on Th17 cells. For example, it was reported that TNF is able to promote Th17 cells in rheumatoid arthritis (RA) patients [3] and treatment with anti-TNF in patients who showed an adequate response had a decreased number of Th17 cells in the circulation [4, 5]. Paradoxically, patients treated with anti-TNF but had inadequate response have exhibited an increased number of Th17 cells (see below) [5–8]. IL-6 is the major cytokine that has been well established in induction of Th17 cells (see above), and IL-6 was required for regulatory T cells (Tregs) to convert to Th17 cells in the arthritis model [9]. The therapeutic efficacy of blocking IL-6 signaling in RA is also firmly established. Indeed, targeting IL-6 in early RA results in decreased Th17 cells [10, 11].
Tocilizumab is a humanized monoclonal antibody against both membrane and soluble IL-6Rα. Tocilizumab is approved to treat RA and juvenile idiopathic arthritis. Previous case series and pilot studies suggested therapeutic efficacy of tocilizumab in spondyloarthritis and psoriatic arthritis (PsA). However, the recently conducted BUILDER-1 and BUILDER-2 prospective randomized, placebo-controlled trials did not confirm the previous findings in TNF inhibitor-naive and TNF inhibitor-refractory ankylosing spondylitis, even though the IL-6 signaling blockade was effective, which has been demonstrated by the reduction of acute-phase reactants [12]. Furthermore, sarilumab, another monoclonal antibody against IL-6Rα also failed to show efficacy in TNF inhibitor-naive ankylosing spondylitis patients [13].
A humanized anti-IL-6 monoclonal antibody clazakizumab, which had promising results in patients with moderate-to-severe RA, was also recently found to be moderately effective in PsA in Phase IIb clinical trial with a clear response in musculoskeletal disease manifestations (arthritis, enthesitis, and dactylitis) [14]. Interestingly, there is only limited response in skin psoriasis, with a maximal PSAI75 response for clazakizumab at 28 % versus 12.2 % for placebo [14]. This response rate is much lower than those blocking IL-23 or IL-17 cytokines (Fig. 5.2a, b). The less robust response of IL-6 signaling blockade in treating psoriasis may be in line with the notion that in vivo pathogenic Th17 cells are dependent on IL-23; IL-6-dependent Th17 cells are more important in host defense in immunity against pathogens and less pathogenic in autoimmune inflammatory diseases [15].
Figure 5.2
(a, b) Efficacy of monoclonal antibodies targeting IL-17/Th17 pathway in psoriasis. Graphs show the percentage of psoriasis patients that achieved PASI 75 in each individual clinical study, and they are not head-to-head comparison studies. (a) Clazakizumab is a humanized monoclonal antibody to IL-6. Ustekinumab is a humanized monoclonal antibody to IL-12/IL-23 shared p40 subunit. BI-655066 is a human and guselkumab are humanized monoclonal antibodies to IL-23 p19 subunit. (b) Secukinumab is a human and ixekizumab is a humanized monoclonal antibody to IL-17A. Brodalumab is a human monoclonal antibody to IL-17RA. IL interleukin, PASI 75 75 % improvement of Psoriasis Area Severity Index
5.1.2 Blocking IL-23
Given its critical role in the development of Th17 cells, naturally IL-23 is an attractive target. Several monoclonal antibodies are being developed to neutralize IL-23 activity.
5.1.2.1 Monoclonal Antibodies Against IL-12 and IL-23 Shared p40 Subunit
Two monoclonal antibodies have been developed to target the shared p40 subunit of IL-12 and IL-23, namely, ustekinumab and briakinumab.
5.1.2.1.1 Ustekinumab
Ustekinumab in Psoriasis
Ustekinumab is initially developed to target IL-12 activity before the discovery of IL-23. This fully human IgG1 monoclonal antibody binds to the shared p40 subunit of IL-12 and IL-23 and blocks its binding to the IL-12Rβ1 receptor protein on the surface of the immune cell, thereby inhibiting the bioactivity of both IL-12 and IL-23 [16]. Ustekinumab interferes with development of Th1 and Th17 cells and also keratinocyte activation. Ustekinumab was approved for the treatment of moderate-to-severe plaque psoriasis by the European Medicines Agency (EMA) in 2008 and US Food and Drug Administration (FDA) in 2009 and active PsA jointly by EMA and FDA in 2013 in cases of inadequate response to disease-modifying antirheumatic drugs (DMARDs) or alternative to anti-TNF [16]. Data from clinical trials and post-market registries indicate that ustekinumab is a safe and efficacious agent in treating moderate-to-severe plaque psoriasis. In two Phase III parallel double-blind placebo controlled studies (PHOENIX-1 and PHOENIX-2), ustekinumab was administered by subcutaneous injection at 45 and 90 mg every 12 weeks. A 75 % reduction in the Psoriasis Area Severity Index score (PASI 75) was achieved in 66.7–67.1 % of patients taking 45 mg dose and 66.4–75.7 % of patients taking 90 mg while in only 3.1–3.7 % of those taking placebo at 12 weeks [17, 18]. In a randomized comparative study, ustekinumab at both 45 mg and 90 mg doses was shown to be more effective than etanercept at 50 mg twice a week [19] (Fig. 5.2a).
Ustekinumab in PsA
Ustekinumab is also approved for treating adult patients with active PsA who failed methotrexate and/or TNF inhibitors. In a Phase III trial (PSUMMIT-1), 615 patients who were naive to biological therapies were treated with ustekinumab at 45 mg or 90 mg. At week 24, 42.4 % patients treated with 45 mg and 49.5 % treated with 90 mg of ustekinumab achieved the primary end point of an American College of Rheumatology response (ACR20) versus 22.8 % with placebo (p < 0.001 for both comparisons). There were also significant differences between ustekinumab- and placebo-treated groups for ACR50 and ACR70 responses [20]. In the PSUMMIT-2 trial, 312 psoriatic arthritis patients with active disease including those failed TNF inhibitors were treated with ustekinumab. Similar to the findings in PSUMMIT-1, at week 24, the ACR20 response rate was significantly higher in both ustekinumab arms (45 or 90 mg) than placebo regardless of their prior treatment agents. PSUMMIT-2 clearly demonstrates that ustekinumab is a valid therapy for PsA patients who have failed to respond to TNF inhibitors. However, these TNF inhibitor-experienced patients seemed to achieve a less robust response than TNF inhibitor-naive patients. That is, among patients who failed prior TNF inhibitors, only 36.7 % (ustekinumab 45 mg) and 34.5 % (ustekinumab 90 mg) achieved ACR20 response compared with 14.5 % in the placebo-treated group [21]. Ustekinumab slows down radiographic progression in PsA and is also effective for enthesitis and dactylitis [20, 21].
Long-term safety of ustekinumab has been proven in the 5-year extension of two major clinical trials. There are no increased adverse events and no positive or negative effects in cardiovascular outcomes after five continuous years of follow-up [22, 23]. Data from over 12,000 patients in several registries show no increased risk of malignancy, major adverse cardiovascular events, serious infections, or mortality [24–26].
Ustekinumab in Crohn’s Disease
In a small Phase II trial (https://clinicaltrials.gov/NCT00265122) [27], ustekinumab seemed effective at inducing a clinical response at weeks 4 and 6, but not at week 8. Interestingly, a better clinical response was seen in patients who had previously failed TNF inhibitors, for example, in a larger Phase IIb trial (CERTIFI, https://clinicaltrials.gov/NCT00771667) including patients with moderate-to-severe disease who failed previous TNF inhibitors [28]. Ustekinumab was given as an intravenous (IV) infusion at 1, 3, or 6 mg/kg at week 0 for induction therapy. At week 6, Crohn’s Disease Activity Index (CDAI) response was 37 %, 34 %, and 40 % for 1, 3, and 6 mg/kg of ustekinumab, respectively, compared with 23.5 % for placebo (p = 0.02, 0.06, and 0.005). However, rates of remission in ustekinumab-treated groups were not significantly different from those that were placebo-treated. During the maintenance phase, the 145 responders at week 6 were re-randomized to receive either placebo or subcutaneous ustekinumab 90 mg at weeks 8 and 16. At week 22, the ustekinumab-treated group achieved a higher response rate than the placebo group (69 % versus 42.5 %, p < 0.001) and a higher remission rate (42 % versus 27 %, p < 0.03). These results indicate that blocking the shared subunit p40 of IL-12 and IL-23 by ustekinumab is beneficial in those patients with Crohn’s disease who failed TNF inhibitors. Three Phase III trials (https://clinicaltrials.gov/NCT01369329; NCT01369342; NCT01369355) are ongoing to further evaluate the safety and efficacy of ustekinumab in treating moderate-to-severe Crohn’s disease.
It is conceivable that ustekinumab may interfere with both IL-12 and IL-23 signaling and subsequently affect both Th1 and Th17 cells and their cytokines. However, downregulation of p40 and IL-23p19, but not IL-12p35, in psoriatic skin lesions was observed in ustekinumab-treated patients suggesting that interference with IL-23 rather than IL-12 activity is responsible for this clinical improvement [29]. This is in concordance with results of studies in murine experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA), which have indicated that IL-23 rather than IL-12 is responsible for the chronic inflammation [30]. Investigations into expression of Th17 versus Th1 cell cytokines in ustekinumab-treated patients will be required to further verify the exact mechanism of ustekinumab action in vivo.
Ustekinumab in Multiple Sclerosis
Safety and efficacy of ustekinumab was also evaluated in treating in relapsing-remitting multiple sclerosis (https://clinicaltrials.gov/NCT00207727). Contrary to the high expectation, ustekinumab failed to provide improvement in magnetic resonance imaging (MRI) lesions in patients with relapsing-remitting multiple sclerosis [31], in spite of the strong evidence to support the role of IL-23 and Th17 in EAE.
5.1.2.1.2 Briakinumab
Briakinumab is another fully human antibody against the IL-12 and IL-23 shared p40 subunit. Unfortunately it was withdrawn from the market due to the safety concerns of major cardiac events in patients treated with briakinumab. The available data from clinical trials showed that it was a potent agent in treating psoriasis, PsA, and Crohn’s disease [32–36]. Nevertheless, the clinical efficacy of briakinumab in these diseases provided further evidence to prove the importance of IL-23 signaling in these conditions.
5.1.2.2 Monoclonal Antibodies Against IL-23 p19
Various IL-23 p19-specific monoclonal antibodies are currently undergoing clinical development. Specifically targeting the p19 subunit of IL-23 is advantageous because it spares the IL-12-mediated Th1 response [37]. In addition to preservation of Th1 host immunity against infections, it has been stipulated that the intact Th1 pathway may actually contribute to inhibition of Th17 cells. Thus, it has been hypothesized that targeting the p19 subunit of IL-23 may be as effective but safer than blocking p40.
5.1.2.2.1 Tildrakizumab
Tildrakizumab is a humanized monoclonal antibody (IgG1k) against IL-23 p19 subunit. In a randomized, double-blind, Phase IIb clinical trial, tildrakizumab was effective in treating patients with moderate-to-severe plaque psoriasis (Fig. 5.2a). At week 16, a significantly higher proportion of patients treated with tildrakizumab achieved PASI 75 at all doses compared with placebo [38]. In a Phase I trial [39], the main cellular source of IL-23 in the lesional skin was identified to be CD11c+ myeloid dendritic cells, CD15+ neutrophils, and CD163+ macrophages. The number of CD4+ and CD8+ T cells in the skin decreased significantly after tildrakizumab treatment. CD4+ Th17 cells expressing CCR6 binds to CCL20, which is overexpressed in lesional skin in psoriasis. Tildrakizumab significantly reduced CCL20 expression. This is consistent with the reduction of CD4+ T cells [39]. Unfortunately, due to technology limitations, the study did not directly examine the expression of Th17 cells and their cytokines, but this is planned for investigation in subsequent Phase III trials. Two Phase III clinical trials are ongoing for moderate-to-severe plaque psoriasis (https://clinicaltrials.gov/NCT01729754; NCT01722331).
5.1.2.2.2 BI-655066
BI-655066 is a high-affinity monoclonal antibody against the p19 subunit of IL-23. Clinical efficacy was demonstrated in psoriasis in a Phase I trial. After a single dose, PASI 75 was achieved in 87 %, PASI 90 in 58 %, and PASI 100 in 16 % of subjects (Fig. 5.2a) [40]. The most common side effects were mild-to-moderate upper respiratory infections including mild nasopharyngitis and mild-to-moderate headache. BI-655066 treatment resulted in significant reductions relative to placebo in the expression of 192 genes identified in skin biopsy specimens including those in the IL-23/IL-17 pathway related [40]. A dose-ranging Phase II trial in psoriasis in comparison with ustekinumab has been completed, and data publication is pending (https://clinicaltrials.gov/NCT02054481). Several Phase II clinical trials are ongoing to treat moderate-to-severe Crohn’s disease (https://clinicaltrials.gov/NCT02031276), in ankylosing spondylitis (https://clinicaltrials.gov/NCT02047110), and in severe persistent asthma (https://clinicaltrials.gov/NCT02443298). Two Phase III trials in moderate-to-severe plaque psoriasis to compare BI-655066 with ustekinumab are ongoing (https://clinicaltrials.gov/NCT02684357; NCT02684370) as well as one Phase III study in moderate-to-severe plaque psoriasis comparing BI-655066 with adalimumab (https://clinicaltrials.gov/NCT02694523).
5.1.2.2.3 Guselkumab
Guselkumab is a fully human IgG1k monoclonal antibody against p19 subunit of IL-23. In a Phase II clinical trial, patients with moderate-to-severe psoriasis were treated with guselkumab versus adalimumab. Guselkumab-treated patient were significantly more likely to achieve a physician global assessment (PGA) score of 0 (clear of plaque psoriasis) or 1 (almost clear of plaque psoriasis) when compared with placebo. At week 16, a score of 0 or 1 on the PGA was seen in 58 % of patients randomized to adalimumab, which was significantly lower than that achieved by patients on 50, 100, and 200 mg doses of guselkumab: 79 %, 86 %, and 83 %, respectively (p < 0.05 for all comparisons); while 7 % was achieved in the placebo group. Treatment response assessment by PASI 75 also demonstrated that guselkumab is superior to adalimumab (Fig. 5.2a). While 70 % of patients treated with adalimumab achieved PASI 75 response, in guselkumab-treated patients, 76 % in the 15 mg, 81 % in the 50 mg, 79 % in the 100 mg, and 81 % in the 200 mg dose group, respectively, achieved PASI 75 response [41].
In a Phase I trial, guselkumab responders showed significant reductions of the Th17 pathway gene expression in lesional skin and serum IL-17A levels from baseline at week 1 (p = 0.031) and week 12 (p = 0.0015), while there were no significant changes in Th1 cytokines [42]. These data indicate the critical role of IL-23 and the downstream Th17 pathway in the pathogenesis of psoriasis. Three Phase III trials are ongoing to further investigate the therapeutic efficacy in psoriasis (https://clinicaltrials.gov/NCT02207244; NCT02207231; NCT02203032).
5.2 Targeting Th17 Cytokines
Secukinumab and ixekizumab are two monoclonal antibodies, which have already been approved for clinical applications.
5.2.1 Secukinumab
Secukinumab in Psoriasis
Secukinumab is a fully human IgG1k monoclonal antibody against IL-17A [43]. It was first approved in Japan in 2014 for treating psoriasis and PsA and in the USA and in Europe as a first-line drug for the treatment of moderate-to-severe plaque psoriasis in 2015 and later also approved for the treatment of PsA and ankylosing spondylitis.
The therapeutic effect of secukinumab was first demonstrated in three proof-of-concept studies in three different diseases, psoriasis, RA, and uveitis [44]. The most remarkable effect is in patients with psoriasis. A single dose of 3 mg/kg secukinumab was able to reduce the disease severity by 58 % relative to baseline compared with 4 % reduction in placebo-treated patients. The therapeutic effect lasted for 12 weeks. Secukinumab treatment led to the decrease of CD3+ T cells and IL-17A expressing cells in the skin. Decreased gene expression was also observed for IL-17F, IL-21, IL-22, shared p40 subunit of IL-12 and IL-23, TNF, IL-6, and CCL20 [44]. The suppressive effect of secukinumab on both downstream and upper stream cytokines of Th17 cells suggests that IL-17A may act on a positive feedback loop to further promote Th17 cell differentiation.
In later clinical trial phases for treating psoriasis, secukinumab was administered with initial intravenous or subcutaneous loading doses at baseline, weeks 1, 2, 3, and 4, followed by subcutaneous administration every 4 weeks. Four Phase III trials were conducted in plaque psoriasis (ERASURE, https://clinicaltrials.gov/NCT01365455; FIXTURE, NCT01358578; FEATURE, NCT01555125; JUNCTURE, NCT01636687). Across the trials, the co-primary end points were the response rates at week 12 based on PASI 75 and Investigator’s Global Assessment (IGA) scale (proportion of patients with a score of 0–1 plus a reduction of ≥ 2 points from baseline). This IGA scale is a more robust assessment with 0 being clear and 1 almost clear [45]. Secukinumab was administered in 150 and 300 mg. In the ERASURE trial, the PASI 75 response rates were 72 % and 82 % in the secukinumab 150 and 300 mg doses, respectively, compared with 5 % in the placebo group (Fig. 5.2b) [43], and the IGA response rates were 51 % and 65 % versus 2 %, respectively. In the FIXTURE trial, secukinumab was compared with etanercept. Secukinumab at both 150 mg and 300 mg doses achieved significantly higher response rates than etanercept, that is, PASI 75 was 67 % and 77 % for secukinumab 150 mg and 300 mg, respectively, versus 44 % for etanercept (p < 0.001 comparing both secukinumab groups versus etanercept). The IGA response rates in the corresponding treatment groups were 51 %, 63 %, and 27 %, respectively (p < 0.001 comparing both secukinumab groups vs etanercept) [43]. Similar positive results in favor of secukinumab were also observed in the FEATURE [46] and JUNCTURE [47] trials. Across all the trials, maintenance therapy was continued from week 12 to week 52 and efficacy of secukinumab was well maintained.
Secukinumab in PsA
Efficacious treatment of secukinumab for PsA was demonstrated in two Phase III trials (https://clinicaltrials.gov/NCT01392326 and NCT01752634). PsA patients with active disease who failed DMARDs and/or anti-TNF were included [48, 49]. In the FUTURE 1 trial, patients were treated with secukinumab 10 mg/kg intravenously at weeks 0, 2, and 4 followed by 75 or 150 mg subcutaneously every 4 weeks [48]. ACR20 response at week 24 was 51 % and 50 %, respectively, for secukinumab 75 and 150 mg groups compared with 17 % in placebo group. Secukinumab at both doses was also effective for treating dactylitis and inhibiting radiographic structural joint damage. The therapeutic effect was maintained throughout 52 weeks [48]. In the FUTURE 2 trial, patients were treated with secukinumab with loading dose at 75, 150, or 300 mg weekly for 5 weeks and then every 4 weeks. An ACR20 response at week 24 was in achieved in 29 %, 51 %, and 54 % for three doses of secukinumab compared with 15 % in the placebo group [49].
Secukinumab in Ankylosing Spondylitis
For ankylosing spondylitis, secukinumab was tested in two Phase III trials, MEASURE 1 (https://clinicaltrials.gov/NCT01358175) and MEASURE 2 (https://clinicaltrials.gov/NCT01649375) [50]. All patients with ankylosing spondylitis had active disease despite treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), and a proportion of patients had failed anti-TNF and/or DMARDs. In the MEASURE 1 trial, secukinumab was loaded by intravenous infusion at 10 mg/kg at week 0, 2, and 4, while in the MEASURE 2 trial, secukinumab was loaded by subcutaneous injection weekly for 4 weeks. Maintenance therapy was administered by subcutaneous injection every 4 weeks at either 75 or 150 mg. At week 16, in the MEASURE 1 trial, the Assessment of Spondyloarthritis International Society response criteria (ASAS20) response rates were 60 % and 61 % for secukinumab at doses of 75 mg and 150 mg, respectively, versus 29 % for placebo (p < 0.001 for both comparisons with placebo); in the MEASURE 2 trial, the ASAS20 response rates were 41 % and 61 % for secukinumab at 75 mg and 150 mg, respectively, versus 28 % for placebo (p = 0.1 for the 75 mg group; p < 0.001 for the 150 mg group). The improvement was sustained throughout 52 weeks. These results indicate that secukinumab at 150 mg subcutaneous dose with either subcutaneous or intravenous loading is efficacious in treating ankylosing spondylitis [50].
Secukinumab in RA
The therapeutic efficacy of secukinumab in RA was evaluated in a Phase II trial with dose-finding regimens (https://clinicaltrials.gov/NCT00928512). Patients were allowed to have concomitant medications including methotrexate between 7.5 and 25 mg/week and/or prednisone ≤10 mg/day. Patients failed DMARD and/or biological agents had a washout period before randomization. Patients were randomized to receive a monthly subcutaneous injection of 25 mg, 75 mg, 150 mg, and 300 mg or placebo [51]. At week 16, the primary end point was not met. At the dose-escalating phase of the study, patients achieving an ACR20 response continued on the same dose, while nonresponders taking 25 and 75 mg doses were increased to 150 mg; nonresponders taking 150 mg were increased to 300 mg, patients taking 300 mg of secukinumab continued the same dose regardless of their response, and those on placebo were given 150 mg of secukinumab. Responders who kept taking 150 mg of secukinumab had the greatest improvement in response over time with 55 % and 40 % of patients achieving an ACR50 and ACR70 response, respectively, at week 52. Among patients taking the placebo who had achieved an ACR20 response by week 16 and were reassigned to 150 mg of secukinumab at week 20, 50 % achieved an ACR50 response and 22.2 % achieved an ACR70 response by week 52 [52]. In another Phase II trial (https://clinicaltrials.gov/NCT01359943), secukinumab was given as a loading dose with either IV infusion at 10 mg/kg at baseline, weeks 2 and 4, from week 8, 150 mg subcutaneous injection every 4 weeks through to week 48, or secukinumab 150 mg subcutaneous injection loading at baseline, weeks 1, 2, 3, and 4 and then followed by every 4 weeks starting at week 8 through to 48 weeks [53]. No difference was observed between the two loading regimens in terms of the efficacy of secukinumab in achieving rates of ACR20 response at week 16. It was demonstrated that secukinumab improved efficacy in reducing disease activity over placebo as measured by the disease activity score 28 (DAS28) and other secondary end points although the primary end point (ACR20) was not met [53].
Another Phase II trial (https://clinicaltrials.gov/NCT01426789) was designed to identify a biomarker to guide treatment response to secukinumab [54]. Secukinumab induced rapid and significant changes from baseline in DAS28-C-reactive protein (CRP) and in ACR20 and ACR50 response rates compared with placebo. However, human leukocyte antigen (HLA)-DRB1* alleles was not able to predict secukinumab response [54].
Patients who did not respond to TNF inhibitors showed increased Th17 cells and IL-23 expression [5, 6]. It would be particularly interesting to delineate whether those patients who had a good response to secukinumab had previously failed TNF inhibitors. In a Phase II trial (https://clinicaltrials.gov/NCT00928512) [51, 52], up to 22.2 % of patients who had previously been exposed to biologics were included, but the size of the subgroup was too small to allow for meaningful sub-analysis. It is hypothesized that in the following Phase III trials, those patients who have had an inadequate response to TNF inhibitors should have a good response to secukinumab. The four Phase III trials (REASSURE, https://clinicaltrials.gov/NCT01377012; NURTURE 1, NCT01350804; REASSURE2, NCT01770379; REASSURE-E, NCT01901900]) are designed to treat all RA patients who have had an inadequate response to TNF inhibitors.
Secukinumab in Crohn’s Disease
Secukinumab was also trialed in patients with moderate-to-severe Crohn’s disease (https://clinicaltrials.gov/NCT01009281) [55]. In this Phase IIa study, secukinumab was administered as an IV infusion at 10 mg/kg on day 1 and day 22. Safety and efficacy were assessed by the Crohn’s Disease Activity Index. In the secukinumab-treated group, 21 % discontinued treatment prematurely due to insufficient therapeutic effect compared with 10 % in placebo-treated group. A higher rate of adverse effect was also observed in the secukinumab-treated group including local fungal infections. This study demonstrates that secukinumab was not only ineffective in treating active Crohn’s disease but also seemed to be detrimental as was evident by increased adverse effects compared with placebo. Animal models of inflammatory bowel disease and genome-wide association studies clearly suggest an important pathogenic role of IL-17A in perpetuating chronic inflammation by activated T cells [56]. However, results from animals of intestinal inflammation suggested protective roles of IL-17A in T cell-dependent and T cell-independent models of colitis [57, 58].
Secukinumab in Multiple Sclerosis
Secukinumab was tested for multiple sclerosis in a Phase II study (https://clinicaltrials.gov/NCT01051817). Secukinumab reduced the number of new MRI lesions by 63 % compared with placebo-treated patients and saw a trend in reducing annualized relapse rate [59]. Another small Phase II trial (https://clinicaltrials.gov/NCT01433250) to evaluate the safety was completed, but there is no result available. A larger Phase II study (https://clinicaltrials.gov/NCT01874340) was terminated early based on development of another anti-IL-17 fully human monoclonal antibody with better potential for treating multiple sclerosis.
5.2.2 Ixekizumab
Ixekizumab in Psoriasis
Ixekizumab is a humanized, hinge-modified IgG4 monoclonal antibody binding with high affinity to human IL-17A. Ixekizumab is approved by the US FDA for adults with moderate-to-severe plaque psoriasis (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm491872.htm). The efficacy and safety of ixekizumab in treating plaque psoriasis was demonstrated in a Phase II and three Phase III studies, UNCOVER-1 (https://clinicaltrials.gov/NCT01474512), UNCOVER-2 (https://clinicaltrials.gov/NCT01597245), and UNCOVER-3 (https://clinicaltrials.gov/NCT01646177).
These three Phase III trials all had a similar design, and etanercept was compared in UNCOVER-2 and UNCOVER-3 trials [60, 61]. A total of 3866 patients were included in the three trials. Ixekizumab was administered with a loading dose at 160 mg by subcutaneous injection and then followed by 80 mg every 2 weeks or every 4 weeks. All three studies generated similar results. At week 12, ixekizumab demonstrated statistically significant superiority to placebo. The pooled proportion of patients that achieved PASI 75 was 88.7 % and 81.6 % for ixekizumab 80 mg every 2 weeks and 80 mg every 4 weeks, respectively, while this was achieved in only 4.4 % of patients who took placebo (p < 0.001 for all groups compared with placebo). PGA (0 or 1) was 81.8 % and 75 % for ixekizumab 80 mg every 2 weeks and 80 mg every 4 weeks, respectively, compared with 3.9 % in the placebo group. These studies showed that ixekizumab was superior to etanercept (50 mg twice weekly). The pooled PASI 75 for the etanercept-treated groups was 47.5 % (p < 0.0001, comparing ixekizumab with etanercept groups) (Fig. 5.2b). The pooled PGA (0 or 1) for etanercept was 38.5 % [60, 61].
Ixekizumab in PsA
Efficacy and safety of ixekizumab in treating patients with PsA has been tested in a Phase III study. During the 24-week, SPIRIT-P1 (https://clinicaltrials.gov/NCT01695239) trial, patients who were naive to biologic DMARDs were treated with a 160 mg loading dose followed by 80 mg every 2 weeks or 4 weeks. Both dosage regimens achieved an ACR20 response that was statistically superior to placebo. At 24 weeks, 62 % of patients treated with 80 mg every 2 weeks and 58 % of patients treated with 80 mg every 4 weeks achieved ACR20 response, respectively, compared with 30 % in the placebo group. ACR50 response was 47 % and 40 % for 80 mg every 2 weeks and every 4 weeks groups, respectively, compared with 15 % of patients treated with placebo [62]. Patients treated with both dosing regimens also experienced significantly less radiographic progression of structural joint damage than those treated with placebo. Patients treated with ixekizumab experienced significantly improved quality of life, physical function, and work productivity [63].
Ixekizumab in Ankylosing Spondylitis
Ixekizumab is also being tested for ankylosing spondylitis in two Phase III trials in biologic-naive patients with radiographic axial spondyloarthritis (https://clinicaltrials.gov/NCT02696785) and in patients that are TNF inhibitor-experienced with radiographic axial spondyloarthritis (https://clinicaltrials.gov/NCT02696798).
Ixekizumab in RA
The therapeutic effect of ixekizumab was tested in a Phase I trial in patients with RA by adding it to baseline DMARD therapy [64]. The safety was established in a single-dose treatment regimen. Then the efficacy was demonstrated in regimens where ixekizumab was administered every 2 weeks in various doses. The efficacy was demonstrated by a significant reduction of DAS28 at 10 weeks [64].
The efficacy of ixekizumab in treating RA was first noticed in the proof-of-concept study (https://clinicaltrials.gov/NCT01236118) [64]. In the Phase II trial (https://clinicaltrials.gov/NCT00966875), the efficacy of ixekizumab in treating active RA was further demonstrated [65, 66]. Both patients who were biologic-naive and had inadequate response to TNF inhibitors were included. Patients who were biologic-naive were treated with a wide range of doses (3, 10, 30, 80, and 180 mg) of ixekizumab every 2 weeks, while patients who had previously had an inadequate response to TNF inhibitors were treated with ixekizumab at 80 mg and 180 mg. At week 12, the primary end point was met in both the biologic-naive and inadequate responder to TNF inhibitor therapy cohorts as measured by rates of ACR20 and ACR50 response and reduction of DAS28-CRP and CDAI. During the long-term observation, the clinical responses observed at week 16 remained the same or improved through to week 64. Further Phase III studies are needed to fully understand the efficacy and safety of long-term treatment with ixekizumab.
5.3 Antibody Against IL-17RA
5.3.1 Brodalumab
Brodalumab in Psoriasis
Brodalumab is a fully human IgG2 monoclonal antibody against IL-17RA. It is known that IL-17A, IL-17A/F, IL-17F, IL-17C, and IL-17E (IL-25) all use IL-17RA for signaling (see Fig. 1.1). The broader target of brodalumab while increasing the potential benefit may also pose a higher risk for more adverse effects. For instance, IL-17E plays a role in Th2-type inflammatory diseases, parasitic infections, and allergic reactions, such as asthma and atopic dermatitis, and promotes eosinophilia in mice. Targeting IL-17RA may interfere with those mechanisms mediated by IL-17E [67]. More data and longer time are required to fully appreciate the pros and cons of blocking the IL-17 receptor versus the ligands.
Brodalumab has been evaluated for therapy in psoriasis and PsA. In a Phase I study conducted in psoriasis patients, a single dose of brodalumab was able to normalize thousands of aberrantly expressed genes in lesional skin within 2 weeks. Interestingly, keratinocyte-expressed genes appeared to be normalized rapidly, whereas T cell-specific gene expression normalization occurred over 6 weeks. These data clearly demonstrated the potency of brodalumab in blocking IL-17RA-mediated signaling [68].
In psoriasis, the effective doses of brodalumab were determined in a Phase II trial [69]. In the Phase III AMAGINE-1 (https://clinicaltrials.gov/NCT01708590) study, at week 12 PASI 75 was achieved in 83.3 % patients treated with brodalumab at 210 mg and 60.3 % at 140 mg compared with 2.7 % in the placebo group. PGA (0–1) was 75.7 % with brodalumab at 210 mg and 53.7 % at 140 mg group compared with 1.4 % in placebo group [70]. In Phase III trials, AMAGINE-2 (https://clinicaltrials.gov/NCT01708603) and AMAGINE-3 (https://clinicaltrials.gov/NCT01708629), patients with moderate-to-severe plaque psoriasis were treated with 140 mg or 210 mg of brodalumab every 2 weeks in comparison with ustekinumab. At 12 weeks, 85–86 % of patients in the brodalumab 210 mg group and 67–69 % in the 140 mg group achieved a PASI 75 compared with 69–70 % in the ustekinumab-treated group as well as 6–8 % in the placebo group [71]. PGA score (0–1) was higher at 79–80 % in the brodalumab 210 mg group and 58–60 % in the 140 mg group compared with 57–61 % and 4 % in the ustekinumab and placebo groups, respectively (Fig. 5.2b) [71].
Brodalumab in PsA
Brodalumab was tested for patients with PsA in a Phase II trial. Patients with active PsA were treated with brodalumab at 140 mg or 280 mg at day 1, week 1, 2, 4, 6, 8, and 10 followed by an open-label extension starting at week 12 with 280 mg every 2 weeks. At week 12, 37 % and 39 % of patients treated with 140 mg and 280 mg of brodalumab, respectively, achieved an ACR20 response compared with 18 % in the placebo group [72].
5.4 Bispecific Antibodies Simultaneously Targeting IL-17 Cytokines and Other Inflammatory Cytokines
In RA, simultaneous blockade of TNF and IL-1 with a combination of etanercept and anakinra resulted in increased rates of serious infections without extra benefit [73]. Similarly, combination therapy with abatacept (blocking T cell co-stimulation) and etanercept also increased the rate of infection in spite of a small therapeutic benefit [74]. Therefore, caution has been taken in designing therapeutic strategies blocking two cytokine activities concomitantly for therapy of inflammatory diseases. However, blocking TNF and IL-17 simultaneously seems to be safe and may achieve a synergistic therapeutic benefit in an animal model of arthritis [6, 75]. Clinically, blocking two cytokine activities at the same time can be achieved by using bispecific therapeutic monoclonal antibodies. Two bispecific antibodies catumaxomab (anti-CD3 and anti-epithelial cell adhesion molecule) and blinatumomab (anti-CD3 and anti-CD19) are approved to treat malignancy [76]. Currently, three bispecific antibodies against IL-17A and IL-17F, three against IL-17A and TNF, and one against IL-23 and IL-17A are under development to treat various autoimmune inflammatory diseases (see Table 5.1). The rationale for blocking TNF and IL-17A is supported by data from observations in patients with RA, ankylosing spondylitis AS, or PsA who were treated with anti-TNF. Interestingly, those patients who had an inadequate response to anti-TNF displayed an increased number of Th17 cells and increased levels of IL-23 [5–8]. These data suggest that the IL-17 pathway is dominated in patients who are not responding to anti-TNF. The hypothesis is that anti-TNF and anti-IL-17 will have a synergistic therapeutic effect. Early-phase clinical studies in RA patients using bispecific antibodies to inhibit both TNF and IL-17 A activities have demonstrated no increased rate of infection [77]. The agent bimekizumab, which blocks both IL-17A and IL-17F, has been tested in a Phase I study to treat patients with psoriasis. A single-dose IV injection demonstrated no serious adverse effects, but clinical meaningful improvement of skin lesions supported the continued development of bimekizumab for treatment of diseases mediated by both IL-17A and IL-17F [78].
Table 5.1
Bispecific antibodies inhibiting IL-17 cytokines and other inflammatory cytokines in clinical development
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