Drug Profile
Ixekizumab for treatment of psoriasis Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 08/05/15 For personal use only.
Expert Rev. Clin. Immunol. 11(4), 435–442 (2015)
Beatrice Dyring-Andersen, Lone Skov and Claus Zachariae* Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Kildegaardsvej 28, DK-2900 Hellerup, Denmark *Author for correspondence: [email protected]
Psoriasis is a prevalent chronic inflammatory skin disease of unknown etiology. Recent advances in understanding the pathogenesis of psoriasis suggest that IL-17 is a key proinflammatory mediator present in the skin. Several agents targeting IL-17 or its receptor are in clinical trials for the treatment of psoriasis. This review focuses on the biological rationale and the results of clinical trials with ixekizumab, a humanized IgG4 monoclonal antibody. Ixekizumab binds the IL-17A homodimer, thereby blocking the binding of IL-17A to the IL-17 receptor. The currently available Phase I–III data indicate that ixekizumab is a promising drug, although long-term data of efficacy and safety are needed before ixekizumab and other IL-17 targeting therapeutics can find their place in clinical practice. KEYWORDS: IL-17A . IL-17F . IL-22 . ixekinumab . psoriasis
Psoriasis is a prevalent inflammatory skin disease affecting 1–4% of the adult population in westernized countries [1]. The clinical features of chronic plaque psoriasis are well-demarcated scaly erythematous plaques. Although the etiology of psoriasis remains unknown, it is considered an immune-mediated disease, previously believed to be Th1-mediated. With the increased understanding of human adaptive immunology and the recognition of IL-17producing CD4+ T cells, revising the Th1/ Th2-paradigm of Mosmann and Coffman, focus on the immune pathogenesis of psoriasis has been directed toward the importance of the IL-17 cytokine family [2,3]. Current treatment of psoriasis includes emollients, local vitamin D analogs, topical corticosteroids and phototherapy, as well as systemic agents such as retinoids, cyclosporine and methotrexate. In recent years, a number of therapies specifically targeting immunological pathways, including TNF-a inhibitors and IL-12/ IL-23 inhibitors, have been approved. These biological treatments have been successful in treating psoriasis; however, some patients remain refractory to treatment or the treatment loses effect over time, creating a need for further development of biologics against other potential targets. New biologic drugs targeting the IL-17 pathway are in clinical development for psoriasis treatment. This review gives an overview of the current development of the inhibitors of the IL-17 pathway with focus on ixekizumab. informahealthcare.com
10.1586/1744666X.2015.1023295
IL-17 in the context of psoriasis immune pathology
Several immune cell subsets in psoriatic skin produce IL-17A, including the adaptive subsets Th17 cells/Tc17 cells; cells bridging innate and adaptive immunity – namely the gd T cells; and more recently also innate cell subsets, such as mast cells and neutrophils [4,5]. IL-17A is a member of the IL-17 cytokine family. To date, the IL-17 cytokine family comprises the six cytokine members IL-17 A-F and five receptors, namely IL-17RA-RE [6]. IL-17A, -C and -F are elevated in lesional psoriatic skin [7]. IL-17RA was initially identified as the receptor for IL-17A and IL-17F. The observation that the affinity of IL-17RA for IL-17A was lower than the concentration required to initiate response led to the hypothesis that another receptor subunit was required for signaling. The subsequent observation that IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA could not be complemented by human IL-17RA led to the finding of the second component of the IL-17 receptor – the IL-17RC subunit [8,9]. Partly due to lack of homology with other classic cytokine receptors the dynamics and composition of IL-17 receptor signaling are just recently beginning to be defined. Although not an exclusive mechanism, recent findings suggest that transcription factor ACT1, including a TIR-IL-1 receptor-like
2015 Informa UK Ltd
ISSN 1744-666X
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Drug Profile
Dyring-Andersen, Skov & Zachariae
signaling domain, termed SEFIR found in most IL-17R family members, seems to be an important factor for NF-kB activation and subsequent gene target expression [10]. In keratinocytes, these target genes are associated with skin inflammation leading to increased production of cytokines (TNF-a, IL-1b, IL-8 and IL-6) and chemokines [11,12]. Stimulation of keratinocytes with IL-17 also upregulates gene expression of b-defensin 2 and antimicrobial peptides (cathelicidin, S100A7, S100A8, S100A9), which can disrupt both bacterial membranes and viral envelopes and induce angiogenic changes, the latter is highly relevant in the context of psoriasis pathogenesis [13,14]. IL-17A also upregulates expression of chemokine CCL20 [15,16]. CCL20 was previously believed to be expressed by keratinocytes but recent data suggest that dermal dendritic cells and CD3+ cells can express CCL20 and attract CCR6+ cells, creating a partly IL-17-driven proinflammatory loop in the skin [17]. The effects of IL-17A on keratinocytes have been shown to be amplified by IL-22, another psoriasis-associated cytokine, which to some extent is co-produced with IL-17A by Th17 cells [18]. IL-22 induces psoriatic features in vitro, such as increased keratinocyte proliferation and migration [19,20]. IL-17A has also been reported to induce differentiation and maturation of neutrophil granulocytes, directly or through G-CSF, a feature that now seems relevant in the context of anti-IL-17 treatments for psoriasis [21]. Patients with psoriasis have significantly increased levels of IL-17A in the sera compared with healthy individuals, and increased numbers of IL-17A-positive CD4– and CD8 T cells are found in psoriatic lesions [22–25]. The development and maintenance of the IL-17 response has been linked to IL-23, the latter being produced by keratinocytes, Langerhans cells, dermal dendritic cells and macrophages in the skin and can stimulate Th17 to produce IL-17 (and IL-22), thereby initiating or strengthening the IL-17-mediated effects. IL-23 is increased in lesional psoriatic skin and the importance of the IL-23/IL-17 axis in the pathogenesis of psoriasis is underlined by the efficacy of IL-23/IL-12 targeting treatments used in psoriasis [26–28]. Th17 cell differentiation is regulated by the transcription factors STAT3, retinoic acid receptor-related orphan receptor C (RORC) and is driven by TGF-b, IL-1, IL-6 and IL-23 [29]. Overview of the market
Currently, three new biologic drugs targeting the IL-17A pathway are in clinical development for psoriasis treatment. Ixekizumab is a humanized IL-17A monoclonal antibody and secukinumab is a fully human IL-17A monoclonal antibody, both acting by neutralizing IL-17A. Brodalumab is a human IgG2 monoclonal antibody that antagonizes the IL-17RA receptor. Ixekizumab
Ixekizumab (LY2439821, Eli Lilly, Indianapolis, IN, USA) is a humanized IgG4 monoclonal antibody that binds the IL-17A homodimer, thereby blocking the binding of IL-17A to the IL-17 receptor. Ixekizumab can also bind the IL-17A/F heterodimer but not the IL-17F/F homodimer or other IL-17 family 436
members (IL-17B-E) [30]. To date, no further data on the chemistry or on how the product is derived have been published. Nor are there published data concerning the immunogenicity of ixekizumab. Clinical trials with ixekizumab treatment are underway in patients with rheumatoid arthritis, psoriatic arthritis and psoriasis [31–34]. Pharmacokinetics
In a Phase I trial with ixekizumab treatment for rheumatoid arthritis, the mean elimination half-life ranged from 14 to 18 days. Dose proportionality and linear pharmacokinetics were observed across the doses tested [35]. Due to the relatively long half-life, dosing every 2 weeks resulted in accumulation [35]. No data are available on the equilibrium dissociation constant or on when the maximal serum concentration is found after treatment in psoriasis patients. There is a possibility that ixekizumab-specific antibodies are induced after treatment, and the antibody titer is mentioned in Tham et al., although no further data have been published [30]. Clinical efficacy
The clinical efficacy of ixekizumab in psoriasis was tested in a dose-escalation Phase I study and subsequently in a doubleblinded, placebo-controlled Phase II study followed by an open-label extension study. A Phase III trial including patients with psoriasis, erythrodermic psoriasis and generalized pustular psoriasis has recently been published. Phase I
The clinical efficacy, safety and tolerability of ixekizumab in patients with psoriasis were tested in a 20-week randomized, double-blinded, placebo-controlled, dose-escalation Phase I study with 40 patients with moderate-to-severe psoriasis [32]. The secondary objectives were to determine the dose needed to inhibit IL-17 signaling and the pathologic disease features regulated by IL-17. Patients were randomized to five groups receiving placebo or 5, 15, 50, 150 mg of subcutaneous ixekizumab at weeks 0, 2 and 4. Clinical efficacy of ixekizumab was assessed using the Psoriasis Area and Severity Index (PASI). PASI was evaluated at week 2, 6 and 20 (TABLE 1). Punch biopsies were collected at baseline, week 2 and 6. At week 6, PASI 75 was significantly greater in the treatment groups receiving 15, 50 and 150 mg compared with the placebo and the 5 mg group (TABLE 1). Significant differences in efficacy were sustained throughout the 20-week trial. Histological evaluation confirmed normalization of the skin histology with normalized keratinocyte proliferation, reversal of epidermal hyperplasia and decreased dermal infiltration [32]. Based on RT-PCR on mRNA extracted from skin homogenates of punch biopsies collected at baseline and after 2 and 6 weeks, a dose-dependent reduction in the expression of cathelicidin, S1007A, S1008A and b-defensin 2 was observed. Dermal infiltration of T cells and dendritic cells decreased considerably and the mRNA levels of cytokines were also reduced including levels of IL-17A, IL-22, IFN-g and IL-23. Furthermore, analyses Expert Rev. Clin. Immunol. 11(4), (2015)
Ixekizumab for treatment of psoriasis
Drug Profile
Table 1. The ixekizumab Phase I trial was a 20-week randomized, double-blinded, placebo-controlled, dose-escalation study including 40 patients with moderate-to-severe psoriasis. Trial
Ixekizumab Phase I
Doses (patients [n])
Treatment (week)
Follow-up, total (week)
5 mg (n = 8)
0, 2, 4
20
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15 mg (n = 8)
50 mg (n = 8)
150 mg (n = 8)
Placebo (n = 8)
0, 2, 4
0, 2, 4
0, 2, 4
0, 2, 4
20
20
20
20
Results PASI 75 (%)
PASI 90 (%)
PASI 100 (%)
Week 6
0% (0/8)
0% (0/8)
NR
Week 20
0% (0/8)
0% (0/8)
NR
Week 6
25% (2/8)
12.5% (1/8)
NR
Week 20
50% (2/4)
50% (2/4)
NR
Week 6
71.4% (5/7)
43% (3/7)
NR
Week 20
57.1% 4/7)
14.4% (1/7)
NR
Week 6
100% (8/8)
62.5% (5/8)
NR
Week 20
74.1% (5/7)
74.1% (5/7)
NR
Week 6
0%
0%
NR
Week 20
0%
0%
NR
PASI assessment (week)
Patients were randomized to five groups receiving placebo or 5, 15, 50, 150 mg of subcutaneous ixekizumab at weeks 0, 2 and 4. PASI was evaluated at week 2, 6 and 20, the latter is shown in TABLE 1 [32].
of whole genome microarray on RNA from lesional skin biopsies (week 2) collected from patients receiving 150 mg ixekizumab or placebo revealed that ixekizumab had a profound effect on gene expression. The effects were also profound when compared with the gene expression data from a previous study investigating the effects of etanercept [36]. Krueger et al. underline the suppression of IL-19, a cytokine that can induce keratinocyte hyperplasia and IL-8, CXCL1 and CCL20, all potent attractants for neutrophils and CCR6+ cells [32]. These results represent changes in gene expression at week 2 and no conclusion can be drawn on the temporal development during treatment [32]. Phase II
After the encouraging results from the izekizumab Phase I study on moderate-to-severe psoriasis, a Phase II trial followed with an open-label extension study [33,34]. The safety and efficacy of ixekizumab was evaluated including 142 patients with moderate-to-severe plaque psoriasis in double-blinded, placebocontrolled Phase II trial [33]. Eligible study patients were adults with a history of at least 6 months moderate-to-severe psoriasis with a PASI score ‡12, 10% BSA and a static Physician’s Global Assessment of ‡3. Patients with non-plaque psoriasis, clinical flare of psoriasis within 12 weeks of study start, infections, systemic therapy within 4 weeks and topical therapy within 2 weeks of study start were not eligible for inclusion. Patients were randomized to five groups receiving either placebo or 10, 25, 75, 150 mg of subcutaneous ixekizumab at weeks 0, 2, 4, 12 and 16 followed by a 4-week follow-up for a total study period of 20 weeks (TABLE 2). At week 12, the primary end point, PASI 75, was achieved in 76.7% (25 mg), 82.8% (75 mg) and 82.1% (150 mg) of the patients compared with 7.7% in the placebo group (p < 0.001 for each comparison). A significant percentage of patients achieved informahealthcare.com
PASI 90 (50.0% [25 mg], 58.6% [75 mg], 71.4% [150 mg] vs 0% in the placebo group) and some achieved PASI 100 (16.7% [25 mg], 37.9% [75 mg], 39.3% [150 mg] vs 0% in the placebo group) (TABLE 2). A significant decrease in Dermatology Life Quality Index scores and itching severity was also found at week 8 and sustained throughout the study in the 25, 75 and 150 mg groups – consistent with the clinical improvements observed. All patients included in the Phase II study by Leonardi and collaborators were offered inclusion in a 52-week open-label extension study with 120 mg subcutaneous injections of ixekizumab every 4 weeks. Patients with less than 75% improvement from baseline to week 20 were offered inclusion in the open-label extension study following the RCT. Patients who had reached PASI 75 at week 20 were offered inclusion in the extension study after a treatment-free period from week 20–32 and were eligible to enter the open-label extension study at the study visit where they fell below PASI 75 or at week 32 if PASI 75 or higher had been maintained throughout the treatment-free period [34]. The majority of patients (n = 120, 93%) entered the open-label extension study and received at least 1 dose of study drug; 103 patients (86%) completed at least 52 weeks of treatment. Early discontinuation was imputed as non-response at week 52. At week 52, 77% of patients had a PASI 75, 68% reached PASI 90 and 48% had a PASI 100 response (TABLE 2). Interestingly, of the 69 patients who had reached PASI 75 at week 20, only 24 lost response during the 12-week treatmentfree period, which suggests that treatment intervals longer than every 4th week could be advisable for some patients. Phase III trials
There are several completed Phase III trials comparing ixekizumab with placebo or etanercept, but only one study has been published to date. This is a Phase III, open-label study that included 437
Drug Profile
Dyring-Andersen, Skov & Zachariae
Table 2. In a double-blinded, placebo-controlled Phase II trial with ixekizumab treatment of patients with psoriasis, 142 patients with moderate-to-severe plaque psoriasis were enrolled. Trial
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Ixekizumab Phase II
Ixekizumab Phase II open-label extension
Results
Doses (patients [n])
Treatment (week)
Follow-up, total PASI (week) assessment (week)
PASI 75 (%)
PASI 90 (%)
PASI 100 (%)
10 mg (n = 28)
0, 2, 4, 8, 12, 16
20
Week 12
28.6% (8/28)
17.9% (5/28)
0% (0/28)
25 mg (n = 30)
0, 2, 4, 8, 12, 16
20
Week 12
76.7% (23/30)
50.0% (15/30)
16.7% (5/30)
75 mg (n = 29)
0, 2, 4, 8, 12, 16
20
Week 12
82.8% (24/29)
58.6% (17/29)
37.9% (11/29)
150 mg (n = 28)
0, 2, 4, 8, 12, 16
20
Week 12
82.1% (23/28)
71.4% (20/28)
39.3% (11/28)
52
Week 52
76.7% (92/120)
67.5% (81/120)
48.3% (58/120)
120 mg (n = 120) Every 4th week
Patients were randomized to five groups receiving placebo or 10, 25, 75, 150 mg of subcutaneous ixekizumab at weeks 0, 2, 4, 12 and 16 followed by a 4-week follow-up for a total study period of 20 weeks. The study was followed by an open-label extension study [33,34].
Japanese patients with psoriasis (PASI ‡12, static Physician’s Global Assessment ‡3, BSA ‡10%) with no other treatment within 4 weeks of baseline other than local mild corticosteroid limited to the face, axilla and genitalia. Patients with erythrodermic psoriasis (defined as BSA ‡80%) and those with generalized pustular psoriasis were also included in the study. These patients were eligible for inclusion with concurrent prednisolone treatment of up to 10 mg/day. A total of 91 patients received ixekizumab: 78 patients with plaque psoriasis, 8 patients with erythrodermic psoriasis and 5 patients with generalized pustular psoriasis. Patients received a 160 mg subcutaneous ixekizumab injection at week 0 followed by 80 mg ixekizumab every 2 weeks through week 12 and every 4 weeks through week 24. At week 12, 98.7% (77/78) of patients with plaque psoriasis reached PASI 75, 83.3% (65/78) reached PASI 90 and 32.1% (25/78) reached PASI 100. At week 24, the PASI 75, PASI 90 and PASI 100 response rates were 91% (71/78), 86% (67/78) and 46% (36/78) (TABLE 3) [37]. Although based on a small sample
size, all patients with erythrodermic psoriasis treated with ixekizumab reached PASI 75 at week 12 and maintained the effect throughout the 24-week study. Of the patients with generalized pustular psoriasis, 80% (4/5) reached PASI 75 at week 12 and maintained treatment efficacy throughout the 24 weeks (TABLE 3). Notably, no control group was included in the study. Three additional Phase III studies of ixekizumab in the treatment of psoriasis have been conducted, UNCOVER 1–3. In the first study, a 12-week multicenter, randomized, double-blinded placebo-controlled study, patients were assigned to receive either placebo or ixekizumab 80 mg every 2 or 4 weeks following a 160 mg starting dose. Responders to treatment, defined as PASI 75, were assigned to continue treatment on either placebo or ixekizumab (80 mg every 4 or 12 weeks) for up to 60 weeks. In UNCOVER 2 and 3, patients could be assigned to receive etanercept 50 mg twice weekly for 12 weeks or 80 mg ixekizumab every 2 or 4 weeks following a 160 mg starting dose. The results of these studies have not been published yet.
Table 3. Phase III open-label study including patients with psoriasis, patients with erythrodermic psoriasis and patients with generalized pustular psoriasis. Trial
Ixekizumab Phase III
Doses (patients [n])
Treatment (week)
Follow-up, total (week)
PP (n = 78)
0, 2, 4, 6, 8, 10, 12, 16, 20, 24
24
0, 2, 4, 6, 8, 10, 12, 16, 20, 24
24
0, 2, 4, 6, 8, 10, 12, 16, 20, 24
24
EP (n = 8)
GGP (n = 5)
Results PASI 75 (%)
PASI 90 (%)
PASI 100 (%)
Week 12
98.7% (77/78)
83.3% (65/78)
32.1% (25/78)
Week 24
91.0% (71/78)
85.9% (67/78)
46.2% (36/78)
Week 12
100% (8/8)
62.5% (5/8)
25.0% (2/8)
Week 24
100% (8/8)
87.5% (7/8)
12.5% (1/8)
Week 12
80.0% (4/5)
60.0% (3/5)
20.0% (1/5)
Week 24
80.0% (4/5)
40.0% (2/5)
40.0% (2/5)
PASI assessment (week)
Patients received 160 mg at inclusion and 80 mg every 2 weeks through week 12 and every 4 week through week 24. No control group was enrolled [37]. EP: Erythrodermic psoriasis; GPP: Generalized pustular psoriasis; PP: Pustular psoriasis.
438
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Ixekizumab for treatment of psoriasis
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Safety
Patients displaying deficiencies in IL-17 immunity are prone to developing chronic mucocutaneous candidiasis. Complete autosomal recessive IL-17RA deficiency, partial autosomal dominant IL-17F deficiency and mutations of adaptor protein ACT1 are genetic etiologies associated with chronic mucocutaneous candidiasis [38,39]. Chronic mucocutaneous candidiasis is also found in patients with mutations in the autoimmune regulator gene who have circulating antibodies to IL-17A, IL-17F and IL-22. Murine studies also suggest immunological vulnerability to infections with Klebsiella pneumoniae and Streptococcus aureus [40–42]. In the Phase I study with ixekizumab, 25% of the patients experienced infections in the 5-, 15- and 50-mg groups compared with none in the 150-mg group and placebo control group. In the Phase II trial, the most common adverse effects observed were nasopharyngitis, upper respiratory infection and headache, albeit the frequencies were similar in the treatment and placebo groups with the exception of mild injection-site reaction, which was observed more frequently in the treatment groups with ixekizumab than in the placebo group. No serious adverse events occurred during the Phase II placebo-controlled trial [33]. During the 52-week openlabel extension study, nasopharyngitis (10% incidence), upper respiratory tract infection (7.5% incidence) and sinusitis (5% incidence) remained the most frequently reported adverse effects comparable with the incidence rates in the first part of the trial including the incidence within the placebo group. No cases of tuberculosis or fungal infections were reported in the open-label extension study. In the Phase II trial, asymptomatic grade 2 neutropenia was observed in two patients receiving 75 and 150 mg of ixekizumab. This was also observed in the Phase I trial of ixekizumab for patients with rheumatoid arthritis [32,35]. No cases of neutropenia (
Ixekizumab for treatment of psoriasis Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 08/05/15 For personal use only.
Expert Rev. Clin. Immunol. 11(4), 435–442 (2015)
Beatrice Dyring-Andersen, Lone Skov and Claus Zachariae* Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Kildegaardsvej 28, DK-2900 Hellerup, Denmark *Author for correspondence: [email protected]
Psoriasis is a prevalent chronic inflammatory skin disease of unknown etiology. Recent advances in understanding the pathogenesis of psoriasis suggest that IL-17 is a key proinflammatory mediator present in the skin. Several agents targeting IL-17 or its receptor are in clinical trials for the treatment of psoriasis. This review focuses on the biological rationale and the results of clinical trials with ixekizumab, a humanized IgG4 monoclonal antibody. Ixekizumab binds the IL-17A homodimer, thereby blocking the binding of IL-17A to the IL-17 receptor. The currently available Phase I–III data indicate that ixekizumab is a promising drug, although long-term data of efficacy and safety are needed before ixekizumab and other IL-17 targeting therapeutics can find their place in clinical practice. KEYWORDS: IL-17A . IL-17F . IL-22 . ixekinumab . psoriasis
Psoriasis is a prevalent inflammatory skin disease affecting 1–4% of the adult population in westernized countries [1]. The clinical features of chronic plaque psoriasis are well-demarcated scaly erythematous plaques. Although the etiology of psoriasis remains unknown, it is considered an immune-mediated disease, previously believed to be Th1-mediated. With the increased understanding of human adaptive immunology and the recognition of IL-17producing CD4+ T cells, revising the Th1/ Th2-paradigm of Mosmann and Coffman, focus on the immune pathogenesis of psoriasis has been directed toward the importance of the IL-17 cytokine family [2,3]. Current treatment of psoriasis includes emollients, local vitamin D analogs, topical corticosteroids and phototherapy, as well as systemic agents such as retinoids, cyclosporine and methotrexate. In recent years, a number of therapies specifically targeting immunological pathways, including TNF-a inhibitors and IL-12/ IL-23 inhibitors, have been approved. These biological treatments have been successful in treating psoriasis; however, some patients remain refractory to treatment or the treatment loses effect over time, creating a need for further development of biologics against other potential targets. New biologic drugs targeting the IL-17 pathway are in clinical development for psoriasis treatment. This review gives an overview of the current development of the inhibitors of the IL-17 pathway with focus on ixekizumab. informahealthcare.com
10.1586/1744666X.2015.1023295
IL-17 in the context of psoriasis immune pathology
Several immune cell subsets in psoriatic skin produce IL-17A, including the adaptive subsets Th17 cells/Tc17 cells; cells bridging innate and adaptive immunity – namely the gd T cells; and more recently also innate cell subsets, such as mast cells and neutrophils [4,5]. IL-17A is a member of the IL-17 cytokine family. To date, the IL-17 cytokine family comprises the six cytokine members IL-17 A-F and five receptors, namely IL-17RA-RE [6]. IL-17A, -C and -F are elevated in lesional psoriatic skin [7]. IL-17RA was initially identified as the receptor for IL-17A and IL-17F. The observation that the affinity of IL-17RA for IL-17A was lower than the concentration required to initiate response led to the hypothesis that another receptor subunit was required for signaling. The subsequent observation that IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA could not be complemented by human IL-17RA led to the finding of the second component of the IL-17 receptor – the IL-17RC subunit [8,9]. Partly due to lack of homology with other classic cytokine receptors the dynamics and composition of IL-17 receptor signaling are just recently beginning to be defined. Although not an exclusive mechanism, recent findings suggest that transcription factor ACT1, including a TIR-IL-1 receptor-like
2015 Informa UK Ltd
ISSN 1744-666X
435
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 08/05/15 For personal use only.
Drug Profile
Dyring-Andersen, Skov & Zachariae
signaling domain, termed SEFIR found in most IL-17R family members, seems to be an important factor for NF-kB activation and subsequent gene target expression [10]. In keratinocytes, these target genes are associated with skin inflammation leading to increased production of cytokines (TNF-a, IL-1b, IL-8 and IL-6) and chemokines [11,12]. Stimulation of keratinocytes with IL-17 also upregulates gene expression of b-defensin 2 and antimicrobial peptides (cathelicidin, S100A7, S100A8, S100A9), which can disrupt both bacterial membranes and viral envelopes and induce angiogenic changes, the latter is highly relevant in the context of psoriasis pathogenesis [13,14]. IL-17A also upregulates expression of chemokine CCL20 [15,16]. CCL20 was previously believed to be expressed by keratinocytes but recent data suggest that dermal dendritic cells and CD3+ cells can express CCL20 and attract CCR6+ cells, creating a partly IL-17-driven proinflammatory loop in the skin [17]. The effects of IL-17A on keratinocytes have been shown to be amplified by IL-22, another psoriasis-associated cytokine, which to some extent is co-produced with IL-17A by Th17 cells [18]. IL-22 induces psoriatic features in vitro, such as increased keratinocyte proliferation and migration [19,20]. IL-17A has also been reported to induce differentiation and maturation of neutrophil granulocytes, directly or through G-CSF, a feature that now seems relevant in the context of anti-IL-17 treatments for psoriasis [21]. Patients with psoriasis have significantly increased levels of IL-17A in the sera compared with healthy individuals, and increased numbers of IL-17A-positive CD4– and CD8 T cells are found in psoriatic lesions [22–25]. The development and maintenance of the IL-17 response has been linked to IL-23, the latter being produced by keratinocytes, Langerhans cells, dermal dendritic cells and macrophages in the skin and can stimulate Th17 to produce IL-17 (and IL-22), thereby initiating or strengthening the IL-17-mediated effects. IL-23 is increased in lesional psoriatic skin and the importance of the IL-23/IL-17 axis in the pathogenesis of psoriasis is underlined by the efficacy of IL-23/IL-12 targeting treatments used in psoriasis [26–28]. Th17 cell differentiation is regulated by the transcription factors STAT3, retinoic acid receptor-related orphan receptor C (RORC) and is driven by TGF-b, IL-1, IL-6 and IL-23 [29]. Overview of the market
Currently, three new biologic drugs targeting the IL-17A pathway are in clinical development for psoriasis treatment. Ixekizumab is a humanized IL-17A monoclonal antibody and secukinumab is a fully human IL-17A monoclonal antibody, both acting by neutralizing IL-17A. Brodalumab is a human IgG2 monoclonal antibody that antagonizes the IL-17RA receptor. Ixekizumab
Ixekizumab (LY2439821, Eli Lilly, Indianapolis, IN, USA) is a humanized IgG4 monoclonal antibody that binds the IL-17A homodimer, thereby blocking the binding of IL-17A to the IL-17 receptor. Ixekizumab can also bind the IL-17A/F heterodimer but not the IL-17F/F homodimer or other IL-17 family 436
members (IL-17B-E) [30]. To date, no further data on the chemistry or on how the product is derived have been published. Nor are there published data concerning the immunogenicity of ixekizumab. Clinical trials with ixekizumab treatment are underway in patients with rheumatoid arthritis, psoriatic arthritis and psoriasis [31–34]. Pharmacokinetics
In a Phase I trial with ixekizumab treatment for rheumatoid arthritis, the mean elimination half-life ranged from 14 to 18 days. Dose proportionality and linear pharmacokinetics were observed across the doses tested [35]. Due to the relatively long half-life, dosing every 2 weeks resulted in accumulation [35]. No data are available on the equilibrium dissociation constant or on when the maximal serum concentration is found after treatment in psoriasis patients. There is a possibility that ixekizumab-specific antibodies are induced after treatment, and the antibody titer is mentioned in Tham et al., although no further data have been published [30]. Clinical efficacy
The clinical efficacy of ixekizumab in psoriasis was tested in a dose-escalation Phase I study and subsequently in a doubleblinded, placebo-controlled Phase II study followed by an open-label extension study. A Phase III trial including patients with psoriasis, erythrodermic psoriasis and generalized pustular psoriasis has recently been published. Phase I
The clinical efficacy, safety and tolerability of ixekizumab in patients with psoriasis were tested in a 20-week randomized, double-blinded, placebo-controlled, dose-escalation Phase I study with 40 patients with moderate-to-severe psoriasis [32]. The secondary objectives were to determine the dose needed to inhibit IL-17 signaling and the pathologic disease features regulated by IL-17. Patients were randomized to five groups receiving placebo or 5, 15, 50, 150 mg of subcutaneous ixekizumab at weeks 0, 2 and 4. Clinical efficacy of ixekizumab was assessed using the Psoriasis Area and Severity Index (PASI). PASI was evaluated at week 2, 6 and 20 (TABLE 1). Punch biopsies were collected at baseline, week 2 and 6. At week 6, PASI 75 was significantly greater in the treatment groups receiving 15, 50 and 150 mg compared with the placebo and the 5 mg group (TABLE 1). Significant differences in efficacy were sustained throughout the 20-week trial. Histological evaluation confirmed normalization of the skin histology with normalized keratinocyte proliferation, reversal of epidermal hyperplasia and decreased dermal infiltration [32]. Based on RT-PCR on mRNA extracted from skin homogenates of punch biopsies collected at baseline and after 2 and 6 weeks, a dose-dependent reduction in the expression of cathelicidin, S1007A, S1008A and b-defensin 2 was observed. Dermal infiltration of T cells and dendritic cells decreased considerably and the mRNA levels of cytokines were also reduced including levels of IL-17A, IL-22, IFN-g and IL-23. Furthermore, analyses Expert Rev. Clin. Immunol. 11(4), (2015)
Ixekizumab for treatment of psoriasis
Drug Profile
Table 1. The ixekizumab Phase I trial was a 20-week randomized, double-blinded, placebo-controlled, dose-escalation study including 40 patients with moderate-to-severe psoriasis. Trial
Ixekizumab Phase I
Doses (patients [n])
Treatment (week)
Follow-up, total (week)
5 mg (n = 8)
0, 2, 4
20
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15 mg (n = 8)
50 mg (n = 8)
150 mg (n = 8)
Placebo (n = 8)
0, 2, 4
0, 2, 4
0, 2, 4
0, 2, 4
20
20
20
20
Results PASI 75 (%)
PASI 90 (%)
PASI 100 (%)
Week 6
0% (0/8)
0% (0/8)
NR
Week 20
0% (0/8)
0% (0/8)
NR
Week 6
25% (2/8)
12.5% (1/8)
NR
Week 20
50% (2/4)
50% (2/4)
NR
Week 6
71.4% (5/7)
43% (3/7)
NR
Week 20
57.1% 4/7)
14.4% (1/7)
NR
Week 6
100% (8/8)
62.5% (5/8)
NR
Week 20
74.1% (5/7)
74.1% (5/7)
NR
Week 6
0%
0%
NR
Week 20
0%
0%
NR
PASI assessment (week)
Patients were randomized to five groups receiving placebo or 5, 15, 50, 150 mg of subcutaneous ixekizumab at weeks 0, 2 and 4. PASI was evaluated at week 2, 6 and 20, the latter is shown in TABLE 1 [32].
of whole genome microarray on RNA from lesional skin biopsies (week 2) collected from patients receiving 150 mg ixekizumab or placebo revealed that ixekizumab had a profound effect on gene expression. The effects were also profound when compared with the gene expression data from a previous study investigating the effects of etanercept [36]. Krueger et al. underline the suppression of IL-19, a cytokine that can induce keratinocyte hyperplasia and IL-8, CXCL1 and CCL20, all potent attractants for neutrophils and CCR6+ cells [32]. These results represent changes in gene expression at week 2 and no conclusion can be drawn on the temporal development during treatment [32]. Phase II
After the encouraging results from the izekizumab Phase I study on moderate-to-severe psoriasis, a Phase II trial followed with an open-label extension study [33,34]. The safety and efficacy of ixekizumab was evaluated including 142 patients with moderate-to-severe plaque psoriasis in double-blinded, placebocontrolled Phase II trial [33]. Eligible study patients were adults with a history of at least 6 months moderate-to-severe psoriasis with a PASI score ‡12, 10% BSA and a static Physician’s Global Assessment of ‡3. Patients with non-plaque psoriasis, clinical flare of psoriasis within 12 weeks of study start, infections, systemic therapy within 4 weeks and topical therapy within 2 weeks of study start were not eligible for inclusion. Patients were randomized to five groups receiving either placebo or 10, 25, 75, 150 mg of subcutaneous ixekizumab at weeks 0, 2, 4, 12 and 16 followed by a 4-week follow-up for a total study period of 20 weeks (TABLE 2). At week 12, the primary end point, PASI 75, was achieved in 76.7% (25 mg), 82.8% (75 mg) and 82.1% (150 mg) of the patients compared with 7.7% in the placebo group (p < 0.001 for each comparison). A significant percentage of patients achieved informahealthcare.com
PASI 90 (50.0% [25 mg], 58.6% [75 mg], 71.4% [150 mg] vs 0% in the placebo group) and some achieved PASI 100 (16.7% [25 mg], 37.9% [75 mg], 39.3% [150 mg] vs 0% in the placebo group) (TABLE 2). A significant decrease in Dermatology Life Quality Index scores and itching severity was also found at week 8 and sustained throughout the study in the 25, 75 and 150 mg groups – consistent with the clinical improvements observed. All patients included in the Phase II study by Leonardi and collaborators were offered inclusion in a 52-week open-label extension study with 120 mg subcutaneous injections of ixekizumab every 4 weeks. Patients with less than 75% improvement from baseline to week 20 were offered inclusion in the open-label extension study following the RCT. Patients who had reached PASI 75 at week 20 were offered inclusion in the extension study after a treatment-free period from week 20–32 and were eligible to enter the open-label extension study at the study visit where they fell below PASI 75 or at week 32 if PASI 75 or higher had been maintained throughout the treatment-free period [34]. The majority of patients (n = 120, 93%) entered the open-label extension study and received at least 1 dose of study drug; 103 patients (86%) completed at least 52 weeks of treatment. Early discontinuation was imputed as non-response at week 52. At week 52, 77% of patients had a PASI 75, 68% reached PASI 90 and 48% had a PASI 100 response (TABLE 2). Interestingly, of the 69 patients who had reached PASI 75 at week 20, only 24 lost response during the 12-week treatmentfree period, which suggests that treatment intervals longer than every 4th week could be advisable for some patients. Phase III trials
There are several completed Phase III trials comparing ixekizumab with placebo or etanercept, but only one study has been published to date. This is a Phase III, open-label study that included 437
Drug Profile
Dyring-Andersen, Skov & Zachariae
Table 2. In a double-blinded, placebo-controlled Phase II trial with ixekizumab treatment of patients with psoriasis, 142 patients with moderate-to-severe plaque psoriasis were enrolled. Trial
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Ixekizumab Phase II
Ixekizumab Phase II open-label extension
Results
Doses (patients [n])
Treatment (week)
Follow-up, total PASI (week) assessment (week)
PASI 75 (%)
PASI 90 (%)
PASI 100 (%)
10 mg (n = 28)
0, 2, 4, 8, 12, 16
20
Week 12
28.6% (8/28)
17.9% (5/28)
0% (0/28)
25 mg (n = 30)
0, 2, 4, 8, 12, 16
20
Week 12
76.7% (23/30)
50.0% (15/30)
16.7% (5/30)
75 mg (n = 29)
0, 2, 4, 8, 12, 16
20
Week 12
82.8% (24/29)
58.6% (17/29)
37.9% (11/29)
150 mg (n = 28)
0, 2, 4, 8, 12, 16
20
Week 12
82.1% (23/28)
71.4% (20/28)
39.3% (11/28)
52
Week 52
76.7% (92/120)
67.5% (81/120)
48.3% (58/120)
120 mg (n = 120) Every 4th week
Patients were randomized to five groups receiving placebo or 10, 25, 75, 150 mg of subcutaneous ixekizumab at weeks 0, 2, 4, 12 and 16 followed by a 4-week follow-up for a total study period of 20 weeks. The study was followed by an open-label extension study [33,34].
Japanese patients with psoriasis (PASI ‡12, static Physician’s Global Assessment ‡3, BSA ‡10%) with no other treatment within 4 weeks of baseline other than local mild corticosteroid limited to the face, axilla and genitalia. Patients with erythrodermic psoriasis (defined as BSA ‡80%) and those with generalized pustular psoriasis were also included in the study. These patients were eligible for inclusion with concurrent prednisolone treatment of up to 10 mg/day. A total of 91 patients received ixekizumab: 78 patients with plaque psoriasis, 8 patients with erythrodermic psoriasis and 5 patients with generalized pustular psoriasis. Patients received a 160 mg subcutaneous ixekizumab injection at week 0 followed by 80 mg ixekizumab every 2 weeks through week 12 and every 4 weeks through week 24. At week 12, 98.7% (77/78) of patients with plaque psoriasis reached PASI 75, 83.3% (65/78) reached PASI 90 and 32.1% (25/78) reached PASI 100. At week 24, the PASI 75, PASI 90 and PASI 100 response rates were 91% (71/78), 86% (67/78) and 46% (36/78) (TABLE 3) [37]. Although based on a small sample
size, all patients with erythrodermic psoriasis treated with ixekizumab reached PASI 75 at week 12 and maintained the effect throughout the 24-week study. Of the patients with generalized pustular psoriasis, 80% (4/5) reached PASI 75 at week 12 and maintained treatment efficacy throughout the 24 weeks (TABLE 3). Notably, no control group was included in the study. Three additional Phase III studies of ixekizumab in the treatment of psoriasis have been conducted, UNCOVER 1–3. In the first study, a 12-week multicenter, randomized, double-blinded placebo-controlled study, patients were assigned to receive either placebo or ixekizumab 80 mg every 2 or 4 weeks following a 160 mg starting dose. Responders to treatment, defined as PASI 75, were assigned to continue treatment on either placebo or ixekizumab (80 mg every 4 or 12 weeks) for up to 60 weeks. In UNCOVER 2 and 3, patients could be assigned to receive etanercept 50 mg twice weekly for 12 weeks or 80 mg ixekizumab every 2 or 4 weeks following a 160 mg starting dose. The results of these studies have not been published yet.
Table 3. Phase III open-label study including patients with psoriasis, patients with erythrodermic psoriasis and patients with generalized pustular psoriasis. Trial
Ixekizumab Phase III
Doses (patients [n])
Treatment (week)
Follow-up, total (week)
PP (n = 78)
0, 2, 4, 6, 8, 10, 12, 16, 20, 24
24
0, 2, 4, 6, 8, 10, 12, 16, 20, 24
24
0, 2, 4, 6, 8, 10, 12, 16, 20, 24
24
EP (n = 8)
GGP (n = 5)
Results PASI 75 (%)
PASI 90 (%)
PASI 100 (%)
Week 12
98.7% (77/78)
83.3% (65/78)
32.1% (25/78)
Week 24
91.0% (71/78)
85.9% (67/78)
46.2% (36/78)
Week 12
100% (8/8)
62.5% (5/8)
25.0% (2/8)
Week 24
100% (8/8)
87.5% (7/8)
12.5% (1/8)
Week 12
80.0% (4/5)
60.0% (3/5)
20.0% (1/5)
Week 24
80.0% (4/5)
40.0% (2/5)
40.0% (2/5)
PASI assessment (week)
Patients received 160 mg at inclusion and 80 mg every 2 weeks through week 12 and every 4 week through week 24. No control group was enrolled [37]. EP: Erythrodermic psoriasis; GPP: Generalized pustular psoriasis; PP: Pustular psoriasis.
438
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Ixekizumab for treatment of psoriasis
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Safety
Patients displaying deficiencies in IL-17 immunity are prone to developing chronic mucocutaneous candidiasis. Complete autosomal recessive IL-17RA deficiency, partial autosomal dominant IL-17F deficiency and mutations of adaptor protein ACT1 are genetic etiologies associated with chronic mucocutaneous candidiasis [38,39]. Chronic mucocutaneous candidiasis is also found in patients with mutations in the autoimmune regulator gene who have circulating antibodies to IL-17A, IL-17F and IL-22. Murine studies also suggest immunological vulnerability to infections with Klebsiella pneumoniae and Streptococcus aureus [40–42]. In the Phase I study with ixekizumab, 25% of the patients experienced infections in the 5-, 15- and 50-mg groups compared with none in the 150-mg group and placebo control group. In the Phase II trial, the most common adverse effects observed were nasopharyngitis, upper respiratory infection and headache, albeit the frequencies were similar in the treatment and placebo groups with the exception of mild injection-site reaction, which was observed more frequently in the treatment groups with ixekizumab than in the placebo group. No serious adverse events occurred during the Phase II placebo-controlled trial [33]. During the 52-week openlabel extension study, nasopharyngitis (10% incidence), upper respiratory tract infection (7.5% incidence) and sinusitis (5% incidence) remained the most frequently reported adverse effects comparable with the incidence rates in the first part of the trial including the incidence within the placebo group. No cases of tuberculosis or fungal infections were reported in the open-label extension study. In the Phase II trial, asymptomatic grade 2 neutropenia was observed in two patients receiving 75 and 150 mg of ixekizumab. This was also observed in the Phase I trial of ixekizumab for patients with rheumatoid arthritis [32,35]. No cases of neutropenia (
