Keywords
Ixekizumab, Taltz, Interleukin-17A, Monoclonal antibody, UNCOVER-2, UNCOVER-3
Key points
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Ixekizumab is a humanized monoclonal antibody against interleukin-17A.
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Ixekizumab is more efficacious in the treatment of plaque psoriasis in comparison to etanercept and placebo.
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Ixekizumab has led to higher clinical response rates and skin clearance rates in clinical trials than any other agent currently approved by the US Food and Drug Administration for the treatment of psoriasis.
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The most common side effects attributable to ixekizumab are injection-site reactions, upper respiratory tract infections, nausea, and tinea infections.
Introduction
Ixekizumab, a biologic marketed under the brand name Taltz, was approved in March 2016 for the treatment of moderate-to-severe plaque psoriasis by the US Food and Drug Administration (FDA). Another drug that targets a specific cytokine to reducing inflammation and skin lesions, ixekizumab is 1 of 3 biologic agents, including secukinumab and brodalumab, that targets the interleukin-17 (IL-17) pathway in the pathogenesis of psoriasis.
Ixekizumab currently does not have any other FDA-approved indications other than plaque psoriasis (although it is also effective for psoriatic arthritis). The current recommended dosing of ixekizumab is subcutaneous injection of 160 mg at baseline, followed by 80 mg every other week (EOW) until week 12, followed by 80 mg every 4 weeks for maintenance dosing ( Fig. 13.1 ). In comparison to secukinumab and brodalumab, the dosing regimen for ixekizumab is more favorable because there are fewer injections required overall in the loading and maintenance phases (secukinumab requires 10 injections in the loading phase, and brodalumab requires EOW injections in the maintenance phase).
Mechanism of action
Ixekinumab is a humanized monoclonal immunoglobulin G4 (IgG4) antibody that targets the IL-17 pathway in the pathogenesis of psoriasis. IL-17 is produced by Th17 cells and functions in the activation/recruitment of neutrophils, blockade of neutrophil apoptosis, release of inflammatory cytokines, and stimulation of psoriasis angiogenesis. Th17 cells and IL-17 messenger RNA are increased in psoriasis lesions, and Th17 cells are increased in the blood of psoriasis patients. Of the 6 isoforms of IL-17, ixekizumab specifically binds to and inhibits IL-17A, the most potent isoform involved in psoriasis.
IL-17A dimerizes with itself to form a homodimer or with IL-17F to form a heterodimer, rendering it functionally active. T cells, natural killer cells, mast cells, and neutrophils all produce IL-17A and IL-17F; however, Th17 cells characteristically produce IL-17A. These homodimers and heterodimers bind to and activate the IL-17 cell surface receptors IL-17RA and IL-17RC, triggering the inflammatory cascade that leads to psoriasis lesions.
Other IL-17 blocking agents include secukinumab and brodalumab. Similarly to ixekizumab, secukinumab (IgG1 mAb) targets IL-17A, whereas broadalumab (IgG2 monoclonal antibody [mAb]) is specifically directed against the IL-17 receptor IL-17RA. However, as opposed to secukinumab and broadalumab, which are fully human mAbs, ixekinumab is a humanized mAb. Fully human antibodies are thought to have less immunogenicity, which could in turn imply less risk for loss of efficacy, although high-titer antibodies that affect ixekizumab efficacy are uncommon (occurring in only about 2% of treated patients).
Efficacy
Ixekizumab is highly effective in clinical trials, with higher response and clearance rates than other FDA-approved psoriasis treatment agents.
Phase 2 Trial and Open-Label Extension Study
A phase 2 double-blinded, multicenter, randomized, dose-ranging study was performed in 142 adults (18 years or greater) with moderate-to-severe plaque psoriasis for at least 6 months. Subjects were required to have a Psoriasis Area Severity Index (PASI) score of at least 12, Physician Global Assessment (PGA) score of at least 3, and a minimum of 10% body surface area (BSA) affected with psoriasis. Patients were randomized to receive subcutaneous injections of placebo or 10 mg, 25 mg, 75 mg, or 150 mg of ixekizumab at weeks 0, 2, 4, 8, 12, and 16. The primary outcome was the proportion of patients achieving 75% improvement in PASI score (PASI-75) at 12 weeks. Secondary assessments included achievement of PASI-90, PASI-100, PGA score, joint-pain visual analogue scale (VAS) to assess psoriatic arthritis joint pain, Nail Psoriasis Severity Index (NAPSI), the Psoriasis Scalp Severity Index (PSSI), an itch VAS, and Dermatology Life Quality Index (DLQI).
By week 12, PASI-75 and PASI-90 were achieved by more patients in the 25-mg, 75-mg, and 150-mg ixekizumab groups, and PASI-100 by more patients in the 75-mg and 150-mg groups ( P <.001 for each PASI level and group vs placebo). Statistically significant differences in outcome were seen as early as week 1 in the 75-mg and 100-mg groups, and with more patients achieving PASI-75 as early as week 2 in the 150-mg group as compared with placebo ( Table 13.1 ).
| Placebo | Ixekizumab 10 mg | Ixekizumab 25 mg | Ixekizumab 75 mg | Ixekizumab 100 mg | |
|---|---|---|---|---|---|
| PASI-75 (% of patients) | 8 | 29 | 77 | 83 | 82 |
| PASI-90 (% of patients) | 0 | 18 | 50 | 59 | 71 |
| PASI-100 (% of patients) | 0 | 0 | 17 | 38 | 39 |
| NAPSI % change (from baseline ± what?) | 6.8 ± 41.1 | 14.3 ± 97.8 | −24.0 ± 32.8 | −57.1 ± 36.7 | −49.3 ± 35.9 |
| PSSI % change (from baseline) | 6.8 ± 41.1 | −43.4 ± 62.8 | −87.1 ± 23.6 | −94.8 ± 14.5 | −84.8 ± 41.5 |
| Joint-pain VAS score change (from baseline) | 4.8 ± 48.2 | −5.9 ± 47.6 | −17.0 ± 28.1 | −18.6 ± 13.4 | −39.0 ± 27.5 |
| DLQI score change (at 8 wk) | −2.4 ± 4.4 | Not provided | −7.1 ± 6.5 | −8.5 ± 5.1 | −7.8 ± 5.7 |
By week 12, there was more improvement in PSSI score in the 25-mg, 75-mg, and 150-mg groups versus placebo. Greater reduction in NAPSI score occurred as early as week 2 versus placebo in the 75-mg group, and greater reduction in joint-pain VAS occurred by week 12 in the 150-mg group. DLQI score and itch severity improved with ixekizumab treatment as well (see Table 13.1 ).
A 52-week, open-label extension (OLE) study of this trial enrolled patients from the original trial who achieved less than PASI-75 improvement from baseline ( Table 13.2 ). Patients with PASI-75 or greater entered a treatment-free period (weeks 20–32) and were entered into the OLE after falling to less than PASI-75, or at week 32 if PASI-75 was maintained throughout the treatment-free period. The 120 patients who enrolled were scheduled to receive 120 mg of ixekizumab every 4 weeks; 103 patients completed this OLE study until the end. By week 52, 77% of patients achieved PASI-75, 68% PASI-90 response, and 48% PASI-100. Patients who responded to treatment in the original trial continued to maintain high levels of response at week 52 (PASI-75 maintained in 95% of original PASI-75 responders, PASI-90 maintained in 94% of original PASI-90 responders, and PASI-100 maintained in 82% of PASI-100 responders). Response rates were unaffected by dosing group from the original trial.
| Placebo (n = 27) | Ixekizumab 10 mg (n = 28) | Ixekizumab 25 mg (n = 30) | Ixekizumab 75 mg (n = 29) | Ixekizumab 150 mg (n = 28) | OLE Study (n = 120) | |
|---|---|---|---|---|---|---|
| Serious AEs | 0 | 0 | 0 | 0 | 0 | 8.3% (10) |
| Serious infection | — | — | — | — | — | 1.7% (2) |
| Cardiovascular | — | — | — | — | — | 2.5% (3) |
| Malignancy (rectal cancer) | — | — | — | — | — | 0.8% (1) |
| Hidradenitis suppurativa | — | — | — | — | — | 0.8% (1) |
| AEs | 63% (17) | 75% (21) | 70% (21) | 59% (17) | 46% (13) | 66.7% (80) |
| Nasopharyngitis | 19% (5) | 11% (3) | 10% (3) | 10% (3) | 14% (4) | 10% (12) |
| Upper respiratory infection (URI) | 4% (1) | 4% (1) | 10% (3) | 3% (1) | 4% (1) | 7.5% (9) |
| Sinusitis | — | — | — | — | — | 4.2% (5) |
| Diarrhea | — | — | — | — | — | 4.2% (5) |
| Basal cell carcinoma | — | — | — | — | — | 0.8% (1) |
| Allergy/hypersensitivity | 7% (2) | 4% (1) | 3% (1) | 7% (2) | 4% (1) | — |
| Injection-site reaction | 0 | 0 | 10% (3) | 3% (1) | 7% (2) | — |
| Headache | 4% (1) | 14% (4) | 13% (4) | 3% (1) | 4% (1) | — |
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