Ixekizumab

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 ).

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.

UNCOVER-2 and UNCOVER-3 Phase 3 Trials

UNCOVER-2 and UNCOVER-3 were both 12-week, prospective, double-blinded, multicenter phase 3 trials in patients age 18 years or greater, designed to assess whether ixekizumab every 2 weeks or every 4 weeks was superior to placebo and noninferior or superior to etanercept. Trial patients were required to have a diagnosis of moderate-to-severe plaque psoriasis (defined as >10% BSA, PGA score of 3 or greater, PASI score of 12 or more) for at least 6 months. A total of 1224 patients in UNCOVER-2 and 1346 patients in UNCOVER-3 were randomized in a 2:2:2:1 ratio to receive 1 of 2 dosing schedules of ixekizumab, etanercept, or placebo. These dosing schedules consisted of a 160-mg loading dose of ixekizumab followed by 80 mg every 2 weeks or every 4 weeks, etanercept 50 mg twice weekly, or placebo injections. Primary endpoints of this study were achievement of PASI-75 or greater and static physician global assessment (sPGA) scores of clear or minimal with at least a 2-point reduction from baseline at the start of the 12 weeks. Secondary assessments included sPGA, PASI-90, PASI-100, itch numeric rating scale (NRS), and DLQI.

Both dosing regimens of ixekizumab had greater efficacy than placebo and etanercept at week 12 ( P <.0001). In addition, greater numbers of ixekizumab-treated patients achieved PASI-75 as early as week 1 as compared with etanercept (UNCOVER-2: P <.0001 for 4-week group, P = .22 for 2-week group; UNCOVER-3: P = .35 for 4-week group, P = .0003 for 2-week group). In UNCOVER-2 and UNCOVER-3, complete clearing occurred in 41% and 38% of patients given ixekizumab every 2 weeks, 31% and 35% given ixekizumab every 4 weeks, 0.6% and 0% of patients given placebo, and 5% and 28% of patients given etanercept, respectively. Greater DLQI improvement in patients receiving ixekizumab was observed as soon as week 2 and in greater proportions thereafter compared with placebo and etanercept ( P <.0001). Greater improvement in itch NRS scores occurred with ixekizumab versus placebo and etanercept ( P <.0001 for each ixekizumab dose vs placebo or etanercept) ( Fig. 13.2 , Table 13.3 ).

Overall, these studies demonstrated that ixekizumab has greater efficacy in the treatment of moderate-to-severe psoriasis than placebo and etanercept. PASI-75 was achieved by 90% of patients by week 12 in patients receiving ixekizumab every 2 weeks, with rapid onset of efficacy.

Efficacy in Other Forms of Psoriasis

A Japanese open-label study of ixekizumab investigated efficacy in erythrodermic psoriasis (EP) and generalized pustular psoriasis (GPP) in addition to moderate-to-severe plaque psoriasis. A total of 78 plaque psoriasis, 8 EP, and 5 GPP patients received standard loading and maintenance doses of ixekizumab. By week 12, PASI-75 and PASI-90 were achieved by 98.7% (77/88) and 83.3% (65/78) of plaque psoriasis patients, 100% (8/8) and 62.5% (5/8) of EP patients, and 80% (4/5) and 60% (3/5) of GPP patients, respectively. Overall, these results emphasize the potential of ixekizumab to treat less common forms of psoriasis.