Efficacy and Safety of Ixekizumab in a Randomized, Double-blinded, Placebo-controlled Phase IIIb Study of Patients With Moderate-to-severe Genital Psoriasis

C. Ryan; A. Menter; L. Guenther; A. Blauvelt; R. Bissonnette; K. Meeuwis; J. Sullivan; J.C. Cather; G. Yosipovitch; A.B. Gottlieb; J.F. Merola; K. Callis Duffin; S. Fretzin; O.O. Osuntokun; R. Burge; A.N. Naegeli; F.E. Yang; C.-Y. Lin; K. Todd; A. Potts Bleakman; on behalf of the IXORA-Q Study Group

Disclosures

The British Journal of Dermatology. 2018;179(4):844-852. 

In This Article

Results

Patients

Patients (n = 149) were randomized from 5 May 2016 to 1 December 2016 to receive placebo (n = 74) or ixekizumab 80 mg every 2 weeks (n = 75) during the 12–week blinded treatment period. Overall, 99% (n = 74) of patients randomized to ixekizumab and 88% (n = 65) of those randomized to placebo completed the blinded treatment period (Figure S1; see Supporting Information).

Figure S1.

Genital psoriasis. Patient flow during the blinded treatment period of IXORA-Q.

The baseline demographics and disease characteristics were similar between the placebo and ixekizumab treatment groups (Table 1). Overall, 75·8% of patients were male (the ixekizumab treatment group included one transgender patient in the male population who identified as female but had male genitalia). The mean ± SD age was 43·7 ± 12·7 years (range 19–77), the mean weight was 93·5 ± 24·7 kg and 39·6% of patients had 1% to < 10% BSA involvement. Previous systemic therapies were used by 52·3% (nonbiologics) and 19·5% (biologics) of patients. The inclusion criteria required all patients to have previously used topical therapies; 35·6% had previously used at least two topical therapies and 83·9% of patients had discontinued previous topical therapy for GenPs because of either inadequate response or loss of response.

Efficacy

The primary and all major secondary end points were met. At week 12, significantly more patients achieved clear or almost clear genital skin (sPGA-G 0/1) with ixekizumab (73%) vs. placebo (8%, P < 0·001). Completely clear genital skin (sPGA-G 0) was achieved in significantly more patients receiving ixekizumab (56%) than placebo (5%, P < 0·001) (Figure 1a). Significant improvement was observed within 1 week of treatment with ixekizumab for both sPGA-G 0/1 (ixekizumab 24%, placebo 1%; P = 0·003) and sPGA-G 0 (ixekizumab 8%, placebo 0%, P = 0·028). At week 12, response rates for sPGA-G 0/1 were consistent across lower (1 to < 10%) and higher (≥ 10%) BSA subgroups with ixekizumab (BSA 1 to < 10%, 71%; BSA ≥ 10%, 75%), and were significantly greater than with placebo (both P < 0·001) (Figure 1b). Similarly, week 12 sPGA-G 0/1 response rates were consistent between male and female patients, and response was significantly greater (P < 0·001) with ixekizumab (male 71%, female 79%) than with placebo (male 9%, female 6%). The LSM ± SE change from baseline in the mGPASI was significantly greater with ixekizumab at week 12 (ixekizumab −23·9 ± 1·48, placebo −3·9 ± 1·56; P < 0·001) (Figure 1c). Figure 1 illustrates the clearance of GenPs for a patient randomized to ixekizumab.

Figure 1.

Effect of ixekizumab (IXE) on the severity of genital psoriasis. (a) The percentage of patients achieving static Physician's Global Assessment of Genitalia (sPGA-G) score of 0 or 1 (circles) or 0 (squares). (b) The percentages of patients achieving sPGA-G 0/1 in lower (1 to < 10%) and higher (≥ 10%) body surface area (BSA) subgroups. (c) The mean change from baseline in modified Genital Psoriasis Area and Severity Index (mGPASI) at week 12. The mixed-effects model for repeated measures includes treatment, baseline BSA category, baseline value, visit, treatment-by-visit interaction and baseline value-by-visit interactions as fixed factors, with variance-covariance structure set to unstructured. IXE vs. placebo (PBO): *P < 0·05, **P < 0·01; ***P < 0·001. A multiple testing strategy was used for statistical analysis of the primary end point and major secondary end points; P–values for other time points and outcome measures were not adjusted for multiple comparisons. Error bars indicate 95% confidence intervals (a, b) or standard error (c).

Figure 2.

Clearance of genital psoriasis in a patient treated with ixekizumab through week 12. Representative photographs at week 0 (baseline), week 2 and week 12 of the genital area of a 53–year-old male patient receiving ixekizumab. Q2W, every 2 weeks; sPGA-G, static Physician's Global Assessment of Genitalia.

Figure 3.

Effect of ixekizumab (IXE) on overall plaque psoriasis, genital itch and the impact of genital psoriasis on sexual frequency. (a) The percentage of patients achieving overall static Physician's Global Assessment (sPGA) scores of 0 or 1 (circles) or 0 (squares). (b) The percentage of patients achieving ≥ 3–point improvement from baseline in genital itch numerical rating scale (NRS) (of patients with a baseline score ≥ 3). (c) The percentage of patients achieving Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) item 2 score of 0 or 1 (of patients with a baseline score ≥ 2). IXE vs. placebo (PBO): *P < 0·05, **P < 0·01; ***P < 0·001. A multiple testing strategy was used for statistical analysis of the primary end point and major secondary end points; P–values for other time points and measures were not adjusted for multiple comparisons. Error bars indicate 95% confidence intervals.

Ixekizumab resulted in significantly greater improvement in overall plaque psoriasis at week 12 vs. placebo for both overall sPGA 0/1 (ixekizumab 73%, placebo 3%; P < 0·001) and overall sPGA 0 (ixekizumab 40%, placebo 0%; P < 0·001) (Figure 1a). Statistically significant improvements were observed with ixekizumab as early as weeks 1 and 4 for overall sPGA 0/1 (ixekizumab 17%, placebo 0%; P < 0·001) and overall sPGA 0 (ixekizumab 16%, placebo 0%; P < 0·001).

Significantly more patients achieved a clinically meaningful (≥ 3–point) improvement (reduction) from baseline in the genital itch NRS with ixekizumab (60%) vs. placebo (8%, P < 0·001) at week 12 among patients with a baseline score ≥ 3 (ixekizumab, n = 62; placebo, n = 60) (Figure 1b). Statistically significant differences in genital itch were observed as early as week 2 (ixekizumab 34%, placebo 5%; P < 0·001). Definitions of response in the itch NRS are provided in Appendix S1 and Table S3, Table S4 and Table S5 (see Supporting Information).

Among patients with a GenPs-SFQ item 2 score of ≥ 2 at baseline (ixekizumab, n = 37; placebo, n = 42), significantly more patients treated with ixekizumab achieved GenPs-SFQ item 2 score 0/1 (indicating GenPs never or rarely limited sexual activity) at week 12 (ixekizumab 78%, placebo 21%; P < 0·001) (Figure 1c). Significant improvement with ixekizumab was observed as early as week 1 (ixekizumab 22%, placebo 5%; P = 0·036).

At week 12, HRQoL significantly improved with ixekizumab as determined by LSM change from baseline in DLQI (ixekizumab −9·7 ± 0·59, placebo −1·4 ± 0·62; P < 0·001) and DLQI 0/1 response rate (ixekizumab 45%, placebo 3%; P < 0·001) (Table 2). A score of 0 or 1 on the DLQI indicates no effect on HRQoL.

Safety

Safety outcomes during the blinded treatment period are summarized in Table 3. TEAEs were more frequent with ixekizumab than with placebo, but were not significantly different between treatment groups (P = 0·19). Most TEAEs were mild or moderate in severity, with three (4%) severe TEAEs in the placebo group vs. one (1%) with ixekizumab. The most common TEAEs (those occurring at a frequency of ≥ 2% in the ixekizumab group and with greater frequency in patients receiving ixekizumab than placebo) were upper respiratory tract infection, injection-site reactions, oropharyngeal pain, pruritus, back pain, eczema and hypertension. Five (7%) patients receiving placebo and one (1%) receiving ixekizumab discontinued due to an AE. One serious AE (acute pancreatitis) occurred in a patient receiving placebo and resolved without discontinuation, and there were no deaths.

Injection-site reactions were mild or moderate in severity and occurred more frequently in the ixekizumab treatment group (11%) than in the placebo group (3%). None of the injection-site reactions resulted in study discontinuation.

Treatment-emergent (TE) infections were more frequent with ixekizumab (24%) than with placebo (18%). Allergic or hypersensitivity reactions occurred at similar rates in the placebo (4%) and ixekizumab (5%) treatment groups. No cases of candidiasis or anaphylaxis were reported, there were no infection-related discontinuations and one patient discontinued due to allergic or hypersensitivity reactions. All TE infections and allergic or hypersensitivity reactions were mild or moderate in severity, except for one patient receiving ixekizumab who experienced two separate severe events during the blinded treatment period, reported by the investigator as a TE infection (infected eczema on the right thigh and right antecubital fossa) and an allergic or hypersensitivity reaction (exacerbation of eczema, resulting in study discontinuation). The sites of eczema were distant from the injection sites (abdomen) and this patient did not experience any injection-site reactions.

TE depression was reported in two patients (3%) in the placebo group, with no resultant discontinuation from the study. At baseline, 11 patients reported a prior history of suicidal ideation or behaviour (ixekizumab, three patients; placebo, eight patients), none of whom reported suicidal ideation or behaviour at any point during the blinded treatment period. Two patients (both receiving placebo) with no history of suicidal ideation or behaviour reported experiencing suicidal ideation or behaviour during the blinded treatment period.

Two patients (3%) in the placebo group developed hepatic-related TEAEs, one of whom discontinued due to an increased liver function test. There were no TE cytopenias, cerebrocardiovascular events, inflammatory bowel disease or malignancies reported during the blinded treatment period.

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