Long-Term Safety and Efficacy of Ixekizumab in Patients With Axial Spondyloarthritis: 3-year Data From the COAST Program

RESULTS

Patients. A total of 932 patients received at least 1 dose of IXE between week 0 of the originating study and week 156. Of these, 773/932 (82.9%) patients entered COAST-Y after completing the originating studies, and 631/932 (67.7%) patients completed 3 years of the COAST program. In total, 414 patients received at least 1 dose of IXE Q4W and 288 (67.9%) of these patients completed 3 years of the COAST program (PBO→IXE Q4W, 88/119 [71.4%]; ADA→IXE Q4W, 36/44 [81.8%]; and IXE Q4W→IXE Q4W, 164/251 [63.7%]; Figure 1). Baseline demographics and disease characteristics for patients have been previously reported.^4-6 In COAST-X, 40 patients had their dose escalated from IXE Q4W to IXE Q2W, whereas in COAST-Y, 86 patients had their dose escalated from IXE Q4W to IXE Q2W. Therefore, in the safety analyses, these 126 patients were counted in both the IXE Q4W and IXE Q2W groups but were only counted once in the total safety population.

Safety outcomes. TEAEs through 156 weeks (52 weeks of the originating studies plus 104 weeks of COAST-Y) of treatment were analyzed for the 932 patients with axSpA who received at least 1 dose of IXE, with 454 patients who received IXE Q4W and 604 patients who received IXE Q2W, representing a total of 2097.7 patient-years (PYs; 878.2 PYs for IXE Q4W and 1219.5 PYs for IXE Q2W). Safety outcomes for patients who received either IXE Q4W or IXE Q2W were analyzed separately. Overall, the safety profile of IXE through 3 years was consistent with what has been previously reported.^8,9 The incidence rates (IRs) for TEAEs for IXE Q4W and IXE Q2W were 43.3 and 37.9 per 100 PYs, respectively (Table 1). AEs leading to discontinuation were reported at a rate of 3.0 per 100 PYs for IXE Q4W and 3.3 per 100 PYs for IXE Q2W. The majority of TEAEs were mild or moderate in severity (Table 1). A total of 3 deaths occurred, 2 while patients were receiving IXE Q4W and 1 while the patient was receiving IXE Q2W (Table 1). One patient died by homicide, 1 patient died by suicide, and the third patient developed sepsis (probable pneumonia with multiorgan failure). These data have been reported and no additional events of death occurred since the previous study report.⁸ The IRs for SAEs for IXE Q4W and IXE Q2W were 5.0 and 4.7 per 100 PYs, respectively, and 4.8 per 100 PYs in total.

AEs of special interest. Of the AEs of interest, injection site reactions were most frequent (IXE Q4W, IR 6.0 per 100 PYs; IXE Q2W, IR 8.8 per 100 PYs), the majority of which were mild or moderate in severity (Table 2). Of the patients who reported injection site reaction, 6 discontinued treatment, all of whom were receiving IXE Q2W (IR 0.5 per 100 PYs). There were 17 cases of IBD in total (IR 1.3 per 100 PYs for IXE Q4W and 0.5 per 100 PYs for IXE Q2W, confirmed by adjudication). Of these, there were 7 cases of Crohn disease (IR 0.3 per 100 PYs), 6 of which were new onset, and 10 cases of ulcerative colitis (IR 0.5 per 100 PYs), 6 of which were new onset. There were 58 patients with anterior uveitis (IR 2.8 per 100 PYs), the majority of which were mild (IR 1.2 per 100 PYs) or moderate (IR 1.5 per 100 PYs). Of the 173 patients who had a previous history of anterior uveitis, 41 patients had an episode of flare (IR 10.7 per 100 PYs), whereas, of the 755 patients with no anterior uveitis, 17 patients were new onset (1.0 per 100 PYs). IRs for MACE (confirmed by adjudication) and malignancies were both ≤ 0.5 per 100 PYs (Table 2). There were no latent cases that presented any sign of active tuberculosis.

Of the reported cases of candidiasis, the majority were mild (12/19) to moderate (7/19) in severity. There was a total of 5 cases of oral candidiasis, 3 of which were mild (IR 0.1 per 100 PYs) and 2 of which were moderate (0.1 per 100 PYs) in severity. Of the 4 cases of esophageal candidiasis reported, 2 were mild (0.1 per 100 PYs) and 2 were moderate (0.1 per 100 PYs) in severity. The 2 cases of skin candida reported were mild in severity (IR 0.1 per 100 PYs), and there was 1 mild case of genital candidiasis (IR 0.0 per 100 PYs). There were 7 reported cases of vulvovaginal candidiasis; 4 were mild (IR 0.2 per 100 PYs) and 3 were moderate in severity (IR 0.1 per 100 PYs). There were 12 cases of herpes zoster, all of which were either mild or moderate. There were no recorded cases of systemic candidiasis.

Efficacy outcomes. ASDAS statuses at week 156 among patients who received ≥ 1 dose of IXE Q4W are shown by treatment arm and by originating study in Figure 2. Of the patients from COAST-V who received IXE Q4W→IXE Q4W, a total of 75% (33/44) achieved either ASDAS ID or ASDAS LDA at week 156 (Figure 2A). Thirty-nine percent (16/41) of patients from COAST-W who received IXE Q4W→IXE Q4W achieved either ASDAS ID or ASDAS LDA at week 156 (Figure 2B), whereas a total of 66% (19/29) of patients from COAST-X who received IXE Q4W→IXE Q4W achieved either ASDAS ID or ASDAS LDA at week 156 (Figure 2C).

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Figure 2.

ASDAS status (as observed) at week 156 among patients from (A) COAST-V, (B) COAST-W, and (C) COAST-X, who received ≥ 1 dose of IXE Q4W. Data are presented as the number and proportion (n [%]) of patients in each category, and the number (n) of patients with ASDAS data available at week 156. ADA: adalimumab; ASDAS: Ankylosing Spondylitis Disease Activity Score; IXE: ixekizumab; PBO: placebo; Q4W: every 4 weeks.

Over half of patients from COAST-V, COAST-W, and COAST-X achieved ASDAS CII by week 52 and sustained that response through week 156 (Figure 3; Supplementary Table S1, available with the online version of this article). In COAST-V, the observed proportions of patients who achieved ASDAS CII who received PBO→IXE Q4W, ADA→IXE Q4W, and IXE Q4W→IXE Q4W were 83%, 62%, and 80%, respectively, at week 156 (Figure 3A, Supplementary Table S1 for IXE Q4W→IXE Q4W only). In patients from COAST-W, the observed proportions who achieved ASDAS CII who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 80% and 73%, respectively, at week 156 (Figure 3C, Supplementary Table S1 for IXE Q4W→IXE Q4W only). In COAST-X, the observed proportions of patients who achieved ASDAS CII who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 74% and 69%, respectively, at week 156 (Figure 3E, Supplementary Table S1 for IXE Q4W→IXE Q4W only).

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Figure 3.

The proportion (%, as observed and NRI) of patients achieving ASDAS CII and ASDAS < 2.1 through 156 weeks in patients who received ≥ 1 dose of IXE Q4W from COAST-V (A and B), COAST-W (C and D), and COAST-X (E and F). Data are presented as observed (solid line) and NRI (dotted line). Observed data while on IXE Q2W escalated dose are excluded. At week 16, patients receiving either PBO (gray) or ADA (purple) were switched to IXE Q4W (orange). ADA→IXE Q4W are patients who were on washout period from weeks 14 to 20 and started the first injection of IXE Q4W at week 20. ADA: adalimumab; ASDAS: Ankylosing Spondylitis Disease Activity Score; CII: clinically important improvement; IXE: ixekizumab; NRI: nonresponder imputation; PBO: placebo; Q2W: every 2 weeks; Q4W: every 4 weeks.

The majority of patients from COAST-V and COAST-W achieved ASDAS < 2.1 by week 52, responses which were sustained through week 156 (Figure 3; Supplementary Table S1, available with the online version of this article). In COAST-V, the observed proportions of patients who achieved ASDAS < 2.1 who received PBO→IXE Q4W, ADA→IXE Q4W, and IXE Q4W→IXE Q4W were 54%, 72%, and 75%, respectively, at week 156 (Figure 3B, Supplementary Table S1 for IXE Q4W→IXE Q4W only). In COAST-W, the observed proportions of patients who achieved ASDAS < 2.1 who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 35% and 39%, respectively, at week 156 (Figure 3D, Supplementary Table S1 for IXE Q4W→IXE Q4W only). In COAST-X, the observed proportions of patients who achieved ASDAS < 2.1 who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 68% and 66%, respectively, at week 156 (Figure 3F, Supplementary Table S1 for IXE Q4W→IXE Q4W only). Of the 86 patients who had their dose escalated from IXE Q4W to open-label IXE Q2W during COAST-Y, at the last visit prior to escalation, the observed proportions of patients who achieved ASDAS < 2.1 who received PBO→IXE Q4W (RWRP) or IXE Q4W→IXE Q4W were 75% (3/4) and 24% (20/82), respectively. The proportion of patients who achieved ASDAS < 2.1 at least once after dose escalation was 100% (4/4) for patients who received PBO→IXE Q4W (RWRP) and were escalated to open-label IXE Q2W, and 39% (32/82) for patients who received IXE Q4W→IXE Q4W and were escalated to open-label IXE Q2W.

Among the patients with r-axSpA from COAST-V who were bDMARD-naïve, observed ASAS40 responses for patients who received PBO→IXE Q4W, ADA→IXE Q4W, and IXE Q4W→IXE Q4W were 54%, 62%, and 68%, respectively, at week 156 (Figure 4A; Supplementary Table S1 for IXE Q4W→IXE Q4W only, available with the online version of this article). Among the patients with r-axSpA from COAST-W who were TNFi-experienced, observed ASAS40 response rates for patients who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 50% and 56%, respectively, at week 156 (Figure 4B, Supplementary Table S1 for IXE Q4W→IXE Q4W only). Observed ASAS40 response rates for patients with nr-axSpA from COAST-X who were bDMARD-naïve and who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 79% and 59%, respectively, at week 156 (Figure 4C, Supplementary Table S1 for IXE Q4W→IXE Q4W only). A total of 86 patients had their dose escalated from IXE Q4W to open-label IXE Q2W during COAST-Y. At the last visit prior to dose escalation, the observed proportions of patients who achieved ASAS40 who received PBO→IXE Q4W (RWRP) and IXE Q4W→IXE Q4W were 50% (2/4) and 41.5% (34/82), respectively. The proportion of patients who achieved ASAS40 at least once after dose escalation was 75% (3/4) for patients who received PBO→IXE Q4W (RWRP) and were escalated to open-label IXE Q2W, and 58.5% (48/82) for patients who received IXE Q4W→IXE Q4W and were escalated to open-label IXE Q2W.

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Figure 4.

The proportion (NRI and as observed) of patients who achieved ASAS40 through 156 weeks in patients who received ≥ 1 dose of IXE Q4W from (A) COAST-V, (B) COAST-W, and (C) COAST-X. Data are presented as observed (solid line) and NRI (dotted line). Observed data while on IXE Q2W escalated dose are excluded. At week 16, patients receiving either PBO (gray) or ADA (purple) were switched to IXE Q4W (orange). ADA→IXE Q4W are patients who were on washout period from weeks 14 to 20 and started the first injection of IXE Q4W at week 20. ADA: adalimumab; ASAS40: 40% improvement in the Assessment of Spondyloarthritis international Society criteria; IXE: ixekizumab; NRI: nonresponder imputation; PBO: placebo; Q2W: every 2 weeks; Q4W: every 4 weeks.

Among the patients from COAST-V who were bDMARD-naïve with r-axSpA, observed BASDAI50 response rates for patients who received PBO→IXE Q4W, ADA→IXE Q4W, and IXE Q4W→IXE Q4W were 62.5%, 62.1%, and 70.5%, respectively, at week 156 (Supplementary Table S1 for IXE Q4W→IXE Q4W only, Supplementary Figure S1A, available with the online version of this article). Among the patients from COAST-W who were TNFi-experienced, observed BASDAI50 response rates for patients who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 45% and 48.8%, respectively, at week 156 (Supplementary Table S1 for IXE Q4W→IXE Q4W only, Supplementary Figure S1C). In COAST-X, the observed BASDAI50 response rates for patients who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 63.2% and 55.2%, respectively, at week 156 (Supplementary Table S1 for IXE Q4W→IXE Q4W only, Supplementary Figure S1E).

Baseline BASDAI scores for patients from COAST-V who received PBO→IXE Q4W, ADA→IXE Q4W, and IXE Q4W→IXE Q4W were 6.9, 6.4, and 6.8, respectively. The mean (observed) change from baseline for patients who received PBO→IXE Q4W, ADA→IXE Q4W, and IXE Q4W→IXE Q4W were −3.9, −3.5, and −4.0, respectively, at week 156 (Supplementary Table S1 for IXE Q4W→IXE Q4W only, Supplementary Figure S1B, available with the online version of this article). Baseline BASDAI scores for patients from COAST-W who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 7.5 and 7.5, respectively. Mean (observed) change from baseline for patients who received PBO→IXE Q4W and IXE Q4W→IXE Q4W was −3.7 and −3.4, respectively, at week 156 (Supplementary Table S1 for IXE Q4W→IXE Q4W only, Supplementary Figure S1D). Baseline BASDAI scores for patients from COAST-X who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 7.0 and 7.0, respectively. Mean (observed) change from baseline for patients who received PBO→IXE Q4W and IXE Q4W→IXE Q4W was −4.4 and −3.4, respectively, at week 156 (Supplementary Table S1 for IXE Q4W→IXE Q4W only, Supplementary Figure S1F).

Efficacy outcomes analyzed using NRI are reported in Supplementary Tables S2, S3, and S4 (available with the online version of this article) for patients who were assigned to either IXE Q2W or IXE Q4W at entry; data are presented by the originating study.

Patient-reported outcomes assessed through week 156 include SF-36 PCS (SF-36 MCS data are shown in Supplementary Table S1, available with the online version of this article), BASFI, and the ASAS HI (Supplementary Table S1, Supplementary Figures S2 and S3). Baseline SF-36 PCS scores and improvements from baseline are shown in Supplementary Figure S2. In COAST-V, the mean (observed) changes from baseline in SF-36 PCS among patients who received PBO→IXE Q4W, ADA→IXE Q4W, and IXE Q4W→IXE Q4W were 11.0, 8.3, and 9.4, respectively, at week 156 (Supplementary Table S1 for IXE Q4W→IXE Q4W only, Supplementary Figure S2A). In COAST-W, the mean (observed) changes from baseline in SF-36 PCS among patients who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 7.2 and 9.7, respectively, at week 156 (Supplementary Table S1 for IXE Q4W→IXE Q4W only, Supplementary Figure S2C). In COAST-X, the mean (observed) changes from baseline in SF-36 PCS among patients who received PBO→IXE Q4W and IXE Q4W→IXE Q4W were 12.5 and 10.0, respectively, at week 156, respectively (Supplementary Table S1 for IXE Q4W→IXE Q4W only, Supplementary Figure S2E). Similar patterns of improvement were noted for the BASFI and ASAS HI, with the majority of patients achieving improvements from baseline at week 52, which were sustained through week 156 (Supplementary Table S1 for IXE Q4W→IXE Q4W only, Supplementary Figures S2 and S3).