Pharmacokinetics, Exposure-Response Relationships, and Immunogenicity in Crohn's Disease Patients With Ustekinumab Secondary Loss of Response Following Ustekinumab IV Re-Induction: Week 16 Results From the POWER Study

Introduction: The POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction ustekinumab (UST) dose vs continued UST subcutaneous (SC) treatment in Crohn’s disease (CD) patients (pts) with secondary loss of response (LoR) to standard UST maintenance therapy. Here, we present Week (W) 16 pharmacokinetics, exposure–response relationships, and immunogenicity analysis. Methods: Adult pts with moderately–severely active CD who initially responded to UST IV induction therapy per label and later experienced LoR were included. LoR was defined as CD Activity Index (CDAI) score ≥220–≤450, plus elevated C-reactive protein ( >3mg/L)/fecal calprotectin ( >250mg/kg), or endoscopy performed ≤3 months before baseline (W0) with active CD. At W0, randomized pts received ∼6mg/kg IV UST, or SC UST 90mg, followed by SC UST 90mg dosing at W8/16. Clinical assessments occurred at W0/8/16. Serum samples evaluated UST concentration (conc) and anti-drug antibodies (ADAs) at W0/8/16 using validated assays. Clinical response (CRes) and endoscopic remission (ERem) were evaluated based on CDAI and centrally read endoscopy, respectively, at W0/8/16. Efficacy outcomes were analyzed by W0 trough conc groups (undetectable, 0.17–< 0.8, 0.8–< 1.3, and ≥1.3µg/mL) and conc quartile groups (QGs) at W16 using a proprietary immunoassay. Results: Serum UST conc data were obtained from 215 pts (SC, n=107; IV, n=108) with ≥1 blood sample collected. Similar at W0, median serum UST concs at W0 (1-hour post-dose)/8/16 were higher in the IV vs SC arm (Table 1). Based on W16 trough concs, 63.9% (69/108) of pts were in the ≥1.3µg/mL group in the IV arm, vs 41.1% (44/107) in the SC arm. The proportion of pts with W16 CRes in the ≥1.3µg/mL group was similar between arms; more pts were in W16 ERem in the IV vs SC arm. By W16 quartile analysis, CRes was numerically higher in the IV vs SC arm in QG1 and 4. More IV arm pts achieved ERem in QG4 vs QG1; a small number of pts in SC arm achieved ERem independent of QGs. Incidence of UST ADAs through W16 was low (SC, n=2; IV, n=0; 0.93% overall). Conclusion: Although, IV re-induction resulted in higher serum concs and proportions of pts with high (≥1.3µg/mL) trough conc at W16; there did not appear to be an exposure-response relationship for CRes. However, quartile analysis showed a relationship between increased exposure in the IV arm and differences in ERem. This observation is consistent with the notion that pts with secondary LoR may benefit from single-dose re-induction. Table 1. - Summary of serum UST concentrations and the proportion of patients in clinical response and endoscopic remission at W16 by UST trough concentrations and trough concentration quartile groups at W16 (full analysis set) Serum concentrations µg/mL (median, IQR) SC arm (N=107) IV arm (N=108) W0 pre-dose 1.26 (0.58; 2.53) 1.30 (0.62; 2.79) W0 post-dose* 1.47 (0.70; 2.62) 105.62 (82.94; 128.13) W8 1.38 (0.85; 2.61) 8.45 (4.25; 10.49) W16 1.41 (0.81; 2.17) 2.99 (1.20; 4.78) W16 outcomes by UST trough concentrations at W16 (µg/mL), n/N (%) Undetectable 0.17–< 0.8 0.8–< 1.3 ≥1.3 Undetectable 0.17–< 0.8 0.8–< 1.3 ≥1.3 Clinical response†‡ at W16 0/1 5/18 (27.8) 8/16 (50.0) 24/44 (54.5) 0/2 8/15 (53.3) 3/7 (42.9) 39/69 (56.5) Endoscopic remission‡§|| at W16 0/1 0/9 1/7 (14.3) /24 (8.3) 0/1 1/6 (16.7) 0/4 10/42 (23.8) W16 outcomes by UST trough concentration quartile groups¶ at W16, n/N (%) QG1 (≤q1) QG2 ( >q1 and ≤q2) QG3 ( >q2 and ≤q3) QG4 ( >q3) QG1 (≤q1) QG2 ( >q1 and ≤q2) QG3 ( >q2 and ≤q3) QG4 ( >q3) Clinical response†‡ by QG 5/20 (25.0) 11/20 (55.0) 12/20 (60.0) 9/19 (47.4) 11/24 (45.8) 11/23 (47.8) 13/23 (56.5) 15/23 (65.2) Endoscopic remission‡§|| by QG 0/10 1/11 (9.1) 0/9 2/11 (18.2) 1/11 (9.1) 2/10 (20.0) 3/14 (21.4) 5/18 (27.8 *The post-dose sample was collected within 24 hours of UST administration.†Clinical response is defined by CDAI <150 or decrease of ≥100 points from W0.‡Patients who had insufficient data to calculate CDAI or SES-CD, a prohibited CD-related surgery, prohibited concomitant medication changes, or discontinued study agent due to lack of efficacy or due to an adverse event indicated to be of worsening CD prior to the designated analysis timepoint are considered not to be in clinical response or endoscopic remission.§Endoscopic remission is defined as an SES-CD score ≤3 or SES-CD=0 for patients who enter the study with an SES-CD=3.||Endoscopy was an optional procedure in the study; only 58 (SC arm) and 59 (IV arm) patients were included in the endoscopic analysis.¶Quartiles are based on patients in each treatment group: SC arm, q1=0.81 µg/mL, q2=1.41 µg/mL, q3=2.17 µg/mL; IV arm, q1=1.20 µg/mL, q2=2.99 µg/mL, q3=4.78 µg/mL. CD, Crohn’s Disease; CDAI, Crohn’s Disease Activity Index; IQR, interquartile range; IV, intravenous; q, quartile; QG, quartile group; SC, subcutaneous; SES-CD; Simple Endoscopic Score in Crohn’s Disease; UST, ustekinumab; W, week.