Clinical Outcomes and Biomarker Normalization Response at Week 16 in Patients With Inadequate Response or Intolerance to Prior Biologics in the POWER Trial

Introduction: The POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction ustekinumab (UST) dose vs placebo on a background of continued UST subcutaneous (SC) treatment in Crohn’s disease (CD) patients (pts) with secondary loss of response (LoR) to standard q8w UST maintenance therapy. This subgroup analysis reports primary and major secondary endpoints up to week (W)16 in pts with/without a history of inadequate response or intolerance to prior biologics. Methods: Adults 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 of ≥220 and ≤450, plus either elevated C-reactive protein (CRP; >3mg/L), fecal calprotectin (fCal; >250mg/kg), or endoscopy performed ≤3 months before W0 with evidence of active CD. At W0 randomized pts received ∼6mg/kg IV UST/SC placebo (IV arm) or IV placebo/SC UST 90mg (SC arm) followed by 90mg SC UST at W8/16. Clinical/biomarker assessments occurred at W0/8/16. Primary endpoint: W16 clinical response (CRes; decrease of ≥100 points from W0 or CDAI < 150). Secondary endpoints: CRes; clinical remission (CRem); normalization of CRP and/or fCal at W8/16. Results: The full analysis set comprised 215 pts at W0 (SC, n=107; IV, n=108). At W16, 86.0% (SC) and 92.6% (IV) of pts completed treatment. Most pts (SC, 92.5%; IV, 88.9%) had a history of inadequate response/intolerance to prior biologics. At W16, while CRes did not statistically differentiate between arms, secondary outcomes indicated a difference in the IV vs SC arm. In this analysis, differences were seen in bionaïve pts and those with inadequate response/intolerance to < 3 biologics. A numerically greater proportion of pts achieved CRes in the IV vs SC arms in all groups except pts with ≥3 prior biologics, with a nominal difference in pts with 1 prior biologic (P=0.043; Table 1). A similar trend was observed for pts achieving W16 CRem, albeit the nominal threshold was not reached. A numerically greater proportion of pts in the IV vs SC arm achieved normalization of CRP and/or fCal at W16, except those with ≥3 prior biologics, and with a nominal difference in pts with 1 prior biologic (P< 0.001). Conclusion: POWER is the first trial to assess the efficacy and safety of UST IV re-induction in pts with secondary LoR. This analysis suggests that both naïve pts and those with prior inadequate response or intolerance to biologics may benefit from UST re-induction therapy. Table 1. - Primary and major secondary endpoints at W8 and W16 for patients with or without a history of inadequate response or intolerance to prior biologic(s) (Full analysis set) Overall population No history of prior biologic* inadequate response or intolerance History of inadequate response or intolerance to 1 prior biologic* History of inadequate response or intolerance to 2 prior biologics* History of inadequate response or intolerance to ≥3 prior biologics* UST SC n=107 UST IVn=108 UST SCn=8 UST IVn=12 UST SCn=37 UST IVn=33 UST SCn=35 UST IVn=35 UST SCn=27 UST IVn=28 Clinical response†‡ at W16 (primary endpoint) 40 (37.4) 53 (49.1)Δ 11.5 (-1.5; 24.5) P=0.089 1 (12.5) 5 (41.7)Δ 29.2 P=0.325 15 (40.5) 21 (63.6)Δ 24.4 (2.0; 46.8) P=0.043 13 (37.1) 18 (51.4)Δ 16.2 (-6.2; 38.7) P=0.177 11 (40.7) 9 (32.1)Δ -8.4 (-33.2; 16.3) P=0.535 Clinical remission‡§ at W16 29 (27.1) 36 (33.3)Δ 5.9 (-6.0; 17.8) P=0.338 0 4 (33.3)Δ 33.3 P=0.117 12 (32.4) 15 (45.5)Δ 11.8 (-9.9; 33.4) P=0.313 8 (22.9) 12 (34.3)Δ 10.6 (-10.7; 31.9) P=0.334 9 (33.3) 5 (17.9)Δ -11.0 (-33.3; 11.2) P=0.359 Patients with normalized CRP and/or fCall‡ ||¶** at W16 14/94 (14.9) 31/93 (33.3)Δ 18.5 (6.8; 30.2) P=0.004 1/8 (12.5) 2/8 (25.0)Δ 12.5 P=1.00 2/31 (6.5) 12/28 (42.9)Δ 37.6 (17.9; 57.4) P< 0.001 6/30 (20.0) 12/32 (37.5)Δ 17.8 (-3.1; 38.7) P=0.131 5/25 (20.0) 5/25 (20.0)Δ 3.8 (-18.8; 26.4) P=0.743 Clinical response†‡ at W8 48 (44.9) 56 (51.9)Δ 7.1 (-6.0; 20.2) P=0.300 3 (37.5) 4 (33.3)Δ -4.2 P=1.00 21 (56.8) 20 (60.6)Δ 4.7 (-18.4; 27.7) P=0.696 12 (34.3) 19 (54.3)Δ 22.0 (-0.2; 44.3) P=0.067 12 (44.4) 13 (46.4)Δ -2.7 (-29.1; 23.6) P=0.844 Clinical remission‡§ at W8 31 (29.0) 38 (35.2)Δ 6.4 (-5.8; 18.6) P=0.314 3 (37.5) 4 (33.3)Δ -4.2 P=1.00 15 (40.5) 14 (42.4)Δ -0.2 (-22.3; 21.8) P=0.985 6 (17.1) 14 (40.0)Δ 21.5 (1.3; 41.6) P=0.049 7 (25.9) 6 (21.4)Δ -2.0 (-24.3; 20.2) P=0.864 Data are presented as n (%) Δ (95% CI) P-value P<0.05 was the threshold for significance; P-values should be considered nominal as primary endpoint was not met.*Tumor necrosis factor inhibitors or vedolizumab.†Clinical response is defined as a decrease of ≥100 points from W0 or CDAI score of <150 points.‡Patients who had insufficient data at the designated analysis timepoint or 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 caused by worsening CD prior to the designated analysis timepoint were not considered to have achieved the endpoint.§Clinical remission is defined as CDAI <150 points.||Abnormal CRP is defined as CRP value >3 mg/L and abnormal fCal concentrations is defined as >250 µg/g.¶Normalized CRP is defined as CRP value ≤3 mg/L and normalized fCal concentrations is defined as ≤250 µg/g. When either the CRP or fCal value is abnormal at baseline and the value of the same parameter normalizes at W16, patients are considered to be normalized at the designated analysis timepoint.**Patients who had insufficient data at the designated analysis timepoint had their last value carried forward.Δ, difference; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CRP, C-reactive protein; fCal, fecal calprotectin; IV, intravenous; SC, subcutaneous; UST, ustekinumab; W, week.