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.
Aims & 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)/faecal 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). 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).
| Table: 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
W0 post-dosea
W8
W16 | 1.26 (0.58; 2.53)
1.47 (0.70; 2.62)
1.38 (0.85; 2.61)
1.41 (0.81; 2.17) | 1.30 (0.62; 2.79)
105.62 (82.94; 128.13)
8.45 (4.25; 10.49)
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 responseb,c at
W16
Endoscopic remissionc,d,e 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) |
| 0/1 | 0/9 | 1/7
(14.3) | 2/24
(8.3) | 0/1 | 1/6
(16.7) | 0/4 | 10/42
(23.8) |
| W16 outcomes by UST trough concentration quartile groupsf 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 responseb,c
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 remissionc,d,e 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) |
aThe post-dose sample was collected within 24 hours of UST administration.
bClinical response is defined by CDAI <150 or decrease of ≥100 points from W0.
cPatients 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.
dEndoscopic remission is defined as an SES-CD score ≤3 or SES-CD=0 for patients who enter the study with an SES-CD=3.
eEndoscopy was an optional procedure in the study; only 58 (SC arm) and 59 (IV arm) patients were included in the endoscopic analysis.
fQuartiles 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. |
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.
Disclosure
S. Schreiber has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Fresenius, Galapagos/Gilead, Hikma, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist, ProventionBio, Takeda, and Theravance Biopharma. S. Lee served as a consultant for Applied Molecular Transport, Arena, Boehringer Ingelheim, Bridge Biotherapeutics, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Cornerstones Health, Eli Lilly and Company, Janssen, KCRN Research, Samsung Bioepis, and UCB; and received research grants from AbbVie, AbGenomics, Arena, Celgene, Janssen, Salix, Takeda, and UCB. C.J. van der Woude received grant support from Falk Benelux, Ferring, and Pfizer; received speaker fees from AbbVie, Takeda, Ferring, Dr Falk Pharma, and Pfizer; and served as a consultant for Janssen. I Marín-Jiménez has served as a consultant, advisory member, speaker or has received research funding from Abbvie, Chiesi, Faes Farma, Dr Falk Pharma, Ferring, Gebro Pharma, Hospira, Janssen, MSD, Otsuka Pharmaceutical, Pfizer, Shire, Takeda, Tillots, and UCB Pharma. D. Wolf has received honoraria as a speaker, consultant and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer, and Takeda. E. Schnoy has received personal fees from AbbVie, Bristol Myers Squibb, Celltrion Healthcare, Dr Falk Pharma, Galapagos/Gilead, I-Mab, Janssen, Lilly, Pfizer, Pharmacosmos, Takeda, and Tillotts Pharma. B. Salzberg served as a consultant for Johnson and Johnson, and has received honoraria as a speaker from AbbVie, Bristol Myers Squibb, and Johnson & Johnson. M. Nazar is an employee of Janssen-Cilag Polska Sp. z o.o. and has restricted stocks. C. Busse, W. Langholff, C Gasink, T. Baker, B. Godwin and Adedokun O.J. report employment with/funding by Janssen Research & Development, LLC, a wholly owned subsidiary of Johnson & Johnson, and stock ownership in Johnson & Johnson. B. Feagan received grant/research support from AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer Ingelheim, Celgene Corporation, Celltech, Genentech Inc./Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc./Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG, and UCB; was a consultant for Abbott/AbbVie, AdMIRx Inc., Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Asta Pharma, AstraZeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Galapagos, Galen/Atlantica, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc., Intact Therapeutics, Johnson & Johnson/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestlé, Nextbiotix, Novo Nordisk, ParImmune, Parvus Therapeutics Inc., Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Qu Biologics, Rebiotix, Receptos, Roche/Genentech, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd., and Zyngenia; was a member of the speakers’ bureau for Abbott/AbbVie, Johnson & Johnson/Janssen, Lilly, Takeda, Tillotts, and UCB Pharma; a member of the scientific advisory board for Abbott/AbbVie, Allergan, Amgen, AstraZeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, Johnson & Johnson/Janssen, Merck, Nestlé, Novartis, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG, and UCB Pharma; and was a Senior Scientific Officer for Robarts Clinical Trials Inc.
