Introduction
Per STRIDE II recommendations, the normalization of high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) should be an intermediate treatment target for patients (pts) with moderate to severe Crohn’s disease (CD).1 The safety and efficacy of risankizumab (RZB), an interleukin (IL)23 p19 inhibitor, and ustekinumab (UST), an IL12/23p40 inhibitor, in pts with CD have been reported previously.2–4 Using data from the phase 3 SEQUENCE study, we compared RZB versus UST for the achievement of biomarker reduction and normalization (alone or in combination with disease remission).
Aims & Methods
SEQUENCE was an open-label, multicenter, randomized, efficacy assessor-blinded study that directly compared the efficacy and safety of RZB vs UST in pts with moderate to severe CD and prior anti-TNF failure (NCT04524611). Pts were randomized 1:1 to receive recommended induction and maintenance doses of RZB (N=255) or UST (N=265). A mandatory steroid taper began at week (W)2. Randomization was stratified by baseline (BL) steroid use and number of failed anti-TNFs. In this post hoc analysis, pts with elevated FCP (> 250 mg/kg) or hs-CRP (> 5 mg/L) at BL were assessed for achievement of normalized FCP (≤ 250 mg/kg)) or hs-CRP (≤ 5 mg/L) at week W8, week W24, and week W48. At week W24 and W48 week 48, achievement of normalized FCP or hs-CRP in combination with CD activity index (CDAI) clinical remission (CDAI < 150) or with inflammatory bowel disease questionnaire (IBDQ) remission (IBDQ total score ≥ 170), as well as achievement of a 50% reduction in hs-CRP or FCP and CDAI response (reduction of CDAI ≥100 points from BL), were examined. Endpoints were analyzed using non-responder imputation, while incorporating multiple imputation to handle missing data due to COVID-19 and/or geopolitical conflict. All P values are nominal.
Results
BL, baseline; CD, Crohn's disease; CDAI, CD activity index; CI, confidence interval; FCP, fecal calprotectin; hs-CRP, high-sensitivity C-reactive protein; IBDQ, inflammatory bowel disease questionnaire.
CDAI clinical remission: CDAI < 150; IBDQ remission: IBDQ total score ≥ 170.
aNormalization of hs-CRP is defined as ≤ 5 mg/L.
bElevated hs-CRP is defined > 5 mg/L.
cNormalization of FCP is defined as ≤ 250 mg/kg.
dElevated FCP is defined > 250 mg/kg.
Efficacy population includes all patients randomized to either ustekinumab (i.e., weight-based induction dose IV followed by maintenance dose 90-mg SC), or the selected dosing regimen for risankizumab (600 mg for induction, 360 mg for maintenance), and who received at least one dose of study drug.
95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 and/or geopolitical conflict or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19 and/or geopolitical conflict.
Response rate difference = (risankizumab - ustekinumab); 95% CI for difference is calculated based on normal approximation to the binomial distribution for the comparison of two treatment groups. P-value is based on Chi-square test. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 and/or geopolitical conflict.
Pooled p-value from Chi-square is calculated following Li et al., Statistica Sinica. 1991; 1, 68-92.
|
Endpoint
n/N
% (95% CI)
| Risankizumab
Week 8
| Ustekinumab
Week 8
| Response Rate Difference %
(95% CI)
P value
| Risankizumab
Week 24 | Ustekinumab
Week 24
| Response Rate Difference %
(95% CI)
P value
| Risankizumab
Week 48
| Ustekinumab
Week 48 | Response Rate Difference %
(95% CI)
P value
|
Normalization of hs-CRPa in patients with elevated hs-CRPb at BL
| 59/163;
35.6%
(28.2, 42.9)
| 56/171;
32.7%
(25.7, 39.8) | 2.8%
(-7.3, 13.0)
P =.6 | 72/163;
44.2%
(36.6, 51.9)
| 48/171;
28.1%
(21.3, 34.8)
| 16.2%
(6.0, 26.3)
P <.01
| 71/163;
43.6%
(35.9, 51.2) | 38/171;
22.2%
(16.0, 28.5) | 21.3%
(11.5, 31.2)
P <.0001 |
| Normalization of FCPc in patients with elevated FCPd at BL | 48/170;
28.8%
(22.0, 35.6)
| 25/180;
13.9%
(8.8, 18.9)
| 14.9%
(6.5, 23.4)
P <.001 | 65/170;
38.2%
(30.9, 45.5)
| 35/180;
19.4%
(13.7, 25.2)
| 18.8
(9.5, 28.1)
P <.0001
| 72/170
42.4%
(34.9, 49.8)
| 24/180;
13.3%
(8.4, 18.3) | 29.0
(20.1, 38.0)
P <.0001
|
Normalization of hs-CRPa or FCPcAND CDAI clinical remission In patients with elevated hs-CRPb or FCPd at BL
|
|
|
| 84/211;
39.9%
(33.3, 46.5)
| 53/218;
24.3%
(18.6, 30.0)
| 15.6%
(6.9, 24.3)
P <.001
| 97/211
46.0%
(39.2, 52.7)
| 54/218;
24.8%
(19.0, 30.5) | 21.2%
(12.4, 30.0)
P <.0001
|
Normalization of hs-CRPa or FCPcAND IBDQ remission in patients with elevated hs-CRPb or FCPd at BL
|
|
|
| 57/211
27.0%
(21.0, 33.0)
| 59/218;
27.1%
(21.2, 33.0)
| -0.1
(-8.5, 8.4)
P = 1.0 | 47/211;
22.3%
(16.7, 27.9)
| 34/218;
15.6%
(10.8, 20.4) | 6.7
(-0.7, 14.1)
P = 1.0 |
| ≥ 50% decrease from BL in hs-CRP or FCP AND CDAI clinical response in patients with elevated hs-CRPb or FCPd at BL |
|
|
| 111/211;
52.6%
(45.8, 59.3)
| 74/218
33.9%
(27.7, 40.2)
| 18.6
(9.4, 27.8)
P <.0001
| 119/211;
56.4%
(49.7, 63.1) | 68/218;
31.2%
(25.0, 37.3) | 25.2
(16.1, 34.3)
P <.0001 |
A greater proportion of pts receiving RZB vs UST achieved normalization of hs-CRP at W24 weeks 24 and W48, as well as normalization of FCP at weeks W8, W24, and 48 (P <.01 for all;
Table). Rates of normalization of FCP or hs-CRP plus CDAI clinical remission were also greater at weeks W24 and W48 in pts receiving RZB vs UST, as were rates of CDAI clinical response and a ≥ 50% reduction in FCP or hs-CRP
(
P <.001 for all;
Table). Rates of normalization of FCP or hs-CRP plus IBDQ remission were similar between pts receiving RZB vs UST (
Table). The safety profiles of RZB and UST in CD have been previously reported.
2–4Conclusion
A greater proportion of pts achieved normalization of biomarkers FCP or hs-CRP with RZB vs UST. Composite endpoints of CDAI clinical remission and biomarker normalization, as well as CDAI clinical response and biomarker reduction (≥ 50%) favored RZB vs UST at weeks 24 and 48.
References
1 Turner, D et al. Gastroenterology. 2021; 160, 1570–1583.
2 D’Haens, G et al. The Lancet. 2022; 399, 2015–2030.
3 Ferrante, M et al. The Lancet. 2022; 399, 2031–2046.
4 Feagan, BG et al. N Engl J Med. 2016; 375, 1946–1960.
Disclosure
Jean-Frederic Colombel: Research grants: AbbVie, Janssen Pharmaceuticals, and Takeda; lecture payments: AbbVie, Allergan, Amgen, Ferring Pharmaceuticals, Shire, and Takeda; consulting fees: AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Imedex, Immunic, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Lilly, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development.
Geert D’Haens: Adviser: AbbVie, Ablynx, Active Biotech AB, Agomab Therapeutics, Alimentiv, Allergan, Alphabiomics, Amakem, Amgen, AM Pharma, Applied Molecular Therapeutics, Arena Pharmaceuticals, AstraZeneca, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, DSM Pharma; Echo Pharmaceuticals, Engene, Exeliom Biosciences, Ferring, Dr Falk Pharma, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Gossamerbio, Immunic, Johnson and Johnson, Kintai Therapeutics, Lilly, Lument, Lycera, Medtronic, Merck Sharp & Dome, Mitsubishi Tanabe Pharma, Novo Nordisk, Otsuka, Pfizer, Photopill, ProciseDx, Prodigest, Progenity, Prometheus laboratories/Nestlé, Protagonist, RedHill, Samsung Bioepis, Sandoz, Seres, Setpoint, Shire, Takeda, Teva, Tillotts, Topivert, Versant, and Vifor.
Bram Verstockt: Research support: AbbVie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares and Takeda; speaker’s fees: Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, Lily, MSD, Pfizer, R-Biopharm, Sandoz, Takeda, Tillots Pharma, Truvion and ViatrisMSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris.; Consultancy fees: Abbvie, Alfasigma, Alimentiv, Applied Strategic, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Galapagos, Guidepont, Landos, Lily, Mylan, Inotrem, Ipsos, Janssen, Pfizer, Progenity, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma, Viatris, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Mylan, Inotrem, Ipsos, Janssen, Pfizer, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma and Viatris; stock options: Vagustim.
Peter Irving: Honoraria: AbbVie, BMS, Celgene, Celltrion, Dr Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Lilly, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire, and Warner Chilcott; advisor: AbbVie, Arena, Boehringer Ingelheim, BMS, Celgene, Celltrion, Connect Biopharma, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott.
Alessandro Armuzzi: Consulting/advisory fees: AbbVie, Allergan, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, and Takeda; speaker’s fees: AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, and Tigenix; research support: MSD, Takeda, Pfizer, and Biogen.
Benjamin Cohen: Consultant: Abbvie, Celgene-Bristol Myers Squibb, Lilly, Pfizer, Sublimity Therapeutics, Takeda, and Target RWE; DSMB for Emmes Biopharma Services LLC; educational grant from Pfizer.
Britta Siegmund: Consultant for AbbVie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer; grant support: Arena/Pfizer (served as representative of the Charité).
Laurent Peyrin-Biroulet: Personal fees from AbbVie, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant, and Vectivbio
Colla Cunneen, Andrew Garrison, Kristina Kligys, Javier Zambrano, and Toni Anschutz are full-time employees of AbbVie and may own AbbVie stock or options.
