Introduction

The combination of two biological agents or a biological agent with novel small molecules, known as advanced combination therapy (ACT), for inflammatory bowel disease (IBD) has shown promising results in phase II studies as well as in real world studies. We describe the real-world experience of 2 Swiss IBD referral centers.

Aims & Methods

A chart review of all IBD patients on ACT from June 2020 to December 2023 was performed in Bern University hospital and the Crohn and Colitis Center Lausanne (Gastro-entérologie Beaulieu SA). Data on disease duration, extension, previous or concomitant treatments as well as efficacy and safety were collected prospectively.

Results

Disease	Combination of advanced therapy (number of patients)	Partial or complete Clinical or biological response	Adverse effects, Infections
Ulcerative colitis (N=11)	Vedolizumab / Tofacitinib (5)	2/5 (40%)	none
	Vedolizumab / Anti-TNFs (3)	2/3 (50%)	none
	Vedolizumab /Cyclosporin or Tacrolimus (2) Ustekinumab / Tacrolimus (1)	1/2 (50%) 1/1 (100%)	none
Crohn’s disease (N= 17)	ustekinumab (5)/ Anti-TNFs(infliximab (1), adalimumab (4))	5/ 5 (100%)	Eczema, tumefaction left parotide
	ustekinumab (4) / JAK inhibitors Upadacitinib,(3) , Tofacitinib (1)	4/4 (100%)	Lymphoma, mycosis, otitis media, lymphopenia, CMV ileitis
	Vedolizumab / Infliximab (1) Vedolizumab / Tacrolimus	0/1 (0%) 1/1 (100%)	none
	Vedolizumab / Upadacitinib (3)	3/3 (100%)	Acnea, Headache, nausea
	Anti-TNF(adalimumab (2), cimzia (1) / Upadacitinib (3)	2/3 (66%)	Ophthalmic zona
Total		21/28 (75%)	11 events (14%)

A total of 25 IBD patients (48% women, 10 ulcerative colitis, 15 Crohn’s disease) received 28 ACT. The indications were extended and refractory luminal disease and/or extraintestinal manifestations. The 25 patients were all steroid dependent or refractory and half of them were either refractory or intolerant to at least two anti-TNF alpha agents. These treatments were started after a median disease duration of 5 years (range 1-31). The mean duration of ACT was 10 months (range 1-40). Most frequent ACT combinations were vedolizumab or ustekinumab combined with either JAK inhibitors or TNF- alpha inhibitors. A partial or complete response was observed in 21/28 therapies (75%) with a mean decrease of CRP of 9,4 mg/l (range - 23 to + 59). Among responders, a median decrease of calprotectin by 871 mcg/g (range 0 – 4002; N=8, skewed) was observed. Concerning safety, 3 infections (ophthalmic herpes zoster, otitis media, cutaneous fungal infection) and 1 case of Non-Hodgkin Lymphoma, were reported. 8 minor adverse events (left parotid gland, tumefaction, eczema, 2 patients with lymphopenia, acne nausea and headaches) were reported, with mostly small molecules implicated. One patient had a successful pregnancy and delivery on combined adalimumab and ustekinumab ACT.

Conclusion

Vedolizumab or ustekinumab combined with either JAK or TNF- alpha inhibitors were the most frequent combinations of ACT in this cohort of severe and steroid-dependent/refractory IBD patients. 75% of patients achieved a clinical /biological response. Small molecules appear to be associated with of lymphopenia, and minor infections. There was one case of Non-Hodgkin Lymphoma while receiving ustekinumab and tofacitinib ACT in the context of previous long exposure to adalimumab.

Disclosure

Marianne Vuillèmoz and Maude Martinho Grueber disclose consulting fees from Bristol Myers Squibb. Giulia Santi has nothing to disclose. Pascal Juillerat discloses consulting and speaker fees from AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Ferring Pharmaceuticals, Gilead Sciences, Janssen, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Sandoz, Takeda, Tillotts Pharma AG, and UCB Pharma. Pierre Michetti discloses a grant form Iqone and personal fees from Takeda, Ferring, Hospira, Janssen, Pfizer, UCB Pharma, Vifor Pharma, Nestlé Health Sciences, MSD.

Introduction

Tumor necrosis factor (TNF)-like ligand 1A (TL1A) mediates a broad spectrum of pro-inflammatory and fibrotic effects and is implicated in the pathogenesis of several immunologic disorders. A pathogenic role for TL1A in IBD is suggested by genetic association. Blockade of the interaction of TL1A with its cognate receptor, DR3, has been shown to ameliorate disease activity in patients with Crohn’s disease (CD) and ulcerative colitis (UC). We have characterized SPY002-091 and SPY002-072, two novel TL1A-specfiic fully human IgG1 monoclonal antibodies (mAbs) with extended pharmacokinetic (PK) half-life. Both antibodies bind soluble and membrane-bound TL1A with high affinity and potently inhibit TL1A-mediated signaling.

Aims & Methods

SPY002-091 and SPY002-072 were evaluated in multiple in vitro and ex vivo assays and compared to other anti-TL1A mAbs in clinical development (MK-7240, RG6631, and TEV-48574). Binding affinity to soluble TL1A was determined by surface plasmon resonance and binding to membrane-bound TL1A was confirmed by flow cytometry (FACS). Competitive blockade of TL1A binding to cell-surface DR3 was determined by FACS, and competition against the decoy receptor, DcR3, was evaluated by ELISA. The binding epitopes of SPY002-091 and SPY002-072 were determined using cryogenic electron microscopy (cryo-EM). TF-1 cell apoptosis and a primary human whole blood-based assay measuring IFNɣ secretion were used to assess functional blockade of TL1A. Half-life extension was measured via pharmacokinetic analysis in cynomolgus monkeys given a single bolus of either SPY002 mAb by intravenous and/or subcutaneous (SC) administration.

Results

SPY002-091 and SPY002-072 each bind to distinct epitopes on TL1A with sub-nanomolar affinity but do not bind the related TNF super family proteins TNF, FasL, TRAIL, or LIGHT. Both antibodies bind soluble TL1A and TL1A expressed on the surface of human embryonic kidney (HEK) cells. Both antibodies potently inhibit TL1A-induced apoptosis in human TF-1 cells and TL1A-induced secretion of IFNɣ in human whole blood, with IC₅₀ values comparable to those of RG6631 and TEV-48574, and a substantially lower IC₅₀ than that of MK-7240.

In cynomolgus monkeys, both SPY002-091 and SPY002-072 exhibit a pharmacokinetic half-life of approximately 25 days compared to an observed half-life of 9-12 days for RG6331 and MK-7240. Structural studies employing cryo-EM show that each SPY002 mAb targets an epitope within a single TL1A subunit enabling binding to both monomeric and trimeric TL1A. Based on allometric scaling of SPY002-091 and SPY002-072 clearance in NHPs, predictive simulations of their human PK properties suggest that Q8W-Q12W SC dosing will achieve therapeutic exposures in patients across a wide range of body weights and albumin concentrations.

Conclusion

We have characterized two anti-TL1A antibodies that exhibit high selectivity and affinity for TL1A, demonstrate effective blockade of the TL1A interaction with DR3, and potently inhibit downstream cellular signaling. With an extended half-life observed in NHP, both SPY002-091 and SPY002-072 demonstrate therapeutic potential for effective and safe treatment of CD and UC with the advantage of infrequent SC dosing. Further preclinical and clinical studies are warranted to demonstrate this potential.

Disclosure

EZ, DR, JM, JM, BK, JO, and HS are employees of Paragon Therapeutics.
JF, DN, AS, and MR are employees of Spyre Therapeutics.

Introduction

A deeper understanding of the pathogenesis of UC has led to the emergence of new therapeutic strategies. One of them consists of targeted exposure with biological drugs to certain molecules that regulate the interaction between leukocytes and endothelial cells in the inflammatory zone (mainly leukocyte integrins and endothelial cell adhesion molecules of the immunoglobulin superfamily).

Aims & Methods

Purpose of the study: To study the content of adhesion molecules ICAM-1, ICAM-2 and L-selectin in the peripheral blood of patients with ulcerative colitis (UC) and the effect of vedolizumab (Intivio) on their levels.
Materials and methods: We examined 12 patients with moderate and severe forms of UC and the ineffectiveness of previous standard therapy. The severity of the UC attack was calculated according to the Mayo index. Antivio® 300 mg was administered to patients intravenously according to the attached instructions. The content of adhesion molecules in the peripheral blood was studied before and 6 weeks after the first injection of vedilizumab. The control group consisted of 15 healthy volunteers. The content of ICAM-1, ICAM-2 and L-selectin in blood serum was determined by multilayer ELISA analysis (Bender med.Systems, Austria). Statistical processing of the obtained results was carried out using SPSS 13.0 software.

Results

It was found that the initial levels of ICAM-1 (461.9±28.4 ng/ml), ICAM-2 (323.3±18.4 ng/ml) and sL-selectin (1650±12.25 U/ml) ) in the peripheral blood of patients with UC were increased (P<0.05 with control), the Mayo index was 9 points. After four infusions of Vedolizumab (week 14), the levels of soluble molecules decreased in 4 patients, with a predominant decrease in sL-selectin (201±9.32 ng/ml, 197±8.54 pg/ml and 1008±15.3 U/ml respectively). The Mayo index was 5 points. In 8 patients, by the 6th week of treatment, the levels of the studied adhesive molecules did not change, although the Mayo index decreased by 3 points.

Conclusion

The initial level of ICAM-1, ICAM-2 and sL-selectin in the peripheral blood of patients with severe forms of UC is increased. The dynamics of the synthesis of adhesive molecules by immunocompetent cells under the influence of the fourth administration of Vedolizumab may predict the possibility of continuing the administration of the drug.

Introduction

^​​​​​​T cells, are a major regulator and source of pro-inflammatory cytokines, which may promote colitis, but be protective in some cancers^1,2. Nevertheless, limited efforts have been made to explore factors which determine the phenotype of T cells and their impact on the above-mentioned phenomena. The adhesion G protein-coupled receptor F5 (ADGRF5) belongs to seven-transmembrane receptor subfamily and may be related to development of some cancer types³.

Aims & Methods

The aim of the study was to assess the significance of ADGRF5 for T cell function and its impact on colitis and colon cancer progression. WT and ADGRF5 knockout CD4⁺ T cells were examined for cytokine genes and proteins using real-time PCR, Western blot and multiplex analysis. Tumor killing assay and flow cytometry analysis were performed to evaluate tumor killing properties of T cells co-cultured with MC38 colon cancer cells. ADGRF5 WT and KO mice were utilized to examine the impact of ADGRF5 on colitis, colitis-associated cancer development and colon cancer growth. Adoptive transfer of WT and ADGRF5 knockout CD4⁺ and CD8⁺ T cells were examined in tumor models to assess their role in disease progression.

Results

In murine model of colon cancer, animals with ADGRF5 knockout developed significantly smaller tumors which was accompanied by enhanced CD3 expression and hyperproduction of cytokines related to T cell action compared to wild type mice. Ex vivo analysis of two main population of T cells obtained from spleen of wild type and ADGRF5 knockout mice revealed that activated CD4⁺ but not CD8⁺ T cells with ADGRF5 were manifested by increased production of major anti-cancer molecules such as interferon γ (IFN- γ), perforin and granzyme B, and were characterized by secretion profile of cytokines related to mixed phenotype of T helper (T_h) 1 and T_h2 cells. Moreover, we documented higher proportion of apoptotic cells in co-culture of MC38 colon cancer cells with ADGRF5 knockout but not wild type CD4⁺ T cells. Finally, in the murine model of colon cancer adoptive transfer of CD4⁺ T cells with ADGRF5 knockout led to a significant reduction of tumor volume which was reversed by administration of antibody against IFN-γ. Nevertheless, ADGRF5 knockout in mice with colitis-associated colorectal cancer and colitis was related to significantly higher number of colon tumors and worse disease activity index compared to wild type animals, respectively. These results together with the analysis of gene expression signature in inflamed colons suggest opposite role for ADGRF5 in colitis than in the allograft colon cancer.

Conclusion

ADGRF5 is a critical regulator of T cell function and specific knockout of ADGRF5 reprograms CD4⁺ T cells into the pro-inflammatory phenotype. Our in vitro and in vivo studies indicated that ADGRF5 knockout in T cells promote pro-inflammatory cytokines, which prevent gastrointestinal cancer progression while boost both colitis and colitis-associated colorectal cancer development.

References

1. Jacenik D., Karagiannidis I., Beswick E.J. 2022. T_h2 cells inhibit growth of colon and pancreas cancers by promoting anti-tumorigenic responses from macrophages and eosinophils. Br J Cancer. 128: 387-397. doi: 10.1038/s41416-022-02056-2.
2. Shale M., Schiering C., Powrie F. 2013. CD4⁺ T cell subsets in intestinal inflammation. Immunol Rev. 252: 164-82. doi: 10.1111/imr.12039.
3. Jacenik D., Hikisz P., Beswick E.J., Fichna J. 2023. The clinical relevance of the adhesion G protein-coupled receptor F5 for human diseases and cancers. Biochim Biophys Acta Mol Basis Dis. 1869: 166683 doi: 10.1016/j.bbadis.2023.166683.

Disclosure

The work was supported by the National Science Centre, Poland under research project no 2019/32/C/NZ5/00064 (DJ).

Introduction

The efficacy and safety of risankizumab (RZB), an anti-interleukin 23p19 monoclonal antibody, as induction and maintenance therapy for adults with moderately to severely active ulcerative colitis (UC) was recently reported.^1,2 Influences of baseline disease characteristics on clinical outcomes are important to consider when optimizing UC treatment. Herein we analyze the efficacy of RZB stratified by baseline UC disease characteristics.

Aims & Methods

In the 12-week phase 3 INSPIRE induction study (NCT03398148) patients with moderately to severely active UC were randomized 2:1 to receive intravenous (IV) RZB 1200 mg or placebo (PBO) at weeks 0, 4, and 8. Patients with clinical response to RZB IV induction at week 12 or 24 in the phase 2b/3 induction studies were randomized 1:1:1 to receive subcutaneous (SC) RZB 180 mg, RZB 360 mg, or PBO (RZB withdrawal) every 8 weeks in the 52-week phase 3 COMMAND maintenance study (NCT03398135). This post hoc analysis evaluates clinical response, clinical remission, endoscopic remission, endoscopic improvement, and histological-endoscopic mucosal improvement (HEMI) at week 12 and 52 in subgroups stratified by baseline disease characteristics (Adapted Mayo score, pancolitis, high‑sensitivity C‑reactive protein [hs‑CRP], Mayo endoscopic subscore [ES], and disease duration).

Results

The induction analysis included 650 and 325 patients who received RZB 1200 mg IV and PBO IV, respectively. The maintenance analysis included 179, 186, and 183 patients who received RZB 180 mg SC, RZB 360 mg SC, and PBO (RZB withdrawal) SC, respectively. At induction week 12, the proportions of patients receiving RZB 1200 mg IV who achieved clinical response were numerically higher for the following baseline characteristic subgroups: pancolitis absence (70.5%) vs pancolitis presence (58.4%), Mayo ES of 2 (75.5%) vs Mayo ES of 3 (59.0%), and hs-CRP ≤ 5 mg/mL (68.9%) vs hs-CRP > 5 mg/mL (57.3%); the proportions of patients receiving RZB 1200 mg IV who achieved clinical remission at induction week 12 were also numerically higher for subgroups with pancolitis absence (25.3%) vs pancolitis presence (15.6%), Mayo ES of 2 (31.7%) vs Mayo ES of 3 (14.9%), and hs-CRP ≤ 5 mg/mL (23.7%) vs hs-CRP > 5 mg/mL (14.5%; Table). Differences in outcomes were not observed between subgroups stratified by Adapted Mayo score or disease duration. At week 52 of the maintenance study, there was no impact of baseline disease characteristics on achievement of clinical response and clinical remission with RZB (Table).

Conclusion

RZB induction and maintenance therapy improved clinical outcomes, regardless of baseline disease characteristics. Numerically higher RZB induction efficacy was observed for patients with no baseline pancolitis, Mayo ES of 2, and hs‑CRP ≤ 5 mg/L. These trends are consistent with prior observations that patients with milder UC disease phenotypes tend to be more responsive to therapy.

Table. Clinical Response and Clinical Remission by Baseline Disease Characteristics
Subgroup Patients, % (95% CI)	Induction Week 12			Maintenance Week 52
		Clinical Response	Clinical Remission		Clinical Response	Clinical Remission
AMS ≤ 7 > 7	PBO RZB 1200 mg IV PBO RZB 1200 mg IV	31.1 (24.5, 37.6) 63.8 (59.4, 70.7) 42.2 (33.9, 50.6) 65.1 (59.4, 70.7)	8.0 (4.1, 11.9) 22.6 (18.4, 26.8) 3.7 (0.5, 6.9) 17.2 (12.7, 21.7)	PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC	57.6 (47.5, 67.7) 66.7 (57.5, 75.8) 63.3 (54.3, 72.4) 42.6 (35.9, 56.4) 70.1 (59.9, 80.4) 61.0 (50.1, 71.9)	29.3 (20.0, 38.7) 41.1 (31.5, 50.6) 36.7 (27.6, 45.7) 20.9 (12.5, 29.2) 39.0 (28.1, 49.9) 39.0 (28.1, 49.9)
Pancolitis Yes No	PBO RZB 1200 mg IV PBO RZB 1200 mg IV	32.8 (25.8, 39.7) 58.4 (53.1, 63.7) 39.1 (31.3, 46.9) 70.5 (65.4, 75.5)	6.5 (2.8, 10.1) 15.6 (11.7, 19.5) 6.0 (2.2, 9.7) 25.3 (20.5, 30.1)	PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC	44.9 (35.1, 54.7) 64.9 (55.2, 74.5) 62.8 (53.0, 72.5) 60.0 (49.3, 70.4) 71.8 (62.2, 81.3) 61.9 (52.0, 71.9)	19.4 (11.6, 27.2) 40.4 (30.5, 50.3) 36.2 (26.5, 45.9) 31.8 (21.9, 41.7) 39.9 (29.4, 50.3) 39.1 (29.2, 49.1)
hs-CRP, mg/L ≤ 5 > 5	PBO RZB 1200 mg IV PBO RZB 1200 mg IV	39.0 (31.8, 46.2) 68.9 (64.3, 73.5) 30.5 (22.9, 38.1) 57.3 (51.1, 63.5)	7.5 (3.6, 11.4) 23.7 (19.4, 27.9) 4.3 (0.9, 7.6) 14.5 (10.1, 18.8)	PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC	58.5 (48.6, 68.5) 62.2 (52.2, 72.2) 67.5 (59.0, 76.0) 47.1 (36.4, 57.7) 73.6 (64.3, 82.8) 53.7 (41.8, 65.7)	28.7 (19.6, 37.9) 42.2 (32.0, 52.4) 41.9 (32.9, 50.8) 22.4 (13.5, 31.2) 37.8 (27.6, 48.0) 31.3 (20.2, 42.5)
Mayo ES 2 3	PBO RZB 1200 mg IV PBO RZB 1200 mg IV	38.3 (28.5, 48.1) 75.5 (69.6, 81.3) 34.6 (28.5, 40.8) 59.0 (54.4, 63.6)	8.5 (2.9, 14.2) 31.7 (25.4, 38.4) 5.3 (2.4, 8.2) 14.9 (11.6, 18.3)	PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC	59.6 (46.3, 73.0) 80.9 (69.6, 92.1) 66.7 (55.0, 78.3) 48.9 (40.3, 57.4) 63.6 (55.4, 71.8) 60.1 (51.5, 68.8)	32.7 (19.9, 45.4) 57.4 (43.3, 71.6) 39.7 (27.6, 51.8) 22.1 (15.0, 29.2) 34.0 (25.9, 42.1) 36.6 (28.1, 45.1)
Duration, years < 2 2–5 5–10 > 10	PBO RZB 1200 mg IV PBO RZB 1200 mg IV PBO RZB 1200 mg IV PBO RZB 1200 mg IV	42.9 (29.9, 55.8) 66.0 (57.0, 75.1) 32.5 (22.0, 42.9) 63.4 (56.5, 70.4) 32.3 (23.1, 41.5) 64.9 (58.0, 71.8) 37.6 (27.8, 47.5) 63.4 (56.2, 70.6)	5.4 (0, 11.3) 25.5 (17.2, 33.8) 9.4 (2.8, 16.0) 19.9 (14.2, 25.6) 2.0 (0, 4.8) 21.5 (15.6, 27.4) 8.6 (2.9, 14.3) 16.3 (10.8, 21.8)	PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC PBO RZB 180 mg SC RZB 360 mg SC	60.9 (40.9, 80.8) 70.4 (53.1, 87.6) 75.0 (53.8, 96.2) 35.3 (22.2, 48.4) 59.1 (44.6, 73.6) 66.6 (54.0, 79.2) 60.0 (47.6, 72.4) 76.5 (64.8, 88.1) 50.0 (34.9, 65.1) 55.1 (41.2, 69.0) 66.7 (54.4, 78.9) 63.5 (52.5, 74.5)	26.1 (8.1, 44.0) 55.2 (36.3, 74.1) 37.5 (13.8, 61.2) 17.6 (7.2, 28.1) 38.6 (24.2, 53.0) 40.7 (27.6, 53.8) 36.7 (24.5, 48.9) 51.0 (37.3, 64.7) 31.0 (17.0, 44.9) 18.4 (7.5, 29.2) 24.6 (13.4, 35.7) 39.2 (28.1, 50.3)
AMS, Adapted Mayo score; ES, endoscopic subscore; hs-CRP, high-sensitivity C-reactive protein; IV, intravenous; PBO, placebo; RBS, rectal bleeding subscore; RZB, risankizumab; SC, subcutaneous; SFS, stool frequency subscore. Data are reported using nonresponder imputation while incorporating multiple imputation to handle missing data due to COVID-19 or the geo‑political conflict in Ukraine and surrounding impacted regions. Clinical response is defined as a decrease in AMS that is ≥ 2 points and ≥ 30% from baseline plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1. Clinical remission is defined as SFS ≤ 1 (and not greater than baseline), RBS = 0, and endoscopic subscore ≤ 1 without evidence of friability.

References

1. Louis E, et al. United Eur Gastroenterol J . 2023;11(S8):26–28. Abstract OP021.
2. Louis E, et al. J Crohns Colitis. 2024;18(S1):i10–12. Abstract OP06.

Disclosure

CH has served as a consultant, advisor, and/or has received education funds from AbbVie, Bausch Health, BMS, the Helmsley Charitable Trust, Janssen, Pfizer, Roivant, and Takeda.
MDL has received consulting fees and/or research grants from AbbVie, BMS, Intercept, Janssen, Lilly, Pfizer, Prometheus, Takeda, and Target RWE.
SRF has served as a consultant or advisor for AbbVie, Janssen, MSD, Takeda, Tillots, and Vitoria.
TF has received research grants and/or speaking honoraria from AbbVie, Ajinomoto, Alfresa, BI, BMS, Celgene, Celltrion, Daiichi Sankyo, EA Pharma, Eisai, Gilead, Janssen, Kissei, Kyorin, Kyowa Hakko Kirin, Lilly, Mebix, Mitsubishi Tanabe, Mochida, Nichiiko, Nippon Kayaku, Pfizer, Sanofi, Taiho, Takeda, and Zeria.
ZR has no disclosures to report.
JK, PL, SC, LC, RV, and PMH are employees of AbbVie and may hold AbbVie stock and/or stock options.
FA-A has served as a consultant and/or has received grants and speaker fees from AbbVie, Celltrion, Kern, MSD, and Takeda.
RA has served as a consultant or advisor for AbbVie, AstraZeneca, BI, Biogen, BMS, CED-Service GmbH, Celltrion, Falk Foundation, Galapagos, Gilead, InDex, Janssen-Cilag, Lilly, MSD, Roche, and Takeda.
Funding
AbbVie funded this study and participated in the study design, research, data collection, analysis, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and the authors thank all trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Morgan A Gingerich, PhD, of JB Ashtin, and funded by AbbVie, and Karen Chien, PhD, of AbbVie.