Review Article: Emerging Drug Therapies in Inflammatory Bowel Disease

Laurie B. Grossberg; Konstantinos Papamichael; Adam S. Cheifetz

Aliment Pharmacol Ther. 2022;55(7):789-804.

Abstract and Introduction

Abstract

Background: The landscape of inflammatory bowel disease (IBD) treatment is rapidly expanding with the development of new therapeutic options.

Aim: To review the mechanisms of action and the available clinical trial data on emerging drug therapies for IBD.

Methods: Pubmed, Medline and Cochrane databases were queried up to July 2021 using keywords "inflammatory bowel disease," "IBD," "Crohn's disease," "ulcerative colitis" and "trial," "phase" and "study." In addition, we manually reviewed the grey literature including clinical trial registries and abstracts from major gastroenterology conferences in 2020 and 2021 to include pertinent information.

Results: In ulcerative colitis (UC), phase 2b and/or phase 3 studies met primary endpoints for S1P receptor agonists (estrasimod, ozanimod), anti-IL-23 agent (mirikizumab), anti-lymphocyte trafficking agents (ontamalimab, subcutaneous vedolizumab), JAK inhibitors (upadacitinib, filgotinib) and TLR9 agonist (cobitolimod). In Crohn's disease (CD), anti-IL-23 agents (risankizumab, mirikizumab, guselkumab), JAK inhibitors (upadacitinib, filgotinib) and anti-lymphocyte trafficking agents (ontamalimab, etrolizumab) met primary endpoints in randomised controlled clinical trials.

Conclusion: Several new IBD drug therapies have positive efficacy and safety data in early clinical trials, and there are several drugs in the therapeutic pipeline. As more treatments for CD and UC are approved for clinical use, research to assess predictors of response to therapy and head-to-head trials is needed to inform providers on how to best position therapeutic options for patients with IBD.

Introduction

Inflammatory bowel diseases (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions of the gastrointestinal tract.^[1] Most patients with these conditions require long-term pharmacological therapy to induce and to maintain remission. These treatments reduce the risk of flare and the need for corticosteroids, hospitalisation and surgery.^[2] Currently, approved biological and small molecule therapies for IBD are anti-TNF drugs (infliximab, adalimumab, golimumab, certolizumab), anti-integrin therapies (vedolizumab, natalizumab), anti-IL-12/23 therapy (ustekinumab), JAK inhibitor (tofacitinib) and S1P modulator (ozanimod).

Despite the available treatments, many patients are in need of new options due to nonresponse, loss of response or intolerance to therapies. Research involving new IBD therapies is expanding rapidly with the development of drugs with novel mechanisms of action, more convenient modes of administration and possibly more favourable safety profiles. Many of these treatments are showing promising data in clinical trials. In this review, we describe novel and emerging drug therapies for CD and UC and summarise available data.

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Emerging drug therapies in IBD (phase 2/3 studies)
Drug class	Drug	Target	Route	IBD type	Drug stage	FDA approvedY/N (indication)
S1P modulator	Etrasimod	S1P1, S1P4 and S1P5	Oral	CD UC	Phase II/III recruiting Phase III recruiting	N
S1P modulator	Ozanimod	S1P1 and S1P5	Oral	CD UC	Phase III recruiting FDA Approved	Y (MS, UC)
Anti-IL-23	Brazikumab	Anti-p19 subunit of IL-23	IV and SC	CD UC	Phase II/III, OLE^a Phase II, OLE^a	N
	Guselkumab	Anti-p19 subunit of IL-23	IV and SC	CD UC	Phase II/III recruiting Phase II/III recruiting	Y (plaque psoriasis, PA)
	Mirikizumab	Anti-p19 subunit of IL-23	IV and SC	CD UC	Phase III recruiting Phase III recruiting	N
	Risankizumab	Anti-p19 subunit of IL-23	IV and SC	CD UC	Phase III completed Phase II/III recruiting	Y (plaque psoriasis)
Anti-lymphocyte trafficking	AJM300	α4 integrin	SC	UC	Phase III active^b	N
	Etrolizumab	α4β7 and αEβ7 integrins	SC	CD UC	Phase III recruiting Phase III completed	N
	Ontamalimab	MAdCAM	SC	UC CD	Phase III active^b Phase III active^b	N
	Vedolizumab SC	α4β7 integrin	SC	UC	Phase III completed	Y (IV for CD and UC)
JAK inhibitor	Filgotinib	JAK1	Oral	CD UC	Phase III recruiting Phase III completed	N (approved for RA in EU and Japan)
JAK inhibitor	Upadacitinib	JAK1	Oral	CD UC	Phase III recruiting Phase III active^b	Y (RA)
Anti-TNF	CT-PI3 (infliximab)	Anti-TNF	SC	CD UC	Phase III, recruiting Phase III, recruiting	Y (IV for UC, CD, RA, plaque psoriasis, PA, AS
Topical treatment	Cobitolimod	TLR9	Topical (enema)	UC	Phase IIb completed, Phase III planned	N

Abbreviations: anti-TNF, anti-tumour necrosis factor; AS, ankylosing spondylitis; CD, Crohn's disease; IBD, inflammatory bowel disease; IL-23, interleukin-23; IV, intravenous; MAdCAM, mucosal addressin cell adhesion molecule-1; MS, multiple sclerosis; OLE, open-label extension; PA, psoriatic arthritis); RA, rheumatoid arthritis; SC, subcutaneous; SIP, sphingosine-1-phosphate; TLR9, Toll-like receptor 9; UC, ulcerative colitis; Y/N, yes/no.
^aEnrolling by invitation.
^bNot recruiting.

Table 2. Future drug therapies for IBD in early development
Drug class	Drug	Target	Route	IBD type	Drug stage	NCT number
S1P modulator	Amiselimod	S1P5	Oral	CD UC	Phase II completed Phase II recruiting	NCT02378688 NCT02389790 NCT04857112
	CBP-307	S1P1	Oral	UC	Phase II recruiting	NCT04700449
	LC51-0255	S1P1	Oral	UC	Phase II^a	NCT04096573
Anti-lymphocyte trafficking	AJM347	α4β7 integrin	Oral	UC	Phase I completed	NCT03133468
	MORF-057	α4β7 integrin	Oral	UC	Phase I completed	NCT04580745
	PN-943	α4β7 integrin	Oral	UC	Phase II recruiting	NCT04504383
Small molecules	ABX464	Cap binding complex	Oral	CD UC	Phase II^a Phase II recruiting	NCT03905109 NCT04023396
	BBT-401-1S	Pellino-1^b	Oral Rectal	UC UC	Phase II^a Phase I, recruiting	NCT04596293 NCT04478825
	BMS-986165	TYK2	Oral	CD UC	Phase II^a Phase II, recruiting	NCT03599622, NCT04877990 NCT03934216, NCT04613518, NCT04877990
	Brepocitinib (PF-06700841)	TYK2/JAK1	Oral	CD UC	Phase II, recruiting Phase II completed	NCT03395184 NCT02958865
	BT-11	LANCL2^b	Oral	CD UC	Phase II, recruiting Phase II, active^c	NCT03870334 NCT03861143
	GB004	PHD inhibitor, HIF-1α stabiliser	Oral	UC	Phase II, recruiting	NCT04556383
	IMU-838	DHODH	Oral	UC	Phase II, recruiting	NCT03341962
	LYS 006	LTA4H	Oral	UC	Phase II, recruiting	NCT04074590
	OST-122	JAK3/TYK2/ARK5	Oral	UC	Phase Ib/IIa, recruiting	NCT04353791
	PBF-677	AA3R^b	Oral	UC	Phase IIa recruiting	NCT03773952
	PF-06651600	JAK3	Oral	CD UC	Phase II recruiting Phase II completed	NCT03395184 NCT02958865
	SHR0302	JAK1	Oral	CD UC	Phase II recruiting Phase II completed	NCT03677648 NCT03675477
	Sibofimloc	FimH^b	Oral	CD	Phase II, recruiting	NCT03943446
	TD-1473	Pan-JAK (gut selective)	Oral	CD UC	Phase II recruiting Phase IIb/III recruiting	NCT03635112 NCT03758443, NCT03920254
	Tilpisertib (GS-4875)	TPL2	Oral	UC	Phase II active^c	NCT04130919
	TOP1288	NSKI	Rectal	UC	Phase IIa, completed	NCT02888379
Biologics targeting interleukins	AMT-101	IL-10 (gut selective)	Oral	UC	Phase II, recruiting	NCT04583358
	JNJ-67864238	IL-23R	Oral	CD	Phase II recruiting	NCT04102111
	LY3471851	IL-2	SC	UC	Phase II, recruiting	NCT04677179
	UTTR1147A	IL-22	IV	CD UC	Phase II, recruiting Phase II, recruiting	NCT03650413 NCT03558152
Other monoclonal antibodies	E6011	Anti-fractalkine	IV	CD	Phase II recruiting	NCT03733314
	JNJ-64304500	NKG2D	SC	CD	Phase IIb active^c	NCT02877134
	PF-06480605	TL1A	IV	UC	Phase IIb, recruiting	NCT04090411
	Ravagalimab	CD40 antigen	IV/SC	UC	Phase II active^c	NCT03695185
	Spesolimab	IL-36R	IV	CD UC	Phase II, recruiting Phase II/III, completed	NCT03752970, NCT04362254 NCT03482635
Oral anti-TNF	AVX-470	TNF	Oral	UC	Phase I, completed	NCT01759056
	OPRX-106	TNF	Oral	UC	Phase II, completed	NCT02768974
	V565	TNF	Oral	CD	Phase II^d	NCT02976129

Abbreviations: AA3R, adenosine A3 receptor; ARK, adrenergic receptor kinase; DHODH, dihydroorotate dehydrogenase; IBD, inflammatory bowel disease; IL, interleukin; JAK, Janus kinase; LANCL2, lanthionine synthetase C-like 2; LTA4H, leukotriene A4 hydrolase; NCT, National Clinical Trial; NKG2D, natural killer receptor group 2 member D; NSKI, narrow spectrum kinase inhibitor; PHD, prolyl hydroxylase inhibitor, HIF-1α, hypoxia-inducible factor 1 alpha; S1P, sphingosine-1-phosphate; TL1A, tumour necrosis factor-like cytokine 1A; TNF, tumour necrosis factor; TPL2, tumour progression locus 2; TYK, tyrosine kinase.
^aNot yet recruiting.
^bGI restricted.
^cNot recruiting.
^dRecruitment status unknown.

Table 3. Clinical trials for emerging drug therapies in IBD (phase 2b or 3)
Drug	IBD type	RCT acronym (phase)	Study design	Primary outcome	Primary outcome met Y/N	Ref.
Etrasimod	UC	OASIS (Phase 2)	Patients were randomised 1:1:1 to receive etrasimod 1 mg daily, etrasimod 2 mg daily or placebo for 12 weeks	Increase in mean improvement in MMS from baseline to week 12	Y (2 mg only)	¹⁰
Ozanimod	UC	TRUE-NORTH (Phase 3)	Patients were randomised at 2:1 to receive ozanimod 1 mg or placebo once daily for 10 weeks. Patients with the clinical response at week 10 were re-randomised 1:1 to ozanimod 1 mg or placebo once daily until week 52	Proportion of patients in clinical remission at week 10 (induction) and week 52 (maintenance), with Mayo subscores of RBS = 0, SF ≤1 and decrease from baseline ≥1, and ES ≤1	Y	^{13, 14}
Ozanimod	CD	STEPSTONE (Phase 2)	Patients were given ozanimod 0.25 mg for 4 d, then 0.5 mg for 3 d, then received 1 mg daily for 11 wks to complete a 12-wk induction, followed by a 100-wk extension	Change in SES-CD from baseline to week 12	Y	¹⁵
Guselkumab	CD	GALAXI (Phase 2)	Patients were randomised 1:1:1:1:1 to receive guselkumab 200 mg, 600 mg, 1200 mg at week 0, 4, 8; ustekinumab 6 mg/kg IV at week 0 followed by 90 mg SC at week 8, or placebo IV	Change in CDAI score from baseline, clinical remission and response, PRO-2 remission, clinical-biomarker response, endoscopic response and safety	Y	²¹
Mirikizumab	UC	I6T-MC-AMAC (Phase 2)	Patients were randomised 1:1:1:1 to receive mirikizumab 600 mg, 200 mg, 50 mg or placebo IV every 4 weeks for 12 weeks (induction). Week 12 responders were randomised 1:1 to 200 mg mirikizumab SC every 4 or 12 weeks through week 52	Clinical remission (Mayo RBS of 0, 0 or 1 with a 1-point decrease from baseline for SF and ES ≤1) at week 12	N	²²
	CD	SERENITY (Phase 2)	In the induction study, patients were randomised 2:1:1:2 to receive 200 mg, 600 or 1000 mg of mirikizumab, and placebo IV at weeks 0, 4 and 8. Patients who received mirikizumab and had ≥1 point improvement at week 12 in SES-CD were re-randomised 1:1 to mirikizumab IV every 4 weeks or mirikizumab 300 mg SC every 4 weeks until week 52	Endoscopic response (50% reduction from baseline in SES-CD) at week 12	Y	²⁴
Risankizumab	CD	ADVANCE (Phase 3)	Patients with inadequate response or intolerance to conventional and/or biologic therapy were randomised 2:2:1 to receive IV risankizumab 600 mg, 1200 mg or IV placebo at weeks 0, 4 and 8	Clinical remission (CDAI <150; or average daily SF ≤2.8 and average daily AP score ≤ 1, not worse than baseline for both), and endoscopic response (decrease in SES-CD >50% from baseline, or for isolated ileal disease and baseline SES-CD of 4, a ≥ 2-point reduction from baseline) at week 12	Y	²⁸
Risankizumab	CD	MOTIVATE (Phase 3)	Patients with inadequate response or intolerance to prior biologic therapy were randomised 2:2:1 to receive IV risankizumab 600 mg, 1200 mg or IV placebo at weeks 0, 4 and 8	Clinical remission (CDAI <150; or average daily SF ≤2.8 and average daily AP score ≤ 1, not worse than baseline for both), and endoscopic response (decrease in SES-CD >50% from baseline, or for isolated ileal disease and baseline SES-CD of 4, a ≥ 2-point reduction from baseline) at week 12	Y	²⁹
Etrolizumab	UC	HIBISCUS I HIBISCUS II (Phase 3)	Induction studies assessing etrolizumab head-to-head with adalimumab and placebo. Anti-TNF naïve patients randomised 2:2:1 to SC etrolizumab 105 mg once every 4 weeks, SC adalimumab (160/80/40 mg at weeks 0/2/4, 6 and 8 respectively) or placebo	Clinical remission at week 10 (MCS ≤2 with individual subscores ≤1 and RBS of 0) with etrolizumab vs placebo	Y (HIBISCUS I only)	⁴⁰
		LAUREL (Phase 3)	Comparison of etrolizumab to placebo in maintenance. Anti-TNF naïve patients received SC open-label etrolizumab 105 mg every 4 weeks. Patients with the clinical response at week 10, randomised 1:1 at week 12 to etrolizumab 105 mg or placebo every 4 weeks for 52 weeks	Clinical remission at week 62 (MCS ≤2 with individual subscores ≤1 and RBS of 0) among patients with clinical response (MCS with ≥3-point decrease and 30% reduction from baseline and ≥ 1-point decrease in RBS or an RBS of 0 or 1) at week 10	N	⁴¹
		GARDENIA (Phase 3)	Comparison of etrolizumab and infliximab in maintenance. Anti-TNF naïve patients randomised 1:1 to SC etrolizumab 105 mg every 4 weeks or IV infliximab 5 mg/kg at weeks 0, 2 and 6 and then every 8 weeks though week 54	Clinical response at week 10 (decrease in MCS of ≥3 and 30% reduction from baseline and ≥ 1-point decrease in RBS or absolute RBS of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1)	N	⁴²
		HICKORY (Phase 3)	Induction and maintenance trial that assessed etrolizumab versus placebo in patients that are anti-TNF experienced. Patient received open-label SC etrolizumab 105 mg every 4 weeks (cohort 1) or blinded 4:1 to etrolizumab vs placebo (cohort 2). Patients with the clinical response at week 14, re-randomised 1:1 to etrolizumab or placebo maintenance treatment	Clinical remission at week 14 (MCS ≤2 with individual subscores ≤1 and RBS of 0) and remission at week 66 in patients with the clinical response at week 14	Y (Week 14 only)	⁴³
	CD	BERGAMOT (Phase 3)	Patients were assigned 2:2:1 to receive etrolizumab 105 mg SC every 4 weeks, 210 mg SC every 4 weeks or a placebo for 14-week induction	CDAI remission (CDAI <150), CDAI-100 and − 70 responses, PRO2 remission (weighted combined score ≤ 11, based on patient report of liquid/very soft SF and AP), symptomatic remission (unweighted SF ≤3 and AP ≤1), and endoscopic improvement (≥50% reduction from baseline SES-CD) at wk 14	Y	⁴⁴
Ontamalimab	UC	TURANDOT (Phase 2)	Patients were randomised to receive ontamalimab 7.5, 22.5, 75, 225 mg or placebo SC at baseline and then every 4 weeks	Proportion of patients achieving remission (total MS ≤2 with no individual subscore >1 and RBS ≤1) at week 12	Y (7.5 mg, 22.5 mg, 75 mg only)	⁴⁵
Ontamalimab	CD	OPERA (Phase 2)	Patients were randomised to ontamalimab 22.5, 75 or 225 mg or placebo	A 70-point decrease in CDAI from baseline at week 8 or 12	N	⁴⁷
Vedolizumab (sc)	UC	VISIBLE 1 (Phase 3)	Patients received vedolizumab IV at weeks 0 and 2. Patients with the clinical response at week 6 were randomised to receive vedolizumab 300 mg IV every 8 weeks, vedolizumab 108 mg SC every 2 weeks or placebo	Clinical remission at week 52, defined as total MS ≤2 and no subscore >1	Y	⁴⁸
Filgotinib	UC	SELECTION (Phase 2b/3)	This trial consisted of two induction studies (biologic-naïve vs biologic-experienced), and patients were randomised 2:2:1 to receive either filgotinib 100 mg, 200 mg or placebo daily for 11 weeks. Patients with clinical response or remission at week 10 entered the maintenance study. Patients who received induction filgotinib were re-randomised 2:1 to continue filgotinib or to placebo. Patients who responded to placebo continued placebo	Clinical remission by Mayo ES ≤1, RBS of 0 and SF decrease of 1 or more points from baseline for a subscore of 0 or 1 at weeks 10 and 58	Y (200 mg only at week 10 and 100 mg and 200 mg at week 58)	⁵³
Filgotinib	CD	FITZROY (Phase 2)	Patients were assigned 3:1 to receive filgotinib 200 mg daily or a placebo for 10 weeks. After 10 weeks, patients who responded to filgotinib 100 mg were re-randomised 2:2:1 to receive filgotinib 200 mg, filgotinib 100 mg or placebo daily. Patients who responded to placebo in induction continued placebo and patients who did not respond to placebo induction were given filgotinib 100 mg daily	Clinical remission (CDAI <150) at week 10	Y	⁵⁴
Upadacitinib	UC	U-ACHIEVE (Phase 2b)	Patients in study 1 part 1 were randomised 1:1:1:1:1 to receive upadacitinib 7.5 mg, 15 mg, 30 mg, 45 mg or placebo for 8 weeks. Once part 1 was completed, additional patients were enrolled in study 1 part 2 and assigned 1:1 to receive upadacitinib 30 or 45 mg daily	Clinical remission according to the adapted Mayo score (excluding Physician Global Assessment) at week 8	Y (15 mg, 30 mg and 45 mg only)	⁵⁵
Upadacitinib	CD	CELEST (Phase 2)	Patients were randomised 1:1:1:1:1:1 to receive upadacitinib 3 mg, 6 mg, 12 mg, 24 mg or placebo twice daily or 24 mg once daily. After 16 wks, patients were re-randomised to upadacitinib 3 mg, 6 mg or 12 mg twice daily for 36 weeks	Clinical remission (average daily SF ≤1.5 and AP score ≤ 1, with neither worse than baseline) at week 16, and endoscopic remission at week 12 or 16 (SES-CD of ≤4 and ≥ 2-point reduction from baseline, with no subscore >1)	Y (6 mg only for clinical remission and 24 mg daily and twice daily for endoscopic remission)	⁵⁶
SHR0302	UC	AMBER2 (Phase 2)	Patients were randomised 1:1:1:1 to receive SHR0302 8 mg daily, 4 mg twice daily, 4 mg daily and placebo	Clinical response at week 8 (decrease from baseline in 9-point MMS of ≤2 and at least 30%, with a decrease in RBS ≤1 or absolute subscore of 0 or 1)	Y	⁵⁸
Cobitolimod	UC	CONDUCT (Phase 2b)	Patients randomised 1:1:1:1:1 to receive rectal enemas of cobitolimod at 31 mg, 125 mg, 250 mg at week 0 and 3, cobitolimod 125 mg at weeks 0, 1, 2, 3 or placebo	Clinical remission (Mayo RBS of 0, SF 0 or 1 [with ≥1-point decrease from baseline], and ES of 0 or 1 at week 6	Y	⁶²

Abbreviations: ADVANCE, a study of the efficacy and safety of risankizumab in participants with moderately to severely active Crohn's Disease; AMBER2, a phase II study in patients with moderate-to-severe active ulcerative colitis; AP, abdominal pain, CDAI, Crohn's disease activity index; CELEST, a multicentre, randomised, double-blind, placebo-controlled study of ABT-494 for the induction of symptomatic and endoscopic remission in subjects with moderate-to-severe active crohn's disease who have inadequately responded to or are intolerant to immunomodulators or anti-TNF therapy; CONDUCT, the efficacy of cobitolimod in patients with moderate-to-severe active ulcerative colitis; ES, endoscopic subscore; FITZROY, Efficacy and Safety of GLPG0634 in subjects with active Crohn's disease; GALAXI 1, a study of the efficacy and safety of guselkumab in participants with moderately to severely active crohn's disease; GARDENIA, a study comparing the efficacy and safety of etrolizumab to infliximab in participants with moderate-to-severe ulcerative colitis who are naïve to tumour necrosis factor (TNF) inhibitors; HIBISCUS I and II, a study comparing the efficacy and safety of etrolizumab with adalimumab and placebo in participants with moderate to severe ulcerative colitis (UC) in participants naive to tumour necrosis factor (TNF) inhibitors; HICKORY, a study of the efficacy and safety of etrolizumab in participants with ulcerative colitis who have been previously exposed to tumour necrosis factor (TNF) inhibitors, BERGAMOT, a study to assess whether etrolizumab is a safe and efficacious treatment for participants with moderate-to-severe active Crohn's disease; I6T-MC-AMAC, a study of Mirikizumab (LY3074828) in participants with moderate to severe ulcerative colitis; LAUREL, a study of the efficacy and safety of etrolizumab treatment in maintenance of disease remission in ulcerative colitis (UC) participants who are naive to tumour necrosis factor (TNF) inhibitors; MMS, modified Mayo Score; MS, Mayo score; OASIS, Safety and Efficacy of Etrasimod (APD334) in patients with ulcerative colitis; OPERA, Study to Test Whether PF-00547659 is safe and improves disease symptoms in patients with Crohn's disease; RBS, rectal bleeding subscore; sc, subcutaneous; SELECTION, study to evaluate the efficacy and safety of filgotinib in the induction and maintenance of remission in adults with moderate-to-severe active ulcerative colitis; SERENITY, A Study of Mirikizumab (LY3074828) in participants with active Crohn's Disease; SES-CD, Simple Endoscopic Score for Crohn's Disease; SF, stool frequency; STEPSTONE, efficacy and safety trial of RPC1063 for moderate to severe Crohn's disease; TNF, tumour necrosis factor; TRUE-NORTH, Safety and Efficacy Trial of RPC1063 for moderate to severe ulcerative colitis; TURANDOT, a study of PF-00547659 in patients with moderate-to-severe ulcerative colitis; U-ACHIEVE, a study to evaluate the safety and efficacy of upadacitinib (ABT-494) for induction and maintenance therapy in participants with moderate-to-severe active ulcerative colitis (UC); VISIBLE 1, efficacy and safety of vedolizumab subcutaneously (SC) as maintenance therapy in ulcerative colitis.