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Abstract

To improve quality of life and prevent long-term risks in patients with inflammatory bowel diseases (IBDs: Crohn’s disease, ulcerative colitis), it is essential to suppress inflammatory activity adequately. However, corticosteroids are only suitable for therapy of acute flares and the evidence for positive effects of immunosuppressive substances like azathioprine or 6-mercapropurine is mainly limited to maintenance of remission. In addition, only subgroups of patients benefit from biologicals targeting tumour necrosis factor α or α4β7 integrins. In summary, until now the disease activity is not sufficiently controlled in a relevant fraction of the patients with IBD. Thus, there is an urge for the development of new substances in the therapy of ulcerative colitis and Crohn’s disease.

Fortunately, new oral and parenteral substances are in the pipeline. This review will focus on oral substances, which have already passed phase II studies successfully at this stage. In this article, we summarize data regarding AJM300, phosphatidylcholine (LT-02), mongersen, ozanimod, filgotinib and tofacitinib. AJM300 and ozanimod were tested in patients with ulcerative colitis and target lymphocyte trafficking through inhibition of the α subunit of integrin, respectively binding to the sphingosine-1-phosphate receptor (subtypes 1 and 5) on lymphocytes. Mongersen was utilized in patients with Crohn’s disease and accelerates the degradation of SMAD7 mRNA, which consequently strengthens the mainly anti-inflammatory signalling pathway of transforming growth factor β1. Various Janus kinase (JAK) inhibitors were developed, which inhibit the intracellular signalling pathway of cytokines. For example, the JAK1 blocker filgotinib was tested in Crohn’s disease, whereas the JAK1/3 inhibitor tofacitinib was tested in clinical trials for both Crohn’s disease and ulcerative colitis. A different therapeutic approach is the substitution of phosphatidylcholine (LT-02), which might recover the colonic mucus. Taken together, clinical trials with these new agents have opened avenues for further clinical studies and it can be expected that at least some of these agents will be finally approved for clinical therapy.

Keywords

AJM300 filgotinib fingolimod inflammatory bowel diseases mongersen oral therapy ozanimod phosphatidylcholine tofacitinib

Introduction

Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD) have a chronic course.^1,2 The incidences of these diseases are increasing.³ Because CD cannot be healed and the only definitive therapy for UC is ileocolectomy, most patients need an anti-inflammatory therapy for life or at least for several decades.^1,2,4

Insufficient control of inflammatory activity leads to a marked decrease in a patient’s quality of life.⁵ In the long term, this situation can result in a higher risk of colon cancer, especially for patients with UC.⁶ In the case of CD, strictures with the need for operative resections of the gut can occur, which could finally lead to intra-abdominal adhesions or a short bowel syndrome.⁷ However, an optimal therapy should not have serious side effects.

Corticosteroids are very potent in inducing remission,^8–10 but due to frequent adverse effects (AEs) and lack of efficacy this class of substances is not suitable for long-term use.^11,12 Mesalamine is the frequent basic therapy for UC, though this substance alone is too weak in many patients with rather severe courses.^13,14 If there is any positive effect concerning the induction of remission in patients with CD at all, this is very small.¹⁵ Furthermore, it has been suggested that this substance decreases the risk of colorectal cancer in patients with UC.¹⁶ In addition to this, immunosuppressive agents like azathioprine and 6-mercaptopurine can support maintenance of remission in subgroups of patients.^17–20

After advances in understanding the pathophysiology of IBD, biologicals have been developed in recent years and are now available for patients with IBD in clinical routine. Currently, not only tumour necrosis factor (TNF)-α inhibitors (infliximab,^21,22 adalimumab,^23,24 certolizumab pegol²⁵ and golimumab^26,27), but also the α4β7 integrin inhibitor vedolizumab^28–30 and the antibody against interleukin (IL)-12 and IL-23 ustekinumab are important parts of the therapy. In addition, in the United States the α4 integrin blocker natalizumab can be used in therapy-refractory patients with CD.³¹ However, approximately one third of patients receiving anti-TNFα therapy have no benefit and roughly another third show a secondary loss of efficacy.³² Thus, the therapeutic success is still limited and in a relevant group of patients inflammatory activity cannot be suppressed sufficiently.³³ Furthermore, the risk of infections and certain types of cancers may be increased by some immunosuppressive substances.³⁴ Fortunately, we can look forward to new substances at the transition to clinical usage.³³

In the following, we describe new oral substances for the therapy of UC and CD. In this review, we confine ourselves to selected oral drugs, which have been recently developed and successful tested in phase II clinical trials. New parenteral drugs are described and discussed elsewhere.³³

Substances

Inhibition of the α4 integrin subunit: AJM300

This small molecule inhibitor is directed against the α4 integrin subunit, which is expressed by lymphocytes and is necessary for homing of these cells [Table 1, Figure 1(b)].³⁵ Thus, the aim of this therapy is to inhibit the lymphocyte trafficking into the gut. Homing is a highly complex process, which is composed of different steps and is regulated by plenty of receptor interactions.³⁶ The type of integrin defines the target tissue. For example, α4β7 integrins are mainly responsible for homing of T cells into the gut,³⁷ whereas α4β1 integrins mediate the migration of lymphocytes to the gut and the brain.^36,38 The α4β7-integrin antibody vedolizumab has already been successfully established in the therapy of patients with IBD.³⁹ This was the proof of principle, that targeting lymphocyte trafficking can reduce inflammation in the gut and improve complaints of patients with IBD. The antibody natalizumab, which binds to the α4 integrin subunit, was effective in the therapy of multiple sclerosis⁴⁰ and CD.^41,42 By application of AJM300 to mice, experimental colitis could be prevented.⁴³ However, inhibition of the α4 integrin subunit by natalizumab also results in a decrease in lymphocyte homing to brain tissue and thus an increased risk for the occurrence of progressive multifocal leukencephalopathy (PML).⁴⁴ PML results from a reactivation of the John Cunningham virus (JCV) in patients with a substantially suppressed immune system.⁴⁴ This disease has been observed in 2 of 1000 patients with multiple sclerosis after therapy with the antibody natalizumab.⁴⁵ PML was also observed during therapy with natalizumab in some patients with CD.⁴⁶

Table 1.

New oral therapeutics and their mechanisms of action.

	AJM300³⁵	LT-02⁴⁷	Mongersen⁴⁸	Ozanimod⁴⁹	Tofacitinib/ filgotinib^50,51
Target	α4 integrin subunit	Colonic mucus	SMAD7 (Mothers against decapentaplegic homolog 7)	S1P-R_1/5 (sphingosine-1-phosphate receptor subtypes 1 and 5)	Tofacitinib: JAK 1+(2)+3 (Janus kinase) Filgotinib: JAK 1
Type of substance	Receptor antagonist, phenylalanine derivative	Phosphatidylcholine formula	21-base antisense oligonucleotide	Receptor modulator	Kinase inhibitor
Mechanism	Inhibition of the α4 integrin subunit	Substitution of phosphatidylcholine in the colonic mucus	Inhibition of SMAD7, whose concentration is elevated in patients with CD and inhibits the intracellular downstream signalling of TGF-β1	Internalization of the S1P-R_1/5 and trapping of lymphocytes in lymph nodes	Inhibition of JAK and thus reduction of multiple receptor-downstream signalling pathways Tofacitinib: e.g. IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-21, IFN-γ Filgotinib: e.g. IL-2, IL-6, IFN-γ
Expression of the target (selection)	Lymphocytes	–	T cells (and other lymphocytes), mucosal cells	Naïve and central memory B and T cells	Lymphocytes, granulocytes, macrophages, stem cells, epithelial cells, hepatocytes
Effect	The homing of lymphocytes to the gut is reduced	Recovery of the intestinal antibacterial barrier	Strengthening of the mainly anti-inflammatory signalling pathway of TGF-β1 in the gut	Reduction of circulating lymphocytes	Inhibition of mainly proinflammatory cytokines
Pharmacokinetics	Mainly local effect; film-coated tablet Intake: 3× per day	Local effect; granules coated with methacrylic acid methyl methacrylate copolymer (1:2); release trigger: pH 7.0; release target: distal ileum Intake: 4× per day⁵²	(Mainly) local effect; tablet coated with methacrylic acid ethyl acrylate copolymers; release trigger: pH 6.6–7.2; release target: terminal ileum + ascending colon Intake: 1× per day⁵²	Local and systemic effect; film-coated tablet Intake: 1× per day⁵³	Local and systemic effect; film-coated tablet Tofacitinib: Intake: 2× per day (later an extended-release formulation was developed, which enabled 1× per day)^52,54 Filgotinib: Intake: 1× per day

CD, Crohn’s disease; IFN, interferon; IL, interleukin; TGF, transforming growth factor.

Figure 1.

Ozanimod and AJM300: mechanisms of action. (a) Ozanimods lead to trapping of T cells in the lymph nodes by inhibition of sphingosine-1-phosphate receptor subtypes 1 and 5 (SP1-R1/5). (b) AJM300 binds to the α4 integrin subunit on different T-cell fractions, which prevent these cells from binding to MadCAM-1 (= mucosal addressin cell adhesion molecule 1; via α4β7) and VCAM-1 (= vascular cell adhesion molecule 1; via α4β1) and thus from homing to the gut.

The therapeutic efficacy and safety of AJM300 was tested in a randomized, double-blind, placebo-controlled phase IIa study with 102 patients with UC in 2015 in Japan (Table 2).³⁵ The substance was given orally for 8 weeks (3 × 960 mg per day) and the primary endpoint was clinical response. The study demonstrated significant improvement in clinical response, endoscopic remission and histological response. The positive effect was observed for extent and duration of disease. No serious AEs (SAEs) occurred in this study; the AEs were mild and self-limiting, and did not markedly differ between drug and placebo groups. However, because of the low number of patients and short time of observation, this study was not able to exclude an association with the rare but often lethal PML. Thus, further studies are necessary to estimate this risk more precisely. In the case of natalizumab, PML occurred less often in patients without antibodies against JCV and within the first 8 months of therapy.⁴⁵ Therefore, this potential risk could be markedly reduced by treating only those patients without detectable anti-JCV antibodies and limitation of therapy duration. Owing to the results of this phase II study, a phase III study has already been initiated. However, the results are not available yet [ClinicalTrials.jp identifier: 152862].

Table 2.

Study results of new oral substances in the therapy of inflammatory bowel disease.

	AJM300³⁵	Filgotinib⁵⁵	LT-02⁵⁶	Mongersen⁷¹	Ozanimod⁴⁹	Tofacitinib^58,59
Further names	–	GLPG0634, GS-6034	–	GED0301	RPC1063	CP-690,550
Entity	UC	CD	UC	CD	UC	UC	CD
Study number	[ClinicalTrials.jp identifier: 132293]	[ClinicalTrials.gov identifier: NCT02048618]	[ClinicalTrials.gov identifier: NCT01011322]	[EudraCT: 2011-002640-27]	[ClinicalTrials.gov identifier: NCT01647516]	[ClinicalTrials.gov identifier: NCT00787202]	[ClinicalTrials.gov identifier: A3921043]
Phase	II
Type of study	Randomized, double-blind, placebo-controlled, multicentre
Number of patients	102	174	156	166	197	194	139
Patient criteria (selection)	Moderate active UC Mayo 6–10 + endoscopic subscore ⩾2 + rectal bleeding subscore ⩾1 Adults	Moderate to severe active CD CDAI 220–450 + SES-CD ⩾7 + ⩾1 in ⩾1 segments Adults	Moderate to severe UC SCCAI ⩾ 5 + subscore in ‘blood in stool’ ⩾2, bloody diarrhoea for at least 6 weeks (despite treatment with mesalazine or mesalazine intolerance) Adults	Moderate to severe active CD CDAI 220–400 + inflammatory lesions in the ileum, right colon or both + steroid-dependent or steroid-resistant disease Adults	Moderate to severe active UC Mayo 6–12 + endoscopic subscore ⩾2 + disease extending ⩾15 cm from the anal verge Adults	Moderate to severe active UC Mayo 6–12 + endoscopic subscore ⩾2 Adults	Moderate to severe active CD CDAI 220–450 Adults
Exclusion criteria (selection)	Proctitis, severe colonic stricture, history of bowel surgery, infectious enteritis, cancer, neurological symptoms, corticosteroid dependence	Stoma, ileanal pouch, (procto-) colectomy, symptomatic stenosis or obstructive strictures, (suspected) abscess, a history of bowel perforation, short bowel syndrome, active infection, cancer	Toxic megacolon, fulminant courses, UC with disease extent <10 cm, condition after surgery of the colon, HIV infection, cancer, budesonide intake	Patients with lesions in stomach, proximal small intestine, transverse colon, or left colon history of strictures, fistulae, perianal disease, extraintestinal symptoms, infection, cancer	Fulminant colitis, prior colectomy, infectious enteritis, cancer, cardiac diseases and major systemic diseases	Fulminant colitis, toxic mega-colon, ulcerative proctitis, conditions that affect oral drug absorption (e.g. gastrectomy), surgery for UC, infections, cancer	History of symptomatic obstructive strictures or short-bowel-syndrome, ostomy, extensive bowel resection (>100 cm), infections, cancer
Allowed drugs	Stable doses of oral mesalamine, prednisolone (30–40 mg per day), budeosnide	Stable doses of oral mesalamine, prednisolone (⩽30 per day), budesonide (⩽9 mg per day)	Stable doses of oral mesalamine, systemic corticoids, azathioprine, mercaptopurine, methotrexat	Stable doses of oral mesalamine, prednisolone (⩽40 mg per day), budesonide (⩽9 mg per day), azathioprine, mercaptopurine, methotrexat	Stable doses of oral mesalamine or prednisolone (⩽30 mg per day)	Stable doses of oral mesalamine or glucocorticoids	Stable doses of oral mesalamine, sulfasalazine, prednisolone (⩽30 mg per day) or budesonide (⩽9 mg per day), rectal mesalamine or corticosteroids
Doses	3 × 960 mg per day	1 × 200 mg per day	4 × 0.8, 1.6 or 3.2 mg per day	1 × 10, 40 or 160 mg per day	1 × 0.5 or 1.0 mg per day	2 × 0.5, 3, 10 or 15 mg per day	2 × 1, 5 or 15 mg per day
Duration of therapy	8 weeks	10+10 weeks	12 weeks	2 weeks	32 weeks	8 weeks	4 weeks
Control time	Week 8	Week 10 (primary) Week 20	Week 12	Week 2 Week 4	Week 8 (primary) Week 32	Week 8	Week 4
Primary endpoint	Clinical response	Clinical remission	Changes in SCCAI	Clinical remission Safety	Clinical remission	Clinical response	Clinical response
Clinical response	Placebo: 26% 960 mg: 63%*** (Mayo score ⩾3 points and ⩾30% and rectal-bleeding subscore ⩾1 or subscore ⩽1)	Placebo: 41% 200 mg: 59%* (CDAI ⩾100)	Placebo: 60% 0.8 g: 77.5% 1.6 g: 73.2% 3.2 g: 82.9% pooled:* (SCCAI ⩾2)	2 weeks: Placebo: 26% 10 mg: 22%^$ 40 mg: 45%^$ 160 mg: 65%*** 4 weeks: Placebo: 17% 10 mg: 37%* 40 mg: 58%* 160 mg: 72%* (CDAI ⩾100)	Placebo: 37% 0.5 mg: 54%^$ 1 mg: 57%* (Mayo score ⩾3 points and ⩾ 30% and rectal-bleeding subscore ⩾ 1 or subscore ⩽ 1)	Placebo: 42% 0.5 mg: 32%^$ 3 mg: 48%^$ 10 mg: 61%^$ 15 mg: 78%*** (Mayo score ⩾3 points and ⩾ 30% and rectal-bleeding subscore ⩾1 or subscore ⩽1)	Placebo: 47% 1 mg: 36%^$ 5 mg: 58%^$ 15 mg: 46%^$ (CDAI ⩾70)
Clinical remission	Placebo: 4% 960 mg: 24%** (Mayo score ⩽2 and 0 subscores >1)	Placebo: 23% 200 mg: 47%** (CDAI < 150)	Placebo: 15%/12.5%^‡ 0.8 g: 27.5%/27.5%^‡ 1.6 g: 22%/22%^‡ 3.2 g: 31.4%/28.6%^‡ pooled: 26.7%/25.9%^‡ ^$/^{$ ‡} (SCCAI ⩽3 and no blood in stool)	Placebo: 10% 10 mg: 12%^$ 40 mg: 55%* 160 mg: 65%* (CDAI < 150; after 2 weeks until at least week 4)	Placebo: 6% 0.5 mg: 14%^$ 1 mg: 16%* (Mayo score ⩽2 + no subscore > 1)	Placebo: 10%0.5 mg: 13%^$ 3 mg: 33%* 10 mg: 48%* 15 mg: 41%* (Mayo score ⩽2 + no subscore >1)	Placebo: 21% 1 mg: 31%^$ 5 mg: 24%^$ 15 mg: 14%^$ (CDAI < 150)
Endoscopic response	–	Placebo: 14% 200 mg: 25%^$ (SES-CD ⩾50%)	–	–	–	Placebo: 46%0.5 mg: 52%^$ 3 mg: 58%^$ 10 mg: 67%^$ 15 mg: 78%** (Mayo endoscopic subscore ⩾1)	–
Endoscopic remission	Placebo: 29% 960 mg: 59%** (Mayo endoscopic subscore ⩽1)	Placebo: 7% 200 mg: 14%^$ (SES-CD ⩽4, ulcerated surface subscore ⩽1 in all five segments)	Placebo: 40%/30%^‡ 0.8 g: 57.5%/52.5%^‡ 1.6 g: 56.1%/53.7%^‡ 3.2 g: 51.4%/48.6%^‡ pooled: 55.2%/51.7%^‡ ^$/*^‡ (Mayo endoscopic subscore ⩽1)	–	Placebo: 12% 0.5 mg: 28%* 1 mg: 34%** (Mayo endoscopic subscore ⩽1)	Placebo: 2% 0.5 mg: 10%^$ 3 mg: 18%* 10 mg: 30%* 15 mg: 27%* (Mayo endoscopic subscore = 0)	–
Histological improvement	Placebo: −0.9 960 mg: −3.0** (Riley score)	–	–	–	–	–	–
Histological remission	–	–	Placebo: 20% 0.8 g: 40% 1.6 g: 41.5% 3.2 g: 40% pooled: *	–	Placebo: 11% 0.5 mg: 14%^$ 1 mg: 22%^$ (Geboes score <2)	–	–
CRP	–	Placebo: +4.93 mg/liter 200 mg: −0.97 mg/liter* (deviation from baseline)	–	Placebo: 12% 10 mg: 11%^$ 40 mg: 46%* 160 mg: 68%*** * (normalization of CRP after 2 and 4 weeks)	Placebo: +0.35 mmol/liter 0.5 mg: + 0.05 mmol/liter^$1.0 mg: –0.6 mmol/liter^$(mean change)	0.5 mg + 3 mg + 10 mg: ^$ 15 mg: *** (mean change)	Placebo: -0.07mg/l15mg: -0.93 mg/l^$(mean change)
Calprotectin	–	Placebo: −58.68 mg/kg 200 mg: −86.65 mg/kg^$ (deviation from baseline)	–	–	Placebo: –455.0 µg/g 0.5 mg: –814.5 µg/g^$1.0 mg: –550.0 µg/g^$(mean change)	0.5 mg + 3 mg: ^$ 10 mg: * 15 mg: *** (mean change)	Placebo: 0.08mg/kg15mg: -0.7 mg/lkg^$(mean change)
Other parameters			Mean change in SCCAI:Placebo: 9.0 → 6.00.8 g: 8.8 → 4.9^$ 1.6 g: 8.6 → 5.1^$ 3.2 g: 8.5 → 4.1*
Adverse events	No SAEs; number of AEs similar to placebo group	Number of SAEs and AEs similar to placebo group;infections ↑ (?)	No SAEs; number of AEs similar to placebo group	Number of SAEs and AEs similar to placebo group	Number of SAEs and AEs similar to placebo group;liver enzymes ↑ (?)	Few SAE; AEs similar to placebo group; cholesterol(LDL + HDL) ↑ (?)	Few SAE; AEs similar to placebo group; cholesterol(LDL + HDL) ↑

This table is an overview and is not intended to be exhaustive. The substances are assorted alphabetically. A direct comparison of parameters between different studies is limited by diverging patient populations. Furthermore, the alpha error is influenced by multiple testing, which varied between different studies.

p values: ^$⩾0.05, *⩽0.05, **⩽0.01, ***⩽0.001, ****⩽0.0001.

‡

Post hoc analysis (consideration of dropouts as failures).

AE, adverse event; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; HIV, human immunodeficiency virus; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SAE, serious adverse event; SCCAI, Simple Clinical Colitis Activity Index; SES-CD, Simple Endoscopic Score for CD; UC, ulcerative colitis.

Substitution of phosphatidylcholine: LT02

The colonic epithelial cells are covered by a layer of mucus, which serves as a barrier for microbiota⁴⁷ and includes antibacterial substances such as defensins.⁶⁰ Phospholipids (mainly phosphatidylcholine) in this mucus could prevent bacteria from invasion.⁶¹ In patients with UC the amount of phosphatidylcholine in colonic mucus is diminished by 70%.^62,63 It is possible that a primary lack of mucus could facilitate bacterial contact with epithelial cells, which results in intestinal inflammation.⁶⁴ Therefore, substitution of phosphatidylcholine in the colonic mucus would be an interesting therapeutic approach (Table 1).⁴⁷

In a double-blind, randomized, placebo-controlled phase IIa study 60 patients with UC were treated with 6 g of phosphatidylcholine-rich phospholipids for 3 months (Table 2). The phospholipids were released in the distal ileum in a pH-dependent manner. A significant improvement in comparison with placebo was shown for the primary endpoints clinical remission and clinical response. Moreover, a significant positive effect in endoscopic and histological assessment was observed.⁶⁵

Because of these encouraging results, a multicentre phase II study with additional patients with UC (n = 156) was performed. The patients were randomized into three treatment groups with 0.8, 1.6 or 3.2 g of a certain phosphatidylcholine formula (LT-02) or the placebo group. Clinical response after 3 months of therapy was the primary endpoint and reached statistical significance. Clinical remission and endoscopic remission were not significantly different between the treatment and placebo group. In a second analysis, considering dropouts as failures, endoscopic remission but not clinical remission reached statistical significance. The histological remission was significantly more often reached in the treatment group. Within the treatment group no SAEs were observed and there were no deviations concerning AEs between the different groups.⁵⁶

In summary, the substitution of phosphatidylcholine had a positive effect on the clinical situation of patients with UC in a phase II study. However, further studies have to clarify its influence on endoscopic response. Due to its different mechanism of action and excellent safety profile it could be a good supplement to immunosuppressive therapies. However, a recent phase III study using LT-02 in UC was not successful, making it unlikely that this substance will be developed further.

Inhibition of SMAD7: mongersen

Mongersen is a 21-base single-strand antisense oligonucleotide, which binds the mRNA of SMAD7 (= Mothers against decapentaplegic homolog 7) and accelerates its degradation (Table 1).⁴⁸ In patients with CD the expression of SMAD7 in T cells, other lymphocytes and mucosal cells is increased.⁶⁶ This is a result of post-transcriptional acetylation by p300, which prevents degradation of SMAD7.⁶⁷ SMAD7 inhibits the transforming growth factor (TGF)-β1 signalling pathway downstream of its receptor.^48,68 The effects of TGF-β1 are predominantly anti-inflammatory.⁶⁹ Thus, higher levels of SMAD7 could have a proinflammatory effect (Figure 2). Therefore, it seems reasonable that inhibition of SMAD7 could be a new therapeutic approach in IBD. This idea was supported by experiments in mouse models of colitis. An oligonucleotide accelerated the degradation of SMAD7 mRNA and as a consequence the intestinal inflammation was suppressed.⁷⁰

Figure 2.

Mongersen, tofacitinib, filgotinib: mechanisms of action. The concentration of SMAD7 is decreased by accelerated degradation of its mRNA after binding to the single-stranded antisense oligonucleotide mongersen. The reduction of SMAD7 leads to less inhibition of the mainly anti-inflammatory signalling pathway of transforming growth factor (TGF)-β1. The Janus kinase (JAK) inhibitors tofacitinib and filgotinib suppress the proinflammatory response following several cytokine receptor interactions [interleukin (IL)-2, IL-7 and IL-10 are only a selection].

In a phase I study, patients with CD treated with mongersen led to a clinical response. Mongersen was enveloped by acid-ethyl acrylate copolymers, which lead to a release of the active substance in the ileum and the right colon. The release was dependent on the gastrointestinal pH value, which can differ intra- and interindividually.⁵² It is postulated that mongersen has a local effect only. This theory is supported by the observation that mongersen was not detectable in the peripheral blood during therapy.⁵⁷

In the following phase II randomized, double-blind, placebo-controlled, multicentre study 166 patients with moderate to severe CD were included (Table 2).⁷¹ Because of pharmacokinetic reasons, patients with lesions at other segments of the gastrointestinal tract than the ileum and the right colon were excluded. As a result of the possible profibrotic effect of TGF-β1, whose signalling pathway is strengthened by mongersen, patients with a history of strictures were not allowed to participate in this study. The primary endpoint of this study was clinical remission. Doses of 10, 40 and 160 mg of mongersen per day were tested. Doses of 40 and 160 mg of mongersen led to significantly higher clinical remission and response rates than placebo therapy. For both these doses of mongersen the frequency of C-reactive protein (CRP) normalization was also significantly better in comparison with the placebo group. A post hoc analysis figured out that patients with higher Crohn’s Disease Activity Index (CDAI) scores (>260) reach clinical remission more frequently with 160 mg than 40 mg. However, disease duration and baseline serum CRP had no detectable influence on the therapeutic efficacy of mongersen.⁷² There were no relevant differences concerning AEs between the study arms. However, the number of patients and duration of therapy in this study limit the evaluation of safety. A further limitation of this study was the lack of endoscopic assessment.⁷¹

Subsequently, a phase Ib randomized study investigated the endoscopic response in 63 subjects with CD after therapy with 160 mg mongersen for 4, 8 or 12 weeks. The endoscopic response was defined as a reduction in Simple Endoscopic Score for CD (SES-CD) of at least 25% in comparison to baseline. Taking all study arms together the primary endpoint of endoscopic response was reached in 37% of the patients. In the case of high endoscopic activity at baseline (SES-CD > 12), a reduction in SED-CD of at least 25% was observed in 63% of the patients. One great limitation of this study was the lack of a placebo group.⁷³

Concerning the potential profibrotic effect of mongersen only few data are available. Indeed, the principally profibrotic impact of TGF-β1 has been repeatedly described (chemotactic effect on fibroblasts, stimulation of fibroblast proliferation, increase of collagen synthesis).⁷⁴ A small phase I open-label trial without a placebo group examined the influence of mongersen on the development of small bowel strictures. Fourteen patients with CD were treated with mongersen for 7 days and were observed for 6 months. In sonographic controls, no small bowel strictures were detected. There were no changes in the concentration of markers for CD-related intestinal strictures (e.g. basic fibroblast growth factor). Nevertheless, this study is limited by the very small number of patients and the short duration of therapy.⁷⁵

Thus, for patients with lesions in the ileum or right colon 40/160 mg mongersen may reach clinical and possibly endoscopic remission in phase II studies. There was no evidence for relevant AEs, but concerning the risk of fibrosis more clinical data are required. Currently, a phase III study with 40 and 160 mg of mongersen per day is being performed [ClinicalTrials.gov identifier: NCT02641392].

Modulation of sphingosine-1-phosphate receptor: ozanimod

Ozanimod is an agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 (S1P-R_1/5).⁷⁶ S1P-R is located on the surface of lymphocytes and is an essential part of the signalling pathway trafficking these cells out of lymph nodes.⁷⁷ S1P is built from sphingosine; this reaction is catalysed by sphingosine kinases (SphKs), which can be distinguished as the homologous kinases SphK1 and SphK2, with SphK1 being the main source for S1P.⁷⁸ In the gut of patients with UC, an increase in the expression of SphK1 and higher levels of S1P were observed.^78,79 Thus, this gradient could be important in attracting lymphocytes to the gut.^78,80 The interaction of ozanimod with S1P-R leads to the internalization of the receptor. Thus, these cells are trapped in the lymph nodes and less lymphocytes are able to migrate into the gut [Table 1, Figure 1(a)].⁷⁸ The S1P-R_1/3/4/5 modulator fingolimod has already been successfully used in the clinical routine of patients with multiple sclerosis.⁸¹ Ozanimod has not only been tested for the therapy of multiple sclerosis,⁸² but also for patients with UC.⁴⁹

In a randomized, placebo-controlled, double-blind phase II study, 197 patients with moderately to severely active UC have been tested for efficacy and safety of ozanimod. Different doses were tested (0.5 and 1.0 mg per day) for 8 weeks; the primary endpoint was clinical remission. A significant improvement concerning clinical remission and clinical response was observed for 1 mg ozanimod per day in comparison to placebo. Endoscopic remission was achieved significantly more often in patients from both treatment groups. However, there were no significant differences in histological remission. Frequency and severity of AEs for patients with ozanimod did not differ significantly compared with patients on placebo. However, greater numbers of patients are needed to estimate the safety of this substance more precisely (Table 2).⁴⁹

Because of these promising results two phase III studies for induction and maintenance therapy, with ozanimod in moderate to severe UC are ongoing [ClinicalTrials.gov identifier: NCT02435992, NCT02531126]. Furthermore, this substance is currently also being tested in patients with CD [ClinicalTrials.gov identifier: NCT02531113]. The therapeutic effect of amiselimod (MT-1303; another modulator of S1P-R_1/5) is currently being investigated in patients with CD (phase II) [ClinicalTrials.gov identifier: NCT02389790, NCT02378688]. The modulator of S1P-R₁ etrasimod (APD334) is being used in a phase II study for patients with UC [ClinicalTrials.gov identifier: NCT02536404, NCT02447302].

Inhibition of Janus kinases: tofacitinib and filgotinib

Tofacitinib is an inhibitor of the Janus kinases (JAK) 1/3 and to a lower extent also JAK 2.⁵⁰ JAKs are expressed in lymphocytes, granulocytes, macrophages and many nonimmune cell types (e.g. stem cells, epithelial cells).⁵¹ These kinases are critical in a huge number of intracellular signalling pathways, especially for those involved in regulation of immune responses. JAKs are part of the signalling pathway of IL-2, IL-4, IL-6, IL-7, IL-9, IL-12, IL-15, IL-21, interferon (IFN)-γ and further cytokines.⁸³ JAK targeting has positive effects on psoriasis⁸⁴ and rheumatoid arthritis.⁸⁵ Therefore, JAK could also be an interesting target for the therapy of IBD (Table 1, Figure 2). Tofacitinib has already been tested in phase III studies of UC and phase II studies of CD, whereas filgotinib has been used in patients with CD.

In a randomized, double-blind, placebo-controlled, multicentre phase II study 194 patients with moderate to severe UC were treated with tofacitinib for 8 weeks (Table 2). The primary endpoint was clinical response at the end of therapy. The highest dose of tofacitinib (15 mg twice a day) led to a better clinical response than placebo therapy. A statistically significant improvement was observed for clinical remission (for 10 and 15 mg), endoscopic response (for 15 mg) and endoscopic remission (3, 10 and 15 mg). The rate of normalization for calprotectin and CRP was significantly higher after therapy with tofacitinib in comparison to placebo. There were no differences concerning the frequency of AEs or SAEs between placebo and tofacitinib. However, the number of patients was too small for the assessment of a relevant increase of cholesterol levels or the rarely observed mild decrease of the absolute neutrophil count.⁵⁸ Two randomized, controlled phase III studies were able to show again significantly better clinical response for 10 mg tofacitinib twice a day in comparison to placebo after 2, 4 and 8 weeks of therapy. In this study AEs and SAEs in general were comparable between the study groups, however increases in cholesterol and creatine kinase were observed in the treatment group (OCTAVE Induction 1 and OCTAVE Induction 2) [ClinicalTrials.gov identifier: NCT01465763, NCT01458951].⁸⁶ Afterwards the efficacy and safety of 5 or 10 mg of tofacitinib as maintenance therapy was tested in these patients (phase III; randomized, placebo controlled). After 52 weeks of maintenance therapy, both doses led to a significant higher proportion of clinical remission and mucosal healing than placebo. Also, the sustained steroid-free remission with tofacitinib was superior to placebo. AEs and SAEs were again similar between the study arms. However, in addition to the already described increase in cholesterol and creatine kinase, a higher rate of herpes zoster was observed in the group with 10 mg tofacitinib (two cases in 23.55 patient years; OCTAVE Sustain) [ClinicalTrials.gov identifier: NCT01458574].⁸⁷ In the associated pharmacokinetic study a stable concentration of the active substance was observed, thus drug-monitoring is not necessary.⁸⁸ Furthermore quality of life was significantly improved with both tested doses in comparison to placebo.⁸⁹ In a meta-analysis, compromising three placebo-controlled, randomized studies and 1355 patients with UC, a significant improvement in clinical remission, mucosal healing and quality of life were observed after therapy with tofacitinib. There were no differences in SAEs between the drug group and the placebo group. However, the rate of infections was slightly but not significantly increased. Interestingly, a marked therapeutic effect was seen in patients previously treated with anti-TNF antibodies.⁹⁰

Tofacitinib has also been tested in patients with moderate to severe CD. A total of 139 patients were included in a randomized, double-blind, placebo-controlled, multicentre phase II study. The primary endpoint was the proportion of clinical responders after 4 weeks of therapy. Concerning clinical response and clinical remission, no differences between placebo and tofacitinib were observed. CRP and calprotectin decrease under therapy with 15 mg tofacitinib two times per day, but statistical significance was not determined. The number of AEs and SAEs did not differ significantly between those patients receiving tofacitinib and those in the placebo group. However, there was a dose-dependent increase in cholesterol (high-density lipoprotein and low-density lipoprotein) levels with tofacitinib.⁵⁹ In a further phase II study, 5 and 10 mg tofacitinib two times per day for 8 weeks of induction and 26 weeks of maintenance were compared with placebo in patients with CD. A positive tendency in clinical outcome was observed in the 10 mg group, but without being statistically significant. However, the decrease in CRP in comparison to baseline was highly significant [ClinicalTrials.gov identifier: NCT01393626, NCT01393899].⁹¹ In a follow-up open-label long-term extension phase IIb study based on 150 patients from the NCT01393899 study no further safety findings were observed during an additional 42 weeks of therapy [ClinicalTrials.gov identifier: NCT01470599].⁹²

In summary, tofacitinib improved clinical activity and the endoscopic situation in patients with UC. It is suitable for induction and maintenance of remission. In CD, however, convincing data on clinical efficacy are still lacking.

Filgotinib is a specific inhibitor of JAK 1. Although the inhibition is limited to fewer cytokine receptors, there is still a pleiotropic anti-inflammatory effect through inhibition of the signalling pathways of IL-2, IL-6, IFN-γ, among others (Table 1).⁵⁰

In a randomized, placebo-controlled, double-blind phase II study of 174 patients with moderately to severely active CD, the efficacy and safety of filgotinib were tested (Table 2). A dose of 200 mg filgotinib was administered once a day for 10 weeks, and the primary endpoint was clinical remission. After 10 weeks of initial therapy the patients were again randomized (placebo, 100 mg filgotinib, 200 mg filgotinib). Treatment with filgotinib significantly improved clinical remission and response in comparison to placebo. However, no significant differences concerning endoscopic response were observed. CRP was decreased more in the filgotinib group than in the placebo group. There were indications of an increased risk of infections in the treatment group.⁵⁵

Thus, filgotinib is able to improve clinical activity in patients with CD in a phase II study, but further studies have to investigate the impact on the endoscopic/histological situation and the potential risk for infections.

Synthesis and outlook

Treatment of IBD has made great progress in the last decades, especially by developing biologicals like TNFα inhibitors.^1,2 However, in a notable proportion of patients with IBD, the therapy is not able to induce clinical remission or control inflammation sufficiently.³³ The systemic immunosuppressive effect may be associated with SAEs.^34,93

Therefore, many new drugs are presently being tested in clinical trials. In addition to subcutaneous and intravenous substances, many oral drugs are now approaching regular clinical application.³³ Due to the discomfort during application of parenteral substances, oral drugs are often better accepted by patients.⁹⁴ However, the intake is not so well controlled. Moreover, in patients with CD in whom the small intestine is affected, oral substances are possibly not sufficiently absorbed. From 8% to 60% of patients with IBD develop antibodies against infliximab, which can lead to a secondary loss of efficacy.⁹⁵ There is hope that immunogenicity is not (or at least more seldom) observed for orally administered small inhibitors. Due to a shorter interval of intake it can be assumed that oral drugs can reach more stable concentration over time, which could support a favourable ratio between efficacy and adverse events. This ratio can be further improved by a locally restricted distribution and effect (e.g. mongersen, phosphatidylcholine).^56,48

AJM300,³⁵ ozanimod,⁴⁹ LT-02⁵⁶ and tofacitinib⁵⁸ have been used in patients with UC in clinical trials. For all substances, a statistically significant improvement in comparison to placebo has been observed for clinical response in phase II studies. A significant positive effect on clinical remission and endosopic remission was shown for all substances except LT-02. AJM300 led to a histological response, whereas ozanimod and LT-02 failed to reach histological remission. For tofacitinib no histological assessment was performed. In clinical trials using AJM300, ozanimod or LT-02 the adverse effects did not differ significantly compared with the placebo groups. AJM300’s mechanism of action makes triggering of PML possible.^45,46 This complication has not been observed after therapy with AJM300 so far. However, the number of patients is too small to rule out this effect.⁴⁵ For tofacitinib, increases in creatinine kinase, cholesterol and rate of herpes zoster⁹⁰ were described. In summary, all four substances showed acceptable ratios between efficacy and safety. Currently, the data are most robust for tofacitinib (the only substance with published positive data from a phase III study).⁸⁹

For CD, mongersen,⁷¹ tofacitinib⁹¹ and filgotinib⁵⁵ have been tested in clinical trials. Tofacitinib failed to significantly improve clinical response or remission in patients with CD. An endosopic evaluation was not performed. Both filgotinib and mongersen were superior to placebo in clinical response and clinical remission. Filgotinib did not lead to an improved endoscopic response or remission. A controlled endoscopic or histological assessment was not performed for mongersen. Whereas filgotinib could be associated with an elevated risk of infections, mongersen was not associated with an increased rate of SAEs or AEs. This agrees with the assumption that mongersen is released at the ileum and right colon without having relevant systemic effects.⁵⁷ Indeed, further studies have to investigate the possible profibrotic effect of mongerson.⁷⁴ An unfavourable effect of the currently available formulation is the inability to reach lesions on the other sides of the gastrointestinal tract or extraintestinal manifestations. In summary, mongersen might be a reasonable approach for the treatment of patients with lesions in the ileum or right colon. Filgotinib could be more suitable for systemic immunosuppression in patients with CD. The differences concerning clinical outcome of filgotinib and tofacitinib could result from the more selective mechanism of action of filgotinib. This might allow a higher dose of the active substance and thus lead to a greater therapeutic effect (tofacitinib: 10/20 mg/day, molar mass: 312 g/mol; filgotinib: 200 mg/day, molar mass: 425 g/mol). However, pharmacokinetic aspects and differences concerning patient populations might also play a role.

It is important to emphasize the limited possibility of comparing such substances without data from head-to-head studies. We are optimistic that some of these drugs will reach clinical approval and improve control of inflammatory activity and life quality.

Improvements have not only been made in active substances but also in drug coatings and specific formulations.⁹⁴ In the case of budesonide and mesalamine, but also the new substances mongersen and LT-02, a pH-dependent release at certain locations of the gastrointestinal tract has already been successfully realized.^52,96,97 In addition to this, the use of nanotherapeutics could increase accumulation of the active substance at the side of inflammation and improve cellular uptake.^94,98 A phase II trial compared a delayed-release formulation of 6-MP (DR-6MP) with purinethol in patients with CD.⁹⁹ The systemic bioavailability of DR-6MP was negligible. This formulation was well tolerated and the frequency of AEs was significantly lower than with purinethol. Furthermore, the combined primary endpoint of clinical response and clinical remission was similar for purinethol and DR-6MP. However, the time until maximal clinical response was shorter with DR-6MP. Thus, the ratio between efficacy and adverse reactions of known substances could be improved by optimizing their formulation. These new release strategies could also be the foundation for new oral and locally effective immunosuppressive agents (e.g. orally administered anti-CD3 antibodies).¹⁰⁰ A suitable coating of processed stool could enable an oral faecal microbiome transfer, which simplifies the realization of this method. Encapsulated stool was successfully tested in patients with Clostridium difficile infection.¹⁰¹ So far, the data for (endoscopically applied) faecal microbiome transfer in UC are contradictory.^102,103 For tofacitinib a new formulation has been designed which reduces the number of intakes per day (one per day versus two per day before). This could enhance therapy adherence.⁵⁴

In addition, adherence monitoring will become increasingly important for orally administered drugs. For some drugs with relevant absorption, such as the orally administered thiopurines¹⁰⁴ or tofacitinib,⁵⁴ it is already possible to measure their concentrations in patients’ blood.

Conclusion

Despite the introduction of biologicals in the last years, disease activity in a relevant number of patients is still not sufficiently under control. Therefore, there is a need for new therapeutic approaches. Fortunately, there are a lot of promising drugs in the pipeline. The oral substances AJM300, filgotinib, LT-02, mongersen, ozanimod and tofacitinib have been successfully tested in (at least) phase II trials for the therapy of patients with IBD. In addition to this, new formulations have been developed, which could improve the efficacy and safety of established drugs or enable the application of new substances. Thus, we have to await the (final) results of phase III studies and hope for substantial improvements in the therapy of IBD.

Footnotes

Funding

MFN was supported by grants from the German Research Foundation.

Conflict of interest statement

MFN has served as an advisor to Pentax, Giuliani, PPM, Takeda, Janssen, MSD, Boehringer and Abbvie. MV was financially supported by MSD, Takeda and Falk (travel grant, speaking fee).

References

Danese

Fiocchi

. Ulcerative colitis. N Engl J Med 2011; 365: 1713–1725.

Baumgart

Sandborn

(eds). Crohn’s disease. Lancet 2012; 380: 1590–1605.

Ananthakrishnan

. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol 2015; 12: 205–217.

Wehkamp

Götz

Herrlinger

et al . Inflammatory bowel disease. Deutsches Ärzteblatt International 2016; 113: 72–82.

Karwowski

Keljo

Szigethy

. Strategies to improve quality of life in adolescents with inflammatory bowel disease. Inflamm Bowel Dis 2009; 15: 1755–1764.

Rogler

. Chronic ulcerative colitis and colorectal cancer. Cancer Lett 2014; 345: 235–241.

Rieder

Zimmermann

Remzi

et al . Crohn’s disease complicated by strictures: a systematic review. Gut 2013; 62: 1072–1084.

Rezaie

Kuenzig

Benchimol

et al . Budesonide for induction of remission in Crohn’s disease. In: The Cochrane Collaboration (ed) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd. Epub ahead of print 3 June 2015. DOI: 10.1002/14651858.CD000296.pub4.

Sherlock

MacDonald

Griffiths

et al . Oral budesonide for induction of remission in ulcerative colitis. In: The Cochrane Collaboration (ed) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd. Epub ahead of print 26 October 2015. DOI: 10.1002/14651858.CD007698.pub3.

10.

Benchimol

Seow

Steinhart

et al . Traditional corticosteroids for induction of remission in Crohn’s disease. In: The Cochrane Collaboration (ed) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd. Epub ahead of print 23 April 2008. DOI: 10.1002/14651858.CD006792.pub2.

11.

Kuenzig

Rezaie

Seow

et al . Budesonide for maintenance of remission in Crohn’s disease. In: The Cochrane Collaboration (ed) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd. Epub ahead of print 21 August 2014. DOI: 10.1002/14651858.CD002913.pub3.

12.

Steinhart

Ewe

Griffiths

et al . Corticosteroids for maintenance of remission in Crohn’s disease. In: The Cochrane Collaboration (ed) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd. Epub ahead of print 20 October 2003. DOI: 10.1002/14651858.CD000301.

13.

Ford

Achkar

J-P

Khan

et al . Efficacy of 5-aminosalicylates, in ulcerative colitis – systematic review and meta-analysis. Am J Gastroenterol 2011; 106: 601–616.

14.

Ford

Khan

Achkar

J-P

. Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in ulcerative colitis: systematic review and meta-analysis. Am J Gastroenterol 2012; 107: 167–176.

15.

Lim

W-C

Wang

MacDonald

et al . Aminosalicylates for induction of remission or response in Crohn’s disease. In: The Cochrane Collaboration (ed) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd. Epub ahead of print 3 July 2016. DOI: 10.1002/14651858.CD008870.pub2.

16.

Rubin

Cruz-Correa

Gasche

et al . Colorectal cancer prevention in inflammatory bowel disease and the role of 5-aminosalicylic acid: a clinical review and update. Inflamm Bowel Dis 2008; 14: 265–274.

17.

Khan

Dubinsky

Ford

et al . Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2011; 106: 630–642.

18.

Chande

Townsend

Parker

et al . Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. In: The Cochrane Collaboration (ed) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd. Epub ahead of print 26 October 2016. DOI: 10.1002/14651858.CD000545.pub5.

19.

Chande

Patton

Tsoulis

et al . Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. In: The Cochrane Collaboration (ed) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd. Epub ahead of print 30 October 2015. DOI: 10.1002/14651858.CD000067.pub3.

20.

Timmer

Patton

Chande

et al . Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. In: The Cochrane Collaboration (ed) Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd. Epub ahead of print 18 May 2016. DOI: 10.1002/14651858.CD000478.pub4.

21.

Hanauer

Feagan

Lichtenstein

et al . Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. The Lancet 2002; 359: 1541–1549.

22.

Rutgeerts

Sandborn

Feagan

et al . Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353: 2462–2476.

23.

Colombel

Sandborn

Rutgeerts

et al . Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007; 132: 52–65.

24.

Sandborn

van Assche

Reinisch

et al . Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012; 142: 257–265.e3.

25.

Schreiber

Khaliq-Kareemi

Lawrance

et al . Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007; 357: 239–250.

26.

Sandborn

Feagan

Marano

et al . Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146: 85–95.

27.

Sandborn

Feagan

Marano

et al . Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146: 96–109.e1.

28.

Feagan

Rutgeerts

Sands

et al . Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369: 699–710.

29.

Sandborn

Feagan

Rutgeerts

et al . Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369: 711–721.

30.

Sands

Feagan

Rutgeerts

et al . Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology 2014; 147: 618–627.e3.

31.

Honey

. The comeback kid: TYSABRI now FDA approved for Crohn disease. J Clin Invest 118: 825–826.

32.

Jarcho

Nielsen

Ainsworth

. Tumor necrosis factor inhibitors for inflammatory bowel disease. N Engl J Med 2013; 369: 754–762.

33.

Neurath

. Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol 2017; 14: 269–278.

34.

Targownik

Bernstein

. Infectious and malignant complications of TNF inhibitor therapy in IBD. Am J Gastroenterol 2013; 108: 1835–1842.

35.

Yoshimura

Watanabe

Motoya

et al . Safety and efficacy of AJM300, an oral antagonist of α4 integrin, in induction therapy for patients with active ulcerative colitis. Gastroenterology 2015; 149: 1775–1783.e2.

36.

Zundler

Neurath

. Novel insights into the mechanisms of gut homing and antiadhesion therapies in inflammatory bowel diseases. Inflamm Bowel Dis 2017; 23: 617–627.

37.

Cassani

Villablanca

Quintana

et al . Gut-tropic T cells that express integrin α4β7 and CCR9 are required for induction of oral immune tolerance in Mice. Gastroenterology 2011; 141: 2109–2118.

38.

Zundler

Fischer

Schillinger

et al . The α4β1 homing pathway is essential for ileal homing of Crohn’s disease effector T cells in vivo. Inflamm Bowel Dis 2017; 23: 379–391.

39.

Eriksson

Marsal

Bergemalm

et al . Long-term effectiveness of vedolizumab in inflammatory bowel disease: a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG). Scand J Gastroenterol 2017; 52: 722–729.

40.

Miller

Khan

Sheremata

et al . A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15–23.

41.

Ghosh

Goldin

Gordon

et al . Natalizumab for active Crohn’s disease. N Engl J Med 2003; 348: 24–32.

42.

Sandborn

Colombel

Enns

et al . Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005; 353: 1912–1925.

43.

Sugiura

Kageyama

Andou

et al . Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice. J Crohns Colitis 2013; 7: e533–e542.

44.

Chalkley

Berger

. Progressive multifocal leukoencephalopathy in multiple sclerosis. Curr Neurol Neurosci Rep 2013; 13: 408.

45.

Bloomgren

Richman

Hotermans

et al . Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366: 1870–1880.

46.

Van Assche

Van Ranst

Sciot

et al . Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005; 353: 362–368.

47.

Stremmel

Ehehalt

Staffer

et al . Mucosal protection by phosphatidylcholine. Dig Dis 2012; 30: 85–91.

48.

Ardizzone

Bevivino

Monteleone

. Mongersen, an oral Smad7 antisense oligonucleotide, in patients with active Crohn’s disease. Ther Adv Gastroenterol 2016; 9: 527–532.

49.

Sandborn

Feagan

Wolf

et al . Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med 2016; 374: 1754–1762.

50.

Boland

Sandborn

Chang

. Update on Janus Kinase antagonists in inflammatory bowel disease. Gastroenterol Clin North Am 2014; 43: 603–617.

51.

Roskoski

. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res 2016; 111: 784–803.

52.

Timmins

Mathias

. Formulation technology can enable oral delivery of new generation medicines for inflammatory bowel disease. Eur Ind Pharm, http://www.phar-in.eu/wp-content/uploads/2017/01/EIPG31_Journal-final-lr.pdf (2016, accessed 6 July 2017).

53.

Juif

P-E

Kraehenbuehl

Dingemanse

. Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators. Expert Opin Drug Metab Toxicol 2016; 12: 879–895.

54.

Lamba

Wang

Fletcher

et al . Extended-release once-daily formulation of tofacitinib: evaluation of pharmacokinetics compared with immediate-release tofacitinib and impact of food: pharmacokinetics of extended-release tofacitinib. J Clin Pharmacol 2016; 56: 1362–1371.

55.

Vermeire

Schreiber

Petryka

et al . Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. The Lancet 2017; 389: 266–275.

56.

Karner

Kocjan

Stein

et al . First multicenter study of modified release phosphatidylcholine ‘LT-02’ in ulcerative colitis: a randomized, placebo-controlled trial in mesalazine-refractory courses. Am J Gastroenterol 2014; 109: 1041–1051.

57.

Monteleone

Fantini

Onali

et al . Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn’s disease. Mol Ther 2012; 20: 870–876.

58.

Sandborn

Ghosh

Panes

et al . Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 2012; 367: 616–624.

59.

Sandborn

Ghosh

Panes

et al . A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn’s disease. Clin Gastroenterol Hepatol 2014; 12: 1485–1493.e2.

60.

Kübler

Koslowski

Gersemann

et al . Influence of standard treatment on ileal and colonic antimicrobial defensin expression in active Crohn’s disease. Aliment Pharmacol Ther 2009; 30: 621–633.

61.

Lichtenberger

. The hydrophobic barrier properties of gastrointestinal mucus. Annu Rev Physiol 1995; 57: 565–583.

62.

Ehehalt

Wagenblast

Erben

et al . Phosphatidylcholine and lysophosphatidylcholine in intestinal mucus of ulcerative colitis patients. A quantitative approach by nanoelectrospray-tandem mass spectrometry. Scand J Gastroenterol 2004; 39: 737–742.

63.

Braun

Treede

Gotthardt

et al . Alterations of phospholipid concentration and species composition of the intestinal mucus barrier in ulcerative colitis: a clue to pathogenesis: Inflamm Bowel Dis 2009; 15: 1705–1720.

64.

Podolsky

. Inflammatory bowel disease. N Engl J Med 2002; 347: 417–429.

65.

Stremmel

. Retarded release phosphatidylcholine benefits patients with chronic active ulcerative colitis. Gut 2005; 54: 966–971.

66.

Monteleone

Kumberova

Croft

et al . Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease. J Clin Invest 2001; 108: 601–609.

67.

Monteleone

Del Vecchio Blanco

Monteleone

et al . Post-transcriptional regulation of Smad7 in the gut of patients with inflammatory bowel disease. Gastroenterology 2005; 129: 1420–1429.

68.

Heldin

C-H

Miyazono

Ten Dijke

. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 1997; 390: 465–471.

69.

Fantini

Becker

Monteleone

et al . Cutting edge-TGF-β induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172: 5149–5153.

70.

Boirivant

Pallone

Di Giacinto

et al . Inhibition of Smad7 with a specific antisense oligonucleotide facilitates TGF-β1-mediated suppression of colitis. Gastroenterology 2006; 131: 1786–1798.

71.

Monteleone

Neurath

Ardizzone

et al . Mongersen, an Oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N Engl J Med 2015; 372: 1104–1113.

72.

Monteleone

Di Sabatino

Ardizzone

et al . Impact of patient characteristics on the clinical efficacy of mongersen (GED-0301), an oral Smad7 antisense oligonucleotide, in active Crohn’s disease. Aliment Pharmacol Ther 2016; 43: 717–724.

73.

Sands

Rossiter

et al . PD-008 A study of oral mongersen (GED-0301) on endoscopy and clinical activity (stool frequency and abdominal pain) in Crohn’s disease. Inflamm Bowel Dis 2017; 23: S8.

74.

Border

Noble

. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331: 1286–1292.

75.

Zorzi

Calabrese

Monteleone

et al . A phase 1 open-label trial shows that smad7 antisense oligonucleotide (GED0301) does not increase the risk of small bowel strictures in Crohn’s disease. Aliment Pharmacol Ther 2012; 36: 850–857.

76.

Scott

Clemons

Brooks

et al . Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P₁ ) and receptor-5 (S1P₅ ) agonist with autoimmune disease-modifying activity: Ozanimod: a S1P_1,5 receptor agonist for autoimmune disease. Br J Pharmacol 2016; 173: 1778–1792.

77.

Matloubian

Cinamon

et al . Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004; 427: 355–360.

78.

Nielsen

Johansson-Lindbom

et al . Sphingosine-1-phosphate signaling in inflammatory bowel disease. Trends Mol Med. 2017; 23: 362–374.

79.

Montrose

Scherl

Bosworth

et al . S1P1 localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity. J Lipid Res 2013; 54: 843–851.

80.

Maceyka

Spiegel

. Sphingolipid metabolites in inflammatory disease. Nature 2014; 510: 58–67.

81.

Kappos

Radue

E-W

O’Connor

et al . A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362: 387–401.

82.

Cohen

Arnold

Comi

et al . Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15: 373–381.

83.

Ghoreschi

Laurence

O’Shea

. Janus kinases in immune cell signaling. Immunol Rev 2009; 228: 273–287.

84.

Papp

Menter

Strober

et al . Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b randomized placebo-controlled dose-ranging study: tofacitinib improves the clinical signs of psoriasis. Br J Dermatol 2012; 167: 668–677.

85.

Fleischmann

Kremer

Cush

et al . Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012; 367: 495–507.

86.

Sandborn

Sands

D’Haens

et al . OP019 Efficacy and safety of oral tofacitinib as induction therapy in patients with moderate-to-severe ulcerative colitis: results from 2 phase 3 randomised controlled trials, https://www.ecco-ibd.eu/index.php/publications/congress-abstract-s/abstracts-2016/item/op019-efficacy-and-safety-of-oral-tofacitinib-as-induction-therapy-in-patients-with-moderate-to-severe-ulcerative-colitis-results-from-2-phase-3-randomised-controlledx00a0trials.html (2016, accessed 22 March 2017).

87.

Sandborn

Sands

Danese

et al . OP032 Efficacy and safety of oral tofacitinib as maintenance therapy in patients with moderate to severe ulcerative colitis: results from a phase 3 randomised controlled trial, https://www.ecco-ibd.eu/index.php/publications/congress-abstract-s/item/op032-efficacy-and-safety-of-oral-tofacitinib-as-maintenance-therapy-in-patients-with-moderate-to-severe-ulcerative-colitis-results-from-a-phase-3-randomised-controlled-trial.html (2017, accessed 22 March 2017).

88.

Mukherjee

D’Haens

Sandborn

et al . DOP074 pharmacokinetics and exposure-response of tofacitinib in a phase 3 maintenance study in ulcerative colitis patients, https://www.ecco-ibd.eu/publications/congress-abstract-s/abstracts-2017/item/dop074-pharmacokinetics-and-exposure-response-of-tofacitinib-in-a-phase-3-maintenance-study-in-ulcerative-colitis-patients.html

89.

Panés

Rubin

Vermeire

et al . P467 maintenance of quality of life improvement in a phase 3 study of tofacitinib for patients with moderately to severely active ulcerative colitis, https://www.ecco-ibd.eu/publications/congress-abstract-s/abstracts-2017/item/p467-maintenance-of-quality-of-life-improvement-in-a-phase-3-study-of-tofacitinib-for-patients-with-moderately-to-severely-active-ulcerative-colitis-2.html

90.

Paschos

Katsoula

Giouleme

et al . P662 Tofacitinib for induction of remission in ulcerative colitis: systematic review and meta-analysis, https://www.ecco-ibd.eu/publications/congress-abstract-s/abstracts-2017/item/p662-tofacitinib-for-induction-of-remission-in-ulcerative-colitis-systematic-review-and-meta-analysis-2.html

91.

Panés

Sandborn

Schreiber

et al . Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials. Gut 2017; 66: 1049–1059.

92.

Panés

D’Haens

Higgins

PDR

et al . OP031 Long-term safety and tolerability of oral tofacitinib in patients with Crohn’s disease: results from a phase 2 open-label 48-week extension study.

93.

Amin

Huang

Yoon

et al . Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis 2015; 21: 445–452.

94.

X-Y

Merlin

Xiao

. Recent advances in orally administered cell-specific nanotherapeutics for inflammatory bowel disease. World J Gastroenterol 2016; 22: 7718.

95.

Nanda

Cheifetz

Moss

. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol 2013; 108: 40–47.

96.

Kamm

Sandborn

Gassull

et al . Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology 2007; 132: 66–75.

97.

Sandborn

Danese

D’Haens

et al . Induction of clinical and colonoscopic remission of mild-to-moderate ulcerative colitis with budesonide MMX 9 mg: pooled analysis of two phase 3 studies. Aliment Pharmacol Ther 2015; 41: 409–418.

98.

Lamprecht

. Nanoparticles enhance therapeutic efficiency by selectively increased local drug dose in experimental colitis in rats. J Pharmacol Exp Ther 2005; 315: 196–202.

99.

Israeli

Goldin

Fishman

et al . Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn’s disease with low rate of side effects: results of double blind phase II clinical trial: non-absorbable DR-6MP for Crohn’s disease. Clin Exp Immunol 2015; 181: 362–372.

100.

Ilan

. Oral immune therapy: targeting the systemic immune system via the gut immune system for the treatment of inflammatory bowel disease. Clin Transl Immunol 2016; 5: e60.

101.

Hirsch

Saraiya

Poeth

et al . Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection. BMC Infect Dis 2015; 15: 191.

102.

Moayyedi

Surette

Kim

et al . Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 2015; 149: 102–109.e6.

103.

Rossen

Fuentes

van der Spek

et al . Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 2015; 149: 110–118.e4.

104.

Gilissen

LPL

Wong

Engels

LGJB

et al . Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy. J Crohns Colitis 2012; 6: 698–707.

Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges

Abstract

Keywords

Introduction

Substances

Inhibition of the α4 integrin subunit: AJM300

Substitution of phosphatidylcholine: LT02

Inhibition of SMAD7: mongersen

Modulation of sphingosine-1-phosphate receptor: ozanimod

Inhibition of Janus kinases: tofacitinib and filgotinib

Synthesis and outlook

Conclusion

Footnotes

Funding

Conflict of interest statement

References