Advances in the Treatment of Moderate-to-severe Ulcerative Colitis: Anti-TNFs and Beyond

Her Hsin Tsai

Advances in the Treatment of Moderate-to-severe Ulcerative Colitis: Anti-TNFs and BeyondCHAPTER 1

Her Hsin Tsai

INTRODUCTION

The incidence and prevalence of inflammatory bowel disease (IBD) have been increasing globally, with the highest incidence in Europe and North America. Ulcerative colitis (UC) is the most common form of IBD with the annual incidence of about 5–20 per 100,000 person years and prevalence of up to 500 cases per 100,000 in some parts of the world. UC affects a variable extent of the colon from the rectum extending proximally with primarily mucosal inflammation. Clinically, it presents as bloody diarrhea, urgency, and abdominal pain, and runs a relapsing and remitting course. It is associated with significant morbidity, with an estimated 30–60% of patients experiencing at least one relapse per year, and approximately 20% of patients suffering from severe form of the disease. These symptoms have a major impact on sufferer's quality of life.

Treatment depends on severity and extent of the disease. The aim is to induce symptom-free remission of the disease and maintaining it. For mild-to-moderate disease, 5-aminosalicylate (orally and rectally) remains useful in both induction and maintenance therapy for UC. For moderate-to-severe disease, corticosteroids remain the primary therapy of UC but are limited by serious side effects. Should induction be successful the steroids are withdrawn and replaced by immunosuppressants such as thiopurine analogs, e.g., azathioprine (AZA) and 6-mercaptopurine (6MP).

More targeted therapies have been developed that specifically inhibit the mediators of gut inflammation. Infliximab is the first, an intravenously administered chimeric monoclonal antibody targeting tumor necrosis factor-alpha (TNF-α), a key proinflammatory cytokine involved in gut inflammation. The ACT 1 trial showed that patients with moderate-to-severe UC had a clinical response rate to infliximab of 65.5% at week 8, and almost 50% maintained response at week 30.¹ Adalimumab, a subcutaneously administered humanized anti-TNF antibody, was subsequently developed, with the ULTRA 2 trial demonstrating a clinical response rate of nearly 50% at week 8.² These biologic therapies are well established and most physicians caring for these patients are comfortable with their use. They are 2also demonstrably cost effective, as prices have tumbled with the advent of generic biosimilars.³

In this chapter, we shall discuss recent advances in the treatment of moderate-to-severe UC. It is not meant to be a comprehensive discussion on the clinical management of UC. It will focus on evolving clinical concepts in optimizing of treatment and new and emerging drug therapy that will likely impact on the clinical management of UC either already licensed or likely to be in the very near future. The number of treatment choices are growing at a remarkable rate and is by understanding the mode of action of the drugs and trial data that the optimal choices can be made for the specific clinical problem.

OPTIMIZING CONVENTIONAL THERAPIES

It is a common tendency to move onto a new treatment before optimizing current and often cheaper or less toxic treatments. This may be due to pressures put onto the physician either from patient or carer or from pharmaceutical sales pitch. There are several questions the physician should ask before escalation of treatment. This is particularly true of IBDs.

1. Are you treating the right disease?

It might seem an obvious question but there are a number of differential diagnoses that may ensnare the physician. The diagnosis is reached by a combination of clinical, radiological, endoscopic, and histological features. This is why a multidisciplinary approach is desirable, even essential if mistakes are to be not made.

2. Has the severity and extent of ulcerative colitis been properly assessed?

It is a common mistake to equate subjective patient symptom reporting with disease activity. While all reported symptoms need to be addressed with a treatment plan, only mucosal inflammation will respond to immunological modulation. There is understandably often a large functional element in the patient's symptoms. Irritable bowel syndrome (IBS) often coexists with IBD and the physician will need to be cautious in equating symptoms with disease severity. Hence before escalation of treatment, the patient needs to be reassessed. The best tool is colonoscopy. It will demonstrate extent and severity of inflammation. A form of mucosal inflammation scoring should be adopted [e.g., Mayo score or Ulcerative Colitis Endoscopic Index of Severity (UCEIS)] and extent recorded. Biopsies may be helpful. In acute severe disease, it should be done cautiously and once it is clear that the disease is severe (Mayo 3; UCEIS > 7) then the scope may be withdrawn and a plain abdominal X-ray taken. This is not only safer but remarkably helpful in demonstrating extent of disease, presence of mucosal thickening, and serious complication of a dilated colon. CT scans (or MRI) can also be very helpful in the severe cases (Figs. 1A and B). In the non-urgent cases, colonoscopy is by far the most useful assessment tool.3

Fig. 1A: Sigmoid inflammation in patient with severe ulcerative colitis.

Fig. 1B: Colonic dilatation in acute severe ulcerative colitis.

In recent years, fecal calprotectin has emerged as a useful tool in monitoring disease activity of UC. If done regularly, serial fecal calprotectin may be indicator of disease flare. However, the test in not reliable in predicting severity or extent of disease and should not be used as a justification for treatment escalation but should be used only as supporting evidence of mucosal inflammation.⁴

3. Is the disease acute severe?

Acute severe UC is a potentially life-threatening condition and patients are at risk for progressing to toxic megacolon (Fig. 1B) or bowel perforation. Hence recognition of this clinical condition is vital. In the original Truelove and Witts’⁵ criteria, it is characterized by:

Bloody stool frequency ≥6 per day4

PLUS at least one of the following evidence of systemic toxicity:

Fever (temperature ≥ 37.8°C)
Tachycardia (heart rate ≥ 90 beats/min)
Anemia (hemoglobin < 105 g/L)
Elevated inflammatory marker [C-reactive protein (CRP) > 100 g/L, erythrocyte sedimentation rate)

A subgroup with abdominal distension and pain is described as acute fulminant colitis.⁵

Patients with acute severe disease have a high risk of requiring colectomy and need to be recognized and admitted as an acute emergency and treated with fluids and intravenous steroids. They should be assessed frequently and if they do not respond within 3–5 days or if day 3 CRP remains very elevated, then they should be considered for treatment with cyclosporine or infliximab or surgery.⁶ Comparative trials have shown no difference between cyclosporine and infliximab.^7,8 Furthermore, there is no evidence that medical therapy results in lower long-term colectomy rates but it is generally accepted that elective surgery carries a lower morbidity.^9,10 The surgical management is discussed in the following chapter.

4. Have you optimized 5-ASA therapies?

5-aminosalicylic acid (5-ASA) treatments are the mainstay in the management of mild-to-moderate UC. This is particularly true of distal disease such as proctitis where the patient may experience a lot of urgency and frequency but may have very limited overall inflammatory load. Formal assessment may classify these patients as having moderate-to-severe disease even though the extent of inflammation may be very limited because of the dependence of scoring systems on bowel frequency counts. In this scenario, immunosuppression may not be the best treatment. Local treatment with 5-ASA products is often the key, with high dose oral and rectal 5-ASA preparations having demonstrable efficacy. This approach is often underused.¹¹

5. Have you optimized immunosuppressive therapies?

Immunosuppressive therapy, mainly the use of AZA and 6MP, is the cornerstone of management of moderate-to-severe UC. Patience is required as the drug is slow acting, taking at least 3 months and sometimes up to 6 months to act. It may be used alongside 5-ASA or as monotherapy in patients intolerant of 5-ASA. It should also be used with biologic therapy where it acts synergistically by suppressing antibody formation.

These drugs have many toxic effects and as many as 25% of patients are intolerant of the drug but only 1–2% develop serious toxicity. Liver toxicity and myelosuppression are the principal severe adverse reactions. Thus physicians may adopt a taciturn approach to the drug use for fear of toxicity and is a reason for suboptimal dosing in UC treatment. Enzyme testing and drug metabolite testing is helpful to in optimizing treatment.5

Fig. 2: Azathioprine metabolism: Azathioprine is serially converted to 6-TGNs and metabolized in a rate-limiting fashion into 6-MMP by TPMT enzyme.

(Aza: Azathioprine; Gmps: Guanosine Monophosphate Synthetase; 6-Mp: 6-Mercaptopurine; 6-Mmp: 6-Methylmercaptopurine; Tgn: Thioguanine Nucleotide; Tpmt: Thiopurine Methyltransferase; Xo: Xanthine Oxidase; Timp: Thioinosine Monophosphate; Txmp: Thioxanthine Monophosphate; Titp: Thioinosine Triphosphate; Tu: Thiouric Acid; Gmps: Guanidine Monophosphate Synthetase; Mtimp: Methylthioinosine Monophosphate)

Thiopurine methyltransferase (TPMT) is the critical (Fig. 2) enzyme in AZA and 6-MP metabolism and determines the levels of active molecule 6-thioguanine (6-TG) and toxic metabolite 6-methylmercaptopurine (6-MMP) levels. Approximately 89% of the population has wild type TPMT, which is associated with normal or “high” TPMT enzyme activity, while 11% are heterozygous and have corresponding low TPMT enzyme activity. A small number (1 in 300) of the population is homozygous for mutations of TPMT and thus have negligible activity, which causes 6-MP to be preferentially metabolized to produce high levels of 6-TG, which then leads to bone marrow suppression. Very high levels of TPMT may result in increased accumulation of 6-MMP increasing risk of liver toxicity. Thus determining the activity of TPMT may help optimize treatment.

Direct measurements of drug metabolite levels are available. Levels of 6-MMP can also be helpful to predict liver toxicity. The active moiety 6-TG can be a good measure of optimal dose of the drug. A recent meta-analysis of studies looking at 6-TG levels also demonstrated that clinical remission was significantly more likely among patients with 6-TG levels over a cut-off value between 230 and 260 (odds ratio 3.2, 95% CI 2.4–4.1).¹²

OPTIMIZING ANTI-TNF TREATMENTS

When it is clear that in the patient who has failed or is intolerant of the conventional treatments for UC, and that the patient has disease of at least moderate severity, then a biologic drug is the next step. It is usual to choose an anti-TNF as it is well established and availability of biosimilars has made it more affordable. There are some recent evolving concepts that may help optimize therapy.6

Addition of Immunosuppressives to Anti-TNF Treatment Improves Efficacy

In a clinical trial of infliximab monotherapy versus infliximab plus azathioprine versus azathioprine alone (UC-SUCCESS), corticosteroid-free remission at week 16 was achieved by 39.7% of patients receiving infliximab/azathioprine, compared with 22.1% receiving infliximab alone (p = 0.017) and 23.7% receiving azathioprine alone (p = 0.032).¹³ The effect is likely to be due to improved infliximab serum concentrations due to reduced antibody development in patients on combination therapy. Sub-analyses of a similar Crohn's study (SONIC) showing higher week 30 infliximab trough levels with combination versus infliximab monotherapy, 3.5 μg/mL versus 1.6 μg/mL (p < 0.001), and lower incidence of anti-infliximab antibody, 0.9% versus 14.6%. Interestingly, serious adverse events were actually lower with combination versus infliximab monotherapy (15.1% vs. 23.9%, p = 0.04).¹⁴

The dose and length of AZA treatment required remain uncertain but antibody suppression requires only a small dose of AZA, hence it is sensible to keep the patient on AZA for at least 3 months.

Treatment Goals and Targets

It has been noted in many trials involving infliximab that patients who had achieved mucosal healing had a more durable remission than those with symptom resolution without complete mucosal healing.¹⁵ In 2015, the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) committee defined the treat-to-target approach for IBD, which shifted the goal of UC treatment from short-term symptom resolution to long-term prevention of disease complications (dysplasia/cancer, hospitalizations, and colectomy).¹⁶ The three most promising composite targets for UC were symptom resolution (normalization of bowel habit and absence of rectal bleeding), endoscopic mucosal healing (Mayo or UCIES inflammation score of 0), and fecal calprotectin <100 µg/g. Although this area is still subject to ongoing long-term clinical investigation, early indication is that target achievement with aggressive medical therapy is associated with better outcome, lower colectomy rates, and hospitalizations.¹⁷

Personalizing Treatment

The ultimate refinement in the management of UC is to accurately personalize treatments for the individual patient. This depends on the ability of the clinician to accurately predict the likely clinical course and prognosis of the disease. This can be difficult to achieve. Currently we depend on clinical features, endoscopic appearance, and response to therapy to help us predict those who are likely to relapse or end up with colectomies. These measures are not adequate. Genetic studies have not been very helpful. Current best 7practice of personalizing treatment is based on optimizing treatments and selecting the right targets as already discussed above. The future may be the identification of biomarkers that can accurately predict the patients who are likely to have more aggressive disease. One concept is to identify T-cell transcriptional signatures using machine learning and a promising biomarker may soon be available.¹⁸

Prospective and Scheduled Therapeutic Drug Monitoring

Therapeutic drug monitoring is now widely available both for thiopurines and anti-TNFs. With anti-TNFs both trough drug levels taken just before a scheduled dose and antibody levels are available. Currently, the majority of clinicians perform trough and antibody levels reactively in response to suboptimal treatment response. Prospective scheduled monitoring is regarded as expensive but with costs of therapeutic drug monitoring falling due to the economies of scale, scheduled testing may become increasingly the norm. There is no doubt that it improves patient outcome and gastroenterological associations are recommending its more widespread use.¹⁹ Recent studies suggest that prospective therapeutic drug monitoring may be highly cost effective.²⁰

NEW DRUGS

Although anti-TNFs have revolutionized treatment of UC, some 40–60% still fail to respond. If the patient initially responded but then lose response (secondary failure to respond) or if antibody formation is identified as the reason for failure, then switching to a different drug within this class may be appropriate. But when the patient never responded to anti-TNFs (primary failure to respond) or when anti-TNFs have been optimized by scheduled therapeutic drug monitoring and patient still has inadequate response to therapy then a change in class of drug is indicated. Fortunately, there are several such drugs to choose from, some already licensed and others in various stages of development and certification.

Anti-adhesion Agents

One of the key components of the inflammatory response is the ability of the body's immune system to recruit immune modulator cells to the part of the body where they are needed. This is through trafficking of inflammatory cells via the circulatory system. To facilitate this, the vascular endothelium of vessels neighboring the areas where inflammatory cells are required express on its surface the mucosal addressin-cell adhesion molecule (usually abbreviated, MadCAM-1) which binds to integrins expressed on circulatory T-cells (Fig. 3).8

Fig. 3: T-cell trafficking.

(MAdCAM: mucosal addressin-cell adhesion molecule)

These integrins are heterodimeric receptors composed of an α and β subunit, that is expressed on the surface of circulating lymphocytes when they are activated. This process leads to the binding of circulating lymphocytes onto the endothelium and migration into the lamina propria and tissue, contributing to the inflammatory process in IBD.²¹

These integrins and MAdCAM-1 are thus potential therapeutic targets for IBD therapy. Integrin antagonists are a class of monoclonal antibodies that can block the trafficking of lymphocytes to the intestinal endothelium. The first integrin antagonist to emerge is natalizumab, a humanized IgG4 monoclonal antibody that leads to inhibition of the α4 integrin. Unfortunately, the use of natalizumab was limited by associated increased incidence of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system (CNS) caused by the opportunistic human John Cunningham (JC) virus. Vedolizumab (also known as LDP-02 and MLN02, MLN002), a humanized monoclonal IgG1 antibody, was subsequently developed as a gut selective anti-integrin specifically targeting α4β7 integrins in the gut and importantly not the integrins found in the CNS.^21,22

The efficacy of vedolizumab was demonstrated in two integrated regulatory trials (GEMINI 1). Response rates at week 6 were found to be 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (95% CI, 11.6–31.7; p < 0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks were in clinical remission [Mayo Clinic Score (MCS) ≤2 and no subscore >1], as compared with 15.9% of patients who switched to placebo (95% CI, 14.9–37.2; p < 0.001).^23,24

There may be advantages of using vedolizumab as a second line biologic therapy in UC. Its mode of action is very different from anti-TNF and represents a change in class. In theory, changing of one anti-TNF to another would only be effective if there is drug tolerance due to antibody formation. Primary infliximab failures, that is, those who have never responded to anti-TNF, are not likely to respond to another anti-TNF. The mode of action of vedolizumab also appears more benign compared to anti-TNFs as it does not interfere with critical antibacterial, especially anti-mycobacterial, 9pathways which make anti-TNFs so hazardous in TB positive individuals. In this respect, there are compelling reasons to suggest that vedolizumab is less harmful than anti-TNFs.²⁵

Treatment is given as an IV infusion with an induction of 300 mg at weeks 0, 2, and 6 followed by 8 weekly dosing of 300 mg. There are indications from studies that vedolizumab may take longer than anti-TNFs to achieve therapeutic results. Clinical response may not be apparent until week 10 and hence a little patience from the clinician and forewarning to the patient would be judicious. Some would advocate an additional dose at week 10 if there is a lack of adequate response at week 8.

Using vedolizumab as a first line biologic therapy also can be considered. At present, the cost differential to generic infliximab is too high to make it a cost effective strategy. This is based on equal efficacy of both biologic treatments. However recent data may suggest otherwise. A network meta-analysis has suggested that vedolizumab is superior to adalimumab.²⁶ This finding is now confirmed by a head-to-head study between adalimumab and vedolizumab. In a randomized trial comparing vedolizumab with adalimumab in over 700 patients with moderately-to-severely active UC, vedolizumab resulted in a significantly higher rate of clinical remission (31% vs. 22%).²⁷ The rate of serious infections was similar in both groups (<2%). The therapeutic gain may well be sufficiently large to make vedolizumab a cost-effective first line therapy for UC.

Etrolizumab is very similar, being a humanized monoclonal antibody against the β7 subunit of integrins α4β7 and αEβ7. Studies on the induction and maintenance treatment of UC are very promising.^28,29 At the time of writing, the drug has not yet been approved by the FDA.

An antibody to the adhesion MadCAM-1 is also under development.³⁰

Anti-interleukin Inhibitors

The proinflammatory cytokines interleukin 12 (IL-12) and interleukin 23 (IL-23) play an important role in the pathophysiology of Crohn's disease (CD) and possibly UC.³¹ These cytokines bind to receptors of CD4+ T-cells and lead to their differentiation into activated Th1 and Th17 cells (Fig. 4). There are multiple lines of evidence suggesting that UC is mediated by Th1 and CD by a combination of Th1 and Th17 cells.³² Furthermore, the IL-23 receptor mutation has been identified as a possible IBD gene.³³ Ustekinumab, a fully human immunoglobulin G1 kappa monoclonal antibody that binds with high affinity to the p40 subunit of human IL-12 and IL-23, has recently been approved for the treatment of moderately to severely active CD in adults. Ustekinumab prevents IL-12 and IL-23 bioactivity by preventing their interaction with their cell surface receptor protein IL-12Rβ1. Through this mechanism of action, ustekinumab effectively neutralizes IL-12 (Th1)- and IL-23 (Th17)-mediated cellular responses.10

Fig. 4: The role of IL-23 and IL-12.

Evidence for the efficacy of ustekinumab in UC had been investigated and encouraging results published recently.³⁴ In this study, the percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg/kg (15.5%) was significantly higher than that among patients who received placebo (5.3%) (p < 0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (p = 0.002 and p < 0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. However, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo. Although these do not constitute a clear hazard signal, some caution must be taken until more data becomes available.

Risankizumab, an IL-23 antibody, is currently being assessed in UC after encouraging results in CD.³⁵

JAK/STAT Pathway Inhibitors

Cytokines are released by the immune system in response to a signal principally by gut stellate cells or macrophages in response to a signal. They bind to specific receptors on the T-cell, triggering activation and synthesis of specific proteins that initiate the immune response. Cytokines can take the form of many structurally unrelated proteins that are typed according to their binding to distinct receptor families, which include type I cytokine receptors, type II cytokine receptors, the TNF receptor family, and the IL-1 receptor family receptors.11

Fig. 5: The JAK-STAT pathway.

(ISRE: interferon-stimulated response element; GAF: gamma activation factor; GAS: gamma activated sequence; IFN: interferon; IRF: interferon regulatory factor)

The cytokines bind to the relevant receptor and trigger intracellular changes, resulting in signal transduction and trigger gene expression. The signal transduction is via various protein kinases. The Janus kinase (JAK) is a family of receptor-associated tyrosine kinases that are essential for the cytokine signaling cascade (Fig. 5), downstream of type I and type II cytokine receptors.³⁶ The JAK-signal transducers and activators of transcription (STAT) pathway plays an important role in innate immunity, adaptive immunity, and hematopoiesis, participating in cellular processes such as cell growth, survival, differentiation, and migration. There are four members of the JAK family (JAK1, JAK2, JAK3, and TYK2) and seven signal transducers and transcription activators called signal transducer and activator of transcription, or STAT (STAT 1–4, 5a, 5b, and 6). The unique structure of each JAK clearly distinguishes them from other members of the protein tyrosine kinase family.³⁷

Ulcerative colitis and Crohn's disease involve many cytokine signaling which in turn depend on JAK-STAT pathway for immune cell gene 12transcription. The key cytokines in the pathogenesis of IBD belong to type I and type II cytokines receptors. These are the receptors of certain key cytokines namely IL-6, IL-5, IL-9, IL-10, IL-13, IL-12/23, IL-22, granulocyte–macrophage colony-stimulating factor (GM-CSF), and IFN-γ. All these cytokines signal through the JAK/STAT pathway. In contrast, the cytokines TNF, IL-1, and IL-17, which are the other major drivers of IBD, do not use the JAK-STAT pathway in their signaling pathways but they do however induce the expression of a wide range of downstream proinflammatory cytokines that, in turn, depend on JAK/STAT signaling.³⁸

Thus specific inhibitors of these kinases are a logical target as a treatment of inflammatory conditions. Several of these molecules are in development and are small, orally active molecules. Tofacitinib is the first JAK inhibitor to be approved for the treatment of moderate to severely active UC by the FDA (US) and EMA (European) agencies. Several other molecules are undergoing trials and are in advanced stages of development. Tofacitinib (Xeljanz, Pfizer) is a pan-JAK inhibitor that preferentially inhibits JAK1 and JAK3, in a dose-dependent fashion. Oral tofacitinib is well absorbed and is cleared principally by the liver. It has a short half-life of 3 hours.³⁹

Tofacitinib was found to be effective for induction of remission for patients with UC. In two randomized trials (OCTAVE Induction 1 and 2 trials of 598 and 541 patients, respectively), patients with moderate-to-severe UC who received tofacitinib 10 mg twice daily experienced remission at 8 weeks more frequently compared with those receiving placebo; for OCTAVE 1, 18% versus 8% (absolute difference 10, 95% CI: 4–16) and for OCTAVE 2, 17% versus 4% (absolute difference 13, 95% CI: 8–18).⁴⁰ In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks which occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (p < 0.001 for both comparisons with placebo).⁴⁰

The onset of action of tofacitinib varies greatly with some patients have responding rapidly, while for other patients, response may take up to 8 weeks. Caution should be used when prescribing tofacitinib for patients with a history of thromboembolic disease, cardiovascular disease, or those ≥50 years old with at least one cardiovascular risk factor because of an increased risk of thromboembolic events and mortality in patients who were treated with tofacitinib.

Sphingosine-1-phosphate Receptor Modulators

Sphingosine-1-phosphate (S1P) is a signaling sphingolipid becoming the active moiety by phosphorylation of sphingosine which is catalyzed by sphingosine kinase, an enzyme found in the cytosol and endoplasmic reticulum of various types of cells and S1P can be dephosphorylated to sphingosine by sphingosine phosphatases.13

Fig. 6: Sphingosine-1-phosphate (S1P) signaling and receptor modulation.

(SL: sphingosine lyase; SK: sphingosine kinase; PINK1: PTEN-induced kinase 1)

S1P produced in endovascular or lymphatic endothelial cells is secreted into the vasculature through the specific transporter SPNS2 (Fig. 6).

Sphingosine-1-phosphate is of importance in the entire human body; it is a major regulator of vascular and immune systems. In the vascular system, S1P regulates angiogenesis, vascular stability, and permeability. In the immune system, it is now recognized as a major regulator of trafficking of T- and B-cells. S1P interacts with its specific receptors S1PR of which there are five subtypes 1–5. S1P1, S1P4, and S1P5 are involved in regulation of the immune system, while S1P2 and S1P3 may be associated with cardiovascular and pulmonary system, and lead to cell proliferation and theoretical cancer-related risks. S1PR1 is of particular importance in immune regulation as it is found on T-cells. It appears to function as an elixir of life to the T-cells ensuring cell survival while a deficiency of S1P results in apoptosis and cell death. There is a concentration gradient between the lymphoid tissue in thymus or nodes and the lymphatic vessels and as the T-cells are attracted to the higher concentration in the vessels, it leads to egress of immune cells from the lymphoid organs (such as thymus and lymph nodes) into the lymphatic vessels.⁴¹

Sphingosine-1-phosphate is thus a promising target for pharmacologic intervention. When a synthetic agonist targets the S1PR receptor, the receptor–drug complex is internalized and voided and the T-cell loses its ability to respond to the S1P concentration gradient and thus remains the lymphoid tissue rather than egress into the lymphatic vessels and thus into the wider circulation and to the target organ like the gut in IBDs.⁴² Several 14small molecule agonists of S1PR have been developed.⁴³ Selective targeting S1P receptors for inflammatory conditions is important to avoid unwanted vascular and proliferative effects. Three S1P modulators with differing selectivity for S1P receptors were in clinical development for IBD—ozanimod, etrasimod, and amiselimod.

In the ozanimod study, the primary outcome of remission occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (p = 0.048 and p = 0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Clinical response (decrease in MCS of ≥3 points and ≥30% and decrease in rectal bleeding subscore of ≥1 point or a subscore ≤1) at 8 weeks occurred in 57% of those receiving 1 mg of ozanimod and 54% of those receiving 0.5 mg, as compared with 37% of those receiving placebo. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. At week 8, absolute lymphocyte counts declined 49% from baseline (BL) in the group that received 1 mg of ozanimod and 32% from BL in the group that received 0.5 mg. There were no safety concerns.⁴⁴

In the OASIS study, etrasimod 2 mg improved change from BL in 3-component MCS versus placebo (difference, 0.99 points; 90% CI, 0.30–1.68; p = 0.009). More patients receiving etrasimod 2 mg achieved endoscopic improvement (41.8% vs. 17.8% for PBO; p = 0.003). At week 12, there was a significant decrease in circulating lymphocyte counts from BL with etrasimod 1 mg and 2 mg relative to PBO (37.2% and 57.3%, respectively; p < 0.001 for both).⁴⁵

Etrasimod demonstrated durable clinical remission in the treatment of moderate to severely active UC in a phase 2 open-label extension study. The 34-week open-label extension study explored the long-term safety, tolerability, and efficacy of etrasimod in 118 patients who completed the 12-week phase 2 OASIS randomized controlled trial. Researchers analyzed the data to determine clinical response, clinical remission, and endoscopic improvement at the end of 46 weeks of treatment. Of the patients who completed 2 mg of etrasimod treatment during the extension study (n = 84), 79% achieved clinical response, 39% achieved clinical remission, and 51% had endoscopic improvement by the end of the study. Among patients who also received 2 mg of etrasimod during the OASIS trial (n = 22), 82% experienced clinical response, 50% were in clinical remission, and 55% had endoscopic improvement. For patients who achieved clinical response or clinical remission after the OASIS trial, 93% experienced sustained response and 75% experienced sustained remission at both 12 and 46 weeks. Investigators found that adverse events in the extension study were mild-to-moderate and did not discover any new safety concerns.⁴⁵15

Choosing a Second (or Third)-line Biologic Therapy

As these newer biologic therapies undergo regulatory trials to achieve certification, the best drug for each clinical scenario is still to be worked out. Until further studies are available, a sensible strategy based on currently available data can be adopted. After optimizing conventional therapies of 5-ASA and immunosuppressives, anti-TNFs in combination with thiopurines can be used a sensible first-line biologic. There may be a case for the use of vedolizumab as a first-line biologic but based on cost and physician familiarity, most experts would regard anti-TNFs to be the logical choice. There may also be a case for using infliximab in preference to adalimumab or golimumab based on network meta-analyses.⁴⁶

In terms of treatment targets, the best single marker is still endoscopic mucosal resolution.⁴⁷ Hence an assessment colonoscopic examination at 6 months after commencement of the drug is sensible. If treatment target is not achieved and if trough drug levels are adequate, then a change in class of drug is indicated. Currently, there are three licensed drugs that may be used; vedolizumab, ustekinumab, and tofacitinib. Vedolizumab is probably the best second line drug after anti-TNF failure. If an oral agent is to be preferred, then a case for tofacitinib can be made. Ustekinumab can be held for use as a third line drug.

The pace of change in the landscape of UC therapy continues unabated and it is challenging for the gastroenterologist to keep in step. However, with a sound grounding in scientific basis of the biology of the disease and with a critical eye over trial data, the IBD physician can optimize and personalize treatment of this disabling disease.

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Chapter Notes

Advances in the Treatment of Moderate-to-severe Ulcerative Colitis: Anti-TNFs and BeyondCHAPTER 1