Evolving Treatment Options for Patients with Ulcerative Colitis (UC)

Corticosteroids are also used for inducing remission, but there are numerous considerations for their use in managing UC, including onset of action, induction of remission, symptom control, and risks of long-term use.^3,4 Despite concerns with long-term use, they are still used in many patients with UC long-term. An international survey of 1030 patients with UC and 654 physicians treating patients with UC revealed that nearly 1 in 5 patients (of the 765 patients on corticosteroids) received corticosteroids for ≥6 months within the last year.⁵ In addition, 43% of the 654 physicians reported using corticosteroids for ≥4 months in a typical year for patients with UC.⁶ Current recommendations indicate if patients fail 2 or more courses of corticosteroid therapy in the past year, or are corticosteroid dependent or refractory, then they should consider other treatment options to manage their UC.⁷

The treatment landscape for UC has evolved and become more focused on specific targets. Targeted therapies, including biologics (vedolizumab, adalimumab) and small molecules (tofacitinib, ozanimod), have demonstrated improvement in clinical measures—rectal bleeding scores and stool frequency scores and providing long-term clinical remission in clinical practice and clinical trials.^8-15 Since the introduction of targeted treatment options, the use of biologics has increased with anti-tumor necrosis factors (anti-TNFs) currently being the most frequently used.¹

Patient clinical outcomes have been associated with improvements in endoscopic and histologic measures. Therefore, both parameters have been incorporated into international UC treatment guidelines. Endoscopy measurements are a standard practice for evaluating the mucosa to make a diagnosis, assessing disease severity and treatment efficacy, and surveilling for cancer.¹⁶ These endoscopic measures are pivotal endpoints in evaluating mucosal healing in UC across clinical trials. However, endoscopic parameters, which can be defined as the absences of friability, blood, erosions, and ulcers of the mucosa, can be subjective, and therefore can present issues in assessing clinical trial outcomes.^17,18 More recent trials have incorporated central reading to help mitigate the variability in assessing endoscopic parameters. The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative recommendations have been updated to take into account the development of new biologic and small molecule treatments, as well as advancements in diagnostic technologies; the recommendations also now include histological healing as a parameter.^19,20 More recently, clinical trials have also evolved the definition of mucosal healing to include histological and endoscopic measures for advanced therapies, such as filgotinib, ustekinumab, vedolizumab, and ozanimod.^14,21-23

Histological remission has been correlated with improved patient outcomes. Based on a systematic review and meta-analysis from 2016, patients with UC had fewer clinical relapses (RR=0.48), less corticosteroid use (RR=0.54), and a decreased risk for colectomies (RR=0.30).²⁴ Another prospective study revealed that histologic remission could predict reduced rates of hospitalization (OR=0.21).²⁵ Furthermore, patients with continued mucosal inflammation at follow-up may be at more than twice the risk of developing colorectal neoplasms than patients who have minimal to no mucosal inflammation.²⁶ Studies have indicated that histological remission is particularly associated with better patient outcomes.²⁷ Therefore, the combined definition of mucosal healing to include both endoscopic improvement and histological remission, can be valuable in determining long-term patient outcomes.^18,27-28

When choosing a treatment option, there are several clinical considerations associated with biologics and small molecules. A patient decision-making survey demonstrated that some of patients’ top concerns were related to efficacy, side effects, and ease of administration.²⁹ Another international survey of 500 gastroenterologists also cited side effects as a barrier when considering use of biologics.³⁰ There are many challenges associated with the initiation of advanced therapy options when treating moderate to severe UC. While patients want long-term efficacy, they may have safety concerns; thus, they are reluctant to consider advanced therapies. They may even view the need for advancing therapy as a sign of worsening disease.^31-33

Targeted therapies have allowed clinicians to shift from prescribing non-specific immunomodulators toward more targeted anti-inflammatories. As more is learned about the disease pathogenesis of UC, more treatment options targeting multiple mechanisms of action have become available. The mechanism of action of small molecules in both approved and in development therapeutic options target molecules that can reduce inflammation through inhibition of internal signaling pathways or modulation of lymphocyte migration.³⁴ Newer small molecule drugs have several advantageous characteristics, including ease of use with an oral route of administration and lack of immunogenetic concerns that may not require drug level monitoring.^35-38 Overall, targeted small molecule therapies seek to address specific causes of UC to improve clinical outcomes.

More patients receiving treatment with ozanimod, tofacitinib, and filgotinib achieved clinical remission than patients who were receiving placebo at both induction and maintenance time points.^14,15,23 Clinical remission was also achieved in both tumor necrosis factors (TNFi)-naive and TNFi-experienced patients with the use of ozanimod, tofacitinib, and filgotinib.^9,39,40 Small molecules offer the promise of clinical remission with fewer safety concerns through more specific targeting of inflammatory mechanisms.⁴¹

Like many of the biologic therapies, small molecules have unique initiation requirements prior to starting the medication and during treatment of UC. Screening and monitoring for infections should be conducted prior to initiating therapy with ozanimod, tofacitinib, or filgotinib.^39,42,43 An electrocardiogram is recommended prior to initiation with ozanimod to rule out any cardiac conditions that can increase the risk of bradycardia with S1P modulators.⁴² Screening for tuberculosis should be completed prior to use with filgotinib or tofacitinib.^39,43 Women of childbearing age should test negative for pregnancy prior to initiation with each of the small molecules and continue to use effective contraception during treatment and after discontinuation of treatment for 3 months.⁴² During treatment with ozanimod, filgotinib, and tofacitinib screening and monitoring for infections and examination of skin should be conducted. In addition, live vaccinations should be avoided during therapy with all three of these drugs.^39,42,43

Long-term safety data of targeted small molecules, such as ozanimod, tofacitinib, and filgotinib, can give clinicians more data and context with regard to the risk profile of each treatment option to best match each patient’s clinical presentation and concerns. Ozanimod has shown a low rate of serious adverse events that was comparable to placebo at the end of the maintenance period.¹⁴ In patients using filgotinib at 100 mg and 200 mg, the risk of serious infections, such as herpes zoster, were similar across all 3 treatment groups including placebo.²³ In patients with existing risk factors for venous thromboembolism (VTE) also receiving tofacitinib 10 mg twice a day—the higher range of the dose—VTEs have occurred.⁴⁴ In February 2019, the FDA issued a boxed warning regarding VTE with high doses of tofacitinib in patients aged >50 years old with a cardiovascular risk factor.⁴⁵ Looking across multiple indications in a larger patient pool, discontinuations of tofacitinib occurred in 48.2%, 13.9%, and 3.8% of patients with rheumatoid arthritis (RA), psoriasis, and ulcerative colitis, respectively, in an open-label, long-term extension study.^46-48 No new safety signals were seen with long-term treatment of ozanimod, and treatment emergent adverse events (TEAEs) were at low rates in both the UC and multiple sclerosis (MS) patient populations. Severe TEAEs occurred in 10.2% and 6.1% of both UC and MS patients, respectively, exposed to ozanimod.⁴⁹

With more known on the long-term safety data of these small molecules, it is helpful to consider them in the context of familiar biologic treatments. GEMINI LTS was an international, single-arm, open-label, phase 3 study of patients with moderately to severely active UC or Crohn’s disease (CD) which investigated the safety and efficacy of vedolizumab. The incidence of any adverse events or serious adverse events was 88% and 20%, respectively.⁵⁰ Another analysis looked at the safety of adalimumab across multiple indications (ie, RA, psoriasis [Ps], CD, ankylosing spondylitis [AS], UC, hidradenitis suppurativa [HS], psoriatic arthritis [PsA], non-infectious uveitis [UV], non-radiographic axial spondyloarthritis [nr-ax-SpA], and peripheral [pSpA]) in 77 randomized, controlled, open-label, and long-term extension studies. Serious infections were the most common serious adverse events across all indications, with the highest incidences in CD, UV, RA, and UC studies.⁵¹ The concerns seen with biologic therapies, such as serious infections, are not that dissimilar from those seen with small molecules.^50,51

While rare, progressive multifocal leukoencephalopathy (PML) is also a risk with some treatment options for UC. PML is a serious opportunistic viral infection of the brain caused by the John Cunningham virus (JCV), typically in immunocompromised individuals, that can lead to permanent disability or death.⁵² Many approved drugs that target the immune response have been associated with some cases of PML. Natalizumab has been associated with the most cases of PML, with over 800 cases reported in literature and the WHO Vigibase.⁵³ Other therapies, including methotrexate, azathioprine, and cyclosporine, all have at least 10 cases reported in the literature, whereas monoclonal antibodies infliximab and adalimumab have under 10 cases reported in the literature.

While some of these drugs used in UC have more cases of PML reported than others, it is important to note that direct comparisons should not be made with respect to case number. Many of these drugs have been available for longer periods of time or given to larger patient populations, which can presumably result in higher amounts of PML reported. Overall, the incidence of PML in many of the drugs used to treat UC remains very rare.

Small molecules and advanced therapies have demonstrated safety and efficacy in the treatment of moderate to severe UC. Treatment goals have evolved to include both endoscopic improvement and histologic remission as data has emerged supporting their association with improved long-term outcomes. Long-term safety data associated with the use of small molecules and biologics can further provide healthcare professionals and patients with insights for making treatment choices that can optimize patient outcomes and ultimately lead to a better quality of life in patients with UC.

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ECCO Faculty Q/A Session

1. Which score should be used in histological assessments? Which histologic measures are used for clinical decision making?
• Dr Dotan: The most used measures include the Geboes, Nancy and Robarts, and we use the Nancy index. Regardless of which scale is preferred, it’s important to have a common tool to understand what histological outcome is meaningful in prospective validated studies

2. What are your personal targets of mucosal healing?
• Dr Dotan Many patients can be on 5-ASAs for a long time and still not have histological remission; in such patients, we begin to implement combination therapies and gauge improvement based on prospective follow-ups

3. When you have a patient with moderate/severe UC who has failed conventional therapy and an anti-TNF treatment, how does this affect your choice of next therapy?
• Dr Dignass: I would not try another anti-TNF if they have already failed therapy. I would choose a medication with a new MOA and with a route of administration preferred by the patient

4. Given your understanding of the risks associated with JAK inhibitors, how do you counsel your patients on these risks?
• Dr Lindsay: We take into consideration any co-morbidities and patient risk factors, and collect a full blood panel to rule out any infections, while also discussing the way the drug works and what to monitor for while the patient is on the therapy

5. Do you think that the mechanism of action of ozanimod is an advantage or disadvantage?
• Dr Lindsay: The ability of this antitrafficking agent to lower lymphocyte levels without altering lymphocyte function, unlike other agents, is an advantage of the MOA. The risk of lymphopenia is due to the MOA of ozanimod, but the recent safety data across MS and UC allow gastroenterologists to better assess the impact of lymphopenia on infection rates compared to other immunomodulators

6. How do you manage the fear of zoster, since you spent some time talking about that?
• Dr Lindsay: I don’t think it’s a new issue for us, and its incidence is rare even though it occurs. Also, it is considered dose dependent with JAKi, so keeping people on the lowest dose seems to be the most appropriate strategy. Educating patients to identify symptoms and rapidly seek treatment, as well as potentially discontinuing the patient’s medication, is important

Disclaimer: This programme is not affiliated with ECCO. This symposium is intended, and should be interpreted, as an information session on scientific progress and latest developments and is not intended, in any manner, as a promotional event or any kind of inducement to prescribe or use any medicinal product(s).

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