DDW 2018: Choice in patient management

IBD specialists have more treatment options than ever before; yet the optimal use of many agents, old as well as new, remains to be defined. A plenary session at DDW 2018 entitled “It’s still a free country: choice in IBD management” aimed to highlight the wide choice available to clinicians and patients.

Interview by Hannah Chatfield

Dr Charles Bernstein (Canada) reviews the improvements in the treatment of IBD, in particular the increase in choices for treatment, the emerging importance of the microbiome and managing other symptoms of IBD, including anxiety and depression.

In the first presentation, Professor Vipul Jairath from Western University Hospital in London, Ontario reminded the audience that 5-aminosalicylic acid continues to be widely prescribed in IBD in the era of biologics. A Cochrane review published in 2016 which included 53 studies with more than 8,500 patients found that 5-ASA was superior to placebo for inducing and maintaining remission in UC, but with no significant difference seen between 5-ASA and sulfasalazine or between different 5-ASA formulations.¹ This result was consistent with previous findings that oral 5-ASA preparations on the market are therapeutically equivalent at equimolar doses in UC.² Once daily dosing may have the added benefit of improving adherence with maintenance therapy in patients with quiescent UC.³ Doses of ≥2g/day have been shown to be more effective than <2g/day for inducing remission and preventing relapse, and UC patients with extensive disease can benefit from doses up to 4.8g daily.⁴ An important aspect of 5-ASA treatment that has gained considerable attention recently is its ability to protect against colorectal cancer (CRC). A meta-analysis of data from population-based cohort studies has shown that UC patients are at more than 2-fold higher risk of developing CRC, especially in male patients and patients diagnosed at young age and/or with extensive disease.⁵ A systematic review and meta-analysis published in 2017 showed that exposure to 5-ASA halved the risk of developing CRC among UC patients (RR 0.50, 95% CI 0.38, 0.64).⁶

In CD, recent Cochrane reviews have shown that 5-ASA is not significantly superior to placebo for inducing and maintaining remission in mild to moderate CD,^{7, 8} and inferior to corticosteroids.⁷ Clinical guidelines for the management of CD published by the ACG earlier this year state that oral mesalamine should not be used to treat active CD, and oral 5-ASA is not recommended for long-term treatment.⁹ Despite this data, 5-ASA is the most commonly prescribed treatment in CD and co-prescription rates are high even in moderate to severe CD. A systematic review and meta-analysis of 42 induction and 10 maintenance trials showed that 44% of patients were co-prescribed 5-ASA in the former and 49% in the latter; in biologic trials 35% of patients were co-prescribed 5-ASA.¹⁰ The investigators hypothesised that prescriber and patient preference for beginning with less aggressive therapy is what drives this.

Dr Jairath also touched upon corticosteroids, which have been a mainstay of IBD treatment since the first published reports in UC in the 1950s. Dr Jairath stressed that although both conventional steroids and budesonide are highly effective for inducing remission in UC and CD,^11-13 their use is associated with serious side effects and adverse outcomes¹⁴ and they should therefore be limited to a defined time period with a clear exit or bridging strategy. Safer, second-generation steroids such as budesonide MMX, which targets delivery to the colon and thus has reduced systemic availability, should be considered ahead of systemic steroids such as prednisone.

Next, Professor Edward Loftus from the Mayo Clinic in Rochester, Minnesota reviewed the role of azathioprine in IBD. Although Cochrane reviews published nearly two decades ago showed that azathioprine was effective for inducing¹⁵ and maintaining¹⁶ remission in CD, more recent studies have shown that early treatment with azathioprine is not superior to placebo or conventional management for inducing remission in active CD.^{17, 18} A later Cochrane review concluded that although azathioprine was superior to placebo for maintaining remission in CD, the evidence for this was of low quality and further that the use of azathioprine is limited by a high rate of adverse effects.¹⁹ Instead, the key role for azathioprine in today’s treatment landscape is as combination therapy with anti-TNF agents. The SONIC study showed that azathioprine in combination with infliximab was significantly superior to both azathioprine monotherapy and infliximab monotherapy for inducing and maintaining corticosteroid-free remission in patients with moderate to severe CD.²⁰ Combination therapy was also associated with significantly higher rates of mucosal healing, and higher serum anti-TNF levels.²⁰ Likewise in UC, combination therapy with azathioprine and infliximab was associated with significantly higher rates of steroid-free remission, clinical response and mucosal healing than either agent as monotherapy.²¹ Managing the toxicity of azathioprine and the risk of serious infections with combination therapy is key in clinical practice, and Professor Loftus advised that thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) assays should be used to predict the starting dose and that blood counts, liver function and thiopurine metabolites should be monitored to optimise efficacy and tolerability.

In his overview of currently available biologic therapies in IBD, Professor William Sandborn from UCSD began by reminding the audience that in both UC and CD, the anti-TNF agents infliximab, adalimumab, golimumab and certolizumab have all been shown to be highly effective for inducing and maintaining remission in moderate to severe disease.^22-31  However, the anti-TNF class is associated with significant toxicity including infusion reactions and delayed hypersensitivity reactions, antibody formation, non-Hodgkin’s lymphoma, serious/opportunistic infections, and in recent reports also CNS demyelination. For this reason, novel biologic agents are expected to meet an important need for effective treatments with more favourable safety and tolerability profiles. Professor Sandborn described the gut-selective anti-α4β7 integrin antibody vedolizumab as the safest among the current agents. Vedolizumab has been shown to be significantly superior to placebo for inducing clinical remission and mucosal healing in moderate to severe UC³² and CD,³³ with no clear signal for either serious/opportunistic infections or cancer. Nor has vedolizumab been linked to herpes zoster infections of hyperlipidaemia; both these adverse events have been reported for oral JAK inhibitor tofacitinib, another novel IBD agent which Professor Sandborn described as ‘a small molecule with the efficacy of a biologic.’ A recent systematic review with network meta-analysis proposed that based on the available data, infliximab and vedolizumab should be first-line treatment options for inducing remission and mucosal healing in moderate to severe UC, with tofacitinib ranked as the most effective second-line agent in UC patients who have failed biologic therapy.³⁴ In the CD analysis infliximab and adalimumab were the preferred first-line treatments for inducing remission, and ustekinumab the most effective as second line although the investigators cautioned that head-to-head trials are necessary to draw firm conclusions.³⁵ Professor Sandborn stressed that clinicians treating IBD patients have an obligation to be aware of the latest data and to apply it to the best of their ability for each individual patient – merely because an agent is available for use, it does not follow that it necessarily should be used!

The session concluded with a presentation by Professor Stefan Schreiber from Kiel in Germany in which he summarised the current biosimilars position and highlighted how cost pressures may in fact be limiting the choice for clinicians and patients, despite the growing number of new treatments. Drugs defined as ‘specialty medicines’, that is, high-cost, high-complexity agents (often biologics, and often drugs for injection or infusion) that are used to treat complex or rare chronic conditions including IBD, now account for 35% of the drug spending in Europe, with a growth rate of 17.6%. Biosimilars represent a huge potential market – at the time when the infliximab patent expired, its market share in Europe was worth just short of 2 billion Euros. For adalimumab which expired earlier this year in Europe, the market is worth over 3 billion Euros. The regulatory framework in which biosimilars are characterised differs from that for originators – whereas the regulatory emphasis for originator biologics is on phase 2 and 3 clinical trials, the focus of the regulatory process for biosimilars is on physicochemical and biological characterisation of the molecule and PK/PD equivalence studies. Biosimilars can be approved for additional indications without having to undergo comparative clinical trials, through a process known as extrapolation. Indication extrapolation can be used in cases where the mechanism of action and/or the receptor target of the innovator are known and identical across all indications, and provided that equivalence and clinical comparative studies have been performed in the indication that is the most sensitive to small difference in efficacy and safety. An example of this is the PLANETRA study in which biosimilar infliximab was compared with the originator in rheumatoid arthritis,³⁶ and the results extrapolated to UC, CD and psoriasis. The recently published NOR-SWITCH randomised controlled trial showed that patients who switched from originator to biosimilar infliximab (CT-P13) had non-inferior outcomes over a study period of 52 weeks to those who continued treatment with originator infliximab across all approved indications.³⁷ Similar results were reported in a study from Professor Schreiber’s own centre which showed that switching between originator and biosimilar infliximab was associated with comparable efficacy, safety and immunogenicity in moderate to severe CD at one year.³⁸ In his talk Professor Schreiber predicted that biosimilars are set to become an inescapable part of clinical practice and that this competitive pressure will result in new trials and improvements in therapy through novel mechanisms of action. However, Professor Schreiber cautioned that whilst switching to a biosimilar will be the choice of the treating physician within the setting of a multidisciplinary team and in consultation with the patient, automatic substitution at the pharmacy level for reimbursement purposes may pose a greater challenge. Several European countries including France and Germany already allow automatic substitution of reference medications without consulting the prescriber.

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