Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that includes an annual national meeting, regional satellites in both official languages, www.mentoringinibd.com, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the contributing editor, Dr William J. Sandborn, at the 21st annual national meeting, Mentoring in IBD XXI: The Master Class, held virtually, November 6, 2020.
The concept of matching drugs to patients with inflammatory bowel disease (IBD) includes sequencing of available drugs, incorporation of new agents, and the individualization of treatment strategies (precision medicine). This review presents a summary of current knowledge on sequencing in ulcerative colitis (UC) and Crohn’s disease (CD), informed by network meta-analyses and head-to-head trials.
Multiple early- and late-stage new agents are being evaluated for IBD, many of which are likely to be approved over the next several years. This review also provides some information on agents in development, including some encouraging clinical trial data with novel biologics and small molecules.
Finally, precision medicine, which includes clinical decision support tools, therapeutic drug monitoring, and companion diagnostic testing is making its way into clinical practice in IBD. The current state of precision medicine for IBD is also discussed in brief below.
In UC, there are no prospective data comparing all of the various potential first- and second-line advanced therapies (i.e., biologics and novel small molecules). However, there is one published head-to-head study (VARSITY: vedolizumab vs. adalimumab) available,(1) and other authors have used network meta-analytic techniques in an attempt to provide evidence-based guidance for treatment selection among all the available advanced therapeutic options.
One such network meta-analysis published in 2020 included data for TNF inhibitors (adalimumab, golimumab or infliximab), the IL-12/23 inhibitor ustekinumab, the anti-integrin vedolizumab and the JAK inhibitor tofacitinib compared with placebo or another active agent in studies published up to September 30, 2019.(2) The key efficacy outcomes were induction and maintenance of remission and endoscopic improvement, while the key safety outcomes were serious adverse events and infections.
The analysis determined that infliximab was ranked highest for induction of clinical remission and endoscopic improvement in biologic-naïve patients, followed by vedolizumab. Among patients with prior exposure to anti-TNF therapy, ustekinumab and tofacitinib were ranked highest for induction of clinical remission (Table).(2) Vedolizumab was found to have the lowest risk of infections in maintenance trials.
The head-to-head VARSITY trial, mentioned above, included 769 patients with moderately to severely active UC, who were randomized to receive either adalimumab or vedolizumab.(1) Most of the subjects were biologic-naïve, but approximately 20% had documented failure with a prior TNF inhibitor. The primary endpoint was clinical remission at week 52.
For the primary outcome, vedolizumab was found to be superior to adalimumab (31.3% achieved clinical remission at week 52 in the vedolizumab group vs. 22.5% for adalimumab; 8.8% absolute difference, 95% CI 2.5 to 15.0; p=0.006). A number of secondary endpoints were also in favour of vedolizumab, including endoscopic improvement. However, corticosteroid-free clinical remission was not significantly different between the groups, and there was a trend towards benefit for adalimumab, as that endpoint was achieved by 12.6% of the patients in the vedolizumab group and 21.8% of the adalimumab group (absolute difference, -9.3%; 95% CI, -18.9 to 0.4). Infection rates were lower with vedolizumab vs. adalimumab (23.4 vs. 34.6 events per 100 patient-years).(1)
In CD, there are currently no published head-to-head studies available for approved agents. However, similar to the work done in UC, network meta-analysis provides some guidance for treatment selection. One of these analyses, published in 2018, included studies of approved anti-TNF agents, vedolizumab and ustekinumab up to May 31, 2017.(3) The key efficacy outcomes were induction and maintenance of clinical remission and the key safety outcomes were serious adverse events and infections.
As shown in the Table, infliximab and adalimumab were ranked highest for induction of clinical remission among biologic-naïve individuals, while for those patients who had prior anti-TNF exposure, adalimumab and ustekinumab were ranked highest. Ustekinumab was associated with the lowest risk of serious adverse events and infection.(3)
While no head-to-head studies have been published comparing approved agents in CD, there is one ongoing trial comparing adalimumab and ustekinumab. This study, the SEAVUE trial, has enrolled 386 biologic-naïve patients with moderately to severely active CD. The primary endpoint is clinical remission at week 52, and the trial is expected to be completed in June 2021.(4)
A host of systemic agents are currently being investigated for use in IBD. These include both biologics and small molecules.(5) Many of these agents are already being investigated in phase 3 studies, including anti-IL-23(p19 subunit) agents brazikumab, guselkumab, mirikizumab and risankizumab; the oral JAK inhibitors filgotinib and upadacitinib and the oral S1P modulators ozanimod and etrasimod.
Two of the anti-IL-23(p19) class agents under phase 3 study in IBD are already approved for use in psoriatic disease in Canada (guselkumab, risankizumab).(6,7) As an example of the phase 2 results already available for this class, guselkumab was evaluated in a placebo-controlled study in CD that also included an ustekinumab reference arm (GALAXI 1).(8) In the primary endpoint analysis for that study, the rate of clinical remission at 12 weeks was 53% for the combined guselkumab group (three different doses), 45% for ustekinumab and 16% for placebo (p≤0.001 for each active therapy vs. placebo).
Ozanimod is the agent in this class with the most advanced clinical trial program. Results from the induction and maintenance periods of the phase 3 True North study were presented in the autumn of 2020.(9,10) This study enrolled 645 subjects with moderate-to-severe UC who did not adequately respond to prior treatment. In the induction phase, a total of 645 patients were randomized to receive ozanimod (n=429) or placebo (n=216); 457 of these individuals were re-randomized to maintenance treatment with either ozanimod (n=230) or placebo (n=227).
In the induction phase, ozanimod demonstrated superiority over placebo for the primary endpoint of clinical remission at week 10 (18.4% versus 6.0%; p<0.0001; Figure).(9) In the maintenance phase, ozanimod was also found to be superior to placebo in rates of clinical remission at week 52 (37.0% vs. 18.5%; p<0.0001) (Figure).(10) Clinical response, endoscopic improvement and mucosal healing were all also significantly in favour of ozanimod at both time points, as was corticosteroid-free remission at week 52.(9,10)
In addition to the work being done with systemic agents, considerable research is also being conducted with approaches that have more local action on the intestinal tract. These modalities include new and old small molecules (e.g., mesalamine, budesonide, izencitinib), antisense agents, antibodies and peptides. This promises to be a fertile area of research for years to come.
Combination therapy is a well established, evidence-based practice in IBD. In CD, for example, more than a decade ago, the SONIC trial showed that combining infliximab and azathioprine was associated with better outcomes than either agent alone.(11)
The focus more recently is on the potential efficacy and safety of combining biologics and advanced small molecules with complementary mechanisms of action. Some of these are being actively investigated in clinical trials. This includes the triple combination of vedolizumab, adalimumab and methotrexate for patients with high-risk CD,(12) and the combination of guselkumab and golimumab for moderate-to-severe UC.(13)
Precision medicine is a collective term that includes tools to help clinicians and their patients select the most appropriate therapy for each individual situation. In the context of IBD, this could include clinical decision support tools (CDSTs), therapeutic drug monitoring (TDM), and companion diagnostic testing. These elements are all making their way, in varying degrees, into clinical practice in IBD.
One of the CDSTs that has been developed used data from the aforementioned GEMINI 1 trial with vedolizumab to identify patients most likely to enter corticosteroid-free remission during vedolizumab therapy.(14) This tool was then validated using data from 199 patients treated with vedolizumab in routine practice in the United States. The tool uses a points system based on five baseline variables: history of bowel surgery (yes or no), history of anti-TNF therapy (yes or no), history of fistulizing disease (yes or no), baseline albumin (points per unit), and baseline CRP (points by CRP range). This tool proved to be able to identify patients most likely to benefit from reducing intervals of vedolizumab administration due to lack of initial response.(14)
TDM is a more well-known example of precision medicine that has proven to be particularly useful for individuals treated with anti-TNF therapy. Algorithms exist to guide clinicians on appropriate interpretation and action based on TDM results.(15)
Biomarkers may also play a role in precision medicine, although this field still requires validation for current therapies. One example from the IBD literature where a biomarker was indeed found to be predictive of outcomes was the measurement of serum IL-22 at baseline among subjects treated with the anti-IL-23 agent brazikumab.(16) In a phase 2 study with this agent, subjects with higher baseline serum concentrations of IL-22 were found to be more likely to respond to brazikumab vs. placebo compared with lower baseline IL-22 concentrations.(16)
The care of patients with IBD continues to evolve. Great strides have been made over the past decade, and the promise of future enhancements is evident in many areas of ongoing research. To provide optimal care to individuals with IBD, specialists will need to be familiar with sequencing an ever-increasing number of IBD therapeutics, as there is a large pipeline of new agents for IBD, including late-stage development for JAK inhibitors, anti-p19 (interleukin 23) antibodies, and S1P modulators. The positioning and sequencing of biologics and novel small molecules can be informed by network meta-analyses and head-to-head trials. In addition, multiple agents targeting gut delivery are in early-stage development. Beyond the therapeutics themselves, precision medicine will also play an increasing role in the care of IBD patients as these are validated and become widely available.
Priya is a 42-year-old director at an IT company. She travels extensively for work and is starting an executive MBA in eight weeks.
She was diagnosed five years ago with left-sided ulcerative colitis. She has been maintained on 5-ASA 3 g/day PO plus 5-ASA enemas on demand. Over the last eight months, she has required three prednisone tapers. Thiopurines were discussed, but she was not comfortable with their safety.
Current Canadian guidelines for the management of UC are now more than five years old.(17) While many of the principles that guide therapy remain true, there has been a substantial amount of important research published since then and the number of therapeutic options has increased.
5-ASA is listed as one of the potential first-line options in the Canadian guidelines. For those who fail this therapy, the guidelines recommend considering changing therapy to one of the other approaches (thiopurine, anti-TNF ± thiopurine or methotrexate or vedolizumab ± thiopurine or methotrexate).
At the time of writing of the guidelines, neither ustekinumab nor tofacitinib were available for this indication. However, in the current context, each of the options presented here is approved in Canada for the treatment of moderate-to-severe UC. While there may be access restrictions for some people depending on their coverage, each is a reasonable choice to consider.
In UC, network meta-analysis has suggested that infliximab and vedolizumab may be the most effective agents in patients who are naïve to biologic therapy.(2) Importantly, these analyses have included all of the options that are presented here.
There has also been a prospective, head-to-head clinical trial in UC (VARSITY) in which vedolizumab was found to be superior to adalimumab.(1) At week 52, clinical remission was observed in a higher percentage of patients in the vedolizumab group than in the adalimumab group (31.3% vs. 22.5%; p=0.006). Endoscopic improvement rates were also significantly better with vedolizumab (39.7% vs. 27.7%; p<0.001). There was no significant difference in corticosteroid-free clinical remission rates, but the trend in this endpoint numerically favored adalimumab (21.8%) compared to vedolizumab (12.6%).
She was started on biosimilar infliximab as per her private insurance company’s tiering. She responded well clinically, biochemically and endoscopically. Her MBA progressed well. However, her symptoms returned after nine months, with elevated inflammatory markers. Therapeutic drug monitoring (TDM) revealed an undetectable trough infliximab level and low-titre anti-drug antibodies.
The results of the TDM (undetectable infliximab trough level and presence of anti-drug antibodies) suggests that it is time to switch from infliximab to another agent. A supratherapeutic dose is highly unlikely to be effective.(18)
The Canadian UC guidelines recommend switching to another anti-TNF agent or to vedolizumab.(17) Again, remember that at the time of writing, tofacitinib and ustekinumab were not available options. Both tofacitinib and ustekinumab have, however, demonstrated efficacy in second-line use after TNF inhibitors.(2) Indeed, network meta-analysis has suggested that tofacitinib and ustekinumab may be the most effective agents in patients who have failed biologic therapy.(2)
The authors of the most recent meta-analysis noted moderate confidence in estimates supporting the use of tofacitinib and ustekinumab over adalimumab (tofacitinib vs. adalimumab: OR, 11.05; 95% CI, 1.79–68.41; ustekinumab vs. adalimumab: OR, 10.71; 95% CI, 2.01–57.20), and over vedolizumab (tofacitinib vs. vedolizumab: OR, 6.18; 95% CI, 1.00–38.00; ustekinumab vs. vedolizumab: OR, 5.99; 95% CI, 1.13–31.76) for induction of clinical remission in patients with prior exposure to TNF inhibitors.(2)
There may also be opportunities to enroll in clinical trials; there are many novel therapies in development for the management of UC.
Tanya is a 29-year-old tattoo artist. She was diagnosed with Crohn’s colitis three years ago. She was treated with sulfasalazine and several courses of oral budesonide. She also adopted a specific carbohydrate diet and uses CBD oil regularly to control symptoms and improve sleep. Medical history includes asthma and depression. At a scheduled colonoscopy, you found deep serpiginous ulceration in the rectum, distortion of the cecum, and extensive aphthous ulceration in the ileum to at least 10 cm. She refused systemic steroids, as she had a bad experience when treated with them for asthma as a child.
This patient’s persistent endoscopic activity, including deep ulcerations, despite sulfasalazine and oral budesonide clearly suggests a change of therapy is indicated. Her refusal to take systemic steroids removes that option from the discussion.
For a patient in this situation, the Canadian guidelines for Crohn’s disease (CD) suggest either a biologic (± thiopurine) or methotrexate (± prednisone).(19) Any of the available biologic therapies would therefore be among the options for this patient, including: intravenous anti-TNF (infliximab) with or without azathioprine; subcutaneous anti-TNF (adalimumab or golimumab); anti-IL-12/23 (ustekinumab); or anti-integrin (vedolizumab).
To date, there have been no head-to-head trials published comparing the different approved biologic agents in this setting, but there are several underway, including a comparison of ustekinumab vs. adalimumab.(4) Additionally, a study comparing guselkumab (an agent currently approved for psoriasis, which targets the p19 cytokine subunit in IL-23 and IL-39) vs. ustekinumab has been presented and publication is expected in 2021.(9,10)
In CD, network meta-analyses have suggested that infliximab and adalimumab may be the most effective agents in patients who are naïve to biologic therapy, and that ustekinumab may be the most effective agent in patients who have failed biologic therapy.(3) There may also be opportunities to enroll in clinical trials; there are many novel therapies in development for the management of CD.
After a discussion of the options, Tanya chose to start on vedolizumab, as she found its safety profile to be appealing. She also heard it would soon be available for self-injection. She does well clinically.
She attends her colonoscopy scheduled after one year of vedolizumab. She has residual erythema and scarring, but no ulceration. In the recovery room she is excited to tell you that she is engaged and wants to have children soon.
Although Canadian guidelines for CD recommend continuing vedolizumab for patients who are responding to this therapy,(19) the fact that the patient would like to get pregnant does have an impact on treatment decisions. There are Canadian guidelines that specifically discuss the management of IBD in pregnancy.(20) However, they offer little guidance with respect to the use of vedolizumab in this setting. At the time of writing (2016), the authors mentioned only a small case series of 24 pregnancies(21) and stated that it would be premature to provide guidance for vedolizumab at that time.
Since then, there has not been much additional information published, although in a prospective comparison study published in 2019, which included 24 women exposed to vedolizumab, the authors concluded that vedolizumab appears to be of low risk during pregnancy.(22) Despite the relative lack of data, American guidelines do suggest that vedolizumab can be continued during pregnancy.(23)
Switching to ustekinumab is also an option, although the evidence base for its use among pregnant women with IBD is also not very large.(20,23,24) The Canadian IBD in pregnancy guidelines treated ustekinumab in the same manner as vedolizumab, making no recommendation due to the lack of evidence.(20) The American guidelines also treated ustekinumab in the same manner as vedolizumab, acknowledging the relative lack of evidence, but suggesting that its use can continue during pregnancy.(23)
Much more robust data are available for TNF inhibitors, which have led to more confident recommendations by expert consensus groups. The Canadian guidelines state that “In pregnant women with IBD on anti–tumor necrosis factor (anti-TNF) maintenance therapy, we recommend continuation of anti-TNF therapy.”(20) For this patient, switching to one of the TNF inhibitors would be a logical choice.
Bruce is a 65-year-old mining engineer, looking forward to retirement. He has a 25-year history of pan-ulcerative colitis. He was treated with golimumab until two years ago, when his disease reactivated despite biweekly dosing and TDM showing no anti-drug antibodies. He was then switched to ustekinumab, but has persistent active disease despite recent intravenous reinduction and escalation to dosing every four weeks. Medical history includes previous actinic keratoses, hypertension and seronegative arthritis.
In the event of lack of response to a biologic, Canadian UC guidelines suggest switching to another biologic.(17) However, at the time of writing, tofacitinib was not an available option (nor was ustekinumab, for that matter).
He has now tried and failed a TNF inhibitor and ustekinumab. One might consider trying another TNF inhibitor, or switching to a biologic with another mechanism of action (e.g., vedolizumab)
Another option is to switch to tofacitinib. Network meta-analysis has suggested that tofacitinib and ustekinumab may be the most effective agents in patients who have failed biologic therapy.(2) The authors of the most recent meta-analysis noted moderate confidence in estimates supporting the use of tofacitinib over vedolizumab: OR, 6.18; 95% CI, 1.00–38.00 for induction of clinical remission in patients with prior exposure to TNF inhibitors.(2) Tofacitinib may also help with his arthritis, whereas vedolizumab would not.
John K. Marshall, MD MSc FRCPC AGAF, Director, Division of Gastroenterology, Professor, Department of Medicine, McMaster University, Hamilton, ON
William J. Sandborn, MD, Distinguished Professor of Medicine, Chief, Division of Gastroenterology, Director, UCSD IBD Center, University of California San Diego, La Jolla, California USA
Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Karen I. Kroeker, MD MSc FRCPC, University of Alberta, Edmonton, AB
Cynthia Seow, MBBS (Hons) MSc FRACP, University of Calgary, Calgary, AB
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON
IBD Dialogue 2021·Volume 17 is made possible by unrestricted educational grants from…
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