Highlights in Crohn’s Disease From the American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting: Commentary

The American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting, which was held in Vancouver, Canada, this October, provided valuable insights into the management of Crohn’s disease (CD). Data focused on the efficacy, safety, and utilization of treatment options among several single-agent therapies, including upadacitinib, filgotinib, risankizumab, guselkumab, ustekinumab, and vedolizumab.

Upadacitinib

Upadacitinib is a synthetic smallmolecule therapy that targets the Janus kinase (JAK) mechanism of inflammation. JAK is a transmembrane enzyme that activates inflammatory pathways, adverse events (AEs), events leading to treatment discontinuation, and serious infections were similar with the 2 doses of upadacitinib (15 and 30 mg) and lower than those observed in the placebo group. This trend is often seen in trials of moderate to severe CD, in which patients receiving a placebo during maintenance phases tend to experience disease relapse or progression because of the lack of treatment. The adjudicated AEs did not show any cardiovascular events, nor were any significant venous thromboembolic (VTE) events noted among a cohort of patients who had severe IBD and would otherwise have had a higher risk for VTE. This analysis is of specific interest because the drug class labeling advises screening and risk assessment for thromboembolic complications, on the basis of prior studies in a high-risk cohort of patients with rheumatoid arthritis who were treated with tofacitinib.⁴ Overall, this analysis was helpful. It showed the benefit of the treatment in patients with moderate to severe CD and moderate to severe UC from a safety point of view. Also, it provided reassurance by not showing any additional safety signals associated with this specific therapy.

ABSTRACT SUMMARY Efficacy and Safety of Mirikizumab in Patients With Crohn’s Disease: 104-Week Extension Results From a Phase 2 Randomized Controlled Trial.

The SERENIT Y trial investigated the safety and efficacy of 3 dose levels of mirikizumab vs placebo in patients with moderately to severely active CD (Abstract P2109). During the extension study (weeks 53-104), patients received mirikizumab either intravenously or subcutaneously. Among the patients who showed endoscopic improvement after 12 weeks of induction therapy, rates of CDAI remission and PRO remission were maintained from week 52 through week 104. At week 104, the rate of CDAI remission was 66.7% with intravenous mirikizumab and was 61.0% with subcutaneous mirikizumab; the rate of PRO remission was 63.6% with intravenous mirikizumab vs 46.3% with subcutaneous mirikizumab. No unexpected AEs were observed.

The second study of interest, which I had the honor of leading, focused on the efficacy of upadacitinib in patients with CD; the Crohn’s Disease Activity Index (CDAI) was used as a measure of efficacy.⁵ This study and upadacitinib inhibits primarily JAK1.^1,2 In a study analyzing the safety of upadacitinib in an inflammatory bowel disease (IBD) pooled analysis of phase 3 maintenance studies, Panaccione and co-investigators reviewed trials in both CD and ulcerative colitis (UC) to explore the safety profile of this therapy for patients with these disorders.³ The study included 2 phase 3 double-blind placebo control trials and more than 1400 patients, with 246.4 patient-years of exposure to placebo, 353.1 patient-years of exposure to upadacitinib at 15-mg dosing, and 395.7 patient-years of exposure to upadacitinib at 30-mg dosing. Notably, the frequencies of serious holds relevance because of the difference in requirements between the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in assessing therapeutic efficacy for CD. In Europe, new therapies are evaluated with patient-reported outcomes of stool frequency and abdominal pain scores, without utilization of the CDAI, whereas in the United States, the FDA has continued to use the CDAI. The reanalysis of the efficacy of upadacitinib in moderate to severe CD with the CDAI was performed to evaluate whether this therapy had a similar benefit when that index was used. The post hoc analysis included 857 patients with a baseline CDAI of 220 points or more. The patients received 12 weeks of a 45-mg induction dose of upadacitinib or placebo. In all, 343 patients from the maintenance trial achieved a clinical response of a 100-point improvement in the CDAI at the 45-mg dose. They were then rerandomized to a maintenance dose of either 15 or 30 mg of upadacitinib or to placebo. The bottom line here for clinicians is to understand that when this other measure of response and remission and inclusion criteria were used, the efficacy of upadacitinib was similar to what had been described when the patient-reported outcomes were used alone. This finding reaffirms our current understanding and does not alter our perspective on this treatment approach.

Another noteworthy abstract involving upadacitinib, presented at the ACG meeting by Krugliak Cleveland, explored the utility of point-of-care intestinal ultrasonography (IUS) as a way to assess response to therapy and adjust treatments.⁶ The study was based on the hypothesis that if a clinician knows that disease is active or not responding to therapy as expected, the therapy can be adjusted sooner than can be done while waiting for the results of standard tests, such as colonoscopy and stool markers, or waiting for complications to arise. The study reviewed 30 of 105 patients receiving upadacitinib at our center, and these patients were stratified into groups; 11 received management guided by IUS, and 19 matched controls underwent conventional management without IUS. Among those patients who had access and were monitored with IUS, therapy was adjusted and remission was achieved statistically sooner than among those managed conventionally. This finding demonstrates the spreading wave of knowledge and excitement about IUS, both in the United States and globally, as point-of-care testing facilitates real-time decision making and therapy adjustments.

Filgotinib

Filgotinib is a different synthetic small molecule that selectively targets JAK1. Vermeire and colleagues presented the phase 3 DIVERSITY1 study, which looked at the efficacy and safety of filgotinib as a treatment for moderate to severe CD.⁷ The study compared 2 different doses (200 and 100 mg) with a placebo during a 10-week induction, followed by a subsequent maintenance study extending to week 58. In the maintenance study, patients responding to filgotinib were randomized in a 2:1 ratio to their specific induction dose or to placebo if they had an endoscopic response or a clinical remission. The disappointing result was that filgotinib at 200 mg was not superior to placebo in regard to both coprimary endpoints during the induction phase. However, it did prove efficacious in inducing CDAI clinical remission by week 10. Among patients achieving either endoscopic response or clinical remission in terms of abdominal pain and stool frequency by week 10, filgotinib at 200 mg demonstrated efficacy in sustaining endoscopic response until week 58 in the maintenance trial. Despite these positive aspects, because the therapy failed to meet its primary endpoints, it will not be considered an option for patients with CD. If you look at the trial results, a notable observation is the relatively high placebo rate during induction, which may have been due to concomitant therapies, including corticosteroids.

ABSTRACT SUMMARY Efficacy and Safety of Omilancor in a Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Crohn’s Disease.

A double-blind, parallel-group, phase 2 proof-of-concept study investigated 12 weeks of omilancor (n=12) vs placebo (n=11) in patients with moderately to severely active CD (Abstract P2215). The study demonstrated a superior rate of clinical remission with omilancor vs placebo (25.0% vs 9.1%; Δ=15.9%). Similar differences in clinical remission rates were observed with omilancor vs placebo in patients who had prior exposure to biologic therapy (Δ=20.0%) and patients who were biologic-naive (Δ=14.3%). The rates of clinical response and PRO -2 remission were also superior with omilancor (Δ=32.6% for both). Normalization of the fecal calprotectin level was reported in 33.3% of patients treated with omilancor vs 14.3% of those treated with placebo (Δ=19.0%). Omilancor was generally well tolerated, with no serious AEs that were considered related to study therapy.

Schreiber and colleagues also assessed the safety of filgotinib by looking at data from various trials, including DIVERSITY1 in CD and SELECTION in UC.⁸ Given the availability of other JAK inhibitors to treat IBD and the efficacy of filgotinib in treating moderate to severe UC in Europe and other regions, it is worth noting that the safety profile of filgotinib as a JAK inhibitor is similar to what has been observed with tofacitinib and upadacitinib, showing no new so safety signals. Infections were reported in approximately 25% to 34% of patients with CD and in 23% to 34% of patients with UC, with the rate of serious infections remaining below 2% in both populations. Malignancy occurred only in 1 patient with CD and 1 patient with UC. In the maintenance studies, 1 patient with CD and 1 patient with UC experienced a VTE event; similarly rare occurrences of major adverse cardiovascular events were noted, without any additional concerns raised. Importantly, no deaths occurred in the DIVERSITY1 trial. In the SELECTION trial, 2 deaths occurred, but neither was related to the drug as reported by the investigator and adjudicated by the steering committee.⁹ Overall, the safety assessment for filgotinib provides us with valuable information about the particular mechanism in patients with CD and UC, offering reassurance in terms of safety. However, it is disappointing that filgotinib will not be considered an option to treat patients with moderate to severe CD. Of note, it is not available for UC in the United States.

ABSTRACT SUMMARY The Anti-TL1A Antibody PRA023 Demonstrated Proof of Concept in Crohn’s Disease: Results of the Phase 2a APOLLO-CD Study.

The open-label, multicenter, phase 2a APOLLO CD study investigated the safety and efficacy of MK-7420 [PRA023] as induction therapy in patients with moderately to severely active CD (Abstract P3581). Among 53 patients who completed 12 weeks of induction monotherapy, the rate of endoscopic response was 26% and was significantly better than the rate with a historical placebo control (12%; P=.002). The rate of clinical remission was also superior with MK-7420 vs the historical placebo control (49% vs 16%; P<.001). Among patients with prior exposure to biologic therapy, the rate of endoscopic response was 33% and the rate of clinical remission was 39%. Efficacy was not affected by the concurrent use of steroids or immunosuppressants. No serious or severe AEs were considered related to the study therapy.

Ustekinumab

Ustekinumab, a monoclonal antibody that targets the protein p40, effectively inhibiting both interleukin 12 (IL-12) and IL-23, is available as a treatment for moderate to severe CD and moderate to severe UC. The highly anticipated additional results of the POWER study, initially introduced earlier in the year, were presented at ACG.¹⁰ This study compared the efficacy and safety of an additional intravenous (IV) dose of ustekinumab for reinduction vs subcutaneous dosing in patients who had lost response to standard ustekinumab maintenance therapy. Loss of response to various therapies in CD is well described and unfortunately remains a challenge in managing this condition. Therefore, understanding the potential to optimize existing therapies before transitioning to other treatments is of great interest. The hypothesis here is based on the presumption that sub-therapeutic levels of the drug may be affecting change in patients, leading to a loss of response. The thought was to investigate whether providing an additional IV dose could boost efficacy and recapture and redirect the patient’s response. At ACG, Feagan and colleagues presented updated results of the POWER study, also delving into the details inherent to the hypothesis and the study design, such as how the pharmacokinetics, exposure-response relationships, and the potential for immunogenicity affect how the drug works.¹¹ In the study, patients who had initially responded to induction with IV ustekinumab but later lost response were identified either by a rising CDAI score plus elevated C-reactive protein and fecal calprotectin levels or with endoscopy. This dual assessment ensured confirmation of a biological relapse, differentiating it from a merely symptomatic relapse. When a patient’s loss of response is assessed, it is important to distinguish between symptoms caused by active disease and those unrelated, always seeking objective measures to comprehend the situation, and also, naturally, to exclude infection. The bottom line from this complex analysis revealed that among 2015 patients with ustekinumab concentration data and one or more collected blood samples, on the basis of week 16 trough concentrations, no substantial difference was observed between those who were successfully recaptured and those who were not. However, patients did show increased trough levels with the IV dose vs continuation of the subcutaneous dose, which would have been expected. Although higher drug levels were observed, no significant difference in the clinical response was noted between the IV and the subcutaneous strategies. In a quartile analysis, a relationship was noted between increased exposure in the IV arm and differences in endoscopic remission, but not in the clinical response. The takeaway message for this study is that IV reinduction does not offer much clinical benefit and therefore would not be routinely recommended.

Risankizumab

Risankizumab, which has received approval for treating moderate to severe CD, belongs to the new generation of IL-23 inhibitors. The drug operates as a monoclonal antibody; targeting the protein p19, it is selective for IL-23 and does not affect IL-12.¹² This particular study, presented by Zinger and colleagues at ACG, focuses on the real-world experience when this therapy was used at the University of Chicago and reports induction data outcomes.¹³ The study involved a prospective analysis of clinical outcomes in patients with CD who received risankizumab. Clinical evaluations were performed at weeks 0, 2, 4, 8, and 12 with the Harvey Bradshaw Index (HBI). In all, 94 patients underwent ongoing follow-up for 12 weeks. After a rapid onset of action of risankizumab, with a median HBI reduction as early as 2 weeks, a plateau was reached by week 8, even before the 12-week endpoint. By week 12, 78% of the patients had achieved a clinical response, and 70% achieved clinical remission. Of great interest in this particular study was that most patients had previously received ustekinumab. Interestingly, when patients who had received ustekinumab were compared with those who were ustekinumabnaive, no statistical difference was seen in the likelihood of response. Given the similarity in the mechanisms of action of these 2 therapies, this finding is particularly noteworthy. Notably, the rate of corticosteroid-free clinical remission was higher in ustekinumab-naive patients than in those who were ustekinumab-experienced. Overall, the safety profile aligned with what has been observed in this class of therapy, demonstrating excellent safety. This real-world experience closely mirrors or even slightly surpasses what has been seen in clinical trials and gives us further insight into the utility of this therapy, even in patients previously treated with ustekinumab.

Guselkumab

Guselkumab, another p19 monoclonal antibody that selectively targets IL-23, has been studied in both UC and CD.¹⁴ At ACG, Panaccione and colleagues reported updates from the GALAXI 1 study, assessing patients with moderate to severe CD who had not achieved a clinical response at week 12 with guselkumab.¹⁵ Of the patients who received guselkumab at various doses, those who did not achieve a response were allowed to continue therapy. This post hoc analysis evaluated the patients who continued treatment. By week 24, 46% of the nonresponders had achieved a clinical response. Among those who were in the maintenance study up to week 48, 58.7% achieved clinical response and 47.6% achieved clinical remission. The concept of delayed response has been well documented with other therapies and is a standard approach in these trials, in which the study design of randomizing responders or focusing on post-induction responders and their maintenance outcomes is of particular interest. The secondary analysis that is often performed explores the outcomes of patients who took longer to respond but eventually did. Repeatedly, we have learned that this group of patients, even if they experience moderate improvement without achieving remission or a defined significant response by the trial endpoint, are likely to respond positively if treatment is continued for an additional induction period—in this case, 12 weeks. Those who do eventually respond are equally likely to do well during maintenance. The interpretation of this study suggests that it is beneficial for some patients to continue the therapy beyond week 12 to assess whether control of their CD can be achieved.

The other study of guselkumab, presented by Afzali and colleagues, reported 3-year outcomes in patients from the GALAXI 1 long-term extension.¹⁶ The average duration of follow-up in this analysis from baseline through week 152 was more than 100 weeks in the guselkumab group and 102 weeks in the ustekinumab comparator group. Overall, the 151 patients who were randomized to guselkumab and the 48 patients who were randomized to ustekinumab were treated in the long-term extension. The primary results demonstrated that patients continue to do well, with 54% in CDAI clinical remission and 34% in endoscopic response at week 144. In terms of safety, the mechanism of this particular drug is quite safe. Most infections were not serious and were mild to moderate, resolving without a requirement for drug discontinuation. As we have seen repeatedly with the IL-23 mechanism, no cases of active tuberculosis, opportunistic infections, anaphylaxis or serum sickness, major adverse cardiovascular events, or deaths occurred.

ABSTRACT SUMMARY Real-World Clinical Effectiveness and Safety of Vedolizumab and Ustekinumab in Bio-naïve Patients With Early Crohn’s Disease: Results From the EVOLVE Expansion Study.

A post hoc analysis based on 36 months of follow-up evaluated safety and efficacy outcomes in patients from the EVOLVE clinical trial who received vedolizumab or ustekinumab during the study as their biologic therapy (Abstract P0685). The analysis showed similar outcomes with vedolizumab vs ustekinumab in terms of cumulative rates of clinical response (81.6% vs 80.7%; P=.31), clinical remission (87.9% vs 85.0%; P=.74), and treatment (64.9% vs 78.1%; P=.49). However, the rate of mucosal healing was superior with vedolizumab (92.3% vs 89.0%; P=.03). Safety outcomes were also similar for the 2 biologic therapies in regard to serious AEs (P=.79), serious infections (P=.14), CD exacerbations (P=.91), CD -related surgeries (P=.18), and CD -related hospitalizations (P=.97).

Ustekinumab and Vedolizumab

The EVOLVE expansion study is a multicenter, real-world, retrospective analysis of patients with CD treated with ustekinumab or vedolizumab in Australia, Belgium, and Switzerland from 2016 to 2021. Ferrante and colleagues presented 2 different abstracts at ACG on the relative efficacy and safety of these therapies in patients with complex or noncomplex CD.^17,18 The first abstract explored patients with noncomplex CD who were bionaive and treated with vedolizumab, an anti-integrin therapy that targets the integrins related to lymphocyte trafficking in the gut, or with ustekinumab.¹⁷ Among the patients with noncomplex CD, the 2 therapies were similar in efficacy and the safety was excellent, with no significant differences. We have come to appreciate that both mechanisms are safe, and it is helpful to know that the therapies work well, especially in bio-naive patients. In general, when you treat patients with CD earlier, they are more likely to do well, and according to this retrospective multicenter analysis, they are equally likely to do so regardless of which therapy is used.

In the patients who had complex CD—which is of great interest because of the prevalence of complex disease presentations involving draining fistulas, hospitalization, or surgery—rates of efficacy and safety for ustekinumab and vedolizumab were also similar.¹⁸ CD exacerbations were reduced with both therapies, with a hazard ratio of 0.89. The rates of CD-related surgeries did not differ with the 2 drugs, and CD-related hospitalizations appeared to be reduced during the 36 months of review. The takeaway for clinicians is that both therapies exhibit efficacy and can be utilized in patients with complex presentations. My message would be to ensure that regardless of the chosen treatment, think carefully about measuring that it is actually doing what you need it to do. Remember too that these therapies have different mechanisms and may not work as well for patients with a variety of extraintestinal manifestations.