Raising the Bar in Inflammatory Bowel Disease: A KOL Perspective

August 2023

Dr. Anthony Starling, Vice President

Advanced combination treatment (ACT) combines biologic agents and/or oral small-molecule drugs. The opportunities for ACT to enter the inflammatory bowel disease (IBD) market will likely increase as companies develop evidence to support this approach and the introduction of biosimilars makes it more affordable. Janssen may lead in this field due to its in-house portfolio of products that could be readily combined. Other companies could choose to add their assets to already or soon to be available biosimilars, similarly to Boehringer Ingelheim, whose BI-706321 kinase inhibitor is being studied in combination with ustekinumab.

During Digestive Disease Week (DDW) 2023, key opinion leaders (KOLs) noted two key areas where pharmaceutical companies could improve the drug development process and, possibly, outcomes in IBD:

Simplify the clinical trial process: Clinical trials are growing in number and complexity, leading to recruitment and retention issues
Develop novel strategies to drive efficacy (remission) rates: Despite numerous IBD drug approvals over the last couple of decades, long-term remission rates continue to be modest (30-50%) and biomarkers of efficacy remain elusive

Simplify the clinical trial process

More trials mean more competition for patients, which is leading to lower recruitment rates

A recent analysis¹ showed an alarming drop in recruitment rates in the 20 years (1998-2018) since the initial approval of infliximab for an IBD indication. During that period, recruitment for trials in moderate-to-severe ulcerative colitis (UC) decreased from 0.32 to 0.13 patients per site per month, and recruitment for trials in moderate-to-severe Crohn’s disease (CD) decreased from 0.65 to 0.10 patients per site per month.

These trends are accompanied by a rise in the number of clinical trials over the same period, as seven trials in moderate-to-severe IBD in 2008 (three in UC and four in CD) increased to 147 clinical trials by 2018 (84 in UC and 63 in CD). KOLs at DDW suggested the total figure has since grown to approximately 240 trials in 2023. Not surprisingly, KOLs have noted a difficulty in recruiting patients for drugs not considered to be novel or ‘the next big thing’.

Increasing trial complexity is setting a high bar for success and is leading to increased screening failure rates

The historical goals for IBD treatment involved improving symptoms and quality of life. Recently, these goals have evolved to include prevention of disease progression and the treatment’s impact on subsequent surgery, disability or cancer risk. Accordingly, the endpoints of clinical trials have evolved. In UC, for example, these have changed from clinical remission to endoscopic remission and then to disease clearance (a combination of clinical, endoscopic and histologic remission). The requirement for more ambitious endpoints has increased the number of patients required to demonstrate meaningful differences.

Regulatory requirements and the pharmaceutical industry’s response to these have become burdensome to the development of new IBD therapies.

More potential subjects are being excluded from trials due to central endoscopy requirements and concomitant medications.

Potential solutions include reducing trial requirements, increasing patient involvement and using a centralized approach to trial design and execution:

KOLs are calling for sponsors to make clinical trials simpler, smaller and more attractive to patients to boost recruitment, participation and retention.

Involving patients earlier in the trial design process can help improve the acceptability of trial designs, and a more patient-centric approach can reduce the impact of clinical trials on day-to-day activity. Such an approach could include remote monitoring and data collection, at-home testing for blood and stool samples, and (validated) patient-reported outcome measures.

A centralized trial design and execution system that incorporates master protocols and central reading, using optimized inclusion algorithms and artificial intelligence (AI), might prove useful in streamlining the trial process.

Develop novel strategies to drive efficacy rates

Despite a steady influx of new drugs with different modes of action (MoAs) into the IBD space, objective evidence of disease remission, such as endoscopic healing in UC and CD, remains modest. Clinical remission rates remain in the 30-50% range, and KOLs feel that novel strategies are required to produce rates in the 60-80% range. The most obvious novel strategies would be the use of precision biomarkers or ACT.

Precision biomarkers are ‘a long way off’ from widespread use in clinical practice

Although a number of novel therapies and MoAs have entered the market over the last 20 years, the ability to use them in a rational, targeted way remains elusive. Clinicians continue to rely on clinical markers with poor accuracy and limited predictive value, even though the evidence for their use is derived from retrospective studies and loose definitions of predicted outcomes.

The heterogeneity of IBD suggests the need for multiomics data analysis, which could be made possible by exploiting recent advances in AI and machine learning tools. Multiomics are being increasingly used for diagnosis, prognosis and outcome predictions, although their use in IBD remains in the early stages of development, is unvalidated and continues to be the remit of academic centers. As such, KOLs believe that useful precision biomarkers are several years away from inclusion in clinical practice.

ACT is in the early stages of development

Combination therapy with a biologic agent and an immunosuppressant is well established in the management of IBD. Interest is now growing in the use of ACT, an approach that uses two or more advanced treatments (biologic agents and/or oral small-molecule drugs) to maximize remission rates in IBD patients. The promise of ACT has been demonstrated in a number of case reports and retrospective studies although randomized prospective trials are few and far between.

Case reports and retrospective studies have generally noted improved outcomes without the development of new safety signals. The most common combinations studied were:

• Vedolizumab (Entyvio, Takeda) plus ustekinumab (Stelara, Janssen)
• An anti-TNF agent plus vedolizumab or ustekinumab
• Tofacitinib (Xeljanz, Pfizer) plus a biologic (e.g., vedolizumab or ustekinumab)

A recent paper² summarized the possible ACTs in IBD as follows:

However interesting, these observations require validation in randomized controlled clinical trials.

The first clinical trial to show that ACT was effective and safe was the VEGA study of golimumab (anti-TNF) plus guselkumab (anti-IL-23) in patients with moderate-to-severe UC who were naïve to biologic therapy. This study demonstrated that combination therapy resulted in a greater clinical response than that seen with either agent alone. Endoscopic improvement and histologic remission rates were twice as high for the combination therapy, for both induction and maintenance. No safety issues were reported for combination therapy, reflecting real-world experiences.

The EXPLORER trial demonstrated endoscopic and clinical remission rates of 34.5% and 54.5%, respectively, at 26 weeks for high-risk CD patients receiving triple therapy of vedolizumab, adalimumab and methotrexate.

Although active clinical trials of ACT remain few in number (see table below), and regulatory approvals are ‘at least five years away’, KOLs remain optimistic about the advantages of such an approach.

Multiple ACT strategies are envisioned to move forward in the clinic

KOLs see several different approaches to the clinical development of ACT:

• Company portfolio strategy: Janssen (infliximab, ustekinumab, golimumab, guselkumab) and AbbVie (adalimumab, risankizumab) were cited as being ‘obvious’ companies to develop an ACT approach due to having numerous assets in house
• Backbone strategy: Anti-α4β7 or anti-IL-12/23 treatments were mentioned as particularly good candidates to add to assets with other MoAs due to their safety profiles
• Small-molecule and biologic agent: Upadacitinib (selective JAKi) + risankizumab (anti-IL-23) and ozanimod (S1P receptor modular) + vedolizumab (α4β7) were the most commonly mentioned combinations
• All-oral approach: KOLs feel this option would benefit young and elderly patients and those with needle phobias

From a regulatory point of view, KOLs suggest that combined efficacy must be demonstrated in a Phase III clinical trial and the results need to show a clinical remission rate 10% greater than the active control. Ideally, remission rates for ACT should be above 60%.

KOLs note that clues to the most effective combinations may well come from similar planned trials in rheumatology.

While ACT holds much promise, it is still in the early stages of development, and many additional questions need to be addressed, such as:

• What is the optimal duration?
• What costs will be involved?
• What is the optimal combination?
• Is combination therapy better than sequential therapy?
• Which patients are most likely to benefit?

Biosimilars could address the ‘financial toxicity’ of ACT and establish ustekinumab as a backbone for combination therapy

In addition to the already approved infliximab biosimilars, a wave of adalimumab biosimilar approvals is expected to flood the market in 2023, with as many as 11 assets potentially reaching the market by the end of next year. This is expected to have a huge impact on the cost of IBD treatment. The annual cost of the adalimumab biosimilar branded as Yusimry will be around $13,000, compared with $90,000 for Humira. Recently, Coherus partnered with Mark Cuban Cost Plus Drug Company to sell the biosimilar at $569.27 plus dispensing and shipping fees. KOLs note that biosimilar ustekinumab is ‘next up’ with eight molecules in development and several under FDA review (although the reviews of Alvotech-Teva’s and Amgen’s biosimilars have been delayed to Q1 2025 after a settlement with J&J).

The impact of biosimilars could dictate the path forward for ACT, as an ustekinumab or adalimumab- based combination could be available at a lower price than current novel therapies. KOLs note that an ustekinumab biosimilar could be established as the backbone of combination therapy due to its safety and efficacy profile.

So where do we go from here?

For IBD, no single MoA appears to be the answer, and options are desperately needed for refractory patients. In the absence of compelling biomarkers to drive efficacy, ACT appears to be an approach that offers significant promise even if most evidence remains anecdotal, especially since proof of concept for it exists. Surprisingly, there are only a few ongoing clinical trials looking at ACT; more are necessary and opportunity remains for a company to take a leadership role using this approach. Trials must also be simplified to facilitate patient recruitment and retention, and to, therefore, enable therapies to get to market more rapidly. Biosimilars (especially ustekinumab biosimilars) might also make ACT a more attractive proposition to pharmaceutical companies with single novel assets in their pipeline.

Sources:

“The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment).” Gut. 2022;71(12):2380-2387.
“Competition for Clinical Trials in Inflammatory Bowel Diseases.” Gastroenterology. 2019 Dec;157(6):1457-1461.e2.