Gastroenterology Archives

IBD Clinical Trial Landscape: 3 Greatest Unmet Needs in IBD Clinical Development in 2023

Leave a Comment / News article / By Ashley Stufano

With the steady increase in the prevalence of inflammatory bowel disease (IBD) worldwide and the discovery of new disease pathways, there has also been a renewed interest in IBD drug development. During the ten years from 2010 to 2020, the number of clinical trials in the IBD therapeutic area almost doubled due to a combination of factors, including the continuous development of biologics, the discovery of new pathways, and, consequently, the introduction of new classes of medications such as JAK–STAT pathway inhibitors.

Our new white paper Inflammatory Bowel Disease: Current Status and Future Perspectives offers insights into recent trial and research developments that will most impact study design and operationalization for various IBD therapies and indications. In our previous post, we discussed the common challenges in IBD patient enrollment. In such a competitive landscape, it is also critical for drug developers to understand the major unmet needs in IBD management.

1. Lack of Predictive Biomarkers for Early Diagnostic Testing

There are a number of biomarkers, divided into two groups based on their application, currently used in clinical practice, but there is no single one that can help with an accurate diagnosis of IBD. The first group, aimed at diagnosis and monitoring of IBD, contains blood-based biomarkers of inflammation (C-reactive protein and erythrocyte sedimentation rate) and stool-based biomarkers (e.g., fecal calprotectin, fecal lactoferrin, fecal neopterin, and polymorphonuclear neutrophil elastase). The second group of biomarkers, aimed at the subclassification of IBD between UC and CD, includes blood-based biomarkers such as antineutrophil cytoplasmic antibodies (ANCAs), anti–outer membrane protein C (Anti-OmpC), anti–S. cerevisiae antibodies (ASCA), and anti-I2, anti-carbohydrate, and pancreatic antibodies.ⁱ These biomarkers can only be used as supporting data secondary to clinical data and endoscopic examination. Another limitation of biomarkers is their inability to predict response to therapy in patients with IBD.

2. Lack of Drugs with Minimal Side Effects

Conventional therapy methods, including 5-aminosalicylates, corticosteroids, thiopurines, anti-TNFs, and others, are generally effective in controlling symptoms, but adverse side effects such as immunosuppression, systemic fungal infections, and possible cancer development may have an overall negative impact on the disease outcome. There continues to be an unmet need for long-term treatments with minimal side effects, one of the greatest motivators for driving new IBD biologic development. For instance, all anti-TNF-α drugs in the US carry a boxed warning due to the increased risk of infections in 25–30% of patients, with limited treatment options afterwards. Etrolizumab was a potentially promising drug that was thought to close this gap, but as of November 2022, etrolizumab met its primary endpoint of inducing remission versus placebo for patients with UC in only two out of five studies and failed to meet its primary endpoint versus placebo as maintenance therapy.ⁱⁱ

3. Lack of Oral Drug Formulations

Based on the literature analysis and feedback from clinical trial investigators (and indirectly from the patients), the primary unmet need in management of moderate to severe IBD is lack of oral drug formulations: patients would prefer an oral formulation over the subcutaneous or intravenous administration. If the disease progresses further, requires hospitalization and IV corticosteroids, treatment options are limited with options of infliximab or cyclosporin, that in turn have significant side effects and they are at risk of toxic megacolon or bowel perforation with subsequent surgery. Prevention of this outcome is another focus of drug development – finding effective drugs for a late-stage disease.

Key Takeaways

IBD therapeutics and biologic developments have, thus far, not been able to provide substantial holistic solutions that improve a patient’s quality of life. More than that, limitations in testing, serious side effects, recalls and a lack of convenient therapeutic options have made minimal improvements upon current therapies. With the growing number of IBD studies, it is essential to consider and choose the right partner to help your IBD clinical trial stand out.

Despite the competition, PSI continues to deliver higher enrollment rates than typical across the industry due to our relationships with more than 3,900+ IBD sites around the world. Our studies are successful due to our long-term relationships with recruiting sites; we know the investigators on a personal level and they are motivated to work with us. Visit us online to learn more about our IBD therapeutic experience.

Meet our experts at DDW 2023!

Schedule a meeting to discuss your upcoming IBD trial in Chicago May 6-9.

References

ⁱ Soubières, A. A., & Poullis, A. (2016). Emerging Biomarkers for the Diagnosis and Monitoring of Inflammatory Bowel Diseases. Inflammatory Bowel Diseases, 22(8), 2016–2022. https://doi.org/10.1097/MIB.0000000000000836 

ⁱⁱ M. Agrawal, B. Verstockt. (2021) Etrolizumab for ulcerative colitis: beyond what meets the eye. Lancer Gastoenterology and Hematology 7(1): P2-4. https://doi.org/10.1016/S2468-1253(21)00369-1 

Top 4 Sponsor Challenges in IBD Patient Enrollment

Leave a Comment / News article / By Ashley Stufano

The number of IBD clinical studies grows each year; however, the number of patients enrolling in these studies has not increased proportionally. Instead, patient enrollment rates for IBD trials in recent years have shown a significant decline: from 1998 to 2018, the average recruitment rate in moderate-to-severe UC decreased from 0.32 to 0.13 patients per site per month, while the average recruitment rate in moderate-to-severe CD decreased from 0.65 to 0 to 0.10 patients per site per month.ⁱ

In PSI’s white paper Inflammatory Bowel Disease: Current Status and Future Perspectives, Senior Medical Advisor Maxim Kosov breaks down recent trends in IBD clinical research, including insights into patient recruitment and retention. Read on to discover the top four challenges to consider when enrolling IBD patients for your next trial.

1. Availability of Existing Treatments

The success of FDA-approved treatments, particularly vedolizumab in 2014, ustekinumab in 2016, and tofacitinib in 2018, often leads to a decreased patient enrollment rate in placebo-controlled randomized controlled trials. When the currently approved drug provides effective treatment with minimal side effects, patients will often opt for this method instead of enrolling in a study where they may receive a placebo drug. This is often a leading factor contributing to slow enrollment.

2. Competition Between Trials

When it comes to site choices and geomix, many sponsors and their partners approach larger academic centers first, assuming that these sites will have more experienced staff and equipment. One study found patients followed at academic centers are almost twice as likely to have participated in randomized clinical trials. However, the study also found over half of enrolled patients were followed in private practice settings.2 Focusing on large institutions leads to higher competition rates. For instance, as of October 2022, in the University of California San Francisco alone, there were 29 active IBD clinical trials, and 9 of them were enrolling.ⁱⁱ

3. Country and Site Selection

Additional factors may influence low enrollment potential, including site choice and geomix. When choosing the right geomix of sites, sponsors must consider the incidence of the disease, treatment standards, and availability of the medications. The incidence of IBD is increasing in Asia, Africa, and Latin America, driving interest in shifting clinical trials to these regions.ⁱⁱⁱ Additional factors to consider when selecting sites include the health insurance environment (the likelihood that insurance companies will approve less efficient generic medications over specialty ones) and the presence of preferred study sites (sites with whom the CRO has a long history of cooperation and appropriately trained study teams).

4. Screen Failure Rates

Over the past decade, screen failure rates in IBD trials have grown, approaching 50% in UC and 70% in CD, primarily due to failure to meet minimal endoscopic or biomarker criteria for active disease and a growing list of exclusionary concomitant medications. In PSI studies, we’ve seen a screen-out rate of 26-48% in UC and up to 64% in CD.

Some general recommendations to minimize screen failure and aid in patient enrollment rates include higher drug-to-placebo rates (such as a ratio of 2:1 or 3:1 rather than 1:1), broader use of patient-reported outcomes as the primary study endpoint, and optimization of study visits’ duration and complexity (including fewer procedures and endoscopies). Additional options for trial design include adding a long-term open-label extension for patients responding to therapy, and more involvement from the patient’s primary GI physicians at local hospitals and private practices. Primary care doctors see patients at the earlier stages of the disease course. There is a better chance that such patients are more likely to meet eligibility criteria than those admitted to larger hospitals or academic institutions, where the disease is often more severe and potential complications more frequent.

Conclusion

IBD patient recruitment and retention depends on the study protocol criteria and complexity, which must be scientifically sound to achieve the goals of the study as well as being attractive to patients. PSI provides a thorough review of the protocol by internal therapeutic area experts and harnesses the power of AI and machine-learning through our INTELIA ™ platform, combined with strong site relationships around the globe, to ensure your study meets enrollment goals. If you’d like to learn more about PSI can support your global Phase 2 and 3 IBD trials, click here.

References

ⁱ Harris, M. S., Wichary, J., Zadnik, M., & Reinisch, W. (2019). Competition for clinical trials in inflammatory bowel diseases. Gastroenterology, 157(6), 1457–1461. https://doi.org/10.1053/j.gastro.2019.08.020

ⁱⁱ Heyman, M., Terdiman, J., Lewin, S., Verstraete, S. G., & Mahadevan, U. (2022, November 7). UCSF inflammatory bowel disease clinical trials – San Francisco Bay Area. UCSF Clinical Trials. Retrieved November 21, 2022, from https://clinicaltrials.ucsf.edu/inflammatory-bowel-disease

ⁱⁱⁱ Ng, S. C., Shi, H. Y., Hamidi, N., Underwood, F. E., Tang, W., Benchimol, E. I., Panaccione, R., Ghosh, S., Wu, J. C., Chan, F. K., Sung, J. J., & Kaplan, G. G. (2017). Worldwide incidence and prevalence of inflammatory bowel disease in the 21st Century: A systematic review of population-based studies. The Lancet, 390(10114), 2769–2778. https://doi.org/10.1016/s0140-6736(17)32448-0

5 IBD Clinical Development Trends to Watch From ECCO 2022

Leave a Comment / News article / By Paul Mirek

Last month, I had the honor of representing PSI CRO at the European Crohn’s and Colitis Organization (ECCO) 2022 Congress. Now in its seventeenth year, this is the biggest event for all those working at the forefront of inflammatory bowel disease (IBD) clinical research, with nearly 6,000 attendees representing more than 100 countries.

This year’s theme was “Navigating the Oceans of IBD,” focusing on what it takes to transform the latest science into practical approaches. The numerous sessions discussing novel treatments made it clear that IBD is an exciting therapy area with many new treatments on the horizon. While new therapies will offer more choice for patients and the potential for more personalized treatment in IBD, studies testing the efficacy and safety of novel combinations will be required. In addition, presenters highlighted the need for head-to-head comparative trials to help guide treatment decisions. I’ve identified five IBD clinical development trends to watch as you plan your next study.

#1: The potential of JAK inhibitors for improving the efficacy of ulcerative colitis (UC) therapy

The latest data on Janus kinase (JAK) inhibitors demonstrates that these therapies have a rapid onset of action, are associated with durable efficacy, and achieve stringent composite endpoints encompassing both endoscopic and histologic assessments with a favorable benefit-risk profile. The key to clinical efficacy for these therapies is selectivity. With a highly selective agent, we can suppress JAK1 with a higher dose while remaining below the threshold of JAK2 activation. Selectivity brings us to a different level of clinical efficacy, and greater JAK1 selectivity over JAK2 could potentially translate into a more favorable benefit-risk profile.

We started to see it with tofacitinib, a pan-JAK inhibitor. With selective JAK inhibition, we now see striking deltas in all endpoints, including rapid efficacy and superior mucosal healing. Efficacy must be balanced with safety. For example, consider the increased risk of herpes zoster related to certain JAK inhibitors. Filgotinib and upadacitinib, selective JAK1 inhibitors, show a much lower incidence of herpes zoster than tofacitinib, a JAK pan-inhibitor. However, even with selective JAK inhibitors, the incidence of herpes zoster is higher than with placebo.

As a systemic inflammatory disease, IBD can affect other organs, and more than 40% of patients with IBD have at least one extra-intestinal manifestation. Selective JAK inhibitors may also make an impact here. One study found that a 45-mg induction dose of upadacitinib resolved more extra-intestinal manifestations at eight weeks than placebo (40% versus 33%) with an even more striking difference in resolution of peripheral or axial arthropathies (55% versus 42%). Similar effects were observed in a maintenance phase.

#2: Tailoring each clinical trial to the drug’s individual safety profile

Patients’ top concerns when choosing treatment include the achievement of long-term remission; route/frequency of administration; and such safety considerations as risk of infections (particularly of herpes zoster and tuberculosis), cardiac toxicity, and lymphoma risk (the last one is most relevant to biologics and small molecules). Some of these safety concerns, such as the risk of serious infections, vaccination status prior to initiation, and liver function, are universal and relevant to all drugs. Some are drug-specific; for instance, viral reactivation and non-melanoma skin cancer for tofacitinib and filgotinib.

Certain safety-related inclusion criteria for clinical trials with small molecules should therefore be universal: pregnancy test, vaccination (including herpes zoster), infections (screening for viral hepatitis), blood test (lymphocytes, neutrophils, hemoglobin), ECG, tuberculosis screening, and skin assessment (risk of skin cancer). However, each study protocol’s design must also consider the individual safety profile of the drug.

#3: The need for additional research into long-term effects

Additional research is needed into the IBD therapies’ potential for long-term effects, such as progressive multifocal leukoencephalopathy (PML), which is associated with certain inflammatory disorders. PML is a rare, opportunistic viral infection of the brain caused by the John Cunningham virus (JCV), typically in immunocompromised individuals. The seroprevalence of JCV antibodies ranges between 35% and 90% in the adult population as a latent or persistent infection. PML is also seen in inflammatory disorders such as systemic lupus erythematosus (SLE), sarcoidosis, polymyositis, and myasthenia gravis. Most cases were seen in multiple sclerosis with natalizumab. Patients with IBD are also considered at risk and need to be monitored for PML.

#4: An increased understanding and treatment options for patients who don’t respond to anti-TNF therapies

A significant number of patients fail to respond to anti-tumor necrosis factor (anti-TNF) therapy. New data suggests that interleukin 23 (IL-23) may be a key driver of molecular resistance to anti-TNF therapy, and blocking IL-23 may restore the balance between pro- and anti-inflammatory responses in the inflamed gut. There are several treatment options for such patients, but there have been no attempts to compare efficacy of different drugs until recently.

Two studies were presented at the congress that addressed this gap. The first one compared tofacitinib with vedolizumab in adults with symptomatic UC with prior exposure to at least one anti-TNF treatment. Both groups met the primary endpoint of corticosteroid-free clinical remission at 16 weeks (45% for the tofacitinib group and 40% for the vedolizumab group); however, the endoscopic improvement at week 16 showed the superiority of tofacitinib with a 24% rate versus 7% in vedolizumab patients.

The second study compared vedolizumab to ustekinumab after at least one anti-TNF treatment failure in subjects with Crohn’s disease. The study’s main objective was to compare the short- and long-term treatment survival rates with efficacy and safety as secondary objectives. The study showed a statistically significant higher five-year survival rate with ustekinumab, with the safety profile being similar for both drugs.

#5: New approaches to defining treatment goals in both UC and Crohn’s disease studies

In all international guidelines, treatment goals include endoscopic parameters (normal mucosa or Mayo endoscopic score 0-1). Most recent clinical trials include endoscopic subscore 0-1 and both central reading and histology during initial trial. Mucosal healing can now also include histologic improvement, as seen in the ustekinumab program.

The upadacitinib program looked at the composite endpoint endoscopic-histological score and histologic remission defined as a Geboes score of less than 2.0, which means the absence of neutrophils both in the epithelium and the lamina propria. The Geboes score is a six-grade classification scoring system to assess inflammation in UC. The most stringent definition is Geboes score 0-1: no eosinophils, no neutrophils in lamina propria, no neutrophils in the epithelium, no erosion, and no ulceration. Achieving histologic remission may be correlated with improved patient outcomes: decreased risk of clinical relapse, decreased corticosteroids use, lower risk for colectomy, and lower risk of hospitalization. Increased mucosal inflammation in UC may be associated with an increased risk for colorectal cancer.

Another study compared endoscopic healing at one year with different biologics. The best endoscopic healing for ileal involvement was seen with the infliximab biosimilar (37% of patients) and the lowest rate with ustekinumab (23%) and vedolizumab (19%). In the case of colonic involvement, the lowest rate of endoscopic healing was observed with ustekinumab (29%) and vedolizumab (31%), and the highest for adalimumab (62%).

Final thoughts

As the need for clinical trials in Crohn’s disease and ulcerative colitis grows, CRO collaboration matters more than ever. At PSI CRO, we’re committed to keeping abreast of the latest scientific advances and partnering with the companies doing the most exciting work in the IBD space. Learn more about our IBD expertise here and how we can support your next study.

Learn How PSI Delivered 10 Global Studies in MS & IBD for a Future Blockbuster Drug

Leave a Comment / Case Study / By Paul Mirek

Click to read Case Study: Delivering 10 Global Studies for a Future

Details

THERAPEUTIC AREA: MS & Gastroenterology
GEOGRAPHY: 40 countries
SITES: 720
PATIENTS: 2,600+

Highlights:

LPI delivered ahead of schedule by as much as 12 months for one study
2 FDA approvals & 2 EMA approvals to date
Low turnover rate of just 15% for key staff

Summary:

A Phase 2/3 study in relapsing multiple sclerosis patients was failing to recruit, so the sponsor, a global pharmaceutical company, engaged PSI to get enrollment back on track.

We delivered Last Patient In (LPI) ahead of schedule – which led to us supporting a number of other studies in the sponsor’s portfolio. We’ve since completed recruitment in five other studies, each with LPI ahead of schedule. Most recently, we rescued enrollment in a global two-study ulcerative colitis pivotal program, delivering LPI a year sooner than expected.

Read our case study to learn how our team built a strong, lasting partnership with the sponsor to help deliver results. For more information on how we can help deliver your pivotal Phase 2 and Phase 3 trials on time, contact us here.

Complete Enrollment of IBD Studies on or Ahead of Time

Leave a Comment / Case Study, News article / By Paul Mirek

The number of IBD trials initiated per year grows every year, meaning competition for sites and patients alike. To make sure one of our longtime clients’ IBD studies stood out, we drew on our database of more than 3,900 sites in 40+ countries to find the geo-mix that worked for them—and fast. (And they’re not our only repeat clients: about 95% of our business is repeat and referral.)

To help engage sites for an IBD study in an increasingly competitive landscape, we put together a 3-step early engagement campaign, including investigator letters, 1-to-1 calls, and webinars. Within four weeks, we’d collected 170 CDAs and 150 completed e-questionnaires from 20 countries. Building great relationships isn’t easy, but at PSI, we think it’s worth it.

With the combined efforts of our feasibility, site identification, and startup teams, we were able to complete enrollment two months ahead of schedule in a highly competitive indication—and with 40 more subjects randomized than planned. In today’s crowded IBD clinical trials landscape, surprise yourself. Contact us to learn how PSI CRO can deliver your next IBD trial on time.