Comparing the efficacy of approved TNF-α inhibitors and the emerging field of JAK inhibitors in the treatment of Crohn’s Disease

Comparing the efficacy of approved TNF-α inhibitors and the emerging field of JAK inhibitors in the treatment of Crohn’s Disease

Chaemin Joseph Kim – James Ruse Agricultural High School

Abstract

Crohn’s Disease is a progressive inflammatory bowel disease that is increasing in prevalence around the world. The current standard of care involves TNF-α inhibitors to suppress the expression of TNF, a cytokine responsible for the inflammatory response. However, not all patients respond to this treatment and efficacy wanes in some patients after a period of time. JAK-inhibitors are an emerging field of biologics that target the JAKSTAT pathway, which targets a wider range of cytokines. This study investigated and compared the efficacy of JAK inhibitors and TNF-α inhibitors through a thorough review of the published clinical trial data.12 articles from a controlled search on PubMed were analysed and summarised in a table. Each inhibitor was rated out of 5 using efficacy criteria. It was found that some JAK inhibitors did not induce a significant difference in clinical or endoscopic remission and the clinical development of one was discontinued, which failed to contend with TNF-α inhibitors which were reliable for safety, clinical and endoscopic remission. This study was significant as it provides CD patients and healthcare professionals with a comparison between the two classes of inhibitors to assist them with their treatment options.

Literature review

Crohn’s Disease

Crohn’s Disease (CD) is an inflammatory bowel disease (IBD) that is characterised by the chronic inflammation of the gastrointestinal tract. It can affect any part of the intestines, but most commonly impacts the end of the small intestine and colon. Patients alter between remission status and relapses(flares). Damage to the mucosal intestinal barrier is often observed, but whether this is a cause or consequence of CD is still unknown and is an area for further research (Ahluwalia, B. et al. 2018).

Figure 1: Inflammation in the gastrointestinal tract of CD patients

SOURCE: Crohn’s and Colitis Foundation

Role of cytokines

Cytokines are cell signalling molecular proteins that support communication between cells in immune responses and exhibit their effects when they bind to specific cell surface receptors. Cytokines are important in the inflammatory response, as it sends signals to other inflammatory cells which trigger the recruitment and movement of inflammatory cells towards sites of inflammation, infection and trauma. (Sanchez-Munoz, F. et al. 2008). Cytokines involved in CD include interleukin (IL)-6, IL-10, IL-23 and TNF-α.

Cause

While the exact cause behind Crohn’s Disease remains unknown, the consensus in the literature suggests that genetic and environmental factors, gut microbiota and a dysregulated immune system play an important role in the pathogenesis 1 of CD.

In CD, epithelial barrier dysfunction (resulting from, for example, polymorphisms 2 in NOD2 and nuclear factor- κB (NF- κB) signalling pathway genes) results in the luminal contents entering the lamina propria. This triggers dendritic cells to activate inflammatory T cell types, (e.g. naive T helper (TH0) cells, T helper 1 (TH1) cells, TH17 cells and TH2 cells) which produce proinflammatory cytokines, such as tumour necrosis factor (TNF) [see Figure 2]. Furthermore, macrophages respond to the luminal contents 3 by producing the proinflammatory cytokines IL-12 and IL23, which activate natural killer (NK) cells. This leads to a cycle of intestinal inflammation with the production of more proinflammatory cytokines, which eventuates in chronic tissue injury and epithelial damage (Ahluwalia, B. et al. 2018).

1 Where the disease originates and how it develops

2 presence of two or more variant forms of a specific DNA sequence that can occur among different individuals or populations

3 Luminal contents include dietary components and the gut microbiota

Figure 2: The working theory behind what causes the inflammation in Crohn’s Disease. Bacteria attack weakened intestinal walls which leads to contents in the intestinal lumen to enter the intestinal lamina propria. This triggers the release of various cytokines such as IL6 and TNF-alpha which causes inflammation. The inflammatory cytokines involved recruit more inflammatory cytokines, leading to a cycle of inflammation that eventuates in chronic tissue injury and epithelial damage, further weakening the intestinal walls.

SOURCE: “Crohn’s disease” (2020). Nature Reviews Disease Primers.

Impacts on individuals and the broader society

From 1990 to 2017, the prevalence of IBDs had increased substantially in many regions which poses a substantial social and economic burden on governments and health systems in the future (GBD 2017 Inflammatory Bowel Disease Collaborators, 2020).

Crohn’s disease also affects the physical, emotional, social and financial well-being of patients, impacting their quality of life. (see figure 3).

Figure 3: How CD affects patients’ quality of life.

Source: “Crohn’s disease”. (2020) Nature Reviews Disease Primers

Current Treatment Methods (Standard of Care)

Table 1: Summary of Current Treatment Options for CD patients.

Source: “Medical Management of Crohn’s Disease”. (2020) Cureus

Combination treatment (i.e. TNF-α inhibitors are administered alongside MTX is undertaken in most, if not all CD patients. While initially, this was a natural transition from the medication mentioned above, to biologics such as TNF-α inhibitors, there are ongoing investigations into whether the use of both classes of medications together might be superior to one or the other alone. (Sultan, K. S. et al. 2017). While there is a range of treatment options available for CD patients, each treatment has its own flaws (as seen in Table 1). Therefore, more treatment options are beneficial in empowering patient choice.

Table 2: The specific inhibitors considered for this review.

What are TNF-α Inhibitors?

Tumour necrosis factor (TNF) is a highly pro-inflammatory cytokine that induces fever, insulin resistance, bone resorption, anaemia, inflammation in CD and in sepsis. It is mainly produced by monocytes, macrophages and T lymphocytes, but also by mast cells, granulocytes, fibroblasts and several other cell types. (Tracey, D. et al. 2008). TNF reacts with two distinct receptors (TNF receptor 1 [see figure 4] and TNF receptor 2) which exerts their biological effects, which include the increased production of proinflammatory cytokines and the inhibition of apoptosis of inflammatory cells (Sanchez-Muñoz, F. 2008).

TNF-α inhibitors reduce the overexpression of TNF-α, by binding soluble and transmembrane TNF-α and inhibiting binding to its receptors (see figure 4), resulting in the blockage of proinflammatory signals. It also induces apoptosis of activated lamina propria T lymphocytes, countering a proposed pathological mechanism in CD, where mucosal T cell proliferation exceeds T cell apoptosis (Adegbola, S. 2018). TNF-α inhibitors have led to a paradigm shift in CD treatments, allowing rapid, sustained and deep remission. Short and long-term clinical and endoscopic endpoints can now be reached that were previously unachievable. (Rutgeerts, P. et al. 2012).

Figure 4: The basic mechanism of TNF-α inhibition. The binding of TNF to TNFRI and TNFRII (a) activates several signalling pathways. This signalling leads to activation of the target cell leading to the inflammatory and immune response by releasing several cytokines and apoptotic pathway initiation (b).

SOURCE: “Nature Reviews Drug Discovery” and “StatPearls - TNF Inhibitors”

4 Death of cells which occurs as a normal and controlled part of an organism's growth or development.

Examples of TNF-α inhibitors

Infliximab was the first biological response modifier to be used in the treatment of IBD and is a genetically engineered chimeric (mouse/human) immunoglobulin anti-human TNF agent. It can induce the downregulation of the inflammatory mechanisms in the entire mucosal area, by fixing complement and lyse cells that express membrane-bound TNF-α (D’Haens, G. et al. 1999). It is administered intravenously.

Adalimumab is a human immunoglobulin 5 antibody that also fixes complement and lyse cells that express TNF-α and is administered subcutaneously (via autoinjector pen) every two weeks (Rutgeerts, P. et al. 2012).

Certolizumab pegol is a chimeric humanized antibody fragment against TNF. Unlike infliximab and adalimumab, it does not contain the crystallisable fragment (Fc) region of a typical antibody. Its function is also different - it does not induce apoptosis as one of its mechanisms of action. It is thought to have a higher binding affinity 6 for TNF than adalimumab or infliximab (Adegbola, S. et al. 2018). CP is administered subcutaneously and has a longer half-life with maintenance dosing every four weeks (as opposed to adalimumab’s two weeks).

Issues

An issue often faced by clinicians and patients once remission has been achieved is whether to stop the anti-TNF therapy. Despite the multiple studies that have addressed this issue in Crohn’s Disease, no conclusive strategy has yet emerged (Adegbola, S. 2018).

There are up to 30% of primary nonresponders who do not respond to antiTNF therapy and almost half of the patients who experience a benefit with these drugs will lose clinical benefits within the first year, requiring dose escalation or therapy change. (Sandborn, W. 2007). Why this occurs is still discussed in the current literature and is an area for further research.

What are Janus Kinase (JAK) Inhibitors?

Janus Kinase (JAKs) are the enzymes that determine the signal transduction (process by which foreign DNA is introduced into a cell) by interaction with signal transducers and activators of the transcription (STATs) pathway (Dudek, P. 2021). It is named after Janus, the Roman god of doorways, to highlight how JAKs facilitate signals from the cell surface into the cell. JAK inhibitors are biologics, small molecules that prevent the signalling of many of the cytokines implicated in the pathogenesis of Crohn’s Disease, such as IL-6 and IL-23. Due to the different patient-to-patient specific cytokine profiles, widening the target of action to JAK-STAT pathways (see figures 5 and 6) is advantageous compared to selective biologic agents like TNF-α inhibitors. (Dudek, P. 2021).

5 A critical part of the immune response that specifically recognises and binds to particular antigens, such as bacteria or viruses, and aids in their destruction.

6 the strength of the binding interaction between a single biomolecule (e.g. protein or DNA) to its ligand/binding partner (e.g. drug or inhibitor).

Figure 5: Cytokine signalling through their respective JAKs.

SOURCE: Nature Reviews Rheumatology

Mechanism of action

A simplified diagram of the JAK-STAT Pathway. 1) Ligand (usually a cytokine) binds and cross-links its receptor. 2) The associated JAKs transphosphorylate and activate each other. 3) The activated JAKs phosphorylate the receptor tail (introduce a phosphate group into a molecule or compound). 4) The receptor tail becomes a docking site for recruited STAT proteins, which themselves are phosphorylated by the activated JAKs. 5) The phosphorylated STATs dissociate from the receptor and dimerise. 6) STAT dimers translocate to the nucleus where they regulate gene transcription.

SOURCE: “Basic Mechanisms of JAK Inhibition”. (2020). MEDITERRANEAN JOURNAL OF RHEUMATOLOGY

Overexpression of the JAK-STAT pathways is associated with both autoimmune disease and malignancy (Lin, C. et al. 2020). JAK inhibitors block these pathways, which simultaneously allows a blockade of multiple key cytokines associated with CD, thus reducing the severity of disease.

Examples of JAK Inhibitors

Current JAK inhibitors that are undergoing clinical trials for CD include tofacitinib, filgotinib and upadacitinib (table 2). Tofacitinib is a pan-JAK inhibitor that besides having a main activity for JAK1 and JAK3 also inhibits tyrosine kinases outside the JAK family, which

raises questions about whether its action can solely be attributed to JAK inhibition (Rogler, G. 2020). Filgotinib is a selective janus kinase (JAK1) inhibitor with about 30 times selectivity for JAK1 over JAK2 in human whole blood (Vermeire, S. et al. 2016). Upadacitinib is a JAK1 inhibitor with increased selectivity for JAK1 compared with JAK2, JAK3, and TYK2, and down-regulates multiple proinflammatory cytokines, including interleukin(IL)-2, IL-4, IL-6 and interferon gamma, that are relevant to the pathogenesis of CD (Sandborn, W. 2020). All three are orally administered.

Issues

However, as JAK inhibitors in CD is an emerging field, there is uncertainty surrounding the ideal dosage to maximise efficacy and minimise adverse effects. Appropriate biomarkers to determine whether a failure to respond to JAK inhibitors is due to inadequate dosing or that the disease is not mediated by JAKdependent cytokines is an area for further research, as the precise tissue-specific roles of JAKs are incompletely understood.(Gadina, M. et al. 2019).

Another significant issue of JAK inhibitors in current clinical practice is the risk of thromboembolic events (i.e. blocking of blood vessel by a particle from blood clots), which is even greater in patients with COVID-19 (Dudek, P. 2021).

Scientific research question

The purpose of this study is to assess and compare the efficacy of three different types of JAK Inhibitors and TNFα inhibitors to determine which class of inhibitor is more favourable in treating adult (age 18+) patients with Crohn’s Disease.

This report aims to provide CD patients and healthcare professionals with a comparison between the two classes of inhibitors to assist them with their treatment options.

Methodology

1. Randomised clinical trials were found using PubMed using the search tags and settings:

Figure 7: Settings used for the controlled PubMed search. “(Inhibitor drug name) Crohn’s Disease NOT recurrence”. Clinical Trial, Randomised clinical trial in last 15 years (20072022), Language set to English, age set to adults: 18+

Adalimumab, infliximab and certolizumab pegol were the TNF-α inhibitors considered for this report. These drugs are the most commonly used TNF-α inhibitors for CD patients and clinical trial reports for these were the most accessible given the resources available.

Tofacitinib, filgotinib and upadacitinib were the JAK-inhibitors considered for this report as they were the only JAKinhibitors that had investigated in clinical trials for CD patients.

Randomised clinical trial data was used to minimise bias, improving validity.

A time span of 2007 to 2022 inclusive was decided to find more relevant articles for the TNF-α inhibitors. In the case of infliximab, it was first approved by the US Food and Drug Administration (FDA) for treating Crohn’s disease in 1998. As these TNF-α inhibitors have been an aspect of the standard of care for a more extended period of time than the emerging field of JAK inhibitors, research articles for the TNF-α inhibitors within the last decade were scarce. Therefore a wider time span was necessary to acquire the research articles.

2. Articles were removed depending on:

a) Relevance (Crohn’s disease the main focus, not another disease + excluded articles only determining safety profiles)

b) Long term studies

c) Full article accessible through the University of Sydney or is free

d) Had a measure of remission, either by CDAI 7 scores or by endoscopy

e) Duplicate studies

Long term studies for TNF-α inhibitors could not be compared with JAK inhibitors as there was a lack of long term studies in the emerging field of JAK inhibitors, so long term studies were not considered for this study.

Following initial search on PubMed and Step 2, Infliximab - 1 result Duplicates, irrelevant and inaccessible articles were excluded.

Adalimumab - 3 results Duplicates, irrelevant and inaccessible articles were excluded.

Certolizumab pegol - 3 results. 19 results removed - duplicates, relevance (different disease, focused on safety profile)

Filgotinib - 1 Results 2 results removed - both for relevance (One focused on pharmacokinetics and the other on drug-drug interactions)

Tofacitinib - 2 Results. 2 results removed - both were duplicates

Upadacitinib - 2 Results. 2 results removed - both for relevance (one focused on Rheumatoid Arthritis and the other on quality of life and work productivity improvements)

7 Crohn’s Disease Activity Index - Determines the current severity (disease activity) of Crohn's disease using a points-based system

3. Remaining articles were placed into a table (appendix 1) and efficacy was determined using the following criteria: significant clinical remission when compared to placebo, significant endoscopic remission when compared to placebo, safety profile and bioavailability.

Each of these efficacy criterias were then rated out of five for both inhibitor classes (tables 4, 5, 6 and 7) and compared.

4. A thorough review of the current literature is most appropriate given the time constraints and the resources available to a student.

Figure 8: A flowchart of the methodology

Table 3: Rating and justification for the clinical remission (and clinical response, where mentioned) of JAK and TNF-α inhibitors

Table 4: Comparison between endoscopic remission in TNF-α inhibitors and JAK inhibitors

Table 5: Ratings and justification for safety profile of TNF-α and JAK inhibitors

Table 6: Rating and justification for bioavailability of TNF-α inhibitors and JAK inhibitors

Please refer to Appendix 1 for full results table.

Discussion

Clinical remission

Clinical remission was defined as CDAI<150 for all studies. Not all studies considered clinical response, but the reports that did, considered CDAI-70 8 , CDAI-100 9 or both.

Adalimumab, infliximab and to a lesser extent, CP all showed a significant difference in clinical remission and, where it was included, clinical response. The double-blind, placebo-controlled “GAIN Study” for adalimumab showed a significant difference in clinical remission, CR100 and CR70 between adalimumab and placebo. However, the short 4-week duration 10 limited the study. The article was also very short, with no discussion and a brief explanation of methodology despite being published in the reputable AJG. 11

For JAK inhibitors, only Filgotinib and upadacitinib achieved a significant difference in clinical remission with placebo. The randomised, double-blind, placebo-controlled FITZROY trial for filgotinib showed a significant difference. However, it had a small sample size (n=128) and the data was inclusive i.e. some patients who achieved clinical response also achieved CR100, which may have overrepresented the findings.

However, the randomised, double-blind, placebo-controlled “Phase 2 study of Tofacitinib” did not show significant differences in CR70, CR100 or clinical remission with placebo, with some P values greater than .999 for CR70 and CR100 due to small sample sizes. The short duration of 4 weeks limited the study, which was chosen to reduce placebo response rates. These rates were still high 12 and may be due to selection bias toward the enrollment of patients with a more benign natural history. (Sandborn, W.J. et al. 2014.). The study also could not determine if the failure of tofacitinib to show efficacy for CD was due to a high placebo response rate or a true negative result.

Subsequently, the clinical development of tofacitinib in CD was discontinuedhowever, it was still included due to the lack of JAK inhibitor trials for CD treatment and as it showed efficacy in ulcerative colitis (UC), another IBD.

Tofacitinib targets multiple JAK pathways while the other two are selective JAK Inhibitors. The pathways targeted and why the inhibition of those pathways worked for UC and did not work for CD is an area of further study. This could reveal why some cytokine pathways may be more responsible for disease activity in CD than others, which can provide further insight into the pathogenesis and pathophysiology of CD. (Rogler, G. 2019).

Endoscopic remission

Across the studies, most articles did not consider endoscopic remission as an endpoint, highlighting a clear limitation.

8 Reduction of CDAI score by 70 points

9 Reduction of CDAI score by 100 points

10 The trial was induction therapy

11 American Journal of Gastroenterology

12 20.6% of placebo group achieved clinical remission

Where it was considered, the same standardised measure was not used across all studies.

From the TNF-α inhibitors, adalimumab and infliximab were assessed for endoscopic remission. The randomised, double-blind, placebo-controlled “EXTEND” trial for adalimumab used mucosal healing 13 as a measure of endoscopic remission. At week 12, the difference between the remission rates was considered not statistically significant between placebo and adalimumab groups (P=0.056). However, at week 52, there was a significant difference between the placebo and inhibitor group (P<0.001). A limitation of this study in regards to the research question is its focus on the ileocolon, a specific part of the GI. More studies are needed to confirm endoscopic remission across different areas of the GI.

From the JAK inhibitors, endoscopic remission was measured for filgotinib and upadacitinib. The “FITZROY” filgotinib trial used SES-CD 14 to determine endoscopic remission in the placebo and filgotinib groups. There was no significant difference between the filgotinib and placebo groups after 10 weeks (P=0.31). However, due to the transmural 15 nature of CD, a longer treatment period may be required to achieve endoscopic remission (Vermeire, S. et al. 2016). Extended studies of filgotinib for CD patients are therefore required.

Safety profile

SAEs 16 included CD flares, sepsis and UTIs 17. While the studies determined that all six inhibitors had acceptable safety profiles, upadacitinib was concerning. SAEs were common in the randomised, blinded upadacitinib trial (Sandborn, W. et al. 2020), where all of the four doses displayed a higher incidence of SAEs than the placebo. In the 12 mg group, 25% of patients discontinued the treatment due to SAEs compared to the discontinuation of 13.5% of the placebo group. Two intestinal perforations were observed during the induction period. Intestinal perforations were initially reported with tofacitinib and may be related to an effect on IL-6, confirming its significance in the intestinal barrier. (Sandborn, W.J. et al. 2020). The study also found that intestinal perforation events occurred in areas of active intestinal inflammation of CD in patients treated with upadacitinib and corticosteroids, raising questions on whether combination therapy with upadacitinib is recommended in inducing remission for patients with active CD as opposed to maintaining remission.

Therefore, TNF-α inhibitors are preferable from a safety perspective at this time, although filgotinib is also a good alternative.

Bioavailability

Adalimumab and CP can be selfadministered via a needle, similar to how patients with diabetes inject insulin by themselves. However, as it does involve needles, immunogenecity 18 is a concern. (Adegbola, S. et al. 2018). Needle disposal and the costs associated with the equipment required are also other disadvantages to consider. Since the inhibitor is administered over a period of time (e.g. every 2 weeks) to induce or maintain remission, continuous injections can cause discomfort.

13 Ileocolonoscopy was used to determine if the ileocolon had ulcerations after treatment

14 Simplified Endoscopy Score for Crohn’s Disease

15 Existing or occurring across the entire wall of an organ or blood vessel.

16 Severe adverse event

17 Urinary tract infection

JAK inhibitors are orally administered and are pain-free. It can be self-administered which offers patient control and the lack of needles and other equipment make JAK inhibitors more convenient for patients. While this report does not focus on children and adolescents, JAK inhibitors could be preferable for younger people with CD as opposed to regular injections. Also, they were shown to exert no immunogenicity (Dudek, P. et al. 2021), an added benefit over TNF-α inhibitors.

Limitations

A limitation of this report is the lack of other efficacy measures, such as CRP levels and IBDQ which were not assessed. These other factors and biomarkers were not assessed due to time constraints. While this report still compares the efficacy of TNF-α inhibitors and JAK inhibitors, it does not capture the entire complexity of the inhibitor’s effects which limits its usefulness in providing advice for personalised treatment options for CD patients. Further studies into these factors and biomarkers can provide more insights into the inhibitors’ mechanism of action and guide treatment options.

More specificity for induction and maintenance treatments is also needed to narrow down the research question further, as results differed for maintenance and induction treatments. However, due to the lack of clinical trial data available for JAK inhibitors, a limitation of the field itself, this was not considered for the report. More clinical trials of JAK inhibitors in treating CD are therefore needed.

Limitations of the field include the lack of JAK inhibitor studies, small patient sample sizes for both classes of inhibitors, outdated TNF-α 19 studies and the lack of focus on endoscopic remission as a measured endpoint.

Future directions

To overcome the limitations of the field mentioned above, more trials should be conducted with larger patient sample sizes with a focus on endoscopic remission, which will significantly contribute to this field. Understanding why some JAK and TNF-α inhibitors work while others don’t through these clinical trials can reveal further insights into the various mechanisms of cytokines and JAK-STAT pathways, which can provide a greater understanding of the pathogenesis of CD.

Conclusion

While JAK inhibitors show promise in treating CD, TNF-α inhibitors remains as the gold standard for treatment, in terms of clinical remission and response, endoscopic remission and safety. A controlled PubMed search was conducted to gather articles that were analysed and synthesised into tables based on a set of efficacy criteria. The treatments were hen rated out of 5 for each criteria.

The benefits of oral administration of JAK inhibitors and the clinical and endoscopic remission in filgotinib and upadacitinib could not outweigh the discontinuation of tofacitinib due to the lack of clinical remission and the concerning safety profile of upadacitinib, and so failed to contend with the accepted TNF-α inhibitors. Therefore, TNF-α inhibitors are more efficacious than JAK-inhibitors in treating adult patients with CD.

Further investigations into the efficacy of these biologic treatments can improve patient care and lead to a better understanding of the pathology of CD.

18 Occurs when the immune system administered a drug recognises it as foreign and generates a cellular immune response. Can cause loss of response to treatments.

19 majority of studies were over 15 years ago, which could not be considered for this report.

Acknowledgements

I would like to thank Dr Dennis for her dedication and tireless support towards my project, without which I would not have been able to complete it.

I also thank Dr Vicki Xie for her valuable guidance and insightful comments in fleshing out the details of this report, for answering my questions and for teaching me the various clinical aspects of science.

I would also like to thank Mr Michael Chen for his valuable support in proofreading this report and for providing me with advice.

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Appendix 1