Inflammatory Bowel Disease (IBD) is presented in two main forms, Crohn's Disease (CD) or Ulcerative Colitis (UC) and can last for more than 20 years, with periods of remissions and relapses, for which there are treatment options but no cure.
The proportion of patients with CD vs. UC varies geographically, with a reported prevalence of 100-200 per 100,000 for UC and 50-100 per 100,000 for CD in western societies. In the U.S. alone, IBD affects 1.6 million Americans (among them 80,000 children) and as many as 75,000 news cases are diagnosed every year. In fact, it appears that the problem has been overly underestimated. A more recent survey indicated that 3.1 million Americans reported a diagnosis of IBD in year 2015.
The impact of the disease to society is disproportionally high, since the majority of patients are diagnosed before the age of 35. Often, disease symptoms like abdominal pain and cramps, urgency, bloody diarrhea, fatigue and weight loss are precipitated under psychological stress and severely compromise the patient's quality of life. Indeed, due to their affliction, about 15% of patients with IBD cannot sustain a full time job (Carter et al., Gut 53 Suppl 5: v1-16, 2004). In addition to frequent hospitalizations, more than half of the patients with IBD require some type of surgical intervention during their lifetime, despite the introduction recently of biological therapies that have revolutionized the medical management of IBD.
Part of the problem that hampers the development of effective treatments for IBD is that disease etiology remains unclear. The current prevailing notion is that an inappropriate activation of the mucosal immune response to intestinal microbiome in genetically predisposed individuals leads to local invasion of effector immune cells, unbalanced production of cytokines and chronic tissue injury (Abraham et al., Pharmacol Ther 117:244-279, 2008).
One of the prominent cytokines secreted during the process is TNFα. TFNα can be produced by different immune and non-immune cell types including macrophages, T-cells, granulocytes, NK cells, fibroblasts and smooth muscle cells in a form of a soluble cytokine (sTNF) or a cell surface bound precursor (tmTNF) (Tracey et al., Pharmacol Ther 117:244-279, 2008; Aggarwal et al., Blood 119:651-665). Both TNF forms are biologically active and interact with two distinct receptors, TNFR1 and TNFR2; of them TNFR1 is rather ubiquitously expressed while TNFR2 is inducible on hematopoietic and endothelial cells. sTNFα favors signaling via TNFR1 and the NFκB pathway while mTNF generally stimulates cells via TNFR2. TNFα expression can be triggered by diverse stimuli including bacteria, viruses, immune complexes, cytokines (IL-1β, IL-17A, IFNγ, GM-CSF) as well as tissue hypoxia or trauma (Tracey et al., 2008). Therefore, while under homeostatic responses TNFα plays an important role in host defense against intracellular bacteria (Mycobacterium or Listeria) and malignant cells, unbalanced TNFα activity has been implicated in the pathogenesis not only of IBD but also of rheumatoid arthritis, psoriasis and ankylosing spondylitis (Aggarwal et al., 2012).
Ongoing research on the complex biology of TNFα has uncovered several mechanisms by which TNFα modulates inflammation and matrix destruction in these diseases. TNF receptor signaling promotes activation of proinflammatory pathways or apoptosis, depending on the metabolic state of the cell (Brenner et al., Nat Rev Immunol 15:362-374, 2015; Pimentel-Muinos et al., Immunity 11:783-793, 1999). In several target cells, TNFα stimulates the production of cytokines such as IL-1β, IFNγ, IL-6 and IL-2, which in turn can act as TNFα inducers, as well as some negative feedback regulators like IL-10 and PGE2 (Tracey et al., 2008).
Current medical management for IBD aims to relieve symptomatology and improve the patient's quality of life. Patients can initially be treated with corticosteroids, aminosalicylates (sulfasalazine, mesalamine), and immunomodulators (azathioprine, 6-mercaptopurine, methoxetrate), followed by biologic therapies like anti-TNFα (infliximab, adalimumab, certolizumab, golimumab).
TNFα antagonists like infliximab, adalimumab, golimumab and certolizumab pegol are humanized or human/mouse chimeric antibodies (infliximab) to TNFα, and are parentally administered protein therapeutics (biologics). For example, infliximab (Remicade) is a chimeric mouse/human monoclonal antibody against TNFα with an indication for the treatment of moderately to severely active CD or UC in patients who have not responded well to the more conventional therapies. The current therapeutic scheme for infliximab is three doses (usually 5 mg/kg) of induction (week 0, 2 and 6) followed by maintenance therapy every 8 weeks. The exact mechanisms of action of these drugs in IBD remain largely unknown (Oikonomopoulos et al., Curr Drug Targets 14:1421-1432, 2013).
The introduction of the anti-TNFα antibodies to IBD treatment has revolutionized the field of IBD therapeutics. Indeed, in the past, 70%-80% of patients with CD would require some form of surgical intervention during their lifetime and up to one third of patients with UC would be subjected to colectomy.
TNFα blockers have improved symptomatology in a significant percentage of patients with IBD (Colombel et al., N Engl J Med 362:1383-1395, 2010; Rutgeerts et al., N Engl J Med 353:2462-2476, 2005). Primary response rates to induction therapy with infliximab are up to 60% in randomized clinical trials of CD and UC while placebo responses range from 25-35% (Papamichael et al., Inflamm Bowel Dis 21:182-197, 2015).
However, only a fraction of IBD patients commenced on anti-TNFα treatment achieve clinical remission; and about half of the patients who initially benefit the treatment will lose response within 1 year of maintenance therapy. For example, sustained response rates beyond week 30 are substantially lower (30-40% infliximab versus 15-25% placebo treatment), and are comparable between the different anti-TNFα biologics, leaving a concerning number of IBD patients with active disease (Sands et al., Dig Dis 32 Suppl 1:74-81, 2014). While it has become well accepted that secondary loss of response to infliximab is mainly due to the development in 10% of patients of anti-drug antibodies (ADA) which might directly block drug activity or enhance its clearance, the causes of primary non-response are less clear and might be attributed to inadequate dosing, drug pharmacokinetics, the patient's genetic make-up but also to a non-TNF-driven disease (Papamichael et al., 2015).
The beneficial effect of anti-TNFα treatment appears to be overestimated when patient-reported outcomes are used, since those have been linked with higher drug and placebo responses. In the ACT1 study that examined the efficacy of infliximab in UC, clinical response rates during induction with 10 mg/kg of infliximab (week 8) were 61.5% (vs 37.2% in placebo), and dropped to 19.8% at week 53 of maintenance therapy (1 vs 9.8% in placebo). The association between serum infliximab levels and efficacy has been evaluated in many studies and it is well accepted now that therapeutic drug monitoring and adjustment of the drug dose can further improve therapeutic outcomes.
Several factors can contribute to low infliximab levels. For example, in severe UC, high CRP and TNF and low albumin and hemoglobin levels, have been associated with more rapid drug clearance and increased drug leakage in the stool. One of the main reasons of low drug levels is the development of anti-drug antibodies (ADA) which can accelerate drug clearance through the reticuloendothelial system. Evaluation of 483 patients with CD during maintenance therapy has shown that 23% of patients had undetectable infliximab serum levels; of those 72% were positive for anti-drug antibodies (ADA). A recent metanalysis estimated a 3.2-fold risk (95% CI:2-4.9) to loose response to infliximab in the presence of ADA. Moreover, the presence of ADA almost doubles the risk for acute reactions following drug infusion often resulting in drug discontinuation. The addition of an immunomodulator such as azathioprine to anti-TNF therapy has been shown to reduce the incidence of ADA (38% in monotherapy vs 22% in combined therapy). In the SONIC trial, 508 patients with moderate-to-severe CD were randomized to receive azathioprine, infliximab, or the two drugs combined. Mucosal healing rates at week 24 of intervention were 16.5% vs 30.1% vs 43.9%, respectively.
These results clearly indicate that even under optimized treatment conditions, a significant percentage of patients with IBD can remain unresponsive to anti-TNF therapy. As a result, there is increasing pressure from stakeholders to develop new and more effective treatments for IBD and with fewer side effects.
In addition to a severe unmet need for more effective treatments in IBD, there is also a significant unmet need for personalized treatments in IBD.
Specifically, regarding long term safety, several studies attempted to quantify the risks associated with anti-TNF treatment with mixed results so far, primarily due to concomitant or previous patient exposure to immunosuppressants. Blocking TNFα, an important pathway in host defense, might reduce the patient's ability to fight infections, especially in older individuals, or increase susceptibility to certain cancers (hepatosplenic T-cell or other non-Hodgkin's lymphomas, non-melanoma skin cancer) in younger individuals. The FDA has already issued a black box warning for infliximab about “tuberculosis and additional serious opportunistic infections such as histoplasmosis, listeriosis and pneumocystosis.”
Thus it has become increasingly apparent that “one size does not fit all” in IBD therapeutics. Following the FDA approval of newest therapies for IBD, like vedolizumab (Entyvio, May 2014), an antibody against alpha4beta7 integrin that blocks lymphocyte trafficking, and ustekinumab (Stelara, September 2016), an antibody against the common p40 subunit of IL-12 and IL-23, it is becoming even more urgent to identify those IBD patients who are less likely to benefit from an anti-TNFα treatment and offer them alternative options, while sparing them for potential health risks associated with ineffective therapies.
In fact, “imprecision medicine” is not restricted to IBD. A recent analysis estimates that for the ten highest-grossing drugs in the US (including three anti-TNFα drugs), for every person they do help, they fail to improve the clinical condition of 3-24 patients. Besides poor clinical outcomes, imprecision medicine has a tremendous impact on health care costs, since waste therapies can account for up to 30% of health care spending.
Thus it becomes imperative to identify among patients with IBD those whose disease is not TNFα dependent, since these individuals are not good candidates for treatment with anti-TNFα.
For example, infliximab therapy requires hospital infusions which are quite uncomfortable for some patients while in others may trigger allergic reactions or flu-like symptoms further diminishing the patient's quality of life (Hansel et al., Nat Rev Drug Discov 9:325-338, 2010). Most importantly, and particularly for the pediatric IBD population, anti-TNFα treatments have been associated with rare but life threatening adverse effects, including opportunistic infections, demyelinating disease and certain malignancies (Lichtenstein et al., Am J Gastroenterol 107:1409-1422, 2012; Ford et al., Am J Gastroenterol 108:1268-1276, 2013; Bosch et al., Nat Rev Neurol 7:165-172, 2013; Bongartz et al., JAMA 295:2275-2285, 2006; Targownik et al., Am J Gastroenterol 108:1835-1842, 2013; Slifman et al., Arthritis Rheum 48:319-324, 2003).
Over the years, several biological predictors of response to anti-TNFα in IBD have been offered, including polymorphisms in TNFα and its receptors, apoptotic genes and downstream targets (Bank et al., Pharmacogenomics J 14:526-534, 2014; Pierik et al., Aliment Pharmacol Ther 20:303-310, 2004; Hlavaty et al., Aliment Pharmacol Ther 22:613-626, 2005); various mucosal gene expression signatures (Leal et al, 2015; Olsen et al, Cytokine 46:222-227, 2009; Arijs et al., Gut 58:1612-1619, 2009; Arijs et al., Inflamm Bowel Dis 16:2090-2098, 2010; Montero et al., PLoS One 8:e76235, 2013; Rismo et al., Scand J Gastroenterol 47:538-547, 2012); serum factors like CRP (Jurgens et al., Clin Gastroenterol Hepatol 9:421-427 e421, 2011; Cornillie et al., Gut 63:1721-1727, 2014) or VEGF (Algaba et al., Inflamm Bowel Dis 20:695-702, 2014) and fecal biomarkers (Molander et al., Inflamm Bowel Dis 18:2011-2017, 2012). However, none of them has found its way to the clinical practice.
On the other hand, studies have shown that patient enrichment using various biomarkers can significantly improve clinical responses to anti-TNFα therapy. For instance, using confocal endomicroscopy in combination with fluorescent adalimumab to quantify the number of TNFα positive cells in the affected mucosa (mTNF(+) cells) of 25 patients with Crohn's disease prior to initiation of treatment, Atreya et al. (Nat Med 20:313-318, 2014) found that patients with high numbers of mTNF(+) cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNFα therapy, as compared to patients with low amounts of mTNF(+) cells (15%) (p=0.0002). This clinical response in the former patients was sustained over a follow-up period of 1 year, and was associated with mucosal healing observed in follow-up endoscopy. In general, when patients were enriched based on a screening test, the clinical response rate rose from 52% to 92%.
The described tool appears to be a robust predictor; however, it requires advanced technology, is target specific and does not allow flexibility in testing different drugs in parallel or their combinations.
Accordingly, there is a pressing and still unmet need for utilization of new markers, which can be tied to existing therapeutic regimen, which will help maximize therapeutic benefit in responders while concomitantly reducing the risk of unnecessary exposure in subjects who are unlikely to respond. Such goals are particularly important in the context of diseases such as IBD which are characterized by wide biological variability. See, Gerich et al., Gastroenterol Hepatol 11:287-299, 2014.