I don't know what my path is yet. I'm just walking on it.—Olivia Newton-John As our understanding of immune pathways has evolved, targeted therapies for ulcerative colitis (UC) have emerged. These advances have resulted in safe and effective therapies for patients, but have placed a responsibility on clinicians to understand the complicated mechanisms of actions, and resulting attributes of each therapeutic class. This presents a challenge because our understanding of the pathophysiology of disease continues to evolve. As the path of discovery continues to unwind, each step has laid the foundation for the next stage in the evolution of therapies. In UC, the next wave of therapies is based on direct interleukin inhibition. Given the success of IL-12 and IL-23 blockade in psoriasis (Lancet 2008;371:1665–1674), and the emergence of ustekinumab (UST) as a promising new strategy for the treatment of Crohn’s disease (CD), it has been assessed for the treatment of UC. UST is an IgG1 kappa monoclonal antibody directed at the shared p40 subunit of IL-12 (p35/p40) and IL-23 (p19/p40) (N Engl J Med 2004;351:2069–2079; MAbs 2009;1:216–221; Expert Opin Biol Ther 2010;10:587–604; MAbs 2011;3:535–545). IL-12 promotes differentiation of naïve T cells down the Th1 immune pathway which culminates in release of IFN-γ; whereas IL-23 stimulates differentiation of the Th17 pathway which has been implicated in many chronic inflammatory diseases. Blockade of 2 important immune pathways led to theoretical concerns regarding safety, especially in the era of selective immunosuppression. The development of more targeted therapies required an understanding of the relative importance of IL-12 or IL-23. Based on murine models, IL-12 was initially implicated as the dominant cytokine in the pathogenesis of inflammatory bowel disease. In murine models of 2,4,6-trinitrobenzene sulfonic acid–induced colitis (World J Gastroenterol 2006;12:5606–5610; Nat Med 2007;13:26–28; Ann Med 2011;43:503–511), clinical improvement was demonstrated after the administration of a monoclonal antibody directed against IL-12 (Nat Med 2007;13:26–28). Additional support for the importance of IL-12 was obtained from IL-23/p19 knockout mice who developed severe colitis in the setting of robust IL-12 production that was induced by the lack of IL-23 inhibition (J Immunol 2006;177:2760–2764). However, the pivotal role of IL-23 became apparent in a subsequent backcross experiment conducted in IL-10–deficient mice (J Clin Invest 2006;116:1310–1316). In this study, IL-10/IL-23p19 mice did not develop colitis, even in the presence of IL-12; however, IL-10/IL-12p35–deficient mice developed colitis in the presence of IL-23. Further evidence for the role of IL-23 was derived from murine models of T-cell transfer. After the administration of naïve T cells (CD4+CD45RBhigh) or memory T cells (CD4+CD45RBlow), the development of colitis in these animals was accelerated from 10–12 to 4 weeks with the concomitant administration of IL-23. T-cell transfer colitis is both prevented and treated with anti–IL-23p19 agents that inhibit cytokine production and induce Th17 cell apoptosis (Gastroenterology 2007;132:2359–2370). Despite these advances, considerable gaps in our understanding of these complex mechanisms are exemplified by 2 trials conducted in CD. Given the abundance of evidence supporting the therapeutic benefit of blocking the Th17 pathway, selective inhibition of the IL-17A isotype with secukinumab was assessed for the treatment of moderate to severely active CD. A surprising excess of serious infections was observed with this highly specific therapy (Gut 2012;61:1693–1700). In contrast, broad-spectrum immunosuppression with a IL-17 receptor inhibitor, which inhibits several isoforms of IL-17, including IL-17A, was terminated prematurely for worsening CD symptoms. Notably, an increase in other adverse events was not seen. These unexpected results highlight our lack of understanding of these immune pathways, including the possible differential role of agents in UC and CD. Despite these knowledge gaps, it is understood that binding of UST to p40 prevents interaction of IL-12β1 receptors located on natural killer with T cells to prevent signaling, differentiation (MAbs 2009;1:216–221), and release of IFN-ɣ and tumor necrosis factor-α by mononuclear cells (Cell Immunol 2007;247:1–11). Because these cytokines are important in the pathophysiology of UC, attention has turned toward the therapeutic role of this agent for this disease. The phase III trials of UST in UC were reported in the September 2019 issue of the New England Journal of Medicine (N Engl J Med 2019381:1201–1214). In the UNIFI study, 961 patients with moderate to severely UC (defined as a total Mayo score of 6–12 with an endoscopic subscore of 2 or 3), were randomized to receive placebo (n = 319), 130 mg of intravenous (IV) UST (n = 320), or approximately 6 mg/kg IV UST (n = 322). At week 8, the primary end point of clinical remission, defined as a total Mayo score of ≤2 with no individual subscore of >1, was observed in 5.3%, 15.6%, and 15.5% of these groups, respectively (P < .001 for both UST groups compared with placebo). The corresponding values at week 44 in patients who responded at week 8 was 38.4% in the UST subcutaneously every 12 weeks arm, 43.8% in the UST subcutaneously every 8 weeks arm, and 24% for those patients receiving placebo (P = .002 and P < .001 respectively). The rates of endoscopic response, defined as a Mayo Endoscopic Score of 0 or 1 were 13.8%, 26.3%, and 27.0% respectively (P < .001 for both UST groups compared with placebo) at week 44 were 28.6%, 43.6%, and 51.1% (P = .002, and P < .001, respectively). These results demonstrate the efficacy of UST induction therapy for UC. Furthermore, the results are particularly impressive given the low clinical remission and endoscopic healing rates observed in the placebo arm of the trial. However, perhaps the most novel results were obtained using a new, definition endorsed by the US Food and Drug Administration of mucosal healing comprised of both endoscopic response (Mayo endoscopic subscale of 0 or 1) and histologic (minimal neutrophilic infiltrate on mucosal biopsy) components. Mucosal healing rates in the overall population at week 8 based upon this end point for the placebo, 6 mg/kg IV dose, and 130 mg IV dose arms were 8.9%, 20.3, and 18.4% respectively (P < .001 for both comparisons to placebo) at week 8. Adverse events were similar for the UST and placebo groups. These data indicate that inhibition of the IL-12/23 is beneficial for the treatment of UC, although concerns regarding adverse events with suppression of 2 immune pathways were not realized. Our inability to predict outcomes with this pathway highlights our limited understanding of the immune mechanisms. Sands et al have provided new data regarding the efficacy of UST, a therapy with a novel mechanism of action, for the induction and maintenance of UC but have also highlighted new endpoints in UC trials including histologic healing. These results are consistent with previously published studies targeting the IL-12/23 pathways in CD (N Engl J Med 2019381:1201–1214). These data have led to the regulatory approval of UST for UC. Clinicians now have many therapeutic options available for the treatment of UC, including biologic therapy with three distinct mechanisms of action. However, several unanswered questions remain regarding UST. First, the exact effect of UST on the immune pathways remains unknown. As a result, concern remains regarding the potential safety of long-term inhibition of 2 immune pathways. The UNIFI studies did not demonstrate concerning safety signals, but long-term data are required. Based on preliminary data from the Psoriasis Longitudinal Assessment and Registry (PSOLAR), an international, prospective registry that contains 11,900 patients with psoriasis, including 3796 with UST exposure, no clear safety signal was observed for UST (J Drugs Dermatol 2015;14:706–14). Reported malignancy rates were 0.36 and 0.56, respectively (EAVD 2013;Abstract P6448), for patients who were exposed and unexposed to UST. Serious infection occurred at a rate of 0.98, 2.71, 1.49, 1.01, and 1.44 per patient-year for UST, adalimumab/etanercept, infliximab, or nonbiologic therapy, respectively (EAVD 2013;Abstract P6343). The development of antibodies occurred in 4.6% of patients; however, only 22% had neutralizing antibodies. It should be noted that the dose of therapy used in psoriasis is substantially lower than in UC, which may alter the safety profile. However, the evidence for dose toxicity has not been established. Second, the optimal dose of therapy has not been determined. Numeric benefit of the 6 mg/kg dose of UST compared with the 130 mg dose was observed followed by subcutaneous dosing; however, other dosing regimens have not been examined. In fact, pharmacokinetic data from the UNITI trials demonstrated that higher UST serum concentrations were associated with greater rates of clinical remission at 1 year in CD (N Engl J Med 2019381:1201–1214). Although a therapeutic drug monitoring algorithm, with optimized serum concentrations, has not yet been defined, these data suggest a role for dose intensification in selected patients. Despite the lack of clarity regarding the optimal dose, the UNIFI studies have provided an advance in the delivery of clinical care with the use of IV induction therapy, followed by subcutaneous maintenance. IV induction therapy rapidly achieves therapeutic serum drug concentrations for prompt resolution of symptoms, and subcutaneous maintenance is convenient for long-term drug administration. This paradigm is likely to change therapeutic algorithms for the treatment of UC. Third, UST is a recombinant protein that could theoretically invoke host immune responses including the development of antidrug antibodies that inhibit the drug efficacy. However, in previous trials with UST, the rates of antibody formation have been reported to be low. In fact, in the original UST trial in CD, no patients were reported to have developed antibodies by week 54. However, it should be noted that a drug-sensitive assay was used which would have impaired detection of antibodies, in the presence of measurable drug. In the CERTIFI trial of UST in CD, 0.7% (3 of 427) of patients developed antibodies to UST by week 36 (N Engl J Med 2012;367:1519–1528). Most recently, in the maintenance phase of the UNITI trials (N Engl J Med 2016;375:1946–1960), the prevalence of antibodies to UST using a drug-tolerant assay was 2.3% in patients who received therapy for 1 year. In a pooled analysis of studies from psoriasis (www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000958/WC500058513.pdf), the observed rates of antibody formation to UST were <5%. However, long-term data are required to determine the rate of antibody formation in clinical practice and to evaluate the need for concomitant immunosuppression with UST for antibody prevention. Fourth, questions remain regarding the efficacy of UST in particular patient populations, such as individuals with extraintestinal manifestations, disease subtypes, and in the treatment of tumor necrosis factor-induced psoriasis. In the immediate future, it is conceivable that this agent will be used as a first-line biologic therapy in patients with concomitant psoriasis. As our clinical experience grows, and as we continue to understand the immune mechanisms that contribute to inflammatory disease, we will refine our choice of therapy for each individual patient. Finally, the relative benefit of inhibiting IL-12 and IL-23 compared with IL-23 alone remains to be determined. Selective inhibition of IL-23, by targeting p19 has emerged as a potential target for therapy, to reduce potential off-target adverse events from concomitant blockade of both IL-12 and IL-23. Several such molecules are in development and are showing promise for the treatment of inflammatory bowel disease. As clinicians continue down the path of understanding immune mechanisms, and as our clinical experience grows, answers to several of these questions will become clear. Sands and colleagues have demonstrated the safety and efficacy of UST in patients with and without prior tumor necrosis factor antagonist exposure. Emerging data also suggest selective inhibition of IL-23 is an effective strategy for the treatment of UC. However based our experience with IL-17 inhibition, our ability to predict the efficacy of agents is suboptimal. The results of the UNIFI trials indicate inhibition of the IL-12/23 pathway has therapeutic benefit in UC, and in the coming years the specific component of this cascade that maximizes therapeutic efficacy and minimizes adverse effects will be identified. We may not know that final destination, but as we continue along the path of discovery, advances will lead to progress for our patients.
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Mar 18, 2024
Yusuke Takizawa + 8
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