Rational Combination Therapy to Overcome the Plateau of Drug Efficacy in Inflammatory Bowel Disease

Current treatments for inflammatory bowel diseases (IBDs) are suboptimal. Approximately 30% of patients are primary nonresponders to initial treatment, and approximately 50% of patients become secondary nonresponders to drugs, including the recently approved or to be approved therapies.1Chang J.T. Pathophysiology of inflammatory bowel diseases.N Engl J Med. 2020; 383: 2652-2664Crossref PubMed Scopus (446) Google Scholar A review of the rates of clinical remission across the various tumor necrosis factor-α (TNF-α) inhibitors demonstrates a ceiling effect ranging from 18% to 48% at the end of the induction phase and from 25.6% to 59% at weeks 20 to 30, even among initial responders.2Peyrin-Biroulet L. Lémann M. Review article: remission rates achievable by current therapies for inflammatory bowel disease.Aliment Pharmacol Ther. 2011; 33: 870-879Crossref PubMed Scopus (150) Google Scholar The pooled rates of mucosal healing in placebo-controlled trials of TNF-α inhibitors and vedolizumab are similar and vary from 29% to 45% after 6 to 12 weeks of the induction phase and from 28% to 33% after 32 to 54 weeks of maintenance on these biologics.3Cholapranee A. Hazlewood G.S. Kaplan G.G. et al.Systematic review with meta-analysis: comparative efficacy of biologics for induction and maintenance of mucosal healing in Crohn's disease and ulcerative colitis controlled trials.Aliment Pharmacol Ther. 2017; 45: 1291-1302Crossref PubMed Scopus (217) Google Scholar It is unlikely that the advent of new oral small molecules will break this ceiling. As an example, tofacitinib, an oral inhibitor of Janus kinase 1 and 3, achieved clinical remission at 8 weeks (Study Evaluating The Efficacy And Safety Of CP-690,550 In Patients With Moderate To Severe Ulcerative Colitis [OCTAVE] Induction 1 and 2 trials) in 16.6% to 18.5% of the patients in the 10-mg tofacitinib group, and remission at 52 weeks (OCTAVE Sustain) ranged from 34.3% to 40.6% in the 5-mg and 10-mg tofacitinib induction responder groups, respectively.4Sandborn W.J. Su C. Sands B.E. et al.Tofacitinib as induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2017; 376: 1723-1736Crossref PubMed Scopus (1023) Google Scholar Similarly, in a double-blind, placebo-controlled phase 3 True North study (NCT02435992) evaluating the efficacy and safety of ozanimod, an oral sphingosine-1-phosphate receptor agonist, in inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis, only 47.8% of the patients in the ozanimod group achieved clinical response (based on the 3-component Mayo score) at week 10 of the induction arm.5William S. Doug W. Stephen H. et al.P025 ozanimod efficacy, safety, and histology in patients with moderate-to-severe ulcerative colitis during induction in the phase 3 True North Study.Am J Gastroenterol. 2020; 115: S6-S7Crossref PubMed Scopus (9) Google Scholar During the maintenance phase of the trial of those who had responded to ozanimod during induction, only 37.0% of patients in the ozanimod group achieved the primary end point of clinical remission (3-component Mayo score) at week 52.6Silvio D. Brian F. Stephen H. et al.P030 ozanimod efficacy, safety, and histology in patients with moderate-to-severe ulcerative colitis during maintenance in the Phase 3 True North Study.Am J Gastroenterol. 2020; 115: S8Crossref PubMed Scopus (9) Google Scholar Among those patients with TNF-α inhibitor exposure, the proportions of patients achieving clinical remission were even lower, at 28.9% at 52 weeks of the trial.6Silvio D. Brian F. Stephen H. et al.P030 ozanimod efficacy, safety, and histology in patients with moderate-to-severe ulcerative colitis during maintenance in the Phase 3 True North Study.Am J Gastroenterol. 2020; 115: S8Crossref PubMed Scopus (9) Google Scholar Although many strategies are attempted in clinical practice to maintain or enhance response or remission, such as monitoring of therapeutic drug levels, tight control using existing biomarkers, and multiple drug sequencing, the long-term rates of response or remission remain unsatisfactory. This ultimately leads to disease progression and complications, including surgery in many patients.7Ma C. Moran G.W. Benchimol E.I. et al.Surgical rates for Crohn's disease are decreasing: a population-based time trend analysis and validation study.Am J Gastroenterol. 2017; 112: 1840-1848Crossref PubMed Scopus (118) Google Scholar So the question is, how can we overcome this response plateau? The first possibility is a precision medicine-like, biomarker-based approach as in oncology. Availability of validated drug-specific or agnostic biomarkers targeting patients likely to respond to a new therapy could enable more effective and innovative drug development through implementation of biomarker-stratified clinical trial design.8Verstockt B. Noor N.M. Marigorta U.M. et al.Results of the Seventh Scientific Workshop of ECCO: precision medicine in IBD-disease outcome and response to therapy. J Crohns Colitis. Published online March 17, 2021.https://doi.org/10.1093/ecco-jcc/jjab050 2021Google Scholar With the limited yield of clinical factors to predict the outcome of biologic and small-molecule treatments, studies have focused on identifying genetic alterations and circulating, tissue, or more recently, microbiome biomarkers to identify patients who are likely to respond to therapy. Given the anatomical and functional complexity of the mucosal immune system,9Mowat A.M. Agace W.W. Regional specialization within the intestinal immune system.Nat Rev Immunol. 2014; 14: 667-685Crossref PubMed Scopus (1013) Google Scholar the poorly understood bidirectional interactions with the enteric microbiome,10Caruso R. Lo B.C. Núñez G. Host-microbiota interactions in inflammatory bowel disease.Nat Rev Immunol. 2020; 20: 411-426Crossref PubMed Scopus (343) Google Scholar fungome,11Underhill D.M. Iliev I.D. The mycobiota: interactions between commensal fungi and the host immune system.Nat Rev Immunol. 2014; 14: 405-416Crossref PubMed Scopus (474) Google Scholar and virome,12Neil J.A. Cadwell K. The intestinal virome and immunity.J Immunol. 2018; 201: 1615-1624Crossref PubMed Scopus (71) Google Scholar and the context-dependent nature of mucosal responses,13Ahmad R. Sorrell M.F. Batra S.K. et al.Gut permeability and mucosal inflammation: bad, good or context dependent.Mucosal Immunol. 2017; 10: 307-317Crossref PubMed Scopus (148) Google Scholar integrating mucosal parameters into a robust, predictive model of response to treatment that is reproducible, accurate, and affordable has remained so far elusive. A second and perhaps more practical approach is combination therapy. The most successful example of combination therapy in IBD so far has been the Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC) trial, in which the combination of infliximab and azathioprine was superior to monotherapy with the individual drugs.14Colombel J.F. Sandborn W.J. Reinisch W. et al.Infliximab, azathioprine, or combination therapy for Crohn's disease.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2633) Google Scholar Here the researchers identified that that the use of azathioprine had the primary value of enhancing the bioavailability of infliximab and the prevention of antibodies to infliximab rather than providing an additive effect of their different mechanisms of action on the inflammation cascade,14Colombel J.F. Sandborn W.J. Reinisch W. et al.Infliximab, azathioprine, or combination therapy for Crohn's disease.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2633) Google Scholar although other mechanisms may also exist.15Colombel J.F. Adedokun O.J. Gasink C. et al.Combination therapy with infliximab and azathioprine improves infliximab pharmacokinetic features and efficacy: a post hoc analysis.Clin Gastroenterol Hepatol. 2019; 17: 1525-1532.e1Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Recent years have seen the publication of anecdotal evidence as well as of review articles proposing drug combinations, including biologics and small molecule-based therapies.16Alayo Q.A. Fenster M. Altayar O. et al.Safety and effectiveness of combining biologics and small molecules in IBD: systematic review with meta-analysis. Preprint. Posted online March 1, 2021. SSRN.https://doi.org/10.2139/ssrn.3790447Google Scholar While some of these studies have provided preliminary safety data, caution is needed about the effectiveness claims given the inherent heterogeneity in the time points and methods of clinical and endoscopic response evaluation and duration of follow-up in these studies, which are largely conducted in a retrospective fashion. More insights regarding efficacy should be available from ongoing prospective studies. However, a review of the list of ongoing studies (Table 1) clearly shows that the choice of combination has been primarily opportunistic, combining drugs that were available, rather than driven by mechanistic hypotheses about possible additive or synergistic effects.Table 1Current Clinical Trials of Combination Therapies in Inflammatory Bowel DiseaseMechanismStudyVitamin DHigh Dose Interval Vitamin D Supplementation in Patients with IBD Receiving Biologic Therapy. NCT04331639Adjunctive Treatment with Vitamin D3 in Patients with Active IBD (ACTIVATED). NCT04225819Can Vitamin D Supplementation in People with CD Improve Symptoms as an Adjunct Therapy? (D-CODE). NCT03718182Anti-tumor necrosis factor-α productsCurcumin Supplementation as an Add on Treatment for Patients with IBD Treated with Vedolizumab. NCT03500653Synergistic Effect of Vedolizumab and Pentoxifylline. NCT02953275Curcumin Associated with Thiopurine in the Prevention of Post-op Recurrence in CD (POPCUR). NCT02255370Curcumin + Aminosalicylic Acid (5ASA) Versus 5ASA Alone in the Treatment of Mild to Moderate UC (5ASA) NCT01320436Microbiome alterationBoosting Biologics in UC. NCT04241029Pilot and Feasibility Study of 2'-FL as a Dietary Supplement in IBD Patients Receiving Stable Maintenance Anti-TNF Therapy (PRIME), NCT03847467The Effect of Mycobiome Supplementation on Gastrointestinal Symptoms in IBD Patients. NCT04329481Antibiotics as an Adjuvant in Patients with Acute Severe UC (AAASUC). NCT03794765Fecal Transplantation Using a Diet for Donor and Recipient in Refractory Colitis. NCT02734589Mediterranean Diet as an add-on Therapy for Induction of Remission in Patients With Active CD. NCT02825316Effect of the Exclusive Enteral Nutrition Combined with Azathioprine for Remission of CD After Surgery. NCT04160325Efficacy Study of Tripterygium Glycoside Combined with Enteral Nutrition in the Treatment of CD for Induction Remission. NCT01820247Impact of Additional Treatment with Saccharomyces Boulardii on Quality of Life in Patients with Mild Forms of UC and CD. NCT03941418Treatment of UC With a Combination of Lactobacillus Rhamnosus and Lactobacillus Acidophilus. NCT00374725Effectiveness of Rifaximin Combined with Thiopurine on Preventing Postoperative Recurrence in CD. NCT03185611Combination Therapy with Fecal Microbiota Transplantation and Vedolizumab for Induction of UC. NCT04231110Combination of Diet and 5ASA (5-aminosalicylic Acid) for UC (INDUCT). NCT03980405Food Supplementation With VSL#3 as a Support to Standard Pharmaceutical Therapy in UC. NCT00951548Evaluating the Combined Effect of Vedolizumab and Semi-Vegetarian Diet on UC. NCT03662542Combining other immunosuppressionAn Open-Label, Proof of Consent Study of Vorinostat for the Treatment of Moderate-to-Severe CD and Maintenance Therapy With Ustekinumab. NCT03167437.Triple Combination Therapy of anti-integrin (vedolizumab intravenous [IV]), a tumor necrosis factor (TNF) antagonist (adalimumab subcutaneously [SC]), and an immunomodulator (oral methotrexate) in High Risk CD (Explorer Trial). NCT02764762Efficacy Study of Granulocytapheresis Plus Steroids vs Steroids Alone in Active Steroid Dependent UC (ATICCA). NCT00702611A Randomized, Multicenter Open Label Study Comparing Early Administration of Azathioprine Plus IFX to Steroids Plus Azathioprine for Acute Severe Colitis (ACTIVE). NCT02425852Vedolizumab Monotherapy Vs Combination Therapy with Tacrolimus in UC (COVET). NCT02954159A Study of Efficacy and Safety of Combination Therapy with Guselkumab and Golimumab in Participants with Moderately to Severely Active UC (VEGA). NCT03309865Efficacy, Safety and Tolerability of PF-06687234 as Add-on Therapy to Infliximab in Active UC Subjects Not in Remission. NCT03269695A Study in Patients with Mild or Moderate UC Who Take a TNF Inhibitor. The Study Investigates Whether Bowel Inflammation Improves When Patients Take BI 655130 in Addition to Their Current Therapy. NCT03123120Antibiotics and Hydroxychloroquine in CD (APRiCCOT). NCT01783106MiscellaneousEffect of Iron and Vitamin E Supplementation on Disease Activity in Patients with Either CD or UC. NCT001528415-HTP in Patients with IBD in Clinical and Biologic Remission: Effect on Fatigue Scores (TRP-IBD). NCT03574948The Influence of Hyperbaric Oxygen in Patients with Perianal CD Already Treated with Treated with TNF Alpha Blockers. NCT01828190CD, Crohn's disease; IBD, inflammatory bowel disease; IFX, infliximab; TNF, tumor necrosis factor; TRP, tryptophan; UC, ulcerative colitis; 2'-FL, 2'-fucosyllactose; 5-HTP, 5-hydroxytryptophan. Open table in a new tab CD, Crohn's disease; IBD, inflammatory bowel disease; IFX, infliximab; TNF, tumor necrosis factor; TRP, tryptophan; UC, ulcerative colitis; 2'-FL, 2'-fucosyllactose; 5-HTP, 5-hydroxytryptophan. This report is thus a call for initiating rational drug combinations in IBD therapeutics. This concept (Figure 1), with precedence in other disciplines, such as neurology, can be quoted as "The principle that the combination of two medications with differing mechanisms of action may result in at least additive, supra-additive, or synergistic effects, with infra-additive toxicity."17Gidal B.E. Seeking the rational (or at least avoiding the irrational).Epilepsy Curr. 2015; 15: 260-262Crossref PubMed Scopus (5) Google Scholar This approach also requires that candidate drugs have compatible pharmacokinetic profiles. Perhaps just as important is the need to avoid "irrational" combinations with antagonistic effects that worsen IBD or with perhaps supra-additive adverse effects. The rational combination approach, therefore, clearly requires underpinnings not only in mucosal immunology and bacteriology but also in systems biology to achieve a relevant understanding of individual drug mechanism(s), as well as the potential impact on intersecting biological pathways and networks across different compounds. At its most basic level, this would seem to be an entirely simple, straightforward therapeutic approach.17Gidal B.E. Seeking the rational (or at least avoiding the irrational).Epilepsy Curr. 2015; 15: 260-262Crossref PubMed Scopus (5) Google Scholar There are various recent examples of rational combination therapy being implemented successfully for various diseases. The most common and successful area has been in hepatitis C virus (HCV).18Ioannou G.N. Feld J.J. What are the benefits of a sustained virologic response to direct-acting antiviral therapy for hepatitis C virus infection?.Gastroenterology. 2019; 156: 446-460.e2Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar The newer, directly acting agents targeting different components of the viral assembly mechanisms have dramatically altered the landscape of HCV therapeutics, transforming HCV from a chronic, potentially fatal disease into a treatable infection. The benefits of rational combination therapy are also evident in other infections, such as human immunodeficiency virus 1, in which the advent of combination antiretroviral therapy has resulted in a paradigm shift in the management of patients.19Günthard H.F. Saag M.S. Benson C.A. et al.Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society-USA Panel.JAMA. 2016; 316: 191-210Crossref PubMed Scopus (521) Google Scholar Noninfectious diseases where rational combination therapy is successful include cardiovascular diseases20Foody J.M. Toth P.P. Tomassini J.E. et al.Changes in LDL-C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy.Vasc Health Risk Manag. 2013; 9: 719-727Crossref PubMed Scopus (29) Google Scholar as well as in oncology.21Palmer A.C. Sorger P.K. Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy.Cell. 2017; 171: 1678-1691.e13Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar In this regard, the field of IBD therapeutics, driven by a plateau in treatment response as outlined above, is primed for rational drug combinations. Chang1Chang J.T. Pathophysiology of inflammatory bowel diseases.N Engl J Med. 2020; 383: 2652-2664Crossref PubMed Scopus (446) Google Scholar recently summarized the relevant disease mechanisms in IBD and mechanisms of actions (MOAs) of various effective molecules. While many drugs with different MOAs have shown activity, there is considerable overlap in the MOAs where most of the drugs are nonspecific anti-inflammatory drugs, because inflammation is a key driver of symptoms and subsequent complications of IBD. Reducing the inflammatory burden causes improvement of symptoms and healing of ulcers in many patients. Inflammation may be necessary to initiate gut damage, but reducing the inflammatory burden does not ensure that all patients will have complete remission of symptoms, as has been demonstrated by clinical trials.22Colombel J.F. Keir M.E. Scherl A. et al.Discrepancies between patient-reported outcomes, and endoscopic and histological appearance in UC.Gut. 2017; 66: 2063-2068Crossref PubMed Scopus (101) Google Scholar Other mechanisms may have initiated the signaling pathways that cause inflammation or complement the chronic inflammatory damage. The blockade of TNF, interleukin 12 and 23, or many of the other targets has overlapping actions (Supplement 1 in Chang1Chang J.T. Pathophysiology of inflammatory bowel diseases.N Engl J Med. 2020; 383: 2652-2664Crossref PubMed Scopus (446) Google Scholar). To determine which of the compounds could benefit patients with IBD by being used in combination, the direct MOA needs to be different, and the downstream cascade resulting from the MOA needs to have few overlaps. Drygiannakis et al23Drygiannakis I. Valatas V. Sfakianaki O. et al.Proinflammatory cytokines induce crosstalk between colonic epithelial cells and subepithelial myofibroblasts: implication in intestinal fibrosis.J Crohns Colitis. 2013; 7: 286-300Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar used the term "cross talk" to define the interaction of multiple pro- and anti-inflammatory cytokines and chemokines. The direct MOA of these molecules is like a key to a door into a labyrinth. This key may result in various mechanisms of disease suppression, but other "keys" or doors may end up with the same biological process. If we want to achieve enhanced activity, mechanistically, we have to consider therapies with minimal cascade or cross talk interaction. To paraphrase, we may have different doors to one room, but we may need to get to many rooms to better control the disease(s). Once we can determine the overlap in cascades or "cross talks" between the drugs, we may find that the potential combinations that may offer enhanced activity are very few or that the increase in efficacy will be limited. Whether the MOA is directly anti-inflammatory (such as cytokine or Janus kinase inhibitors) or inhibit the trafficking of proinflammatory cells, their activity will overlap sufficiently to have a low chance of an enhanced effect. In the design of therapies for HCV, the term "orthogonal" antivirals was used to explain activities in nonoverlapping viral targets.24Wagner R. Randolph J.T. Patel S.V. et al.Highlights of the structure-activity relationships of benzimidazole linked pyrrolidines leading to the discovery of the hepatitis C virus NS5A inhibitor pibrentasvir (ABT-530).J Med Chem. 2018; 61: 4052-4066Crossref PubMed Scopus (42) Google Scholar However, if one therapy has only a partial anti-inflammatory effect, it is theoretically possible that a "complementary" therapy may still add some efficacy. So, what do we recommend for the next steps to break this impasse, this plateau of efficacy? We propose that a mechanistic map of the inflammation cascades with relevant cross talk for the therapeutic alternatives be developed. Selecting agents that are at a greater distance in the cascade/cross talk maps or orthogonal to each other will provide us with a higher chance of enhanced efficacy. In addition, because the disease phenotypes themselves manifest differently with, for example, isolated ileal Crohn's disease behaving differently from colonic Crohn's disease, the cascades that should be activated may be different.25Atreya R. Siegmund B. Location is important: differentiation between ileal and colonic Crohn's disease.Nat Rev Gastroenterol Hepatol. Published online March. 2021; 12https://doi.org/10.1038/s41575-021-00424-62021Crossref Google Scholar Ileal disease, for example, manifests with lower inflammatory markers, and pure anti-inflammatory agents have shown lower efficacy in this disease.25Atreya R. Siegmund B. Location is important: differentiation between ileal and colonic Crohn's disease.Nat Rev Gastroenterol Hepatol. Published online March. 2021; 12https://doi.org/10.1038/s41575-021-00424-62021Crossref Google Scholar Thereby, agents with higher interagent mechanistic distance or their ability to target complementary pathways within the inflammatory cascade could have a higher chance of success within specific disease phenotypes. Additionally, agents targeting immune pathways (immunome) might be combined with those targeting the microbiome or the metabolome. The only major advances in response and remission will occur when agents with no or minor direct anti-inflammatory activity are tested in combination with current agents. Although inflammation is the primary driver of symptoms, treating it closer to the cause of IBD may be required to reach major improvements. We still need better information on what those causes may be! Current therapeutic approaches in IBD have reached a plateau in the rates of response and/or remission. Overcoming this plateau requires the identification of rational combinations of therapies with complementary mechanisms of action. A deeper understanding of the individual drug mechanism(s), as well as the potential impact on intersecting biological pathways and networks across different compounds through mucosal immunology, bacteriology, and systems biology, may lead to the realization of potential combinations.