Why Have We Not Finally Figured Out Combination Therapy?

Jun 6, 2018 - Classic Edition | IBD Dialogue | Volume 14 • 2018

Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that includes an annual national meeting, regional satellites in both official languages, www.mentoringinibd.com, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation created by the contributing editor for the annual national meeting, Mentoring in IBD XVIII: The Master Class, held November 3, 2017 in Toronto, Ontario.


Introduction

Biologic therapies—including anti-TNF antibodies (infliximab, adalimumab), integrin inhibitors (vedolizumab) and anti-IL12/23 antibodies (ustekinumab)—are mainstays of treatment for IBD. There is considerable evidence to support combining a non-biologic immunomodulator (e.g., a thiopurine or methotrexate) with the biologic; however, this evidence has been generated in specific populations using specific combinations and may not be generalizable beyond those scenarios. Additionally, combination therapy is associated with a different safety profile than biologic monotherapy, which warrants review and discussion with patients.

Rationale for Combination Therapy in IBD

The rationale for adding an immunomodulator to biologic therapy includes the desire for additional and potentially synergistic efficacy, lower rates of anti-drug antibody formation, higher drug levels, lower rates of infusion reactions and better clinical outcomes.(1,2) These potential benefits do, however, need to be balanced against the potential safety concerns associated with combination therapy.

Review of Clinical Trial and Observational Evidence

The evidence for combination therapy differs among biologics. The following sections summarize the key clinical trial and observational data for each of the biologics indicated for the treatment of IBD in Canada.

Infliximab

Evidence of additional efficacy with combination therapy is strongest with infliximab. The SONIC study was a double-blind, placebo-controlled study prospectively comparing the efficacy of infliximab, azathioprine or their combination among patients with Crohn’s disease (CD).(1) For the primary efficacy endpoints (corticosteroid-free remission at week 26), the combination therapy arm was superior to either monotherapy arm. In terms of mucosal healing, combination therapy was superior to azathioprine monotherapy, and numerically better than the infliximab monotherapy arm, although the latter did not reach statistical significance. Some of the additional benefit of combination therapy may have been due to the higher infliximab levels in the combination-arm patients. As shown in Figure 1, the difference in median infliximab serum trough concentration was significantly higher in the combination therapy arms than the infliximab monotherapy arm.

Similar findings were reported in the SUCCESS trial, which evaluated infliximab, azathioprine or their combination in patients with ulcerative colitis (UC).(2) Combination treatment in that study was associated with significantly greater rates of corticosteroid-free remission and mucosal healing relative to either monotherapy alone.(2) In a post-hoc analysis of the SONIC data, investigators stratified mono- vs. combination therapy outcomes by quartile of serum infliximab concentrations.(3) Combination therapy did not show consistent benefit when corrected for trough infliximab concentrations. The authors concluded that the benefit of combination therapy was primarily due to azathioprine’s effects on the pharmacokinetics of infliximab.

SONIC and SUCCESS both involved the simultaneous start of infliximab and azathioprine. What these data do not tell us is the impact of adding azathioprine to the regimen when patients start to lose response to infliximab. An intriguing but very small (n=4) study conducted in Israel showed that adding either azathioprine or methotrexate to patients with detectable infliximab anti-drug antibodies (ADAs) and loss of clinical response led to a reduction in ADAs and increased infliximab trough concentrations.(4) Observational data have also suggested that introducing an immunomodulator can reverse immunogenicity. In a retrospective multicenter cohort study, among patients losing response to infliximab (18 patients with available data), introduction of an immunomodulator was able to restore infliximab trough level to within the therapeutic range and to induce clinical remission in 55% patients (10/18).(5)

Combination therapy may be particularly relevant in complex disease such as perianal fistulizing disease, where higher drug concentrations are desirable. In a cross-sectional study of 117 CD patients with active fistulas on infliximab for more than 24 weeks, higher trough infliximab levels (>10 𝝻g/mL) were associated with higher rates of fistula healing compared to lower levels.(6) Rates of mucosal healing and fistula closure were also higher among patients with higher infliximab levels in that study.(6)

Infliximab has also been studied together with subcutaneous methotrexate among patients with CD.(7) While there was no significant difference observed in this study for the primary efficacy endpoint of steroid-free remission at week 14, the study did show that methotrexate can modify immune response to infliximab. There were lower rates of anti-drug antibodies in the combination arm (4% vs. 20%, P=0.01), and a trend towards higher infliximab trough levels, 6.35 μg/mL vs. 3.75 μg/mL (P=NS).

Adalimumab

Evidence of additional efficacy with immunomodulator combination therapy is considerably less compelling with adalimumab. In the prospective DIAMOND study, in which the combination of azathioprine and adalimumab was compared to adalimumab monotherapy among patients with CD, there was no significant between-group difference observed for either clinical remission rate or mucosal healing at week 52.(8) Patients treated with the combination therapy did, however, achieve mucosal healing more rapidly than those in the adalimumab monotherapy arm. Mucosal healing rates at 26 weeks were 84.2% with the combination and 63.8% with adalimumab monotherapy (P=0.019).(8)

These observations from the DIAMOND trial make it clear that biologics with similar mechanisms of action (e.g., adalimumab and infliximab—both TNF inhibitors) may not have the same or even similar pharmacokinetic and pharmacodynamic properties and that data with one molecule may not be extrapolated to others.

With adalimumab, a meta-analysis of 14 studies that included pharmacokinetic data showed that while clinical response was associated with higher drug trough and low antibody to adalimumab, and that antibodies to adalimumab appear to cause low trough concentration and lessened clinical effect, there was no evidence suggesting that combination therapy influenced adalimumab antibody or drug trough levels.(9)

There is, however, some real-world evidence suggesting benefit of early combination therapy with adalimumab in CD. The REACT study was an open-label, cluster randomized, controlled trial in which community gastroenterologists in Belgium and Canada provided data on up to 60 patients with CD from their practices.(10) The practices were randomly assigned to either conventional management with adalimumab or an accelerated step-care algorithm that featured early use of combined adalimumab antimetabolite therapy. Although there was no difference between groups with respect to the primary efficacy endpoint (corticosteroid-free remission at one year), there were significant differences observed in time to first hospitalization, surgery or complication in favor of the combination arm (Figure 2).

The CALM study also supports the benefit of using a step-care approach with adalimumab.(11) In this open-label, randomized, controlled phase 3 study, patients with CD were randomly assigned to tight control or clinical management groups. Both groups’ treatment algorithm involved escalation to combination therapy when treatment failure criteria were met. In the tight control group, this included biomarker and clinical criteria, while the clinical group used only clinical variables. The tight control group fared better in the primary endpoint, mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomization: 46% for tight control vs. 30% with clinical management (P=0.01).

Vedolizumab

The evidence base for vedolizumab is more limited than it is for the more established anti-TNF biologics discussed above. In the pivotal clinical trials in IBD (GEMINI 1 and 2), approximately 30% of the patients treated with vedolizumab were also receiving an immunomodulator.(12-14) In those studies, antibodies to vedolizumab were found infrequently (3.7%-4.1%) in patients at “any time” during testing. During active treatment, combination therapy patients had a 3% risk of antibodies, compared to 4% for vedolizumab monotherapy. Following completion of vedolizumab therapy, there were substantial differences observed in anti-drug antibodies among those patients without IMM compared to those with ongoing IMM use (18% vs. 3%). What these observations mean clinically remains unclear.

Ustekinumab

As was the case with vedolizumab, in the ustekinumab pivotal trials, approximately 30% of patients were receiving concomitant immunomodulator therapy.(15) It has been reported that there were low rates of antidrug antibodies at 44 weeks (2.3%), but there are no published data to date analyzing the effect of combination vs. monotherapy in the ustekinumab clinical trial experience.

There are, however, some real-life data with ustekinumab that are informative on this subject. In the retrospective, observational GETAID study, there were 122 patients with CD treated with ustekinumab, all of whom had previously failed TNF-inhibitor therapy.(16) Of these, 18 were taking concomitant immunomodulator therapy. In this cohort, immunomodulator use was found to be a predictor of three-month clinical benefit (odds ratio 5.43; 95%CI: 1.14-25.77; P=0.03).

Summary of evidence

As shown in Table 1, the evidence base upon which to base decisions regarding combination therapy varies across different biologics and the decision should be individualized based on patient and safety profile and choice of biologic.(17)

The SONIC trial in CD and SUCCESS trial in UC showed that the combination of infliximab and azathioprine is superior to monotherapy with either agent alone at inducing clinical remission in treatment-naïve patients with moderate-to-severe disease. Studies with adalimumab have suggested that the presence of anti-drug antibodies is associated with low levels of trough adalimumab and an attenuated clinical effect. Using an immunomodulator concomitantly can prevent sensitization. Currently, we also lack prospective evidence addressing the role of combination therapy with vedolizumab or ustekinumab. While subanalyses of clinical trials suggest that adding an immunomodulator to these biologics reduces sensitization, overall rates of antibodies to vedolizumab and ustekinumab are low.

Why Not Combination for Everyone?

The three key reasons that argue against the universal use of combination therapy are: 1) overtreatment of patients with mild IBD who are unlikely to have progression of disease; 2) increased susceptibility to adverse effects from two drug classes rather than one; and 3) other important safety concerns.

For the latter, unlike short term clinical trials, long-term retrospective and prospective series have shown that adding azathioprine to anti-TNF agents is associated with higher relative risks of opportunistic infection, lymphoma and non-melanoma skin cancer.(18-20)

A systematic review published in 2011 compiled data on the association between hepatosplenic T-cell lymphoma (HSTCL) and combination therapy for IBD from published reports and the MedWatch reporting system of the US Food and Drug Administration.(21) As shown in Table 2, there was a substantial increase in risk associated with thiopurines, either as monotherapy or combined with anti-TNF therapy, when compared with anti-TNF monotherapy. The overall risk increases dramatically among men younger than 35 years old.

With respect to other malignancies, a large global, multicenter prospective cohort study (DEVELOP, n=5,402) examined rates of malignancies among pediatric patients with IBD treated with biologics.(22) Comparing the rates to the general population using the SEER database as the comparator, the authors did not observe any overall risk of malignancy with the biologics alone, but there was a 2.7-fold increased risk of malignancy in thiopurine-exposed patients irrespective of biologic exposure.

Real-life data with adalimumab in IBD have also demonstrated an increase in serious safety events with combination therapy. The PYRAMID registry, which includes more than 5,000 patients with CD treated with adalimumab followed for up to seven years, showed that the incidence of serious infections was significantly higher among patients receiving concomitant immunomodulators (12.7%) compared to those on adalimumab monotherapy (12.7% vs. 9.6%, P=0.007).(23) Overall malignancy risk was also higher with combination therapy in this cohort: 3.1% for adalimumab + immunomodulator and 1.9% for adalimumab monotherapy (P=0.014).

Conclusions

Analysis of the currently available evidence for combination therapy in IBD shows that data obtained for one biologic agent may not apply to others. Combination therapy is more effective for infliximab, especially in those without prior immunomodulator or infliximab use. Combination may be less important for adalimumab, and to date, data are lacking for the other biologics used in IBD. The main mechanism of benefit of combination therapy is likely through favorable effects on immunogenicity and pharmacokinetics. In general, one might consider combination therapy patients with risk factors for disabling disease, complications or surgery. However, as always in evidence-based medicine, we need to consider the populations studied in the trials when applying their findings to clinical practice. The safety signals that have been observed with combination therapy also make it important to evaluate the benefits and risks of combination vs. monotherapy on a patient-by-patient basis. On a population level, this is not yet resolved.


Clinical Case

The patient is 31-year-old male smoker working as a French teacher. He presents to the ER with a two-month history of right-lower-quadrant (RLQ) pain, five to eight non-bloody liquid stools per day, perianal discharge and a 4.5 kg (10 lb) weight loss.

In the emergency department, he is seen by the GI service. On physical exam, the RLQ is tender, there is a thickened bowel loop and small perianal fistula.

Laboratory investigations show:

  • White blood cell count of 14 x 109/L
  • Hemoglobin 119 g/L
  • C-reactive protein (CRP) 72 g/L
  • Stool culture and sensitivity and C. difficile are negative

A computed tomography scan of the abdomen and pelvis showed 40 cm thickened terminal ileum and proximal colon with mucosal enhancement; no abscess; and small perianal fistula. Colonoscopy reveals deep, discrete ulcerations of the terminal ileum, ascending and rectosigmoid colon.

He is started on prednisone. You see him in the office one week later. He feels better but his symptoms persist. The biopsy results are compatible with IBD.

Commentary

With respect to therapeutic decision making, first we should look at the risk profile. The key features of this patient’s CD are ileal disease, deep ulcerations and perianal fistula. He is also a smoker.

This profile gives us a fairly clear path to selection of induction treatment. He has moderate-to-severe disease, which is an indication for biologic therapy; the perianal disease suggests that anti-TNF therapy (adalimumab or infliximab) might be favored over the α4β7 integrin inhibitor vedolizumab or the IL-12/23 inhibitor ustekinumab.

Both adalimumab and infliximab (as well as certolizumab pegol) have clearly demonstrated benefit for the induction and the maintenance of remission in perianal CD.(24)

The next question to address is whether or not we consider combination therapy with the chosen anti-TNF and a nonbiologic immunosuppressant (i.e., thiopurine [azathioprine or 6-mercaptopurine] or methotrexate). This continues to be a matter of debate. There is indeed compelling evidence of additional benefit beyond anti-TNF alone for CD, for example in the SONIC study with infliximab and azathioprine.(1) With adalimumab, the story is less clear. In subgroup analyses from the adalimumab clinical trial program(25,26) and meta-analyses of adalimumab studies,(27,28) there has been limited evidence of additional benefit for combination therapy. In the REACT study, for example, early combined immunosuppression with a thiopurine was not associated with additional efficacy for the primary endpoint of remission, but did demonstrate an improvement in composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications vs. adalimumab alone.(10)

With respect to safety, there are some well known risks of thiopurine therapy that should be considered, including increased risk of infections(29) and of malignancy, particularly Hepatosplenic T cell lymphoma.(30)

Should one decide to include a non-biologic immunosuppressant in the regimen, there is also the question of whether to use a thiopurine or methotrexate, and what dose to use.

Case Evolution

After discussion, the patient is ready to start a biologic and he says he understands the benefits and risks. Because he often travels, he wishes to have a subcutaneous agent. You therefore start him on adalimumab, in combination with 6-mercaptopurine. You see him three months later and he is doing well. He comes for a subsequent follow-up at nine months. At this visit, he says that he has done a lot of reading and is worried about combination therapy and wishes to stop one of the two agents.

Commentary

Although the patient is motivated to stop one of the therapies to reduce the risk of undesired adverse drug effects, you should also talk to him about the risks of stopping one of the agents. There is evidence showing that approximately half of patients who stop an anti-TNF relapse within the first year.(31) On the other hand, stopping the 6-MP may be considered. A study in which this was investigated among patients with stable disease for at least six months showed that there was no difference in outcomes between continuing combination therapy and proceeding with anti-TNF monotherapy.(32)

If he wants to stop the 6-mercaptopurine, consider what should be done first: should one reassess disease activity? Should therapeutic drug monitoring (TDM) be conducted to ensure adequate adalimumab levels before and after the cessation?

You might also consider counseling the patient that his disease is well controlled on the current therapy, and that he needs to weigh this benefit and the potential risk of losing his response against the potential risks of combination therapy before deciding.

Case Evolution

You reassess disease activity. Complete blood count, fecal calprotectin and CRP are all normal. A colonoscopy shows scarring in the rectosigmoid and ascending with normal remaining colon and distal ileum. You inform the patient he is in remission and decide he can stop the thiopurine.

Six months later, the patient returns to your office complaining of three to four loose stools per day, with abdominal pain. The perianal fistula is inactive. His hemoglobin is 121 g/L, CRP is 22 g/L and fecal calprotectin is > 2100 mcg/g.

Commentary

The discussion at this point should focus on choosing between one of three options: restart the 6-MP; do therapeutic drug monitoring; or switch biologic therapy.

Restarting the thiopurine may be considered, given the previous response to the combination and the loss following its withdrawal. TDM should also be considered, as multiple studies have confirmed a correlation between clinical response and trough serum levels of anti-TNF medications.(33) Furthermore, evidence has shown that a thiopurine can increase the levels of infliximab, (e.g., in the SONIC study[1]) which may be relevant here, depending on the findings of TDM.

Consider a switch of biologic may be premature here, but should the other strategies not be effective in restoring remission, there is certainly evidence of benefit for a subsequent biologic after failure of the first in CD.(34)

Case Evolution

You measure adalimumab levels and they are 40 mcg/mL with no antibodies.

Commentary

The adalimumab drug level is more than adequate, at 40 mcg/mL. The threshold below which one might be concerned has been found to be much lower (e.g., 5.85 mcg/mL in one study[35]). So insufficient drug level for adalimumab is not the cause of the patient’s loss of remission.

The discussion here should focus on the other options at this point – restarting the thiopurine or switching to another biologic.

Case Evolution

You discuss the possibility of switching biologic therapy. The patient agrees and says that he still wishes to have a subcutaneous agent. You prescribe ustekinumab.

Commentary

Ustekinumab and vedolizumab are both relatively new agents in CD, compared to adalimumab and infliximab. There is limited evidence to guide us with respect to the impact of combination therapy with either of these two agents plus a nonbiologic immunosuppressant.

The registration trials for these agents primarily used the agents in monotherapy, although there were a minority of patients included who continued their previous immunosuppressant into the trials.(13,15,36,37) Further research is needed into the impact of combination therapy.

Immunogenicity is also a consideration with biologic therapies. Although there were no anti-drug antibodies to which we could attribute the failure of adalimumab, it is still worth considering in the context of a new biologic start. TDM is also a consideration with either ustekinumab or vedolizumab, and threshold drug levels have been established for each in CD.(38,39)


References

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  17. Sultan KS, Berkowitz JC, Khan S, et al. Combination therapy for inflammatory bowel disease. World J Gastrointest Pharmacol Ther. 2017;8(2):103–13.
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  35. Mazor Y, Almog R, Kopylov U, et al. Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn’s disease. Aliment Pharmacol Ther. 2014;40(6):620–8.
  36. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012;367(16):1519–28.
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Editor-in-Chief

John K. Marshall, MD MSc FRCPC AGAF, Director, Division of Gastroenterology, Professor, Department of Medicine, McMaster University, Hamilton, ON

Co-Editor-in-Chief

Richard N. Fedorak, MD FRCPC FRCP (London) FRCP (Edinburgh) FRCS, Dean, Faculty of Medicine and Dentistry, Professor of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB

Contributing Editor

Siew Ng, MBBS, FRCP (Lon, Edin) PhD (Lond) AGAF FHKCP FHKAM (medicine), Department of Medicine and Therapeutics, Chinese University of Hong Kong


Mentoring in IBD Curriculum Steering Committee

Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, NS
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Craig Render, MD FRPCP, University of British Columbia, University of Alberta, Kelowna, BC
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON


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