The 2016 Advances in Inflammatory Bowel Disease (AIBD)conference included a robust clinical agenda featuring presentations bynationally recognized gastroenterologists.
New data continue to rapidly evolvethe field of inflammatory bowel disease (IBD) management. Experts presented evidencefrom the latest studies that impact best practices for patient care, choice oftherapy, and techniques used to monitor and optimize therapy. Hot topics in IBD management addressed during the meeting shareda common theme of improving the patient experience and quality of care whilereducing costs. Withthe recent FDA approval of Inflectra, a biosimilar to Infliximab (IFX)NR1 ,the impact that biosimilars are anticipated to have on clinical practice has receivedmuch attention.
1 Biosimilars must be highly “similar” to an originator or”reference” biologic therapy; clinical and nonclinical studies evaluating thepharmacokinetics, efficacy, safety, and immunogenicity of the biosimilarmolecule are required in order to establish that there are no clinicallymeaningful differences between the biosimilar and the reference product.1,2NR2 Due to thelower costs associated with the development of biosimilars, their use mayreduce health care expenditures associated with biologic medications. Thepotential for cost savings, along with comparable efficacy, make it likely thatbiosimilars will be widely used for the treatment of IBD.NR3 2Therapeuticdrug monitoring (TDM) of IFX has improved response rates to IFX, and is gainingacceptance as a tool for the management of patients experiencing loss ofresponse to IFX; TDM is expected to play a key role in the management of IBDfor patients treated with Inflectra as well.
NR4 2With3 classes of biologics available now for the management of IBD,gastroenterologists are armed with more options than ever before to help theirpatients reach their treatment goalsJA5 .3,4In orderfor the availability of additional medications to translate to improved patientoutcomes, it is important to determine which medication is best for eachpatient and at each stage of treatmentNR6 .3In addition to TNF? inhibitors, the anti-integrin antibodyNR7 ,vedolizumab(VDZ) is indicated for the management of patients with ulcerative colitis andCrohn’s diseaseNR8 ,and most recently, theinterleukin-12/23 inhibitorNR9 ,ustekinumab,was approved for patients with Crohn’s disease.4,5 NR10 Prospective studies to evaluate the comparativeefficacy of these treatment options are on the horizon.
Until additional dataare available, clinicians can select among treatment choices based on reportedefficacy and safety profiles from separate studies, and a number ofpatient-specific factors, such as severity of disease, risk for disease-relatedcomplications, age, concomitant medications, likelihood of adherence, and theavailability of assays to measure drug and antibody levels.3 NR11 The Prometheus Anser® tests offerquantitative monitoring assays to measure drug and anti-drug antibody levelsfor TNF? inhibitors adalimumab (ADA) and IFX, as well as biosimilar IFX and VDZ, to assist clinicians in adoptingthese treatment options into clinical practice. As part of our commitment to improving the lives of patientswith IBD by promoting individualized patient care, PROMETHEUS® continues to workin partnership with clinical investigators to support ongoing research thataims to define drug and antibody levels associated with improved clinicaloutcomes and to identify strategies that maximize the clinical benefits ofavailable IBD therapies. The results of 3 such studies that were presented atthe 2016 AIBD conference are featured in this issue of Clinical Insights. Establishing an Anti-infliximabAntibody Threshold Predictive of Infliximab Durability Thedurability of response to treatment with infliximab (IFX) in patients with IBDis negatively impacted by the presence of antibodies to IFX (ATI).
There may bea threshold level of ATI below which clinical efficacy is not compromised. Insome cases where drug concentration remains detectable, maintenance of responseis possible in the presence of ATI. However, exactly where this threshold liesremains unknown. Furthermore, the most appropriate strategies to optimize durabilityin the presence of ATI have not previously been investigated. NR12 Astudy by Greywoode and colleagues aimed to determine what ATI level yields clinicaldurability and to explore the value of various optimization strategies commonlyemployed in attempt to preserve clinical durability. NR13 Theinvestigators conducted a retrospective chart review of patients with ulcerativecolitis and Crohn’s disease who had received treatment with IFX at a tertiarycare IBD center.
Eligible patients had at least one documented measurement of IFXdrug concentration and ATI level over the course of their treatment. IFX andATI levels were measured using a drug-tolerant, homogenous mobility shift assay(Anser® IFX, Prometheus Labs Inc, San Diego, California), and all ATI-positivepatients (N=62) were included in the analysis. The primary outcome evaluatedwas clinical durability, defined as steroid-free remission with IFX treatmentmaintained at the final follow-up visit. NR14 Only16 of the 62 patients (25%) analyzed met the primary end point of steroid-free remission;those patients maintained treatment with IFX at their last follow up visits(Figure 1). NR15 Examination ofclinical durability by ATI level showed that ATI levels ?9.7 U/mL arepredictive of clinical durability (Figure 2). NR16 The true positive rate, or sensitivity, of theATI threshold was plotted against the false positive rate, or specificity, in areceiver operating characteristic (ROC) curve in order to evaluate the accuracyof this prediction.
This ROC analysis demonstrated that ATI levels ?9.7 U/mL reliablypredicted clinical durability with 76.1% specificity and 81.2% sensitivity (P<0.001). Themean ATI level in patients who maintained response to IFX was significantlylower than in patients who discontinued treatment with IFX due to loss ofresponse (7.
6 U/mL vs 31.0 U/mL; P=0.005).Conversely, detectable IFX concentrations were significantly more common inpatients who maintained their responses than in those who did not (44% vs 17%; P=0.03). Mean IFX levels were alsohigher in patients who maintained response compared with patients whodiscontinued treatment due to loss of response (3.9 U/mL vs 1.1 U/mL), althoughthe trend did not reach significance (P=0.
07).NR20 Amongthe 16 patients who maintained their responses to IFX, ATI measurements wererepeated in 13 (81%). Repeat measurements showed that 11 of the 13 patients(85%) achieved ATI clearanceNR21 .
The most frequent strategy associated with ATIclearance in those 11 patients was dose escalation, which was effective in in 5patients (45%), followed by the addition of an immunomodulator, which waseffective in 3 patients (27%). NR22 Thesedata demonstrate that discontinuation of IFX is not necessary in all patientswith ATI. In particular, low levels of ATI (<9.7 U/mL) can be overcomesuccessfully by optimizing dosage, thus maintaining steroid-free remission inpatients treated with IFXNR23 . Therefore, it is important to determineATI levels in order to guide clinical decisions regarding the addition of animmunomodulator or dose escalation before discontinuing IFX therapy.Combination Therapy WithIFX and an Immunomodulator Is Associated With Higher IFX Trough Levels and DecreasedLikelihood of Antibody Formation IFXtherapy for patients with IBD is limited by loss of response (LOR), whichresults in the need to change medications.
2 In addition to ATIformation, previous studies suggest that low serumtrough levels of infliximab (IFXL) may also lead to LOR. In studies of adultpatients with IBD, combination therapy with an immunomodulator (ie, thiopurineor methotrexate) and IFX has been shown to decrease ATI formationNR25 , but the risks and benefits ofcombination therapy remain unclear. Furthermore, data from prospective studiesevaluating the relationship among ATI, IFXL, combination therapy, and LOR inpediatric patients are limited. NR26 Resultsfrom a prospective observational cohort study of 227 pediatric and young adultpatients (median age of enrollment: 17.1 years) being treated with IFX werepresented by Zitomersky et al. Patient Characteristics are shown in Table 2. Serumsamples were obtained during clinical infusion visits in order to assay IFXLand ATI levels. Analysisof these patients showed that LOR was more likely to occur in patients with anATI level ?3.
1 U/mL(23 of 58; 40%) than inthose with an ATIlevel <3.1 U/mL (10 of 169; 6%) (P=0.0001).NR29 At their last recorded study visits, 85 of 227(37%) patients were on combination therapy with either 6-mercaptopurine (n=14)or methotrexate (n=71), while the remaining 142 (63%) were receiving monotherapywith IFX. NR30 ATI levels ?3.1 U/mL were more common inpatients on monotherapy (20%) than in those on combination therapy (11%).
NR31 Patientswere divided into 5 groups based on the dose of IFX received per 8 weeksNR32 . Among patients receiving 5 to 10 mg/kg IFXevery 8 weeks, median IFXL was higher in patients who were on concurrentimmunomodulator therapy than in those who were not (P=0.008) (Figure 2).
NR33 In patients receiving 10 to 15 mg/kg IFX every 8weeks, median IFXL was also higher in the combination therapy group compared withthe monotherapy group; however, the difference was not statisticallysignificant. NR34 Thesedata show that the development of ATI was associated with a higher likelihoodof LOR to IFX in this population of pediatric and young adult patients. Combinationtherapy with an immunomodulator was associated with significantly higher IFXtrough levels in patients treated with 5 to 10 mg/kg IFX every 8 weeks, and ATIformation was more likely in patients receiving IFX monotherapy. These resultsindicate that concomitant use of immunomodulatory therapy may reduce thelikelihood of LOR, perhaps by increasing IFX levels and reducing the likelihoodof antibody formation. NR36 Therefore, clinical assessment of ATI inpediatric and young adult patients with IBD may help identify appropriatepatients who could benefit from combination therapy.
Early Initiation of CombinationTherapy: The REACT StudySeveral presenters emphasized the benefits of early initiation of combination therapy,citing the results of the REACT study in support of this management paradigm. REACT, or”Randomised Evaluation of an Algorithm for Crohn’s Treatment,”NR37 was a large trial designed to compare outcomesin patients randomized to receive early combined immunosuppression (ECI) withthose receiving conventional management in community-based gastroenterologypractices. Patients in ECI practices (n=21 practices, n=1084 participants) withcontinuing disease activity after initiation of corticosteroids receivedcombination therapy with a TNF? inhibitor (ADA or IFX) and an immunosuppressant(azathioprine AZA, 6-MP, or MTX). Patients in practices assigned toconventional management (n=18 practices, n=898 participants) were treatedaccording to the usual practice of their physiciansNR38 .9 Patientsat ECI practices were treated with immunosuppressive agents, TNF? inhibitors,and combination therapy earlier than patients at conventional managementpractices, and more patients in ECI practices were being treated withcombination therapy by 12 months than those in conventional practicesNR39 . When assessed at 12 months and at 24 months,more patients in ECI practices achieved remissionNR40 , defined as a score of 4 or less on theHarvey-Bradshaw Index (a composite measure assessing abdominal pain, stoolfrequency, general wellbeing, extra-intestinal manifestations, and presence ofabdominal masses), which ranges from 0 to 12NR41 .
However, differences in remission rates betweenthe 2 groups were not significant. Patients in ECI practices did showsignificantly greater reductions in a composite outcome time to occurrence ofmajor adverse outcomes (P=0.0003), surgeries(P=0.0314), and seriousdisease-related complications at 24 months (P=0.0005)NR42 . These results suggest that timing ofintroduction of combination therapy is important, and demonstrates the safetyof ECI in community practices.
NR43 9Lower rates of ATI formation in patients receivingcombination therapy may be a factor contributing to improved outcomes observedat 2 years. Combination therapy with an immunosuppressant can increase theeffective concentration of the TNF? inhibitor and potentially help morepatients achieve and maintain remission. When using combination therapy, measurements ofdrug and antibody levels may inform dose optimization for the TNF? inhibitorNR44 .
If a thiopurine (AZA or 6-MP) is used as theimmunomodulator in a combination therapy regimen, monitoring of metabolites canhelp clinicians keep dosing within a safe and effective range. NR45 Higher VedolizumabTrough Levels Are Associated With Remission in Patients With IBD DuringMaintenance Therapy Vedolizumab(VDZ) is an anti-integrin biologic therapy that is indicated for the managementof patients with ulcerative colitis and Crohn’s disease. In clinical trials, higher trough levels ofVDZ were associated with higher rates of clinical remission.NR46 Assays to determine VDZ levels haverecently become commercially available.NR47 In order to assess the clinical utility ofmeasuring VDZ levels, Ungaro and colleagues designed a study to evaluate theassociation between trough VDZ levels and remission in a real-world clinical setting.NR48 Investigatorsconducted a cross-sectional study of patients undergoing maintenance VDZtherapy at a tertiary care IBD infusion center. All patients aged 6 years orolder with ulcerative colitis or Crohn’s disease were eligible for the studyNR49 . A total of 113 patients were evaluated: 63patients with Crohn’s disease and 50 patients with ulcerative colitis.
Of thesepatients, 75% had received prior treatment with an anti–tumor necrosis factor-?(TNF?) agent, and 41% remained on an immunomodulator in combination with VDZ. NR50 Troughserum VDZ and antibody-to-VDZ (ATV) levels were measured in all patients usinga drug-tolerant, homogeneous mobility shift assay platform (Anser® VDZ,Prometheus Labs Inc, San Diego, California). Data, including patientdemographics, C-reactive protein (CRP) levels, and disease activity indices,including the Harvey Bradshaw Index (HBI) and the Partial Mayo Score (pMS),were collected at each infusion visit.
Data were analyzed to assess the associationamong VDZ levels, ATVs, and remission. The primary outcome in the study wasremission, defined as normal CRP levels (<5 mg/L) and HBI <5 or pMS of 0or 1. NR51 Overall,patients had received an average of 7.9 prior infusions of VDZNR52 , and the median VDZ level was 10.9 µg/mLNR53 . Patients in remission had significantly highermedian levels of VDZ (12.
1 µg/mL, interquartile range IQR 9.5-19.9) thanpatients not in remission (9.
6 µg/mL, IQR 5.7-16.9) (P=0.008) (Figure 3)NR54 . Higher rates of remission were seen with increasingVDZ quartiles (P=0.01). Patients withVDZ levels below the median were significantly less likely to be in remissioncompared with those who had VDZ levels above the median (37.9% vs 61.
8%; P=0.01). NR55 Patients with VDZ levels above the median also hadsignificantly higher odds of being in remission (odds ratio OR 2.65; 95% CI,1.24-5.
66). Nosignificant differences in VDZ level or remission rate were seen withimmunomodulator use. NR58 Antibody formation was rare in patients treatedwith VDZ—only 4 patients (3.5%) had detectable ATVs; 3 of these 4 patients werenot on an immunomodulator, and all of them had detectable VDZ levels despitethe presence of ATVs.
Thisstudy demonstrated that VDZ levels during maintenance therapy weresignificantly higher in patients in remission, and that the odds of remission aresignificantly higher in patients with VDZ levels over 10.9 µg/mLNR60 . These data suggest that an assay todetermine VDZ levels would be clinically relevant, as it could inform doseadjustments to ensure that VDZ remains at a level likely to increase the oddsof remission. VDZ for Management ofPatients With Ulcerative Colitis and Crohn’s Disease: The GEMINI TrialsGEMINI1 was a phase 3, randomized, double blind, placebo-controlled trial evaluatingthe efficacy of VDZ for the induction and maintenance of clinical response inadult patients with ulcerative colitisNR61 . In the induction phase of the study, patientsreceived VDZ or placebo at weeks 0 and 2 and were evaluated at week 6.
For themaintenance phase, patients who responded to induction therapy at week 6 wererandomized to receive VDZ every 8 week, VDZ every 4 weeks, or placebo for up to52 weeks. JA62 Patients were evaluated using the Mayo Clinic Score, which ranges from 0to 12, with higher scores indicating more active diseaseNR63 . Clinical response was defined as adecrease of ?3 points and ?30% from baseline along with a decrease of ?1 pointon the rectal bleeding subscale (or a rectal bleeding score of 0 or 1).13NR64 Thetrials demonstrated that VDZ was effective for inducing and maintaining aresponse and remission in patients with moderate to severe active ulcerativecolitis.
NR65 More patients showed clinical response toinduction with VDZ vs placebo (47.1% vs 25.5%; P<0.001), NR66 and more patients maintained their clinicalresponse at week 52 with either VDZ every 8 weeks or every 4 weeks vs placebo(41.8% or 44.8% vs 15.9%; P<0.
001for both comparisons).13 NR67 VDZis also considered a safe treatment option: there were no important differencesin the most commonly reported adverse events with VDZ in comparison withplacebo, and serious infections were not more common with VDZ than with placebo(1.9% vs 2.9%).
Importantly, there were no cases of progressive multifocal leukoencephalopathy (PML)NR68 , a serious brain infection which had beena concern with natalizumab, an integrin inhibitor that had shown efficacy inpatients with Crohn’s disease.13 NR69 GEMINI2 shared a similar study design and evaluated patients with moderate to severeactive Crohn’s disease.NR70 Patients with a Crohn’s Disease Activity Index (CDAI) NR71 score of ?150 and a CDAI-100 response wereconsidered responders at week 6NR72 .
Responders continued in the maintenance phaseof the trial and were assessed for clinical remission at week 52.14