The that biosimilars are anticipated to have on

The 2016 Advances in Inflammatory Bowel Disease (AIBD)
conference included a robust clinical agenda featuring presentations by
nationally recognized gastroenterologists. New data continue to rapidly evolve
the field of inflammatory bowel disease (IBD) management. Experts presented evidence
from the latest studies that impact best practices for patient care, choice of
therapy, and techniques used to monitor and optimize therapy.


Hot topics in IBD management addressed during the meeting shared
a common theme of improving the patient experience and quality of care while
reducing costs. With
the recent FDA approval of Inflectra, a biosimilar to Infliximab (IFX)NR1 ,
the impact that biosimilars are anticipated to have on clinical practice has received
much attention.1 Biosimilars must be highly “similar” to an originator or
“reference” biologic therapy; clinical and nonclinical studies evaluating the
pharmacokinetics, efficacy, safety, and immunogenicity of the biosimilar
molecule are required in order to establish that there are no clinically
meaningful differences between the biosimilar and the reference product.1,2
NR2 Due to the
lower costs associated with the development of biosimilars, their use may
reduce health care expenditures associated with biologic medications. The
potential for cost savings, along with comparable efficacy, make it likely that
biosimilars will be widely used for the treatment of IBD.NR3 2
drug monitoring (TDM) of IFX has improved response rates to IFX, and is gaining
acceptance as a tool for the management of patients experiencing loss of
response to IFX; TDM is expected to play a key role in the management of IBD
for patients treated with Inflectra as well.NR4 2

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3 classes of biologics available now for the management of IBD,
gastroenterologists are armed with more options than ever before to help their
patients reach their treatment goalsJA5 .3,4
In order
for the availability of additional medications to translate to improved patient
outcomes, it is important to determine which medication is best for each
patient and at each stage of treatmentNR6 .3
In addition to TNF? inhibitors, the anti-integrin antibodyNR7 ,
(VDZ) is indicated for the management of patients with ulcerative colitis and
Crohn’s diseaseNR8 ,
and most recently, the
interleukin-12/23 inhibitorNR9 ,
was approved for patients with Crohn’s disease.4,5 NR10  Prospective studies to evaluate the comparative
efficacy of these treatment options are on the horizon. Until additional data
are available, clinicians can select among treatment choices based on reported
efficacy and safety profiles from separate studies, and a number of
patient-specific factors, such as severity of disease, risk for disease-related
complications, age, concomitant medications, likelihood of adherence, and the
availability of assays to measure drug and antibody levels.3 NR11 The Prometheus Anser® tests offer
quantitative monitoring assays to measure drug and anti-drug antibody levels
for TNF? inhibitors adalimumab (ADA) and IFX, 
as well as biosimilar IFX and VDZ, to assist clinicians in adopting
these treatment options into clinical practice.


As part of our commitment to improving the lives of patients
with IBD by promoting individualized patient care, PROMETHEUS® continues to work
in partnership with clinical investigators to support ongoing research that
aims to define drug and antibody levels associated with improved clinical
outcomes and to identify strategies that maximize the clinical benefits of
available IBD therapies. The results of 3 such studies that were presented at
the 2016 AIBD conference are featured in this issue of Clinical Insights.


Establishing an Anti-infliximab
Antibody Threshold Predictive of Infliximab Durability


durability of response to treatment with infliximab (IFX) in patients with IBD
is negatively impacted by the presence of antibodies to IFX (ATI). There may be
a threshold level of ATI below which clinical efficacy is not compromised. In
some cases where drug concentration remains detectable, maintenance of response
is possible in the presence of ATI. However, exactly where this threshold lies
remains unknown. Furthermore, the most appropriate strategies to optimize durability
in the presence of ATI have not previously been investigated. NR12 


study by Greywoode and colleagues aimed to determine what ATI level yields clinical
durability and to explore the value of various optimization strategies commonly
employed in attempt to preserve clinical durability. NR13 


investigators conducted a retrospective chart review of patients with ulcerative
colitis and Crohn’s disease who had received treatment with IFX at a tertiary
care IBD center. Eligible patients had at least one documented measurement of IFX
drug concentration and ATI level over the course of their treatment. IFX and
ATI levels were measured using a drug-tolerant, homogenous mobility shift assay
(Anser® IFX, Prometheus Labs Inc, San Diego, California), and all ATI-positive
patients (N=62) were included in the analysis. The primary outcome evaluated
was clinical durability, defined as steroid-free remission with IFX treatment
maintained at the final follow-up visit. NR14 


16 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 of
clinical durability by ATI level showed that ATI levels ?9.7 U/mL are
predictive of clinical durability (Figure 2). NR16 The true positive rate, or sensitivity, of the
ATI threshold was plotted against the false positive rate, or specificity, in a
receiver operating characteristic (ROC) curve in order to evaluate the accuracy
of this prediction. This ROC analysis demonstrated that ATI levels ?9.7 U/mL reliably
predicted clinical durability with 76.1% specificity and 81.2% sensitivity (P<0.001).  The mean ATI level in patients who maintained response to IFX was significantly lower than in patients who discontinued treatment with IFX due to loss of response (7.6 U/mL vs 31.0 U/mL; P=0.005). Conversely, detectable IFX concentrations were significantly more common in patients who maintained their responses than in those who did not (44% vs 17%; P=0.03). Mean IFX levels were also higher in patients who maintained response compared with patients who discontinued treatment due to loss of response (3.9 U/mL vs 1.1 U/mL), although the trend did not reach significance (P=0.07). NR20    Among the 16 patients who maintained their responses to IFX, ATI measurements were repeated in 13 (81%). Repeat measurements showed that 11 of the 13 patients (85%) achieved ATI clearanceNR21 . The most frequent strategy associated with ATI clearance in those 11 patients was dose escalation, which was effective in in 5 patients (45%), followed by the addition of an immunomodulator, which was effective in 3 patients (27%). NR22    These data demonstrate that discontinuation of IFX is not necessary in all patients with ATI. In particular, low levels of ATI (<9.7 U/mL) can be overcome successfully by optimizing dosage, thus maintaining steroid-free remission in patients treated with IFXNR23 . Therefore, it is important to determine ATI levels in order to guide clinical decisions regarding the addition of an immunomodulator or dose escalation before discontinuing IFX therapy. Combination Therapy With IFX and an Immunomodulator Is Associated With Higher IFX Trough Levels and Decreased Likelihood of Antibody Formation   IFX therapy for patients with IBD is limited by loss of response (LOR), which results in the need to change medications.2 In addition to ATI formation, previous studies suggest that low serum trough levels of infliximab (IFXL) may also lead to LOR. In studies of adult patients with IBD, combination therapy with an immunomodulator (ie, thiopurine or methotrexate) and IFX has been shown to decrease ATI formationNR25 , but the risks and benefits of combination therapy remain unclear. Furthermore, data from prospective studies evaluating the relationship among ATI, IFXL, combination therapy, and LOR in pediatric patients are limited. NR26    Results from a prospective observational cohort study of 227 pediatric and young adult patients (median age of enrollment: 17.1 years) being treated with IFX were presented by Zitomersky et al. Patient Characteristics are shown in Table 2. Serum samples were obtained during clinical infusion visits in order to assay IFXL and ATI levels.   Analysis of these patients showed that LOR was more likely to occur in patients with an ATI level ?3.1 U/mL (23 of 58; 40%) than in those with an ATI level <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 monotherapy with IFX. NR30 ATI levels ?3.1 U/mL were more common in patients on monotherapy (20%) than in those on combination therapy (11%). NR31    Patients were divided into 5 groups based on the dose of IFX received per 8 weeksNR32 . Among patients receiving 5 to 10 mg/kg IFX every 8 weeks, median IFXL was higher in patients who were on concurrent immunomodulator therapy than in those who were not (P=0.008) (Figure 2). NR33 In patients receiving 10 to 15 mg/kg IFX every 8 weeks, median IFXL was also higher in the combination therapy group compared with the monotherapy group; however, the difference was not statistically significant. NR34    These data show that the development of ATI was associated with a higher likelihood of LOR to IFX in this population of pediatric and young adult patients. Combination therapy with an immunomodulator was associated with significantly higher IFX trough levels in patients treated with 5 to 10 mg/kg IFX every 8 weeks, and ATI formation was more likely in patients receiving IFX monotherapy. These results indicate that concomitant use of immunomodulatory therapy may reduce the likelihood of LOR, perhaps by increasing IFX levels and reducing the likelihood of antibody formation. NR36 Therefore, clinical assessment of ATI in pediatric and young adult patients with IBD may help identify appropriate patients who could benefit from combination therapy.   Early Initiation of Combination Therapy: The REACT Study Several 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 outcomes in patients randomized to receive early combined immunosuppression (ECI) with those receiving conventional management in community-based gastroenterology practices. Patients in ECI practices (n=21 practices, n=1084 participants) with continuing disease activity after initiation of corticosteroids received combination therapy with a TNF? inhibitor (ADA or IFX) and an immunosuppressant (azathioprine AZA, 6-MP, or MTX). Patients in practices assigned to conventional management (n=18 practices, n=898 participants) were treated according to the usual practice of their physiciansNR38 .9 Patients at ECI practices were treated with immunosuppressive agents, TNF? inhibitors, and combination therapy earlier than patients at conventional management practices, and more patients in ECI practices were being treated with combination 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 the Harvey-Bradshaw Index (a composite measure assessing abdominal pain, stool frequency, general wellbeing, extra-intestinal manifestations, and presence of abdominal masses), which ranges from 0 to 12NR41 . However, differences in remission rates between the 2 groups were not significant. Patients in ECI practices did show significantly greater reductions in a composite outcome time to occurrence of major adverse outcomes (P=0.0003), surgeries (P=0.0314), and serious disease-related complications at 24 months (P=0.0005)NR42 . These results suggest that timing of introduction of combination therapy is important, and demonstrates the safety of ECI in community practices.NR43 9 Lower rates of ATI formation in patients receiving combination therapy may be a factor contributing to improved outcomes observed at 2 years. Combination therapy with an immunosuppressant can increase the effective concentration of the TNF? inhibitor and potentially help more patients achieve and maintain remission. When using combination therapy, measurements of drug and antibody levels may inform dose optimization for the TNF? inhibitorNR44 . If a thiopurine (AZA or 6-MP) is used as the immunomodulator in a combination therapy regimen, monitoring of metabolites can help clinicians keep dosing within a safe and effective range. NR45      Higher Vedolizumab Trough Levels Are Associated With Remission in Patients With IBD During Maintenance Therapy   Vedolizumab (VDZ) is an anti-integrin biologic therapy that is indicated for the management of patients with ulcerative colitis and Crohn's disease. In clinical trials, higher trough levels of VDZ were associated with higher rates of clinical remission.NR46  Assays to determine VDZ levels have recently become commercially available.NR47  In order to assess the clinical utility of measuring VDZ levels, Ungaro and colleagues designed a study to evaluate the association between trough VDZ levels and remission in a real-world clinical setting. NR48    Investigators conducted a cross-sectional study of patients undergoing maintenance VDZ therapy at a tertiary care IBD infusion center. All patients aged 6 years or older with ulcerative colitis or Crohn's disease were eligible for the studyNR49 . A total of 113 patients were evaluated: 63 patients with Crohn's disease and 50 patients with ulcerative colitis. Of these patients, 75% had received prior treatment with an anti–tumor necrosis factor-? (TNF?) agent, and 41% remained on an immunomodulator in combination with VDZ. NR50    Trough serum VDZ and antibody-to-VDZ (ATV) levels were measured in all patients using a drug-tolerant, homogeneous mobility shift assay platform (Anser® VDZ, Prometheus Labs Inc, San Diego, California). Data, including patient demographics, 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 association among VDZ levels, ATVs, and remission. The primary outcome in the study was remission, defined as normal CRP levels (<5 mg/L) and HBI <5 or pMS of 0 or 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 higher median levels of VDZ (12.1 µg/mL, interquartile range IQR 9.5-19.9) than patients 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 increasing VDZ quartiles (P=0.01). Patients with VDZ levels below the median were significantly less likely to be in remission compared 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 had significantly higher odds of being in remission (odds ratio OR 2.65; 95% CI, 1.24-5.66).  No significant differences in VDZ level or remission rate were seen with immunomodulator use. NR58 Antibody formation was rare in patients treated with VDZ—only 4 patients (3.5%) had detectable ATVs; 3 of these 4 patients were not on an immunomodulator, and all of them had detectable VDZ levels despite the presence of ATVs.  This study demonstrated that VDZ levels during maintenance therapy were significantly higher in patients in remission, and that the odds of remission are significantly higher in patients with VDZ levels over 10.9 µg/mLNR60 . These data suggest that an assay to determine VDZ levels would be clinically relevant, as it could inform dose adjustments to ensure that VDZ remains at a level likely to increase the odds of remission.   VDZ for Management of Patients With Ulcerative Colitis and Crohn's Disease: The GEMINI Trials GEMINI 1 was a phase 3, randomized, double blind, placebo-controlled trial evaluating the efficacy of VDZ for the induction and maintenance of clinical response in adult patients with ulcerative colitisNR61 . In the induction phase of the study, patients received VDZ or placebo at weeks 0 and 2 and were evaluated at week 6. For the maintenance phase, patients who responded to induction therapy at week 6 were randomized to receive VDZ every 8 week, VDZ every 4 weeks, or placebo for up to 52 weeks. JA62 Patients were evaluated using the Mayo Clinic Score, which ranges from 0 to 12, with higher scores indicating more active diseaseNR63 . Clinical response was defined as a decrease of ?3 points and ?30% from baseline along with a decrease of ?1 point on the rectal bleeding subscale (or a rectal bleeding score of 0 or 1).13 NR64    The trials demonstrated that VDZ was effective for inducing and maintaining a response and remission in patients with moderate to severe active ulcerative colitis.NR65  More patients showed clinical response to induction with VDZ vs placebo (47.1% vs 25.5%; P<0.001), NR66 and more patients maintained their clinical response at week 52 with either VDZ every 8 weeks or every 4 weeks vs placebo (41.8% or 44.8% vs 15.9%; P<0.001 for both comparisons).13 NR67  VDZ is also considered a safe treatment option: there were no important differences in the most commonly reported adverse events with VDZ in comparison with placebo, 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 been a concern with natalizumab, an integrin inhibitor that had shown efficacy in patients with Crohn's disease.13 NR69    GEMINI 2 shared a similar study design and evaluated patients with moderate to severe active Crohn's disease.NR70  Patients with a Crohn's Disease Activity Index (CDAI) NR71 score of ?150 and a CDAI-100 response were considered responders at week 6NR72 . Responders continued in the maintenance phase of the trial and were assessed for clinical remission at week 52.14