P049 Biologic effect of anti-TNF exposure on vedolizumab induction
Authors: Jacqueline Jossen , Ryan Ungaro , Becky Phan , Anjali Jain , Kelly Hester , Edvelyn Webster , Marla Dubinksy 
Published: July 2019

BACKGROUND:
There are conflicting data on the impact of anti-TNF exposure on response to vedolizumab (VDZ). Post-hoc analyses of the VDZ registration (GEMINI) trials demonstrated decreased efficacy of VDZ in anti-TNF exposed subjects with real life experience reporting comparable efficacy rates. Reasons for this possible discrepancy remain unclear but include alterations in the biology post anti-TNF versus a marker of disease severity. We aimed to determine the influence of anti-TNF exposure on VDZ clinical, pk and biologic outcomes.

METHODS:
As part of an ongoing intensive pharmacokinetics (PK) monitoring IBD registry we identified patients initiating VDZ. Anti-TNF exposure history was recorded and categorized into none/remote or recent with exposure within 100 days of starting VDZ. Anti-TNF serum concentrations and anti-drug antibodies (ADA) were measured at week 0. Biomarker data including serum MAdCAM-1, α4β7, and TNFα were collected at each infusion. Pre-dose serum VDZ concentrations and anti-VDZ antibodies (ATV) were measured (Prometheus Laboratories Inc. San Diego, CA) at weeks 2, 6, and 14. Primary endpoint was steroid free clinical remission (SFCR) defined as a Harvey Bradshaw Index of <5 or a partial Mayo ≤1 at week 14 and off steroids. Descriptive statistics (frequency and medians (interquartile range [IQR]) summarized data and univariate statistics tested associations.

RESULTS:
A total of 44 patients (17 CD; 27 UC) were included. Median age was 35 [18.5–47] years and disease duration was 7 [1.5–20.5] years. Forty-one percent (18/44) of patients were anti-TNF naïve and 73% of the 26 ever exposed were recent. Anti-TNF therapy was discontinued for primary non-response (n = 3), secondary loss of response (n = 15), adverse event (n = 8). Forty-three percent (19/44) achieved Week 14 SFCR (47% CD, 41% UC; P = 0.68). Median VDZ concentrations trended higher at weeks 6 and 14 in those who achieved week 14 SFCR (week 2: 30 vs 30.8 μg/mL, P = 0.76; week 6: 32.1 vs 27.1 μg/mL, P = 0.06; week 14: 16.5 vs 10.8 μg/mL, P = 0.13). SFCR was achieved in 42% of patients with recent anti-TNF exposure and 44% with remote/no anti-TNF exposure (P = 0.9). Median anti-TNF concentration at week 0 was 15.5 μg/mL [IQR 2.5–22.4] and correlated with week 0 TNFα concentration (r: −0.53, P = 0.05), but not with week 0 MAdCAM-1 (r = 0.04, P = 0.89), week 0 α4β7 (r = 0.06, P = 0.84) or VDZ concentration at week 2 (r: −0.28, P = 0.35). Weeks 0 and 14 serum MAdCAM-1 and α4β7 concentrations were not associated with SFCR nor anti-TNF exposure. Those achieving SFCR had similar percent decreases in serum MAdCAM-1 and percent increases in serum α4β7 concentrations as those who did not achieve SFCR. Within UC, median delta α4β7 concentrations were higher at all points in those achieving SFCR and could be seen as early as week 2 (week 2: 10,823 [IQR 9,235–16,425] vs 7,673 pg/mL [IQR 4,757–10,490], P < 0.05; week 14: 15,118 [IQR 7,995–15,118] vs 7,833 pg/mL [IQR 7,986–10,628] P = 0.02).

CONCLUSION(S):
Unlike GEMINI, recent anti-TNF exposure did not influence VDZ induction of remission. Our findings suggest that the impact of anti-TNF may not be explained by its biologic effects and further research needed to understand the impact of anti-TNF and VDZ efficacy.