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Subclinical Fibrosis in Inflammatory Bowel Disease Patients on Thiopurines and Methotrexate
Su1935
AGA Abstracts
ETROLIZUMAB DEMONSTRATED NO DIFFERENCE AMONG DOSES IN SYMPTOMATIC AND ENDOSCOPIC-BASED EVALUATION OF REMISSION IN ANTI-TNF-α NAÏVE PATIENTS IN A POST HOC ANALYSIS OF THE PHASE 2 ULCERATIVE COLITIS TRIAL (EUCALYPTUS) William J. Sandborn, Stefan Schreiber, Meina Tang, Amanda Tatro, Young S. Oh, Romeo Maciuca Background: The use of the Physician Global Assessment (PGA) subscore, a component of the full Mayo Clinic Score (MCS), has been discouraged as a primary end point by the US Food and Drug Administration (FDA) and the European Medicines Agency in 2016 draft guidance. Instead, a composite, clinical remission primary end point based on stool frequency (SF), rectal bleeding (RB), and endoscopic subscores (ES) (i.e., MCS w/o PGA) is recommended by the FDA. Etrolizumab, a humanized anti-β7 mAb, showed greater clinical remission at week (wk) 10 based on the full MCS (w/PGA) compared with placebo (PBO) in the phase 2 EUCALYPTUS trial (Vermeire et al. Lancet 2014). The percentage of patients (pts) achieving clinical remission was numerically lower with higher versus lower etrolizumab dose. This treatment effect was more prominent in antitumor necrosis factor-α (aTNF)naive pts. We evaluated overall symptomatic and endoscopic remission end points in aTNFnaive pts enrolled in EUCALYPTUS. Methods: EUCALYPTUS was an international, multicenter, double-blind, PBO-controlled, randomized, phase 2 study (NCT01336465) in 124 pts with moderate-to-severe UC who had not responded to conventional therapy. Eligible pts were randomly assigned (1:1:1) to subcutaneous etrolizumab (100 mg at wks 0, 4, and 8, with PBO at wk 2; or 420-mg loading dose at wk 0, followed by 300 mg at wks 2, 4, and 8), or matching PBO. The primary end point was clinical remission (full MCS ≤ 2, with no individual subscore > 1 at wk 10). Post hoc analyses assessed SF remission (SF ≤ 1 and ≥ 1-point decrease from baseline), RB remission (RB = 0), symptomatic remission (SF and RB remission — SFRB), endoscopic remission (ES ≤ 1), and a composite of both SFRB and ES remission in aTNF-naive pts at wk 10. Results: PBO-adjusted treatment differences observed with symptomatic and endoscopic remission assessments were similar (30%-37%) to those of the primary full MCS remission end point (36%), except for RB remission, which had the highest PBO rate and the smallest treatment effect size (24%). Remission rates based on symptomatic remission (SF, SFRB), endoscopic remission (ES), or ES + SFRB were similar between the 100 and 300 mg etrolizumab arms. Conclusion: When PGA is removed from the MCS-defined remission assessment, aTNF-naive pts experienced similar rates of remission whether treated with low- or high-dose etrolizumab. Treatment effects observed with SFRB remission and ES + SFRB remission were of similar magnitude to that observed for the primary MCS remission end point.
Su1937 SUBCLINICAL FIBROSIS IN INFLAMMATORY BOWEL DISEASE PATIENTS ON THIOPURINES AND METHOTREXATE Winnie Szeto, Laura Chiu, Michelle T. Long, David Nunes, Francis Farraye Background: Liver and gastroenterology societies recommend periodic monitoring of AST, ALT, and albumin levels in patients on thiopurines (TP) and methotrexate (MTX) due to the risk of developing liver fibrosis. One previous study documented a rate of severe fibrosis in 5 of 124 Crohn's disease (CD) patients on methotrexate. The aim of our study was to assess for subclinical liver disease using transient elastography in a group of inflammatory bowel disease (IBD) patients with exposure to TP and/or MTX. Methods: Patients seen in the IBD Center at Boston Medical Center were approached to participate in this IRB approved study. Study groups included patients on mesalamine, monotherapy with biologics, or no therapy (unexposed group) and patients presently or previously on TP and/or MTX (exposed group). At entry, enrolled patients underwent vibration-controlled transient elastography. The AST to Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4) were calculated. A retrospective chart review recorded demographics, BMI, alcohol consumption, demographics, and cumulative dose of TP and MTX. Results: A total of 47 patients were enrolled in the study from 8/16 to 11/16. In the unexposed group, there were 8 patients (50 % women, 75 % CD). In the TP and MTX exposed group, there were 39 patients, (51% women, 74% CD). In the exposed group, the average duration of treatment for azathioprine was 71.1 months, mercaptopurine 36.8 months and MTX 30.2 months. The average total dose of azathioprine was 106.1 gm, 6MP 72.2 gm, and MTX 2.75 gm. Of the 39 patient with a history of previous or current exposure to TP and/or MTX, 3 (7.6%) were noted to have a liver stiffness measurement > 7.1 kPa. A 72 year old male with CD, and a BMI of 32.3, status post proctocolectomy and permanent ileostomy, previously on 62 months of MTX (cumulative dose of 6.2 gm) had an elastography score of 7.9kPa, FIB-4 3.9 and APRI 0.78. A 68 yo male with a 35 year history of perianal CD on MTX for 8 months (cumulative l dose of 0.800 grams) had an elastography score of 20.9 kPa, FIB-4 7.24 and APRI 1.60. Finally, a 65 year old female with a 13 year history of ileal CD on mercaptopurine (1.0 - 1.5 mg/kg) for 60 months (cumulative dose of 91.3 grams) had an elastography score of 12.4 kPa on Fibroscan, FIB-4 0.78 and APRI 0.364. None of these patients reported a history of alcohol use. No other patients in group 1 or 2 were found to have fibrosis. See Table 1 for baseline characteristics. Conclusions: In this pilot study of 47 patients with IBD, one patient with a history of TP use and two with a history of MTX use were found to have significant fibrosis. Our study is ongoing with plans to enroll 400 patients in an effort to determine the prevalence and risk factors for the development of fibrosis in IBD patients on TP and/ or MTX. Supported by a gift from Aimee and Kleanthis Dendrinos and Susan Nicol. Table 1. Baseline characteristics of patients with fibrosis on vibration-controlled transient elastography.
Su1936 ETROLIZUMAB TREATMENT LEADS TO EARLY IMPROVEMENT IN SYMPTOMS AND INFLAMMATORY BIOMARKERS IN ANTI-TNFREFRACTORY PATIENTS IN THE OPEN-LABEL INDUCTION COHORT OF THE PHASE 3 HICKORY STUDY Laurent Peyrin-Biroulet, Brian G. Feagan, John Mansfield, David T. Rubin, Udayasankar Arulmani, Romeo Maciuca, Helen Tyrrell, James Thommes, Swati Tole Background: Etrolizumab, an anti-β7 mAb targeting integrins α4β7 and αEβ7, showed significantly greater clinical remission at wk 10 versus placebo (PBO) in the phase 2 EUCALYPTUS trial. We assessed changes in symptoms and inflammatory biomarkers in aTNF refractory or intolerant (aTNF-IR) pts treated in a nonpivotal open-label induction (OLI) cohort of a phase 3 study. Methods: HICKORY is a multicenter, randomized, doubleblind, PBO-controlled phase 3 study (NCT02100696) evaluating the safety and efficacy of etrolizumab during induction and maintenance in aTNF-IR pts with moderate-to-severe UC. The study includes a nonpivotal OLI cohort that treated 130 pts with etrolizumab 105 mg every 4 wk for 14 wk. Symptomatic improvement in this cohort was assessed based on the change in weekly mean rectal bleeding (RB) and stool frequency (SF) scores (each scored on a scale of 0-3), derived from pts' daily eDiary entries. SF remission was defined as a weekly mean score of ≤ 1 (rounded to the nearest integer) with ≥ 1 point reduction from baseline (BL). RB remission was defined as a weekly mean score of 0 (rounded to the nearest integer) with ≥ 0.5 point reduction from BL. Fecal calprotectin (FC) and C-reactive protein (CRP) were measured at BL and wk 14 or early termination. Changes in SF, RB, PRO score (SF + RB), FC, and CRP were assessed descriptively. Results: Of 130 treated pts, 97% received all induction doses, 80% had a BL Mayo Clinic endoscopic score of 3, and 45% had received ≥ 2 prior aTNFs. RB remission rates improved from BL to wk 4 (~30%) and 14 (~50%). SF remission rates improved from BL to wk 4 (~10%) and 14 (~25%). PRO scores improved regardless of disease severity and irrespective of previous treatment with 1 or ≥ 2 aTNFs. The mean (± SE) decrease in PRO was 22% (± 3%) at wk 4 and 36% (± 3%) at wk 14; this decrease mirrored mean reductions in FC and CRP. Overall, FC and CRP levels decreased at wk 14 by a mean (95% CI) of 57% (42%-69%) and 33% (15%47%), respectively. Mean decrease in CRP in pts with CRP levels > 2.87 mg/L (ULN) at BL was 47%. Mean decreases in FC and CRP levels at wk 14 were greater in pts in SF remission (FC, 83%; CRP, 54%) and in pts in RB remission (FC, 69%; CRP, 49%). Etrolizumab demonstrated favorable safety and tolerability. Conclusion: aTNF-IR pts with moderate-tosevere UC reported symptom improvement as early as wk 4 during OLI treatment with etrolizumab. Clinically meaningful improvement in disease activity was observed in ptreported SF and RB scores, serum CRP, and FC by wk 14.
Su1938 COLONIC TREG LEVELS ARE REDUCED IN PATIENTS WITH UC ACHIEVING CLINICAL REMISSION, BUT ARE NOT DIFFERENTIALLY AFFECTED BY ETROLIZUMAB DOSE Franklin Fuh, Wei Tew, Mary Keir, Caroline Looney, Romeo Maciuca, Jacqueline McBride, Teresa Ramirez-Montagut Background: Etrolizumab, an anti-β7 mAb targeting integrins α4β7 and αEβ7, showed efficacy and safety compared with placebo (PBO) at induction in patients (pts) with moderateto-severe UC in the phase 2 EUCALYPTUS trial. The percentage of pts achieving clinical remission was numerically lower with the higher dose of etrolizumab compared with the lower dose, which has been hypothesized to be due to dose-related inhibition of regulatory Tcell (Treg) migration to the colon. Using an epigenetic approach, we showed that etrolizumab treatment increased blood levels of CD3+ T cells and Tregs, compared with PBO (Fuh F et
S-603
AGA Abstracts
AGA Abstracts
ETROLIZUMAB DEMONSTRATED NO DIFFERENCE AMONG DOSES IN SYMPTOMATIC AND ENDOSCOPIC-BASED EVALUATION OF REMISSION IN ANTI-TNF-α NAÏVE PATIENTS IN A POST HOC ANALYSIS OF THE PHASE 2 ULCERATIVE COLITIS TRIAL (EUCALYPTUS) William J. Sandborn, Stefan Schreiber, Meina Tang, Amanda Tatro, Young S. Oh, Romeo Maciuca Background: The use of the Physician Global Assessment (PGA) subscore, a component of the full Mayo Clinic Score (MCS), has been discouraged as a primary end point by the US Food and Drug Administration (FDA) and the European Medicines Agency in 2016 draft guidance. Instead, a composite, clinical remission primary end point based on stool frequency (SF), rectal bleeding (RB), and endoscopic subscores (ES) (i.e., MCS w/o PGA) is recommended by the FDA. Etrolizumab, a humanized anti-β7 mAb, showed greater clinical remission at week (wk) 10 based on the full MCS (w/PGA) compared with placebo (PBO) in the phase 2 EUCALYPTUS trial (Vermeire et al. Lancet 2014). The percentage of patients (pts) achieving clinical remission was numerically lower with higher versus lower etrolizumab dose. This treatment effect was more prominent in antitumor necrosis factor-α (aTNF)naive pts. We evaluated overall symptomatic and endoscopic remission end points in aTNFnaive pts enrolled in EUCALYPTUS. Methods: EUCALYPTUS was an international, multicenter, double-blind, PBO-controlled, randomized, phase 2 study (NCT01336465) in 124 pts with moderate-to-severe UC who had not responded to conventional therapy. Eligible pts were randomly assigned (1:1:1) to subcutaneous etrolizumab (100 mg at wks 0, 4, and 8, with PBO at wk 2; or 420-mg loading dose at wk 0, followed by 300 mg at wks 2, 4, and 8), or matching PBO. The primary end point was clinical remission (full MCS ≤ 2, with no individual subscore > 1 at wk 10). Post hoc analyses assessed SF remission (SF ≤ 1 and ≥ 1-point decrease from baseline), RB remission (RB = 0), symptomatic remission (SF and RB remission — SFRB), endoscopic remission (ES ≤ 1), and a composite of both SFRB and ES remission in aTNF-naive pts at wk 10. Results: PBO-adjusted treatment differences observed with symptomatic and endoscopic remission assessments were similar (30%-37%) to those of the primary full MCS remission end point (36%), except for RB remission, which had the highest PBO rate and the smallest treatment effect size (24%). Remission rates based on symptomatic remission (SF, SFRB), endoscopic remission (ES), or ES + SFRB were similar between the 100 and 300 mg etrolizumab arms. Conclusion: When PGA is removed from the MCS-defined remission assessment, aTNF-naive pts experienced similar rates of remission whether treated with low- or high-dose etrolizumab. Treatment effects observed with SFRB remission and ES + SFRB remission were of similar magnitude to that observed for the primary MCS remission end point.
Su1937 SUBCLINICAL FIBROSIS IN INFLAMMATORY BOWEL DISEASE PATIENTS ON THIOPURINES AND METHOTREXATE Winnie Szeto, Laura Chiu, Michelle T. Long, David Nunes, Francis Farraye Background: Liver and gastroenterology societies recommend periodic monitoring of AST, ALT, and albumin levels in patients on thiopurines (TP) and methotrexate (MTX) due to the risk of developing liver fibrosis. One previous study documented a rate of severe fibrosis in 5 of 124 Crohn's disease (CD) patients on methotrexate. The aim of our study was to assess for subclinical liver disease using transient elastography in a group of inflammatory bowel disease (IBD) patients with exposure to TP and/or MTX. Methods: Patients seen in the IBD Center at Boston Medical Center were approached to participate in this IRB approved study. Study groups included patients on mesalamine, monotherapy with biologics, or no therapy (unexposed group) and patients presently or previously on TP and/or MTX (exposed group). At entry, enrolled patients underwent vibration-controlled transient elastography. The AST to Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4) were calculated. A retrospective chart review recorded demographics, BMI, alcohol consumption, demographics, and cumulative dose of TP and MTX. Results: A total of 47 patients were enrolled in the study from 8/16 to 11/16. In the unexposed group, there were 8 patients (50 % women, 75 % CD). In the TP and MTX exposed group, there were 39 patients, (51% women, 74% CD). In the exposed group, the average duration of treatment for azathioprine was 71.1 months, mercaptopurine 36.8 months and MTX 30.2 months. The average total dose of azathioprine was 106.1 gm, 6MP 72.2 gm, and MTX 2.75 gm. Of the 39 patient with a history of previous or current exposure to TP and/or MTX, 3 (7.6%) were noted to have a liver stiffness measurement > 7.1 kPa. A 72 year old male with CD, and a BMI of 32.3, status post proctocolectomy and permanent ileostomy, previously on 62 months of MTX (cumulative dose of 6.2 gm) had an elastography score of 7.9kPa, FIB-4 3.9 and APRI 0.78. A 68 yo male with a 35 year history of perianal CD on MTX for 8 months (cumulative l dose of 0.800 grams) had an elastography score of 20.9 kPa, FIB-4 7.24 and APRI 1.60. Finally, a 65 year old female with a 13 year history of ileal CD on mercaptopurine (1.0 - 1.5 mg/kg) for 60 months (cumulative dose of 91.3 grams) had an elastography score of 12.4 kPa on Fibroscan, FIB-4 0.78 and APRI 0.364. None of these patients reported a history of alcohol use. No other patients in group 1 or 2 were found to have fibrosis. See Table 1 for baseline characteristics. Conclusions: In this pilot study of 47 patients with IBD, one patient with a history of TP use and two with a history of MTX use were found to have significant fibrosis. Our study is ongoing with plans to enroll 400 patients in an effort to determine the prevalence and risk factors for the development of fibrosis in IBD patients on TP and/ or MTX. Supported by a gift from Aimee and Kleanthis Dendrinos and Susan Nicol. Table 1. Baseline characteristics of patients with fibrosis on vibration-controlled transient elastography.
Su1936 ETROLIZUMAB TREATMENT LEADS TO EARLY IMPROVEMENT IN SYMPTOMS AND INFLAMMATORY BIOMARKERS IN ANTI-TNFREFRACTORY PATIENTS IN THE OPEN-LABEL INDUCTION COHORT OF THE PHASE 3 HICKORY STUDY Laurent Peyrin-Biroulet, Brian G. Feagan, John Mansfield, David T. Rubin, Udayasankar Arulmani, Romeo Maciuca, Helen Tyrrell, James Thommes, Swati Tole Background: Etrolizumab, an anti-β7 mAb targeting integrins α4β7 and αEβ7, showed significantly greater clinical remission at wk 10 versus placebo (PBO) in the phase 2 EUCALYPTUS trial. We assessed changes in symptoms and inflammatory biomarkers in aTNF refractory or intolerant (aTNF-IR) pts treated in a nonpivotal open-label induction (OLI) cohort of a phase 3 study. Methods: HICKORY is a multicenter, randomized, doubleblind, PBO-controlled phase 3 study (NCT02100696) evaluating the safety and efficacy of etrolizumab during induction and maintenance in aTNF-IR pts with moderate-to-severe UC. The study includes a nonpivotal OLI cohort that treated 130 pts with etrolizumab 105 mg every 4 wk for 14 wk. Symptomatic improvement in this cohort was assessed based on the change in weekly mean rectal bleeding (RB) and stool frequency (SF) scores (each scored on a scale of 0-3), derived from pts' daily eDiary entries. SF remission was defined as a weekly mean score of ≤ 1 (rounded to the nearest integer) with ≥ 1 point reduction from baseline (BL). RB remission was defined as a weekly mean score of 0 (rounded to the nearest integer) with ≥ 0.5 point reduction from BL. Fecal calprotectin (FC) and C-reactive protein (CRP) were measured at BL and wk 14 or early termination. Changes in SF, RB, PRO score (SF + RB), FC, and CRP were assessed descriptively. Results: Of 130 treated pts, 97% received all induction doses, 80% had a BL Mayo Clinic endoscopic score of 3, and 45% had received ≥ 2 prior aTNFs. RB remission rates improved from BL to wk 4 (~30%) and 14 (~50%). SF remission rates improved from BL to wk 4 (~10%) and 14 (~25%). PRO scores improved regardless of disease severity and irrespective of previous treatment with 1 or ≥ 2 aTNFs. The mean (± SE) decrease in PRO was 22% (± 3%) at wk 4 and 36% (± 3%) at wk 14; this decrease mirrored mean reductions in FC and CRP. Overall, FC and CRP levels decreased at wk 14 by a mean (95% CI) of 57% (42%-69%) and 33% (15%47%), respectively. Mean decrease in CRP in pts with CRP levels > 2.87 mg/L (ULN) at BL was 47%. Mean decreases in FC and CRP levels at wk 14 were greater in pts in SF remission (FC, 83%; CRP, 54%) and in pts in RB remission (FC, 69%; CRP, 49%). Etrolizumab demonstrated favorable safety and tolerability. Conclusion: aTNF-IR pts with moderate-tosevere UC reported symptom improvement as early as wk 4 during OLI treatment with etrolizumab. Clinically meaningful improvement in disease activity was observed in ptreported SF and RB scores, serum CRP, and FC by wk 14.
Su1938 COLONIC TREG LEVELS ARE REDUCED IN PATIENTS WITH UC ACHIEVING CLINICAL REMISSION, BUT ARE NOT DIFFERENTIALLY AFFECTED BY ETROLIZUMAB DOSE Franklin Fuh, Wei Tew, Mary Keir, Caroline Looney, Romeo Maciuca, Jacqueline McBride, Teresa Ramirez-Montagut Background: Etrolizumab, an anti-β7 mAb targeting integrins α4β7 and αEβ7, showed efficacy and safety compared with placebo (PBO) at induction in patients (pts) with moderateto-severe UC in the phase 2 EUCALYPTUS trial. The percentage of pts achieving clinical remission was numerically lower with the higher dose of etrolizumab compared with the lower dose, which has been hypothesized to be due to dose-related inhibition of regulatory Tcell (Treg) migration to the colon. Using an epigenetic approach, we showed that etrolizumab treatment increased blood levels of CD3+ T cells and Tregs, compared with PBO (Fuh F et
S-603
AGA Abstracts