QUASAR Induction Study 1 Cumulative Response to Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis

Introduction: Guselkumab (GUS), an IL-23p19 antagonist, had greater efficacy than placebo (PBO) in achieving clinical response and clinical remission atWeek (Wk) 12 in the randomized, controlled Phase 2b QUASAR Induction Study 1 (NCT04033445) in patients with moderately to severely active ulcerative colitis (UC).1 Patients who were not in clinical response at Wk 12 received GUS treatment through Wk 24. Here, we report GUS cumulative efficacy and safety results for Induction Study 1. Method(s): Eligible patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo endoscopy subscore >=2) at baseline. Patients were randomized 1:1:1 to IV GUS 200mg, 400mg, or PBO at Wks 0, 4, and 8. Patients who were not in clinical response to IV induction at Wk 12 received GUS treatment (PBO IV->GUS 200mg IV;GUS 200mg IV->GUS 200mg SC;GUS 400mg IV->GUS 200mg SC) at Wks 12, 16, and 20 and were evaluated at Wk 24 (Figure). Matching IV or SC PBO was administered to maintain the blind. Result(s): Three hundred thirteen patients were randomized and treated at baseline. Demographic and disease characteristics at baseline were similar among the treatment groups, and approximately 50% had a prior inadequate response or intolerance to advanced UC therapy. AtWk 12, clinical response was achieved by 61.4% (62/101) and 60.7% (65/107) of patients randomized to GUS 200mg and GUS 400mg IV vs 27.6 % (29/105) of patients randomized to PBO IV (both p< 0.001). Of the patients in the GUS groups who were not in clinical response at Wk 12, 54.3% (19/35) in the GUS 200mg IV->200mg SC group and 50.0% (19/38) in the GUS 400mg IV->200mg SC group achieved clinical response at Wk 24. Clinical response atWk 12 or 24 was achieved by 80.2% of patients who were randomized to GUS 200mg IV and 78.5% of patients who were randomized to GUS 400mg IV. For patients who received PBO IV->GUS 200mg IV, clinical response at Wk 24 (65.2%) was similar toWk 12 clinical response following GUS 200mg IV induction (61.4%). The most frequent adverse events among all GUS-treated pts (n=274) were anemia (7.7%), headache (5.1%), worsening UC (4.4%), COVID-19 (3.6%), arthralgia (2.9%) and abdominal pain (2.6%) which are consistent with Wk 12 results. Conclusion(s): Overall, approximately 80% of patients randomized to receive GUS achieved clinical response at Wk 12 or 24. Continued treatment with SC GUS allowed 50-54.3% of IV GUS Wk 12 clinical nonresponders to achieve clinical response at Wk 24. No new safety concerns for GUS were identified. (Figure Presented).

Physiological Metrics Collected from Wearable Devices Identify Inflammatory and Clinical Inflammatory Bowel Disease Flares

BACKGROUND: Inflammatory bowel disease (IBD) flares are common and unpredictable. Disease monitoring relies on symptom reporting or single timepoint assessments of stool, blood, imaging, or endoscopy-these are inconvenient and invasive and do not always reflect the patient perspective. Advances in wearable technology allow for passive, continuous and non-invasive assessment of physiological metrics including heart rate variability (HRV), the measure of small time differences between each heartbeat, a marker of autonomic nervous system function. Our group has previously demonstrated that changes in autonomic function precedes an IBD flare, can predict psychological state transitions and even identify inflammatory events including SARS-CoV-2 infection. To develop algorithms that can predict IBD flares using wearable device signatures, we launched a national wearable device study called The IBD Forecast study. To assess data quality and feasibility, the first 125 Apple Watch users to enroll were evaluated. METHOD(S): The IBD Forecast study is a prospective cohort study enrolling anyone >=18 years of age in the United States (US) with IBD who is willing to (1) use a commercially available wearable device, (2) download our custom eHive app and (3) answer daily survey questions. HRV metrics (mean of the standard deviations of all the NN intervals [SDNN]) were analyzed using a mixed-effect cosigner model that incorporated body mass index, age, and sex. SDNN is a time domain HRV index that reflects both sympathetic and parasympathetic nervous system activity and is calculated from the variance of intervals between adjacent QRS complexes (the normal-to-normal [NN] intervals). Clinical flare was assessed with daily Patient Reported Outcome (PRO)-2 surveys (flare;PRO-2 Crohn's disease >7, PRO-2 ulcerative colitis >2). Inflammatory flare was assessed via patient reported C-reactive protein (CRP), with inflammatory flare defined as >5 mg/L. RESULT(S): The first 125 study participants were enrolled across 29 states in the US (Table 1). Circadian features of changes of HRV were modelled (Figure 1). The mesor, or midline of the circadian pattern of the SDNN was higher in those with clinical flare (mean 44.43;95% CI 41.25-47.75) compared to those in clinical remission (mean 43.03;95% CI 39.94-46.22) (p<0.004). The mesor of the circadian pattern of the SDNN was lower in those with an inflammatory flare (mean 38.16;95% CI 30.86-45.72) compared to those with normal inflammatory markers (mean 49.51;95% CI 43.12-56.26) (p<0.001). CONCLUSION(S): Longitudinally collected HRV metrics from a commonly worn commercial wearable device can identify symptomatic and inflammatory flares. This preliminary analysis of a small proportion of the IBD Forecast Study cohort demonstrates the feasibility of using wearable devices to identify, and may potentially predict, IBD flares. [Formula presented] [Formula presented]Copyright © 2023

QUASAR Induction Study 1 Cumulative Response to Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis

Background: Guselkumab (GUS), an IL-23p19 antagonist, had greater efficacy than placebo (PBO) in achieving clinical response and clinical remission at Week (Wk) 12 in the randomized, controlled Phase 2b QUASAR Induction Study 1 (NCT04033445) in patients with moderately to severely active ulcerative colitis (UC).1 Patients who were not in clinical response at Wk 12 received GUS treatment through Wk 24. Here, we report GUS cumulative efficacy and safety results for Induction Study 1. Method(s): Eligible patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo endoscopy subscore >=2) at baseline. Patients were randomized 1:1:1 to IV GUS 200mg, 400mg, or PBO at Wks 0, 4, and 8. Patients who were not in clinical response to IV induction at Wk 12 received GUS treatment (PBO IVGUS 200mg IV;GUS 200mg IV->GUS 200mg SC;GUS 400mg IV->GUS 200mg SC) at Wks 12, 16, and 20 and were evaluated at Wk 24 (Figure 1). Matching IV or SC PBO was administered to maintain the blind. Result(s): Three hundred thirteen patients were randomized and treated at baseline. Demographic and disease characteristics at baseline were similar among the treatment groups, and approximately 50% had a prior inadequate response or intolerance to advanced UC therapy. At Wk 12, clinical response was achieved by 61.4% (62/101) and 60.7% (65/107) of patients randomized to GUS 200mg and GUS 400mg IV vs 27.6% (29/105) of patients randomized to PBO IV (both p<0.001). Of the patients in the GUS groups who were not in clinical response at Wk 12, 54.3% (19/35) in the GUS 200mg IV->200mg SC group and 50.0% (19/38) in the GUS 400mg IV->200mg SC group achieved clinical response at Wk 24. Clinical response at Wk 12 or 24 was achieved by 80.2% of patients who were randomized to GUS 200mg IV and 78.5% of patients who were randomized to GUS 400mg IV. For patients who received PBO IV->GUS 200mg IV, clinical response at Wk 24 (65.2%) was similar to Wk 12 clinical response following GUS 200mg IV induction (61.4%). The most frequent adverse events among all GUS-treated pts (n=274) were anemia (7.7%), headache (5.1%), worsening UC (4.4%), COVID-19 (3.6%), arthralgia (2.9%) and abdominal pain (2.6%) which are consistent with Wk 12 results. Conclusion(s): Overall, approximately 80% of patients randomized to receive GUS achieved clinical response at Wk 12 or 24. Continued treatment with SC GUS allowed 50-54.3% of IV GUS Wk 12 clinical nonresponders to achieve clinical response at Wk 24. No new safety concerns for GUS were identified.

Physiological Metrics Collected from Wearable Devices Identify Inflammatory and Clinical Inflammatory Bowel Disease Flares

BACKGROUND: Inflammatory bowel disease (IBD) flares are common and unpredictable. Disease monitoring relies on symptom reporting or single timepoint assessments of stool, blood, imaging, or endoscopy-these are inconvenient and invasive and do not always reflect the patient perspective. Advances in wearable technology allow for passive, continuous and non-invasive assessment of physiological metrics including heart rate variability (HRV), the measure of small time differences between each heartbeat, a marker of autonomic nervous system function. Our group has previously demonstrated that changes in autonomic function precedes an IBD flare, can predict psychological state transitions and even identify inflammatory events including SARS-CoV-2 infection. To develop algorithms that can predict IBD flares using wearable device signatures, we launched a national wearable device study called The IBD Forecast study. To assess data quality and feasibility, the first 125 Apple Watch users to enroll were evaluated. METHOD(S): The IBD Forecast study is a prospective cohort study enrolling anyone >=18 years of age in the United States (US) with IBD who is willing to (1) use a commercially available wearable device, (2) download our custom eHive app and (3) answer daily survey questions. HRV metrics (mean of the standard deviations of all the NN intervals [SDNN]) were analyzed using a mixed-effect cosigner model that incorporated body mass index, age, and sex. SDNN is a time domain HRV index that reflects both sympathetic and parasympathetic nervous system activity and is calculated from the variance of intervals between adjacent QRS complexes (the normal-to-normal [NN] intervals). Clinical flare was assessed with daily Patient Reported Outcome (PRO)-2 surveys (flare;PRO-2 Crohn's disease >7, PRO-2 ulcerative colitis >2). Inflammatory flare was assessed via patient reported C-reactive protein (CRP), with inflammatory flare defined as >5 mg/L. RESULT(S): The first 125 study participants were enrolled across 29 states in the US (Table 1). Circadian features of changes of HRV were modelled (Figure 1). The mesor, or midline of the circadian pattern of the SDNN was higher in those with clinical flare (mean 44.43;95% CI 41.25-47.75) compared to those in clinical remission (mean 43.03;95% CI 39.94-46.22) (p<0.004). The mesor of the circadian pattern of the SDNN was lower in those with an inflammatory flare (mean 38.16;95% CI 30.86-45.72) compared to those with normal inflammatory markers (mean 49.51;95% CI 43.12-56.26) (p<0.001). CONCLUSION(S): Longitudinally collected HRV metrics from a commonly worn commercial wearable device can identify symptomatic and inflammatory flares. This preliminary analysis of a small proportion of the IBD Forecast Study cohort demonstrates the feasibility of using wearable devices to identify, and may potentially predict, IBD flares. (Table Presented).

Abx464 (Obefazimod) in Patients with Moderate-to-Severe Ulcerative Colitis: An Interim 48-Week Safety and Efficacy Analysis from an Ongoing 96-Week Open-Label Maintenance Phase 2b Study

Introduction: ABX464 (obefazimod) is an oral small molecule that modulates inflammation by upregulating a specific anti-inflammatory micro- RNA (miR-124). ABX464 has demonstrated safety and efficacy in patients with moderate-to-severe ulcerative colitis (UC) in a randomized, placebocontrolled, phase 2b induction study (NCT04023396)1. This analysis presents interim data at week 48 after enrollment in the open-label (OL) maintenance study. Aims & Methods: During the 16-week induction Phase 2b, patients received placebo or obefazimod 25mg, 50mg or 100mg once daily (od) and, irrespective of their clinical response, could enter the OL 96-week maintenance study with obefazimod 50mg od. Patients were enrolled into this study from January 13, 2020. Here we present data from an interim analysis cut-off date on Feb 13, 2022. Patients were followed monthly for safety and efficacy. Non-responder imputation (NRI) was used for missing efficacy data. All subjects were assessed for safety: treatment emergent adverse events (TEAEs), TEAEs leading to study discontinuation, serious adverse events (SAEs). Result(s): Of 222 patients who completed the phase2b induction study, 217 (97.7%) were enrolled in the OL maintenance study. 33/217 (15.2%) patients dropped out prior to week 48, mainly for UC worsening (10/33). All dropouts were considered as treatment failures for this interim analysis. Main efficacy results are presented in the table below. Among the 96 patients with no clinical response after induction, 42.7% achievedde novo clinical remission at week 48 of the OL maintenance study. Among the 52 patients with clinical remission after induction, 73.1% maintained clinical remission at week 48. In total, 139/217 subjects (64.1%) reported at least one TEAE. TEAEs leading to study discontinuation were reported in 15 subjects (6.9%) and serious adverse events (SAEs) were reported in 17 subjects (7.8%). The most frequent TEAEs (>= 5%) were headache (11.5%), COVID-19 (10.1%), ulcerative colitis (6.5%) and nasopharyngitis (5.9%). No new safety risks were identified over these initial 48 weeks. Conclusion(s): Results from this 48-week interim analysis of the OL maintenance Phase 2b study confirmed excellent long-term efficacy of obefazimod 50mg od in clinical responders and non-clinical responders after induction as well as a favorable long-term safety profile.

Etrasimod 2mg Once Daily as Treatment for Moderately to Severely Active Ulcerative Colitis: Results from the Phase 3 Elevate Uc 52 and Elevate Uc 12 Trials

Introduction: Etrasimod (APD334), an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator, demonstrated efficacy in adults with moderately to severely active ulcerative colitis (UC) in the Phase 2 OASIS trial (NCT02447302). Here, we report data from 2 trials, ELEVATE UC 52 and ELEVATE UC 12, that evaluated the efficacy and safety of etrasimod 2mg for induction and maintenance in adults with UC. Aims & Methods: ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) were global, randomized, double-blind, placebo-controlled trials. In both trials, adults (16-80 years) with moderately to severely active UC (based on modified Mayo Score [MMS] of 4-9 with centrally read endoscopic subscore >=2 and rectal bleeding subscore >=1) and documented history of inadequate response, loss of response, or intolerance to >=1 treatment for UC were randomized 2:1 to once-daily treatment with etrasimod 2mg or placebo. Patients (pts) were stratified by previous exposure to biologic/Janus kinase inhibitor (JAKi) therapy, baseline corticosteroid use, and baseline disease activity (MMS 4-6 or 7-9). ELEVATE UC 52 utilized a treat-through design comprising a 12-week induction period followed by a 40-week maintenance period. Beginning at Week (Wk) 12, all pts could continue their randomized treatment;pts whose disease had not improved or had worsened compared to baseline (based on investigator judgement) could discontinue and enroll in an open-label extension study (NCT03950232). ELEVATE UC 12 comprised a 12-week induction period only. The primary efficacy endpoints were the proportion of pts achieving clinical remission (using the MMS) at Wk 12 and Wk 52 in ELEVATE UC 52, and at Wk 12 in ELEVATE UC 12. Safety was evaluated throughout the trials. Result(s): In ELEVATE UC 52, 433 pts were randomized (etrasimod, n=289;placebo, n=144) and 207 completed Wk 52. In ELEVATE UC 12, 354 pts were randomized (etrasimod, n=238;placebo, n=116) and 316 completed Wk 12. 62.6% of etrasimod-treated pts in both trials and 61.8% and 62.9% of placebo-treated pts in ELEVATE UC 52 and ELEVATE UC 12, respectively, were naive to biologic/JAKi therapy. All primary and key secondary efficacy endpoints were achieved with etrasimod vs placebo at both Wks 12 and 52 in ELEVATE UC 52 and Wk 12 in ELEVATE UC 12 (Table). Most commonly reported TEAEs (>=3% of etrasimod-treated pts and greater than placebo in either trial) were headache, nausea, COVID-19 infection, dizziness, pyrexia, arthralgia, abdominal pain and worsening of UC. Serious AEs were similar between treatment groups in both trials. The overall safety profile was consistent with previous studies. Conclusion(s): Treatment with etrasimod 2mg resulted in statistically significant and clinically meaningful improvements based on clinical, endoscopic, symptomatic, and endo-histologic endpoints at Wks 12 and 52 in adults with moderately to severely active UC. No new safety findings were observed with etrasimod 2mg treatment for up to 52 weeks.