Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies.

BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. INTERPRETATION: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. FUNDING: Arena Pharmaceuticals.

Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial.

BACKGROUND: Despite the introduction of new monoclonal antibodies and oral therapies for the treatment of ulcerative colitis, clinical remission rates remain low, underscoring the need for innovative treatment approaches. We assessed whether guselkumab plus golimumab combination therapy was more effective for ulcerative colitis than either monotherapy. METHODS: We did a randomised, double-blind, controlled, proof-of-concept trial at 54 hospitals, academic medical centres, or private practices in nine countries. Eligible adults (aged ≥18 to 65 years) had a confirmed diagnosis of ulcerative colitis at least 3 months before screening and moderately-to-severely active ulcerative colitis (Mayo score 6-12) with a centrally-read baseline endoscopy subscore of 2 or higher. Patients were randomly assigned (1:1:1) using a computer-generated randomisation schedule to combination therapy (subcutaneous golimumab 200 mg at week 0, subcutaneous golimumab 100 mg at weeks 2, 6, and 10, and intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab monotherapy 100 mg every 8 weeks for 32 weeks), golimumab monotherapy (subcutaneous golimumab 200 mg at week 0 followed by subcutaneous golimumab 100 mg at week 2 and every 4 weeks thereafter for 34 weeks), or guselkumab monotherapy (intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab 100 mg every 8 weeks thereafter for 32 weeks). The primary endpoint was clinical response at week 12 (defined as a ≥30% decrease from baseline in the full Mayo score and a ≥3 points absolute reduction with either a decrease in rectal bleeding score of ≥1 point or a rectal bleeding score of 0 or 1). Efficacy was analysed in the modified intention-to-treat population up to week 38, which included all randomly assigned patients who received at least one (partial or complete) study intervention dose. Safety was analysed up to week 50, according to study intervention received among all patients who received at least one (partial or complete) dose of study intervention. This trial is complete and is registered with ClinicalTrials.gov, NCT03662542. FINDINGS: Between Nov 20, 2018, and Nov 15, 2021, 358 patients were screened for eligibility, of whom 214 patients were randomly assigned to combination therapy (n=71), golimumab monotherapy (n=72), or guselkumab monotherapy (n=71). Of the 214 patients included, 98 (46%) were women and 116 (54%) were men and the mean age was 38·4 years (SD 12·0). At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group (adjusted treatment difference 22·1% [80% CI 12·9 to 31·3]; nominal p=0·0032) and 53 (75%) of 71 patients in the guselkumab monotherapy group (adjusted treatment difference 8·5% [-0·2 to 17·1; nominal p=0·2155). At week 50, 45 (63%) of 71 patients in the combination therapy group, 55 (76%) of 72 patients in the golimumab monotherapy group, and 46 (65%) of 71 patients in the guselkumab monotherapy group had reported at least one adverse event. The most common adverse events were ulcerative colitis, upper respiratory tract infection, headache, anaemia, nasopharyngitis, neutropenia, and pyrexia. No deaths, malignancies, or cases of tuberculosis were reported during the combination induction period. One case of tuberculosis was reported in the combination therapy group and one case of colon adenocarcinoma was reported in the guselkumab monotherapy group; both occurred after week 12. Two deaths were reported after the final dose of study intervention (poisoning in the combination therapy group and COVID-19 in the guselkumab monotherapy group). INTERPRETATION: Data from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials. FUNDING: Janssen Research and Development.

The Effect of Guselkumab Induction Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Results at Week 12 by Prior Inadequate Response or Intolerance to Advanced Therapy

Introduction: QUASAR (NCT04033445) is a phase 2b randomized, double-blind, placebo-controlled study that evaluates guselkumab (GUS), an interleukin-23 p19 subunit antagonist, as induction treatment in patients with moderately to severely active ulcerative colitis (UC) who had an inadequate response or intolerance to conventional (ie, thiopurines or corticosteroids) or advanced therapy (ADT;ie, tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib). Conclusion: Treatment with GUS resulted in greater improvements compared with placebo across key clinical and endoscopic/histologic outcome measures at Week 12 in patients with moderately to severely active UC with or without a history of inadequate response/intolerance to ADT. Efficacy at Week 12 by prior response/intolerance to ADT Placebo IV (N=105) GUS 200 mg IV (N=101) GUS 400 mg IV (N=107) GUS Combined(N=208) Patients with a history of inadequate response/intolerance to ADT 51 46 51 97  Clinical response a1,b,c,d,e (95% CI) 25.5% (14.3, 39.6) 54.3%* (39.0, 69.1) 47.1%* (32.9, 61.5) 50.5%* (40.2, 60.8)  Clinical remission a2,b,c,d,e (95% CI) 7.8% (2.2, 18.9) 17.4% (7.8, 31.4) 17.6% (8.4, 30.9) 17.5% (10.6, 26.6)  Symptomatic remission a3,b,c,d,e (95% CI) 17.6% (8.4, 30.9) 39.1%* (25.1, 54.6) 37.3%* (24.1, 51.9) 38.1%* (28.5, 48.6)  Endoscopic improvement a4,b,c,d,e (95% CI) 9.8% (3.3, 21.4) 23.9% (12.6, 38.8) 21.6% (11.3, 35.3) 22.7% (14.8, 32.3)  Histo-endoscopic mucosal improvement a5,b,c,d,e (95% CI) 5.9% (1.2, 16.2) 13.0% (4.9, 26.3) 19.6%* (9.8, 33.1) 16.5% (9.7, 25.4)  Endoscopic normalization a6,b,c,d,e (95% CI) 5.9% (1.2, 16.2) 10.9% (3.6, 23.6) 5.9% (1.2, 16.2) 8.2% (3.6, 15.6) Patents with no history of inadequate response/intolerance to ADT 54 55 56 111  Clinical response a1,b,c,d,e (95% CI) 29.6% (18.0, 43.6) 67.3%** (53.3, 79.3) 73.2%** (59.7, 84.2) 70.3%** (60.9, 78.6)  Clinical remission a2,b,c,d,e (95% CI) 11.1% (4.2, 22.6) 32.7%* (20.7, 46.7) 32.1%* (20.3, 46.0) 32.4%* (23.9, 42.0)  Symptomatic remission a3,b,c,d,e (95% CI) 22.2% (12.0, 35.6) 58.2%** (44.1, 71.3) 57.1%** (43.2, 70.3) 57.7%** (47.9, 67.0)  Endoscopic improvement a4,b,c,d,e (95% CI) 14.8% (6.6, 27.1) 36.4%* (23.8, 50.4) 39.3%* (26.5, 53.2) 37.8%* (28.8, 47.5)  Histo-endoscopic mucosal improvement a5,b,c,d,e (95% CI) 11.1% (4.2, 22.6) 27.3%* (16.1, 41.0) 33.9%* (21.8, 47.8) 30.6%* (22.2, 40.1)  Endoscopic normalization a6,b,c,d,e (95% CI) 7.4% (2.1, 17.9) 23.6%* (13.2, 37.0) 21.4%* (11.6, 34.4) 22.5%* (15.1, 31.4) * Nominal p-value < 0.05. ** Nominal p-value < 0.001. a1 Clinical response is defined as decrease from induction baseline in the modified Mayo score by ≥30% and ≥2 points, with either a ≥1-point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. a2 Clinical remission is defined as stool frequency subscore of 0 or 1 with no increase from induction baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability present on the endoscopy. a3 Symptomatic remission is defined as a stool frequency subscore of 0 or 1 with no increase from induction baseline and a rectal bleeding subscore of 0. a4 Endoscopic improvement is defined as an endoscopy subscore of 0 or 1 with no friability present on the endoscopy. a5 Histo-endoscopic mucosal improvement is defined as achieving a combination of histologic improvement (neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system) and endoscopic improvement, a6 Endoscopic normalization is defined as an endoscopy subscore of 0. b Patients who had a prohibited change in UC medication, an ostomy or colectomy, or discontinued study agent due to lack of efficacy or an adverse event of worsening of UC prior to the Week 12 visit were considered not to have achieved the endpoint. c Data after discontinuation of study agent due to COVID-19 related reasons (excluding COVID-19 infection) were considered to be missing. d Patients who were issing one or more components pertaining to a specified endpoint at Week 12 were considered not to have achieved the endpoint. e The p-values were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

Induction Combination Therapy With Guselkumab and Golimumab Followed by Guselkumab Monotherapy Maintenance: Results of the Phase 2a, Randomized, Double-Blind, Proof-of-Concept VEGA Study

GUS Clinical remission c,d 16 (22.2) 22 (31.0) 31 (43.7) 21.5 (11.9, 31.2) 0.006 12.7 (2.7, 22.7) 0.109 Clinical remission (based on mMayo) c,e 15 (20.8) 22 (31.0) 34 (47.9) 27.1 (17.7, 36.6) < 0.001 16.9 (7.0, 26.8) 0.033 Symptomatic remission c,f 43 (59.7) 49 (69.0) 49 (69.0) 9.4 (-0.6, 19.4) 0.238 0.0 (-9.7, 9.7) 1.000 Endoscopic improvementc.g 16 (22.2) 23 (32.4) 35 (49.3) 27.2 (17.6, 36.7) < 0.001 16.9 (7.0, 26.8) 0.033 Endoscopic normalization c,h 5 (6.9) 11 (15.5) 18 (25.4) 18.5 (11.1, 25.9) 0.002 9.9 (1.6, 18.2) 0.134 Histologic remission c,i 18 (25.0) 29 (40.8) 36 (50.7) 25.8 (16.1, 35.5) 0.001 9.9 (-0.4, 20.1) 0.224 Both histologic remission and endoscopic improvement c,g,i 10 (13.9) 15 (21.1) 30 (42.3) 28.5 (19.6, 37.4) < 0.001 21.1 (11.8, 30.5) 0.005 Both histologic remission and endoscopic normalization c,h,i 4 (5.6) 9 (12.7) 17 (23.9) 18.5 (11.3, 25.6) 0.002 11.3 (3.3, 19.2) 0.074 a The adjusted treatment difference between the combination therapy vs. the monotherapy groups and the confidence interval were based on the Wald statistic with the Cochran-Mantel-Haenszel (CMH) weight. b The p-value was based on the 2-sided CMH chi-square test, stratified by corticosteroid use at baseline (Yes, No). All P-values are nominal. c Pts who had an ostomy or colectomy, had a protocol-prohibited change in concomitant UC medications, or discontinued study intervention due to lack of a therapeutic effect or an adverse event of worsening UC, or discontinued study agent early due to COVID-19 related reasons (excluding COVID-19 infection) prior to the wk 38 visit were considered to not have achieved the binary endpoints. Pts with missing data at wk 38 were considered to not have achieved the binary endpoints. d Clinical remission is defined as Mayo score ≤2, with no individual subscore >1. e Clinical remission (based on the mMayo) is defined as a stool frequency subscore of 0 or 1, where the stool frequency subscore has not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability present on endoscopy. f Symptomatic remission is defined as Mayo stool frequency subscore of 0 or 1, where the stool frequency subscore has not increased from baseline, and a rectal bleeding subscore of 0. g Endoscopic improvement is defined as an endoscopy subscore of 0 or 1 with no friability present on the endoscopy. h Endoscopic normalization is defined as an endoscopy subscore of 0. i Histologic remission is defined as absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system.

Persistence of Tofacitinib Treatment in Patients With Ulcerative Colitis Who Entered the Open-Label, Long-Term Extension Study, OCTAVE OPEN Without a Clinical Response

Introduction: Drug survival in open-label, long-term extension (OLE) studies may provide information on the long-term efficacy and tolerability of a therapy. Methods: We present data on the persistence of tofacitinib treatment in the OLE study for: (1) delayed responders: induction non-responders (pts who did not achieve a clinical response [CR] after 8 weeks [wks] induction treatment with tofacitinib 10 mg BID) who achieved a CR at Wk 8 (total of 16 wks induction) of the OLE study and continued to receive 10 mg BID;(2) retreatment responders: tofacitinib 10 mg BID induction responders who experienced treatment failure with PBO in OCTAVE Sustain and entered the OLE study and received 10 mg BID, and achieved a CR at Wk 8 of the OLE study;and (3) dose escalation responders: tofacitinib 10 mg BID induction responders who experienced treatment failure with 5 mg BID in OCTAVE Sustain and entered the OLE study and received 10 mg BID, and achieved a CR at Wk 8 of the OLE study (Figure 1). The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19. 3CDAI < 150 4Average daily stool frequency (SF) ≤ 2.8 and not worse than baseline AND average daily abdominal pain (AP) score ≤ 1 and not worse than baseline 5Decrease in SES-CD > 50% from baseline (or for subjects with isolated ileal disease and a baseline SES-CD of 4, at least a 2-point reduction from baseline), as scored by central readers.

Factors Associated With Longitudinal Psychological and Physiological Stress in Health Care Workers During the COVID-19 Pandemic: Observational Study Using Apple Watch Data.

BACKGROUND: The COVID-19 pandemic has resulted in a high degree of psychological distress among health care workers (HCWs). There is a need to characterize which HCWs are at an increased risk of developing psychological effects from the pandemic. Given the differences in the response of individuals to stress, an analysis of both the perceived and physiological consequences of stressors can provide a comprehensive evaluation of its impact. OBJECTIVE: This study aimed to determine characteristics associated with longitudinal perceived stress in HCWs and to assess whether changes in heart rate variability (HRV), a marker of autonomic nervous system function, are associated with features protective against longitudinal stress. METHODS: HCWs across 7 hospitals in New York City, NY, were prospectively followed in an ongoing observational digital study using the custom Warrior Watch Study app. Participants wore an Apple Watch for the duration of the study to measure HRV throughout the follow-up period. Surveys measuring perceived stress, resilience, emotional support, quality of life, and optimism were collected at baseline and longitudinally. RESULTS: A total of 361 participants (mean age 36.8, SD 10.1 years; female: n=246, 69.3%) were enrolled. Multivariate analysis found New York City's COVID-19 case count to be associated with increased longitudinal stress (P=.008). Baseline emotional support, quality of life, and resilience were associated with decreased longitudinal stress (P<.001). A significant reduction in stress during the 4-week period after COVID-19 diagnosis was observed in the highest tertial of emotional support (P=.03) and resilience (P=.006). Participants in the highest tertial of baseline emotional support and resilience had a significantly different circadian pattern of longitudinally collected HRV compared to subjects in the low or medium tertial. CONCLUSIONS: High resilience, emotional support, and quality of life place HCWs at reduced risk of longitudinal perceived stress and have a distinct physiological stress profile. Our findings support the use of these characteristics to identify HCWs at risk of the psychological and physiological stress effects of the pandemic.

Intestinal Inflammation Modulates the Expression of ACE2 and TMPRSS2 and Potentially Overlaps With the Pathogenesis of SARS-CoV-2-related Disease.

BACKGROUND AND AIMS: The presence of gastrointestinal symptoms and high levels of viral RNA in the stool suggest active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication within enterocytes. METHODS: Here, in multiple, large cohorts of patients with inflammatory bowel disease (IBD), we have studied the intersections between Coronavirus Disease 2019 (COVID-19), intestinal inflammation, and IBD treatment. RESULTS: A striking expression of ACE2 on the small bowel enterocyte brush border supports intestinal infectivity by SARS-CoV-2. Commonly used IBD medications, both biologic and nonbiologic, do not significantly impact ACE2 and TMPRSS2 receptor expression in the uninflamed intestines. In addition, we have defined molecular responses to COVID-19 infection that are also enriched in IBD, pointing to shared molecular networks between COVID-19 and IBD. CONCLUSIONS: These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19. Preprint doi: https://doi.org/10.1101/2020.05.21.109124.