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).

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.

Treatment outcome of tofacitinib dose reduction to 5 mg BID vs remaining on 10 mg BID in patients with Ulcerative Colitis who were in stable remission on 10 mg BID: Updated 30-month data from the double-blind, randomised RIVETING study

Background: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. The long-term, Phase 3b/4 RIVETING study (NCT03281304) assessed the efficacy and safety of tofacitinib dose reduction from tofacitinib 10 mg twice daily (BID) maintenance therapy to 5 mg BID in patients (pts) in stable remission. 1 We present a final analysis of the RIVETING study after >=30 months of treatment. Method(s): RIVETING was a double-blind, randomised, parallelgroup study with a 42-month (M) duration. Eligible pts had received tofacitinib 10 mg BID for >=2 consecutive years in an open-label, long-term extension study (NCT01470612), had been in stable remission for >=6 months and corticosteroid-free for >=4 weeks prior to baseline. The primary efficacy endpoint was remission at M6 based on modified Mayo (mMayo) score (endoscopic and stool frequency subscores of <=1 and rectal bleeding subscore of 0).1 RIVETING was terminated (primary objective met) when all pts had passed M30 (or discontinued);some pts had already completed all visits up to M42. Here, we assess efficacy at M30 and safety throughout. Result(s): Overall, 140 pts were randomised (1:1) to tofacitinib 5 or 10 mg BID;50.0% and 62.9% were in remission based on mMayo score at M30 in the 5 and 10 mg BID dose groups, respectively, with consistent findings observed for other secondary efficacy endpoints (Table 1). At M30, observed differences for mMayo remission between tofacitinib 10 and 5 mg BID were generally greater in the subgroup with a baseline endoscopic subscore of 1 vs 0 and in the subgroup with vs without prior tumour necrosis factor inhibitor (TNFi) failure (Table 1). The percentage of pts who experienced loss of remission by M30, as estimated from Kaplan-Meier curves, was numerically higher in the 5 vs the 10 mg BID dose group (28.1%;95% confidence interval [CI], 17.68-39.49 vs 21.7%;95% CI, 12.21-32.95, respectively). Table 2 shows adverse events of special interest, by dose group. One death occurred due to fatal coronavirus disease 2019 pneumonia (10 mg BID). Conclusion(s): These long-term data showed that most pts in stable remission on tofacitinib 10 mg BID maintenance therapy maintained mMayo score remission through M30 after dose reduction to 5 mg BID. Dose group difference in remission at M30 was consistent with that at M6.1 Differences in remission between the tofacitinib 5 and 10 mg BID groups were greater in subgroups with an endoscopic subscore of 1 vs 0 and in subgroups with vs without prior TNFi failure. Overall, safety findings were consistent with tofacitinib's known safety profile;incidence of serious infections and herpes zoster was numerically higher in the tofacitinib 10 vs 5 mg BID group. (Table Presented).

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.

Efficacy and safety of upadacitinib as induction therapy in patientswith moderately to severely active ulcerative colitis: Results from phase 3 u-accomplish study

Introduction: U-ACCOMPLISH is one of two phase 3 induction trials evaluating safety and efficacy of upadacitinib-45 mg once daily (UPA) in adults with ulcerative colitis (UC). Methods: U-ACCOMPLISH, a multicentre, randomized, double-blind, placebo-controlled trial (NCT03653026), enrolled patients (pts) with moderate-to-severe UC (defined as adapted Mayo score 5-9 with centrally read endoscopic score of 2-3) who had inadequate response, loss of response, or intolerance to aminosalicylates, immunosuppressants, corticosteroids and/or biologics. Pts were randomized 2:1 to UPA or placebo (PBO) for 8 weeks (wks). At wk 8, responders entered the maintenance phase and non-responders entered the extended treatment period to receive open-label UPA for additional 8 wks. Primary endpoint (clinical remission per adapted Mayo Score) and ranked secondary endpoints including symptomatic, endoscopic-histologic evaluations from 8-wk PBO-controlled period are reported here. Non-responder imputation incorporating multiple imputation for missing data due to COVID-19 are reported. Results: 522 pts were randomized (UPA, n = 345;PBO, n = 177);intent-to-treat population included 341 pts in UPA and 174 pts in PBO group. Baseline demographics and disease characteristics were similar between groups;50.7% and 51.1% were biologic inadequate responders in UPA and PBO groups, respectively (Table 1). A significantly higher proportion of pts receiving UPA (33.5%) versus PBO (4.1%) achieved primary endpoint (adjusted treatment difference: 29.0% [23.2, 34.7];P<0.001). A significantly higher proportion of pts receiving UPA versus PBO also achieved all ranked secondary endpoints (all P<0.001;Figure 1).Serious adverse events were reported by 3.2% and 4.5% of pts in UPA and PBO groups, respectively (Table 1). Similar rates of serious infection were observed in both groups (0.6%);2 events each of herpes zoster and opportunistic infection were reported in UPA group. No active tuberculosis, malignancy, adjudicated major adverse cardiovascular events, or deaths were reported. One pt with venous thromboembolism (deep vein thrombosis and pulmonary embolism) and 1 pt with gastrointestinal perforation were reported in the placebo group. Conclusion: UPA 45 mg QD induction treatment led to statistically significant improvements in clinical, endoscopic, and combined endoscopic-histologic endpoints. Treatment was well tolerated, and safety profile and AE prevalence were comparable with previous studies of UPA with no new safety signals identified.