THE EFFICACY AND SAFETY OF GUSELKUMAB INDUCTION THERAPY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM THE PHASE 3 QUASAR INDUCTION STUDY

Background: Gut dysbiosis is associated with persistent multi-system symptoms following SARS-CoV-2 infection, or post-acute COVID-19 syndrome (PACS). We performed a randomised controlled trial to assess the effects of gut microbiome modulation on alleviation of PACS symptoms.

Methods: This is a single-centre, triple-blind, randomised, placebo-controlled study in recovered COVID-19 patients who reported persistent PACS symptoms. Eligible subjects were randomly assigned at 1:1 ratio to receive either a novel oral microbiome immunity formula (SIM01, synbiotic) or placebo orally for 6 months. The primary outcome was the alleviation of PACS symptoms by month 6 as compared to baseline, assessed by a structured 14-item symptom questionnaire. Chi-squared test was used to evaluate the association between intervention and symptom alleviation. The secondary outcome was the reduction of gastrointestinal symptoms severity, evaluated by a self-report scale from 1 to 4 (1=none, 4=severe). Wilcoxon signed-rank test was used to compare the changes in severity scores between baseline and month 6. Bonferroni correction was applied to adjust for multiple comparisons of symptoms.

Results: A total of 463 subjects (mean age 49.4 ± 13.4 years, 65.4% female) were randomised at a median duration of 4 (IQR: 3-11) months since COVID-19 diagnosis. All subjects had at least one of 14 common symptoms of PACS at randomisation and were included in the intention-to-treat analysis. A significantly higher proportion of subjects who received SIM01 had improvements in fatigue (62.8% vs 42.6%, p<0.001), memory loss (42.0% vs 26.9%, p=0.002), difficulty in concentration (62.3% vs 38.5%, p<0.001), digestive problems (70.2% vs 54.1%, p=0.001), and general unwellness (77.3% vs 59.0%, p=0.001) by 6 months compared with the placebo group, after adjusting for multiple comparisons. Amongst 134 subjects who reported improvement in digestive problems after SIM01 intervention, we found significant reductions in severity score for 7 out of 8 gastrointestinal symptoms assessed, including diarrhoea (p<0.001), constipation (p<0.001), abdominal pain (p=0.003), epigastric pain (p<0.001), bloating (p<0.001), vomiting (p=0.005) and acid reflux (p<0.001), following Bonferroni correction.

Conclusion: This is the first randomised controlled trial showing that modulation of gut microbiome with a novel oral microbiome formula (SIM01) alleviates gastrointestinal and neuropsychiatric symptoms of PACS.

This study was funded by the Health and Medical Research Fund under the Food and Health Bureau of the Government of the Hong Kong Special Administrative Region, and Hui Hoy & Chow Sin Lan Charity Fund Limited. The authors are partially supported by InnoHK, the Government of the HKSAR.

INTRODUCTION
The QUASAR Phase 3 Induction Study (NCT04033445) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of guselkumab (GUS), an interleukin-23 p19 subunit antagonist, as induction therapy in patients with moderately to severely active ulcerative colitis (UC) who had an inadequate response or intolerance to conventional (i.e., thiopurines or corticosteroids) and/or advanced therapies (i.e., tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib).

METHODS
The primary analysis population included patients with a baseline modified Mayo score of 5 to 9, inclusive, a rectal bleeding subscore ≥ 1, and an endoscopy subscore ≥ 2 evaluated during central review of video endoscopy. Patients were randomized 3:2 to receive IV GUS 200mg or placebo (PBO) at Weeks (Wks) 0, 4, and 8.

The primary endpoint was clinical remission at Wk 12. Symptomatic remission, clinical response, endoscopic improvement, histo-endoscopic mucosal improvement, endoscopic normalization, and safety were also assessed.

RESULTS
Seven hundred one patients were randomized and included in the primary analysis population (mean age, 40.5yrs; female, 43.1%; mean UC duration, 7.5yrs; mean modified Mayo score, 6.9; Mayo endoscopy subscore of 3 indicating severe disease, 67.9%; median fecal calprotectin, 1641.0mg/kg; median C-reactive protein, 4.2mg/L; baseline oral corticosteroid use, 43.1%). Baseline demographic and disease characteristics were balanced across the two treatment groups. Approximately 50% had a prior failure to advanced therapies for UC, and nearly half (47.4%) of these patients failed two or more advanced therapy classes.

A significantly greater proportion of patients treated with GUS compared with PBO achieved clinical remission at Wk 12 (22.6% vs 7.9%, adjusted Δ=14.9%, p<0.001). Relative to PBO, GUS induction treatment resulted in significantly greater proportions of patients achieving symptomatic remission, clinical response, endoscopic improvement, and histo-endoscopic mucosal improvement at Wk 12 and symptomatic remission at Wk 4 (Figure 1).

The frequencies of treatment-emergent adverse events (AEs) in the GUS group were generally similar to PBO (Table 1). There were numerically fewer serious AEs (2.9% vs 7.1%) and AEs leading to discontinuation (1.7% vs 3.9%) in GUS-treated patients compared to PBO. No AEs within 1 hour of infusion were considered serious or resulted in treatment discontinuation.

CONCLUSIONS
In this Phase 3 study, GUS 200mg IV induction was safe and effective in the treatment of patients with moderately to severely active UC compared to PBO with clinically meaningful improvements demonstrated across symptomatic and histo-endoscopic outcome measures. Overall, safety results through Wk 12 were consistent with the known and favorable safety profile of GUS in approved indications.