Exabis Library

An unmet therapeutic need remains in patients with ulcerative colitis (UC). U-ACHIEVE is one of two phase 3 induction trials evaluating the safety and efficacy of the selective Janus kinase–1 inhibitor upadacitinib (UPA) 45 mg once daily (QD) in adults with UC.

U-ACHIEVE is a multicentre, double-blind, placebo (PBO)–controlled trial (NCT02819635) that randomized patients with moderately to severely active UC 2:1 to UPA 45 mg QD or PBO for 8 weeks. Patients were stratified by response to biologic therapy (inadequate vs non–inadequate responder), baseline corticosteroid use (yes or no), and baseline adapted Mayo score (≤7 or >7). The primary endpoint was proportion of patients achieving clinical remission (per adapted Mayo Score) at week 8.Ranked secondary endpoints included endoscopic improvement, endoscopic remission, and clinical response per adapted Mayo Score at week 8; clinical response per partial adapted Mayo Score at week 2; and histologic-endoscopic mucosal improvement at week 8. Non-responder imputation incorporating multiple imputations for missing data due to COVID-19 are reported. Safety was assessed through week 8.

474 patients were randomized (UPA, n=319; PBO, n=155). Baseline characteristics were well balanced between groups (Table 1). A significantly higher proportion of patients receiving UPA (26.1%) vs PBO (4.8%) achieved clinical remission at week 8 (adjusted treatment difference [95% CI], 21.6% [15.8, 27.4]; P<0.001; Figure 1). For all ranked secondary endpoints, UPA was superior to PBO (P<0.001; Figure 1). A significant difference in clinical response favouring UPA vs PBO was seen as early as week 2 (60.1% vs 27.3%) and was sustained over 8 weeks (79.0% vs 41.6%; Figure 2). There were more serious adverse events (AEs), severe AEs, and AEs leading to study drug discontinuation with PBO (Table 2).  The most common AEs were acne, creatine phosphokinase elevation, and nasopharyngitis with UPA and worsening of UC and anaemia with PBO. Incidence of serious infection was similar between UPA and PBO. Neutropenia and lymphopenia were reported more frequently with UPA vs PBO (Table 2).No adjudicated gastrointestinal perforation, major cardiovascular AEs, or thrombotic events and no active tuberculosis, malignancy, or deaths were reported.

In patients with moderately to severely active UC, UPA 45 mg QD induction therapy was superior to PBO in inducing clinical remission/response, and endoscopic remission/response over 8 weeks; responses were significant and rapid. UPA 45 mg QD was well tolerated; safety was comparable with the known safety profile of UPA, and no new safety signals were identified.

Patients with ulcerative colitis (UC) often do not respond to treatment or lose response over time, and thus switch between therapies with various mechanisms of action (MoAs).¹ Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor in development as a UC treatment. We assessed the efficacy of FIL in biologic (bio)-naïve and bio-experienced patients with UC, and in bio-experienced patients with failure of 1 or ≥2 biologics or 1 or 2 MoAs.

SELECTION (NCT02914522) was a phase 2b/3 double-blind, randomised, placebo-controlled trial comprising two induction studies and a maintenance study. Adults (18–75 years) with moderately to severely active UC were randomised 2:2:1 to FIL 200 mg, FIL 100 mg or placebo (PBO) once daily for 11 weeks in Induction Study A (bio-naïve) and B (bio-experienced). Patients in either clinical remission or Mayo Clinic Score (MCS) response at week 10 (responders) could enter the Maintenance Study. Responders who received induction FIL were re-randomised 2:1 to continue their induction regimen or PBO through week 58. Responders who received induction PBO continued PBO. We assessed clinical remission and MCS response at weeks 10 and 58 in bio-naïve patients and bio-experienced patients with failure of 1 or ≥2 biologics and 1 or 2 MoAs (TNF antagonists and vedolizumab). All p values for subgroup analyses are nominal.

At week 10, clinical remission was achieved by a significantly higher proportion of bio-naïve and -experienced patients treated with FIL 200 mg than PBO (Figure 1a). A higher proportion of bio-experienced patients with 1 biologic or MoA failure treated with FIL 200 mg than PBO achieved clinical remission at week 10 (p<0.05); a smaller treatment effect was seen in patients with ≥2 biologic or 2 MoA failures (Figure 1b). None of these comparisons reached p<0.05 for FIL 100 mg. Higher proportions of patients treated with either dose of FIL than PBO achieved MCS response at week 10 in all (sub)groups (Figure 2). At week 58, higher proportions of bio-naïve and -experienced responders, and bio-experienced responders with ≥2 biologic or 2 MoA failures treated with maintenance FIL 200 mg than PBO achieved clinical remission (p<0.05) (Table 1). Higher proportions of responders treated with maintenance FIL 200 mg than PBO achieved MCS response at week 58 in all (sub)groups.

FIL 200 mg was effective in inducing and maintaining clinical remission in bio-naïve and -experienced patients. Induction results suggest FIL 200 mg is most effective in bio-naïve patients, and those who switch after failure of 1 biologic or MoA. Interpretation of week 58 data is limited by low patient numbers.

1. Gemayal NC et al. Gastroenterology 2019;35:1911–23.

Guselkumab (GUS), an IL-23 antagonist, is being investigated for the treatment of IBD. GALAXI 1 is a ph2, double-blind, PBO-controlled study in pts with moderately to severely active CD with inadequate response or intolerance to conventional therapies (corticosteroid, immunosuppressant) and/or biologics (TNF antagonist, vedolizumab). Here we report early clinical outcome measures during induction with GUS vs PBO.

Pts with moderate to severe CD (CDAI score 220-450) were randomized 1:1:1:1:1 to GUS 200, 600 or 1200mg IV at Wks 0, 4, 8; ustekinumab (UST) ~6mg/kg IV at Wk 0 and 90mg SC at Wk8; or PBO IV. Clinical remission (CDAI score<150), clinical response (≥100-point reduction from baseline in CDAI score or CDAI score<150), and clinical-biomarker response (clinical response and ≥50% reduction from baseline in CRP or fecal calprotectin) were evaluated at Wks 4, 8 and 12 for pooled GUS arms vs PBO. UST was a reference arm.

Two hundred fifty pts were evaluated; about 50% failed previous biologic therapy. Baseline demographics and disease characteristics were generally similar among treatment groups (mean CD duration, 8.8yr; mean CDAI, 306.2; median CRP, 5.4mg/L; median fecal calprotectin, 594.0mg/kg). At Wk4, clinical remission was achieved in 20.0% of GUS-treated pts compared with 11.8% of PBO-treated pts. A greater proportion of GUS-treated pts achieved clinical remission compared with PBO-treated pts at Wk8 (42.0% vs 15.7%) and Wk12 (54.0% vs 15.7%). Similarly, within each subgroup of pts who failed biologic therapy(BIO-failures) or conventional therapy(CON-failures), GUS-treated pts achieved a higher rate of clinical remission at Wks 4, 8 and 12 compared with PBO (Fig 1). The proportion of pts who achieved clinical response and clinical-biomarker response was also higher at Wks 4, 8 and 12 among GUS-treated pts compared with PBO-treated pts. From Wks 4 to 8 to 12, the proportion of GUS-treated pts in clinical response increased from 44.0% to 56.0% to 66.0%, respectively, and the proportion in clinical-biomarker response increased from 26.0% to 43.3% to 48.0%. In contrast, the proportion of PBO-treated pts who achieved clinical response and clinical-biomarker response remained stable or decreased from Wks 4 to 8 to 12: 25.5% to 25.5% to 23.5% and 13.7% to 9.8% to 7.8%, respectively (Fig 2).

In pts with moderately to severely active CD, induction treatment with GUS combined treatments versus PBO resulted in higher rates of overall clinical remission, clinical-biomarker response, and clinical response as early as Wk4. This continued to increase through Wk12 with treatment. The early trend for achievement of clinical remission was also evident in sub-groups of pts who failed biologic or conventional therapy.

The gut microbiome directly affects the balance of pro-inflammatory and anti-inflammatory responses in the gut. As microbes thrive on dietary substrates, the question arises whether we can nourish an anti-inflammatory gut ecosystem. In this study, we investigated the relation between 173 dietary factors and the microbiome of 1425 individuals spanning four cohorts: Crohn’s disease, ulcerative colitis, irritable bowel syndrome and the general population.

Shotgun metagenomic sequencing was performed to profile gut microbial composition and function. Dietary intake was assessed through food frequency questionnaires. We performed unsupervised clustering to identify dietary patterns and microbial clusters. Next, linear models were conducted between dietary intake and microbial species and pathways, adding age, sex, caloric intake and sequencing read depth as covariates. Analyses were conducted per cohort, followed by a meta-analysis and heterogeneity estimation. Multiple testing correction was performed on the obtained p-values and a FDR <0.05 was defined as significance cut-off.

We identified 38 associations between dietary patterns and microbial clusters. Moreover, 61 individual foods and nutrients were associated with 61 species and 249 metabolic pathways in the meta-analysis across healthy individuals and patients with IBS, Crohn’s disease and UC (FDR<0.05, heterogeneity p-value>0.05). Processed foods and animal-derived foods were consistently associated with higher abundances of Firmicutes, Ruminococcus species of the Blautia genus and endotoxin synthesis pathways. The opposite associations were found for clusters comprising fish, nuts, bread and legumes. Moreover, while total plant protein intake was associated with a higher Bifidobacterium abundance (FDR=0.048, coef=4.98), animal-derived protein showed a negative association (FDR=1.30x10^-05, coef= -4.1). Lastly, we observed positive associations of fecal calprotectin with a fast food cluster (FDR=4.14x10^-4, coef=0.24) and a cluster comprised of high-fat meat, potatoes and gravy (FDR=0.003, coef =0.22), while the opposite was seen for clusters of fish and nuts (FDR=0.038, coef= -0.1) and bread and legumes (FDR=0.005, coef= -2.48).

We identified dietary patterns that consistently correlate with groups of bacteria with shared functional roles in both, health and disease. Moreover, specific foods and nutrients were associated with species known to infer mucosal protection and anti-inflammatory effects. A decrease in these bacteria has already been associated with both IBS and IBD. We propose microbial mechanisms through which the diet affects inflammatory responses in the gut as a rationale for future intervention studies.