Background Widespread disruption of the mucosal immune system is central to the pathogenesis of ulcerative colitis (UC). One component, tumour necrosis factor (TNF) α-like ligand 1A (TL1A), is upregulated at the site of active disease in UC. Treatment of preclinical rodent models with anti-TL1A antibodies decreases disease activity, highlighting their therapeutic potential for UC. PF-06480605 is a first-in-class fully human immunoglobulin G1 monoclonal antibody targeting TL1A. Methods The Phase 2a, open-label, multicentre, single-arm TUSCANY study (NCT02840721) evaluated the safety, tolerability and efficacy of PF-06480605 in treatment of moderate to severe UC. Participants received 500 mg intravenous (IV) PF-06480605 every 2 weeks (Q2W) for a total of 7 doses, with a 14-week follow-up period. Primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and endoscopic improvement (EI) (Mayo endoscopic subscore [centrally read] of ≤1 without friability) at Week 14, respectively. Secondary efficacy endpoints included remission (total Mayo score ≤2, with no individual subscore >1) and endoscopic remission (Mayo endoscopic subscore = 0) at Week 14. Transcriptomic profiling on intestinal biopsies was performed. Results Of the 50 participants who received PF-06480605, 42 completed the study. The majority were male (56.0%) and white (96.0%), with a mean age of 40.0 years and prior experience of anti-TNF inhibitors (72.0%). Pancolitis (48.0%) and left-sided colitis (32.0%) were the most common forms of UC at baseline. There were 109 TEAEs, of which 18 were treatment-related. Aside from worsening UC, the most common TEAE by system organ class was arthralgia, which occurred in 6 participants, and 1 was treatment-related. Treatment-emergent serious adverse events were reported in 3 participants, and considered treatment-related in 1 participant (Table 1). No malignancies or deaths were reported. At Week 14, statistically significant EI was observed in 38.2% of participants (Table 2). The proportions of participants achieving remission and endoscopic remission at Week 14 were 24.0% and 10.0%, respectively. Transcriptomic analyses demonstrated normalisation towards a non-inflamed transcriptome in participants with EI. Conclusion PF-06480605 exhibited an acceptable safety and tolerability profile and statistically significant EI in participants with moderate to severe UC. These results warrant further evaluation in subsequent studies.
Background Tumour necrosis factor α-like ligand 1A (TL1A) acts as a synergistic cytokine that amplifies pro-inflammatory signals to increase T-cell, natural killer (NK) cell, and innate lymphoid cell production of cytokines, which are thought to be key drivers of inflammatory bowel disease (IBD) and intestinal fibrosis. The recent Phase 2a TUSCANY study demonstrated the efficacy of PF-06480605, a fully human immunoglobulin G1 monoclonal antibody targeting TL1A, in the treatment of participants with moderate to severe active Ulcerative Colitis (UC). Here, we present transcriptomic analysis of intestinal tissue biopsies and metagenomic analysis of the faecal microbiome to further evaluate the treatment effect of PF-06480605. Methods The Phase 2a, open-label, multicentre, single-arm TUSCANY study (NCT02840721) evaluated the safety, tolerability and efficacy of PF-06480605 in participants with moderate to severe UC. Participants received 500 mg intravenous (IV) PF-06480605 every 2 weeks (Q2W) for a total of 7 doses, with a 14-week follow-up period. We performed RNA sequencing of colonic biopsies and metagenomic sequencing (>40 million reads per sample) of faecal samples taken prior to and after 12 weeks of therapy. Differential expression and cell subset deconvolution by CytoReason were used to identify genes and immune cells involved in response to therapy. Differential abundance analyses based on taxonomic profiling was performed using the GOTTCHA metagenome mapping algorithm to discover whether microbial taxa changed in response to treatment. Results Tissue transcriptomic analysis identified a robust inhibition of adaptive (Th1, Th2 and Th17) and innate (macrophage) inflammatory pathways known to be associated with UC pathogenesis and a significant reduction in fibrosis-associated pathways (MMP3, MMP7 and MMP10). Transcriptomic responses were most pronounced in participants achieving endoscopic improvement (Mayo endoscopic subscore of ≤1). A candidate baseline gene signature was predictive of endoscopic improvement (area under the curve [AUC] 0.75; p-value = 0.03). Metagenomic analysis revealed a significant reduction in inflammatory pathobiont species (S. salivarius, S. parasanguinis, and H. parainfluenzae) following treatment. Conclusion These results provide insight into the molecular and microbial mechanisms underlying the efficacy of anti-TL1A therapy for UC. We defined a baseline transcriptomic signature to predict response and a pathobiont treatment signature. These findings may enable the development of precision medicine strategies for anti-TL1A therapy in the treatment of intestinal inflammation.
Background Ritlecitinib (PF-06651600) is an oral Janus kinase 3/TEC inhibitor, demonstrated to be safe, well-tolerated and efficacious in moderate to severe active ulcerative colitis. The aim of this pre-specified biomarker study was to develop serum signatures that could serve as non-invasive indicators of endoscopic improvement and histologic remission after ritlecitinib therapy. Methods Colon biopsies and peripheral blood were obtained from participants for biomarker profiling before and after receiving 8-week induction therapy with oral ritlecitinib (20mg,70mg, 200mg, or placebo N=39, 39, 33, 18 respectively) once daily. Responders were defined by endoscopic improvement (Mayo endoscopic sub-score <=1) or histologic remission (Geboes Score ≤ 3.0). RNA from colon biopsy samples were processed using RNA sequencing (Fulgent Therapeutics, CA). Serum proteins were measured using the Olink Explore Inflammation panel (Olink, Proteomics, Sweden). Linear mixed models were used to estimate the change from baseline (CFB) of each protein/gene at Week 8 by treatment and clinical response. Differences between response groups and treatment arms were also analyzed. Results Analysis of serum revealed 37 proteins significantly changed at week 8 compared to baseline in responders (FDR < 0.05). Changes in four of these proteins (IL4R, TNFRSF4, SPINK4 and LAIR-1) correlate with both endoscopic improvement and histological remission and were able to separate responders from non-responders AUC (area under the ROC curve) = 0.71 [0.61–0.81] based on endoscopic improvement and AUC = 0.60 [0.48–0.71] based on histological remission). To determine if these 37 proteins reflect tissue inflammation, we evaluated the differential expression of genes encoding these proteins with RNA-seq of inflamed biopsies. Ten genes (CXCL1, FCAR, CKAP4, SPINK4, CXCL17, OSM, CD4, CXCL9, IL17A, GZMB) had significant changes from baseline between responders and non-responders at Week 8 (FDR < 0.1) in either endoscopic improvement or histological remission. Furthermore, these ten genes were significantly increased at baseline between inflamed and non-inflamed colon biopsies. Finally, colon biopsy transcription levels of TNFRSF4, SPINK4 and LAIR1 were modulated with marginal significance (P-value < 0.1) in either endoscopic improvement or histological remission at Week 8. Conclusion Serum proteomics revealed a promising signature of endoscopic improvement and histologic remission in UC participants treated with ritlecitinib. Changes in a subset of these serum proteins parallel tissue gene expression and offer insight into a potential non-invasive companion monitoring test to guide clinical management of patients treated with ritlecitinib.
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