Antitumor Necrosis Factor-like Ligand 1A Therapy Targets Tissue Inflammation and Fibrosis Pathways and Reduces Gut Pathobionts in Ulcerative Colitis.

BACKGROUND: The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. METHODS: Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. RESULTS: Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. CONCLUSIONS: The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.

Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study.

BACKGROUND & AIMS: An immune component of inflammatory bowel disease is up-regulated tumor necrosis factor-like ligand 1A (TL1A). Anti-TL1A antibodies such as PF-06480605, a fully human immunoglobulin G1 monoclonal antibody, may have therapeutic potential. METHODS: This Phase 2a, multicenter, single-arm, open-label study (TUSCANY) evaluated safety, tolerability, efficacy, pharmacokinetics, and immunogenicity in PF-06480605-treated participants with moderate to severe ulcerative colitis (UC). Participants received 500 mg intravenous PF-06480605 every 2 weeks, 7 doses total, with a 3-month follow-up period. Primary safety and efficacy endpoints were the incidence of adverse events (AEs) and week 14 endoscopic improvement (EI) (Mayo endoscopic subscore = 0 or 1), respectively. Secondary endpoints included total soluble TL1A (free/drug-bound) (sTL1A), incidence of anti-drug and neutralizing antibodies, PF-06480605 concentrations, and changes in fecal calprotectin and high-sensitivity C-reactive protein. Histology was assessed at week 14. RESULTS: The study enrolled 50 participants; 42 completed. Of 109 treatment-emergent AEs, 18 were treatment-related. The most common AEs were UC disease exacerbation and arthralgia (6 participants each). Four serious AEs, no deaths, and no malignancies were reported. Week 14 EI was observed in a statistically significant proportion of participants (38.2% [uniformly minimum-variance unbiased estimator, per protocol population]). Minimal histologic disease was observed after treatment (Robarts Histopathology Index ≤5: 33.3%; Geboes Index ≤3.2: 47.6%). sTL1A increase over time from baseline indicated sustained target engagement. Forty-one participants (82%) tested positive for anti-drug antibodies and 5 (10%) for neutralizing antibodies. CONCLUSIONS: PF-06480605 demonstrated an acceptable safety profile and statistically significant EI in participants with moderate to severe UC, warranting further study in a larger participant cohort. Tissue histopathology analyses support this conclusion. TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/NCT02840721.

Identification of a locus modulating serum C-reactive protein levels on chromosome 5p15.

OBJECTIVE: Individual propensity to chronic, low-grade inflammation--a determinant of atherosclerosis-is in part under the control of genetic factors. To identify genes involved in this modulation, we performed a 10cM genome screen for linkage with plasma C-reactive protein in 38 extended families including 317 non-diabetic and 177 type 2 diabetic family members (2547 relative pairs). METHODS AND RESULTS: In a variance component analysis, heritability of CRP values was significant (h(2)=0.39, p<0.0001). This effect was independent of BMI and was present in both diabetic (h(2)=0.42, p=0.003) and non-diabetic (h(2)=0.34, p=0.0015) relatives. The strongest evidence of linkage with CRP was on chromosome 5p15, where the LOD score reached genome-wide significance (LOD=3.41, genome-wide p=0.013). Both diabetic and non-diabetic family members contributed to linkage at this location. Smaller linkage peaks were detected on chromosomes 5q35 (LOD=1.35) and 17p11 (LOD=1.33). When the analysis was restricted to diabetic family members, another peak of moderate intensity (LOD=2.17) was evident at 3p21. CONCLUSIONS: A major gene influencing CRP levels appears to be located on chromosome 5p15, with an effect that is independent of diabetes. Another gene on 3p21 may control CRP variation but only in the presence of a diabetic or insulin-resistant environment.

Variation in blood levels of inflammatory markers related and unrelated to smoking cessation in women.

This study assessed the influence of short-term changes in smoking habit on blood levels of inflammatory markers, which have been associated with increased cardiovascular risk. Five inflammatory markers were measured before and 6 weeks after attempting smoking cessation in 138 healthy women. In the 48 participants who stopped smoking, white blood cell count (-0.7+/-1.2 x 10(9)/L; P<.001) and fibrinogen (-0.6+/-1.5 micromol/L; P<.01) decreased, but there was no significant (P>.1) change in the plasma level of C-reactive protein (median change +0.1; interquartile range -0.2, 0.9 mg/L), intercellular adhesion molecule 1 (+17+/-75 ng/mL), or CD40 ligand (+0.4+/-2.1 ng/mL). Most of the individual variation in inflammatory marker levels was unrelated to changes in smoking habit.

Effects of exercise training on 5 inflammatory markers associated with cardiovascular risk.

BACKGROUND: Cross-sectional studies suggest that regular exercise has anti-inflammatory effects, leading to lower levels of several proatherogenic inflammatory markers. However, this has yet to be confirmed by randomized prospective trials. We performed a randomized controlled trial to assess whether exercise training decreases levels of 5 inflammatory markers linked to future cardiovascular risk: white blood cell count, fibrinogen, C-reactive protein, soluble intercellular adhesion molecule 1, and soluble CD40 ligand. METHODS: One hundred fifty-two healthy female smokers were randomized to either 12 weeks of exercise training or health education as part of a smoking cessation program. Smoking was held steady for the first 6 weeks, and thereafter, smoking cessation was actively attempted. One hundred four participants completed 6 weeks, and 88 completed 12 weeks. Fitness and circulating inflammatory marker levels were measured at baseline, 6 weeks, and 12 weeks. To avoid potential confounding from changes in smoking exposure during the second 6 weeks of the trial, the primary end point was change in inflammatory marker levels from baseline to 6 weeks. Change in inflammatory markers from baseline to 12 weeks was a secondary end point. RESULTS: At baseline, greater physical fitness was associated with lower white blood cell, fibrinogen, and C-reactive protein levels, but these associations were not statistically significant after adjusting for body mass index (P > .1 for all). Fitness improved significantly in the exercise group at both 6 and 12 weeks. However, there were no differences in levels of any inflammatory marker between the exercise and control groups at either 6 weeks (primary end point) or 12 weeks (secondary end point) (P > .05 for all comparisons). CONCLUSION: In female smokers, baseline associations between fitness and inflammatory markers were largely attributable to differences in body fat; regular exercise did not reduce levels of any of the inflammatory markers studied despite a significant improvement in fitness at both 6 and 12 weeks.