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1.
J Crohns Colitis ; 2023 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-38141256

RESUMO

BACKGROUND AND AIMS: Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, was well- tolerated and efficacious in the phase 2b VIBRATO study in participants with moderate-to-severe ulcerative colitis (UC). The aim of this study was to identify baseline serum and microbiome markers that predict subsequent clinical efficacy and to develop noninvasive serum signatures as potential real-time noninvasive surrogates of clinical efficacy after ritlecitinib. METHODS: Tissue and peripheral blood proteomics, transcriptomics, and fecal metagenomics were performed on samples before and after 8-week oral ritlecitinib induction therapy (20 mg, 70 mg, 200 mg, or placebo once daily, N=39, 41, 33, and 18, respectively). Linear mixed models were used to identify baseline and longitudinal protein markers associated with efficacy. The combined predictivity of these proteins was evaluated using a logistic model with permuted efficacy data. Differential expression of fecal metagenomic was used to differentiate responders and nonresponders. RESULTS: Peripheral blood serum proteomics identified 4 baseline serum markers (LTA, CCL21, HLA-E, MEGF10) predictive of modified clinical remission (MR), endoscopic improvement (EI), histologic remission (HR), and integrative score of tissue molecular improvement. In responders, 37 serum proteins significantly changed at Week 8 compared with baseline (FDR<0.05); of these, changes in 4 (IL4R, TNFRSF4, SPINK4, and LAIR-1) predicted concurrent EI and HR responses. Fecal metagenomics analysis revealed baseline and treatment response signatures that correlated with EI, MR, and tissue molecular improvement. CONCLUSIONS: Blood and microbiome biomarkers stratify endoscopic, histologic, and tissue molecular response to ritlecitinib, which may help guide future precision medicine approaches to UC treatment.

2.
Clin Gastroenterol Hepatol ; 21(10): 2616-2628.e7, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36623678

RESUMO

BACKGROUND & AIMS: The efficacy and safety of ritlecitinib (oral JAK3/TEC family kinase inhibitor) and brepocitinib (oral TYK2/JAK1 inhibitor) as induction therapy were assessed in patients with active, moderate-to-severe ulcerative colitis. METHODS: This phase 2b, parallel-arm, double-blind umbrella study randomized patients with moderate-to-severe ulcerative colitis to receive 8-week induction therapy with ritlecitinib (20, 70, 200 mg), brepocitinib (10, 30, 60 mg), or placebo once daily. The primary endpoint was total Mayo Score (TMS) at week 8. RESULTS: Of 319 randomized patients, 317 received ritlecitinib (n = 150), brepocitinib (n = 142), or placebo (n = 25). The placebo-adjusted mean TMSs (90% confidence interval) at week 8 were -2.0 (-3.2 to -0.9), -3.9 (-5.0 to -2.7), and -4.6 (-5.8 to -3.5) for ritlecitinib 20, 70, and 200 mg, respectively (P = .003, P < .001, P < .001), and -1.8 (-2.9 to -0.7), -2.3 (-3.4 to -1.1), and -3.2 (-4.3 to -2.1) for brepocitinib 10, 30, and 60 mg, respectively (P = .009, P = .001, P < .001). Estimates (90% confidence interval) for placebo-adjusted proportions of patients with modified clinical remission at week 8 were 13.7% (0.5%-24.2%), 32.7% (20.2%-45.3%), and 36.0% (23.6%-48.6%) for ritlecitinib 20, 70, and 200 mg, respectively, and 14.6% (1.9%-25.7%), 25.5% (11.0%-38.1%), and 25.5% (11.0%-38.1%) for brepocitinib 10, 30, and 60 mg, respectively. Adverse events were mostly mild, and there were no serious cases of herpes zoster infection. Infections were observed with brepocitinib (16.9% [12.5%-23.7%]), ritlecitinib (8.7% [5.2%-13.4%]), and placebo (4.0% [0.2%-17.6%]). One death due to myocardial infarction (ritlecitinib) and 1 thromboembolic event (brepocitinib) occurred; both were considered unrelated to study drug. CONCLUSIONS: Ritlecitinib and brepocitinib induction therapies were more effective than placebo for the treatment of moderate-to-severe active ulcerative colitis, with an acceptable short-term safety profile. CLINICALTRIALS: gov number: NCT02958865.


Assuntos
Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/etiologia , Indução de Remissão , Quimioterapia de Indução/métodos , Método Duplo-Cego , Índice de Gravidade de Doença , Resultado do Tratamento
3.
Inflamm Bowel Dis ; 28(3): 434-446, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-34427649

RESUMO

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.


Assuntos
Colite Ulcerativa , Colite Ulcerativa/tratamento farmacológico , Fibrose/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ligantes , Necrose , Proteômica , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
4.
Clin Gastroenterol Hepatol ; 19(11): 2324-2332.e6, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34126262

RESUMO

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.


Assuntos
Antineoplásicos Imunológicos , Colite Ulcerativa , Doenças Inflamatórias Intestinais , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Humanos , Fator de Necrose Tumoral alfa/uso terapêutico
5.
United European Gastroenterol J ; 6(1): 138-147, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29435324

RESUMO

BACKGROUND: Adherence to mesalazine treatment is essential for the successful treatment of ulcerative colitis. OBJECTIVE: The objective of this study was to compare the efficacy, safety and preference of a novel high-dose 1000 mg mesalazine tablet versus conventional treatment for ulcerative colitis remission. METHODS: This pivotal phase III trial compared one 1000 mg mesalazine tablet (M1000 group) versus two registered 500 mg mesalazine tablets (M2x500 group), both taken three times daily, in patients with mild to moderately active ulcerative colitis. The primary efficacy variable was clinical remission at week 8. RESULTS: A total of 306 patients were considered for intent-to-treat analysis. Clinical remission was achieved in 45.0% of the patients in the M1000 group versus 41.9% in the M2x500 group (P < 0.001 for non-inferiority). Mucosal healing was achieved by 68.9% of the patients in the M1000 group and 68.4% in the M2x500 group. The majority of patients preferred the intake of one high-dose tablet (47.7%) over two low-dose tablets (10.5%). Oral treatment with high-dose 1000 mg mesalazine tablets was well tolerated without new safety signals. CONCLUSIONS: The novel high-dose 1000 mg mesalazine tablet is effective, non-inferior to the registered 500 mg mesalazine tablet, and safe for ulcerative colitis treatment. It was preferred by a majority of patients and may improve ulcerative colitis treatment adherence.

6.
Tumour Biol ; 32(4): 753-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21611786

RESUMO

The chymotrypsin-like (ChT-L) activity is one of the key regulators of intracellular protein degradation. Elevated proteasome ChT-L activity has recently been reported in plasma of patients with leukemia and myelodysplastic syndrome and suggested to have a prognostic significance. The aim of the present study was to evaluate plasma proteasome ChT-L activity in patients with newly diagnosed solid tumors at early and advanced stages of the disease. The activity was assayed using the fluorogenic peptide substrate, Suc-Leu-Leu-Val-Tyr-AMC, in a cohort of 155 patients with early/advanced rectal (n=43/29), gastric (n=6/13), and breast (n=37/27) cancer and compared with that in normal individuals (n=55). The median plasma proteasome ChT-L activity was elevated by 20-32% in patients with advanced stage of rectal, gastric, and breast cancer compared with healthy donors. The difference turned out to be statistically significant (P<0.001). By contrast, values in patients with early stage of malignancies were not significantly different from those observed in normal individuals. We also found that plasma proteasome activity correlated with serum carcinoembryonic antigen levels in the group of patients with rectal cancer (r=0.433, P<0.05). Elevated plasma proteasome ChT-L activity is indicative of advanced stage of rectal, gastric, and breast cancer. However, the activity does not seem to be a parameter with clinically relevant potential in terms of early detection of cancer in this subset of patients.


Assuntos
Neoplasias da Mama/sangue , Quimases/sangue , Complexo de Endopeptidases do Proteassoma/sangue , Neoplasias Retais/sangue , Neoplasias Gástricas/sangue , Adulto , Biomarcadores Tumorais/sangue , Western Blotting , Neoplasias da Mama/patologia , Antígeno Carcinoembrionário/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Retais/patologia , Neoplasias Gástricas/patologia
7.
J Med Food ; 12(4): 914-8, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19735195

RESUMO

The aim of this study was to determine the activity of the lysosomal exoglycosidases: alpha-mannosidase (MAN), alpha-fucosidase (FUC), and beta-glucuronidase (GLUCUR) in serum of alcohol-dependent men supplemented and not supplemented with borage oil enriched with vitamin E. Serum was collected from eight social drinkers and 16 alcohol-dependent men after a drinking period. The activity of exoglycosidases and the concentration of protein in serum were determined. The increase in specific activity of MAN and GLUCUR was significant in serum of alcohol-dependent men both not supplemented and supplemented with borage oil enriched with vitamin E, in comparison with the specific activity in serum of social drinkers. In serum of alcohol-dependent men treated with borage oil enriched with vitamin E, specific activity of MAN and GLUCUR fluctuated in comparison with alcohol-dependent men not supplemented. Specific activity of FUC in serum of alcohol-dependent men both not supplemented and supplemented with borage oil enriched with vitamin E showed a tendency to increase, in comparison with social drinkers. Specific activity of FUC had a tendency to decrease in serum of alcohol-dependent men supplemented with borage oil enriched with vitamin E, in comparison with alcohol-dependent men not supplemented. Thus, supplementation of alcohol-dependent men after a long-lasting drinking period with borage oil and vitamin E did not change the rate of catabolism of the oligosaccharide chains of glycoconjugates, as evaluated by serum activity of exoglycosidases.


Assuntos
Alcoolismo/tratamento farmacológico , Borago/química , Glicosídeo Hidrolases/sangue , Lisossomos/metabolismo , Óleos de Plantas/uso terapêutico , Vitamina E/uso terapêutico , Ácido gama-Linolênico/uso terapêutico , Alcoolismo/sangue , Alcoolismo/enzimologia , Suplementos Nutricionais , Humanos , Masculino , Óleos de Plantas/farmacologia , Vitamina E/farmacologia , Ácido gama-Linolênico/farmacologia
8.
Pol Arch Med Wewn ; 110(3): 981-7, 2003 Sep.
Artigo em Polonês | MEDLINE | ID: mdl-14699691

RESUMO

UNLABELLED: Diabetes occurs in 20-30% of patients above forty years old with chronic pancreatitis (CP). The aim of the present study was to determine the relationship between development of diabetes mellitus in CP patients and insufficiency of pancreatic exocrine secretion as well as changes in composition of pancreatic juice. Ninety CP patients with diagnosis confirmed by endoscopic retrograde pancreatography (ERP) were studied. They were divided into 3 groups in dependency on ERP changes (according to Cambridge classification) and oral glucose tolerance test (OGTT): group A--equivocal or mild changes in ERP and normal OGTT (control group); group B--moderate or marked changes in ERP and normal OGTT: group C--moderate or marked changes in ERP and diabetes mellitus. The exocrine pancreatic function was determined by the secretin-caerulein test; volume of duodenal content and bicarbonate, protein, alpha-amylase activity outputs were measured. RESULTS: All exocrine pancreatic function parameters were diminished in B and C groups compared with A group--differences were statistically significant. However in group C values of volume and bicarbonate, protein and amylase activity were especially low. CONCLUSION: Exocrine pancreatic insufficiency is strongly associated with anatomical changes of the pancreas but also depends on endocrine function.


Assuntos
Ceruletídeo/metabolismo , Diabetes Mellitus/etiologia , Pâncreas/metabolismo , Pâncreas/fisiopatologia , Pancreatite , Secretina/metabolismo , Adulto , Idoso , Colangiopancreatografia Retrógrada Endoscópica/métodos , Doença Crônica , Diabetes Mellitus/diagnóstico , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite/complicações , Pancreatite/diagnóstico , Pancreatite/fisiopatologia
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