Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a randomized phase 3 trial.

Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is a major cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab is a gut-selective anti-α4ß7 integrin monoclonal antibody that reduces gut inflammation by inhibiting migration of GI-homing T lymphocytes. The efficacy and safety of vedolizumab added to standard GVHD prophylaxis (calcineurin inhibitor plus methotrexate/mycophenolate mofetil) was evaluated for prevention of lower-GI aGVHD after unrelated donor allo-HSCT in a randomized, double-blind, placebo-controlled phase 3 trial. Enrollment closed early during the COVID-19 pandemic with 343 patients randomized (n = 174 vedolizumab, n = 169 placebo), and 333 received ≥1 intravenous dose of 300 mg vedolizumab (n = 168) or placebo (n = 165) and underwent allo-HSCT. The primary end point was met; Kaplan-Meier (95% confidence interval) estimated rates of lower-GI aGVHD-free survival by day +180 after allo-HSCT were 85.5% (79.2-90.1) with vedolizumab versus 70.9% (63.2-77.2) with placebo (hazard ratio, 0.45; 95% confidence interval, 0.27-0.73; P < 0.001). For the 5 key secondary efficacy end points analyzed by day +180 after allo-HSCT, rates of lower-GI aGVHD-free and relapse-free survival and grade C-D aGVHD-free survival were significantly higher with vedolizumab versus placebo. No significant treatment differences were found for the other key secondary end points of non-relapse mortality, overall survival and grade B-D aGVHD-free survival, respectively. Incidence of treatment-related serious adverse events analyzed in patients receiving ≥1 dose of study treatment (n = 334) was 6.5% (n = 11 of 169) vedolizumab versus 8.5% (n = 14 of 165) placebo. When added to standard calcineurin inhibitor-based GVHD prevention, lower-GI aGVHD-free survival was significantly higher with vedolizumab versus placebo. ClinicalTrials.gov identifier: NCT03657160 .

Pharmacokinetics, Safety and Efficacy of Intravenous Vedolizumab in Paediatric Patients with Ulcerative Colitis or Crohn's Disease: Results from the Phase 2 HUBBLE Study.

BACKGROUND AND AIMS: To date, there are no systematic pharmacokinetic [PK] data on vedolizumab in paediatric inflammatory bowel disease [IBD]. We report results from HUBBLE, a dose-ranging, phase 2 trial evaluating the PK, safety and efficacy of intravenous vedolizumab for paediatric IBD. METHODS: Enrolled patients [aged 2-17 years] with moderate to severe ulcerative colitis [UC] or Crohn's disease [CD] and body weight ≥10 kg were randomized by weight to receive low- or high-dose vedolizumab [≥30 kg, 150 or 300 mg; <30 kg, 100 or 200 mg] on Day 1 and Weeks 2, 6 and 14. Week 14 assessments included PK, clinical response and exposure-response relationship. Safety and immunogenicity were assessed. RESULTS: Randomized patients weighing ≥30 kg [UC, n = 25; CD, n = 24] and <30 kg [UC, n = 19; CD, n = 21] had a baseline mean [standard deviation] age of 13.5 [2.5] and 7.6 [3.2] years, respectively. In almost all indication and weight groups, area under the concentration curve and average concentration increased ~2-fold from low to high dose; the trough concentration was higher in each high-dose arm compared with the low-dose arms. At Week 14, clinical response occurred in 40.0-69.2% of patients with UC and 33.3-63.6% with CD in both weight groups. Clinical responders with UC generally had higher trough concentration vs non-responders, while this trend was not observed in CD. Fourteen per cent [12/88] of patients had treatment-related adverse events and 6.8% [6/88] had anti-drug antibodies. CONCLUSIONS: Vedolizumab exposure increased in an approximate dose-proportional manner. No clear dose-response relationship was observed in this limited cohort. No new safety signals were identified.

Mongersen (GED-0301) for Active Crohn's Disease: Results of a Phase 3 Study.

INTRODUCTION: The objective was to assess the efficacy and safety of GED-0301, an antisense oligodeoxynucleotide to Smad7, in active Crohn's disease (CD). METHODS: This phase 3, blinded study randomized patients (1:1:1:1) to placebo or 1 of 3 once-daily oral GED-0301 regimens: 160 mg for 12 weeks followed by 40 mg continuously or alternating placebo with 40 or 160 mg every 4 weeks through week 52. RESULTS: In all, 701 patients were randomized and received study medication before premature study termination; 78.6% (551/701) completed week 12, and 5.8% (41/701) completed week 52. The primary endpoint, clinical remission achievement (CD Activity Index score <150) at week 12, was attained in 22.8% of patients on GED-0301 vs 25% on placebo (P = 0.6210). At study termination, proportions of patients achieving clinical remission at week 52 were similar among individual GED-0301 groups and placebo. More placebo vs GED-0301 patients achieved endoscopic response (>50% decrease from baseline Simple Score for CD) at week 12 (18.1% vs 10.1%). Additional endoscopic endpoints were similar between groups at weeks 12 and 52. More placebo vs GED-0301 patients had clinical response (≥100-point decrease in the CD Activity Index score) at week 12 (44.4% vs 33.3%); at week 52, clinical response rates were similar. Adverse events were predominantly gastrointestinal and related to active CD, consistent with lack of clinical and endoscopic response to treatment. Two deaths occurred (GED-0301 total group) due to small intestinal obstruction and pneumonia; neither was suspected by the investigator to be treatment-related. DISCUSSION: GED-0301 did not demonstrate efficacy vs placebo in active CD.

Effects of Mongersen (GED-0301) on Endoscopic and Clinical Outcomes in Patients With Active Crohn's Disease.

GED-0301 is an antisense oligodeoxynucleotide with a sequence complementary to the Smad7 mRNA transcript. Smad7 is a negative regulator of transforming growth factor-ß, which is increased in the intestinal mucosa of patients with active Crohn's disease (CD). We randomly assigned 63 CD patients to 4-, 8-, or 12-week treatment groups receiving oral GED-0301 (160 mg/day). The primary objective was to determine GED-0301's effect on endoscopic CD measures; secondary objectives included effects on clinical activity. Endoscopic improvement was observed in 37% of participants with evaluable endoscopy results at week 12. At week 12, 32% (4 weeks), 35% (8 weeks), and 48% (12 weeks) of patients receiving GED-0301 were in remission (CD activity index score <150); corresponding reductions from baseline in mean CD activity index scores were -124, -112, and -133 points. No new safety signals were observed. These findings support a GED-0301 benefit in active CD. ClinicalTrials.gov no: NCT02367183.

Ligadura variceal endoscópica: experiencia en el Hospital General del Oeste / Endoscopical variceal ligation: experience in the General del Oeste Hospital

El tratamiento de las várices esofágicas sigue siendo controversial existiendo una gama de métodos terapéuticos entre los cuales aún no existe el ideal. En los últimos tres años la ligadura variceal endoscópica ha ganado popularidad en escala internacional. El propósito de este trabajo retrospectivo es presentar la experiencia en los últimos tres años en relación a la ligadura variceal endoscópica en pacientes con hipertensión portal de diversas etiologías. Desde Noviembre de 1.992 hasta Mayo de 1995, evaluamos 19 pacientes por várices esofágicas sangrantes documentada por endoscopia digestiva superior. A todos los pacientes se les practicó ligadura con el sistema de bandas y sobretubo (Bard Interventional Products, Tewksbury Mass). Los resultados fueron evaluados como: satisfactorio en los casos en que las várices disminuyeron a grado 0 ó 1, bueno en los casos en las várices permanecieron en el mismo grado inicial y malo en los casos en que las várices aumentaron de grado. Un total de 19 pacientes se evaluaron en forma retrospectiva, 15 hombres y 4 mujeres con edad promedio de 48,36 años y rango de 17 a 67 años. 10 pacientes ingresaron por emergencia con hemorragia digestiva superior activa y 9 presentaban historia de hemorragia variceal ingresando en forma electiva al procedimiento. 9 pacientes tenían un Child-Pugh A, 8 pacientes Child-Pug B y 2 pacientes Child-Pug C. 11 pacientes recibieron escleroterapia previo al procedimiento de ligadura y 10 pacientes recibieron terapia combinada. Se realizaron un total de 43 sesiones de ligadura endoscópica variceal con un rango de 1-7 sesiones y un promedio de 2,26 sesiones por paciente. se colocaron un total de 138 bandas elásticas con un promedio de 7,26 bandas por paciente (rango 1-20 bandas) y de 3,21 bandas por sesión. La ligadura variceal endoscópica fue satisfactoria en 14 pacientes, buena en 3 pacientes y mala en dos pacientes. Se presentó una complicación (5,26 por ciento) al producirse una hemorragia masiva por desprendimiento de una banda elástica durante el procedimiento que ameritó tratamiento quirúrgico de emergencia. Un total de 11 pacientes consultó por hemorragia digestiva superior activa (57,89 por ciento) lográndose la interrupción del sangrado en 8 pacientes (72,72 por ciento)