Safety, Efficacy, and Tolerability Study of PF-06480605 in Subjects With Moderate to Severe Ulcerative Colitis.

An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. A serious AE (SAE) was any untoward medical occurrence at any dose that (1) resulted in death; (2) was life-threatening (immediate risk of death); (3) required inpatient hospitalization or prolongation of existing hospitalization; (4) resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); (5) resulted in congenital anomaly/birth defect. A treatment-emergent AE (TEAE) was defined as an event that emerged during treatment having been absent pre-treatment, or worsened relative to the pre-treatment state. Causality to study treatment was determined by the investigator.

The following parameters were evaluated: hematology (hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular volume, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time, and prothrombin time), clinical chemistry (bilirubin, direct bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, protein, albumin, blood urea nitrogen, creatinine, urate, sodium, potassium, chloride, calcium, glucose, and creatine kinase), and urinalysis (urine glucose, ketones, urine protein, urine hemoglobin, nitrite, leukocyte esterase, urine erythrocytes, urine leukocytes, hyaline casts, and bacteria).

Vital signs evaluation included sitting diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse rate. Sitting blood pressure was measured with the participant's arm supported at the level of the heart, and recorded to the nearest millimeters of mercury (mm Hg). The same size BP cuff which had been properly sized and calibrated was used to measure BP each time. Number of participants with vital signs data meeting pre-specified criteria is presented.

All scheduled 12-lead ECGs were performed after the participant had rested quietly for at least 10 minutes in a supine position. Number of participants with ECG data meeting pre-specified criteria is presented.

Endoscopic improvement at Week 14 was defined as Mayo endoscopic sub-score of 0 or 1, and without friability. The Mayo scoring system was used to assess ulcerative colitis activity, and it ranges from 0 to 12, calculated as sum of 4 sub-scores, with higher scores indicating more severe disease. The 4 sub-scores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2=3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, mild friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease).

Remission: total Mayo score <=2 with no individual subscore >1. Mayo scoring system was used to assess ulcerative colitis activity (range: 0 to 12, calculated as sum of 4 subscores, higher scores indicating more severe disease). The 4 subscores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2= 3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on modified endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, no friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease).

Remission: total Mayo score <=2 with no individual subscore >1. Mayo scoring system was used to assess ulcerative colitis activity (range: 0 to 12, calculated as sum of 4 subscores, higher scores indicating more severe disease). The 4 subscores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2= 3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on modified endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, no friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease).

Endoscopic remission at Week 14 was defined as Mayo endoscopic sub-score of 0. The Mayo scoring system was used to assess ulcerative colitis activity, and it ranges from 0 to 12, calculated as sum of 4 sub-scores, with higher scores indicating more severe disease. The 4 sub-scores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2= 3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, mild friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease).

Maximum serum concentration (Cmax) of PF-06480605 was observed directly from data.

Average serum concentration (Cav) of PF-06480605 was calculated as AUCtau/tau, where tau was the dosing interval (tau=14 days), and AUCtau was the area under the concentration-time profile from time 0 to time tau.

Lowest serum concentration (Cmin) of PF-06480605 was observed directly from data.

AUCtau of PF-06480605 was calculated using linear/log trapezoidal method; tau was the dosing interval (=14 days).

Serum samples were analyzed using a new ADA assay with acid pre-treatment followed by a more drug-tolerant cell-based NAb assay. For ADA assay with acid pre-treatment, the sample was deemed positive if log titer >=1.30; for cell-based NAb assay, the sample was deemed positive if log titer >=0.699.

Fecal calprotectin has been used to detect intestinal inflammation (colitis or enteritis) and can serve as a biomarker for inflammatory bowel diseases. Elevated fecal calprotectin levels indicate migration of neutrophils into the intestinal mucosa, which occurs during intestinal inflammation.

HsCRP is used mainly as a marker of inflammation.

TL1A is a member of the tumor necrosis factor (TNF) family of cytokines. The investigational product of this study PF-06480605 is a fully human neutralizing antibody against TL1A.