Search

Summary: Background: The ongoing UNIFI long‐term extension evaluates subcutaneous ustekinumab for moderate‐to‐severe ulcerative colitis (UC) from weeks 44 through 220. Aims: To assess efficacy (through week 92) and safety (through week 96) during the long‐term extension Methods: Overall, 399 responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long‐term extension (115 received subcutaneous placebo, 141 received ustekinumab 90 mg every 12 weeks [q12w], and 143 received ustekinumab 90 mg q8w). Placebo treatment was discontinued at unblinding after week 44. Partial Mayo scores were collected every 12 weeks and at each dosing visit after unblinding. Safety was evaluated throughout. Results: Among all patients randomised in maintenance, symptomatic remission rates (stool frequency = 0/1; rectal bleeding = 0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively. Among randomised patients treated in the long‐term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid‐free. Both ustekinumab groups maintained efficacy through week 92. From weeks 44 to 96, adverse events (AEs) per hundred patient‐years (PY) of follow‐up for combined ustekinumab vs placebo were: 255.68 vs 267.93; serious AEs, 9.34 vs 12.69; malignancies (including non‐melanoma skin cancers), 0.93 vs 1.49; and serious infections, 2.33 vs 2.99. One patient with multiple comorbidities who received one ustekinumab dose after dose adjusting from placebo experienced a fatal cardiac arrest. Conclusions: The efficacy of ustekinumab in patients with UC was sustained through 92 weeks. No new safety signals were observed (ClinicalTrials.gov number, NCT02407236). [ABSTRACT FROM AUTHOR]

To characterize the pharmacokinetics (PK) and exposure‐response (E‐R) relationship of ustekinumab, an anti‐interleukin‐12/interleukin‐23 (IL‐12/IL‐23) human monoclonal antibody, in the treatment of moderately to severely active ulcerative colitis (UC), population PK and E‐R modeling analyses were conducted based on the data from the pivotal phase 3 induction and maintenance studies in UC patients. The observed serum concentration‐time data of ustekinumab were adequately described by a 2‐compartment linear PK model with first‐order absorption and first‐order elimination. Body weight, baseline serum albumin, sex, and antibodies to ustekinumab were the covariates to influence ustekinumab PK, but the magnitudes of the effects of these covariates were not considered clinically relevant, and dose adjustment was not warranted. Positive E‐R relationships were demonstrated between ustekinumab exposure metrics and clinical endpoints (including clinical response, clinical remission, and endoscopic healing based on Mayo score) at induction week 8 and maintenance week 44, consistent with the effectiveness of ustekinumab in the induction and maintenance treatment of patients with UC. E‐R modeling results suggest that ustekinumab ∼6 mg/kg intravenous induction and 90‐mg subcutaneous every‐8‐week maintenance dose would produce greater efficacy than the 130 mg intravenous induction and the 90‐mg subcutaneous every‐12‐week maintenance regimen, respectively. Our work provides a comprehensive evaluation of ustekinumab PK and E‐R in a modeling framework to support ustekinumab dose recommendations in patients with UC. [ABSTRACT FROM AUTHOR]

Population pharmacokinetics (PK) and exposure‐response (E‐R) analyses were conducted to compare the PK and E‐R relationships of golimumab between children and adults with ulcerative colitis. PK data following subcutaneous golimumab administration to children with ulcerative colitis (6‐17 years) in the PURSUIT‐PEDS‐PK study, adults with ulcerative colitis in the PURSUIT study, and children with pediatric polyarticular juvenile idiopathic arthritis (2‐17 years) in the GO‐KIDS study, were included in the population PK analysis. E‐R analysis was conducted using logistic regression to link serum golimumab concentration and Mayo score–based efficacy outcomes in pediatric and adult ulcerative colitis. Golimumab PK was adequately described by a 1‐compartment model with first‐order absorption and elimination. Golimumab apparent clearance and volume of distribution increased with body weight. Golimumab apparent clearance was higher in patients with lower serum albumin, no methotrexate use, and positive antibodies to golimumab; age was not an influential factor after accounting for body weight. Model‐estimated terminal half‐life (9.2 days in children; 9.5 days in adults) and other PK parameters suggest that golimumab PK properties are generally comparable between children and adults with ulcerative colitis. Simulations suggest that a higher induction dose than that tested in PURSUIT‐PEDS‐PK may be needed for children ≤45 kg to achieve exposures comparable to adults. Comparable E‐R relationships between children and adults with ulcerative colitis were observed, although children appeared to be more responsive for the more stringent remission end point. The overall comparable PK and E‐R relationships between children and adults support the extrapolation of golimumab efficacy from the adult to the pediatric ulcerative colitis population. [ABSTRACT FROM AUTHOR]