P574 Population pharmacokinetic and exposure-response analyses for efficacy and safety of risankizumab in subjects with active Crohn‘s disease

Abstract

Background In order to support risankizumab dose recommendation for the treatment of Crohn’s disease (CD), population pharmacokinetic (PPK) and exposure-response (ER) analyses were conducted for risankizumab using data from Phases 2 & 3 studies in moderate to severely active CD patients to characterise PK and its relationship with clinical efficacy and safety. Methods PPK analyses used non-linear mixed-effects modelling, leveraging a previously developed PPK model for plaque psoriasis & CD, with additional evaluation of covariates relevant to CD. ER relationships were evaluated for efficacy endpoints (clinical remission/response based on CDAI or stool frequency/abdominal pain, endoscopic endpoints, etc.) at Week 12 (induction), Week 24 (re-induction; exploratory only), and Week 52 (maintenance), using graphical analyses at Week 12, 24 and 52 and logistic regression analyses at Week 12 and 52. ER analyses for safety evaluated key safety variables through Week 12, 24 and 52 using graphical analyses. Results Observed risankizumab concentrations in CD patients were adequately described by the risankizumab PK model. PK in subjects with CD was linear and time-independent, similar to healthy subjects and plaque psoriasis. The majority of the evaluated intrinsic and extrinsic factors showed no statistically significant effect on risankizumab PK, including age, race, country/region, liver function markers, creatinine, baseline CDAI, baseline SES-CD, duration of disease, prior biological therapies, immunosuppressant use, and immunogenicity. Sex, baseline fecal calprotectin, corticosteroid use, baseline creatinine clearance, body weight, and baseline albumin were statistically correlated with risankizumab clearance but their impact on exposure was not clinically relevant for efficacy or safety. ER analyses for induction demonstrated that exposures associated with 600 mg IV at Week 0, 4 and 8 achieved a near maximal response for all evaluated efficacy endpoints at Week 12, with negligible added benefit from 1200 mg IV. ER analyses for maintenance showed higher efficacy response at higher exposures for most of the Week 52 endpoints, particularly the more stringent endoscopic endpoints. ER analyses for safety indicated no apparent relationship between exposure and incidence of any AE, SAE, infection or serious infection over the 12 or 24 weeks of induction or 52 weeks of maintenance treatment. Conclusion PPK and ER analyses of risankizumab in subjects with CD supported the final dose recommendation of 600 mg IV at Week 0, 4, 8 followed by 360 mg SC at Week 12 and Q8W thereafter for the treatment of moderate to severely active CD.