Population Pharmacokinetic and Exposure-Response Modeling to Inform Risankizumab Dose Selection in Patients With Ulcerative Colitis.

Data from phase IIb/III and phase III studies were used to characterize the population pharmacokinetics of risankizumab and its exposure-response relationships for efficacy and safety in ulcerative colitis (UC) patients. A two-compartment model with first-order absorption and elimination accurately described risankizumab pharmacokinetics. Although certain covariates, namely, body weight, serum albumin, fecal calprotectin, sex, corticosteroid use, advanced therapy inadequate response, and pancolitis, were statistically correlated with risankizumab clearance, their impact on exposure was not clinically meaningful for efficacy or safety. Phase II exposure-response analyses demonstrated that the 1,200 mg intravenous (IV) induction dose at Weeks 0, 4, and 8 achieved near maximal response for all efficacy end points, with suboptimal efficacy from the 600 mg and little added benefit from the 1,800 mg regimens, justifying 1,200 mg IV as the induction dose in the phase III study. Phase III exposure-response analyses for efficacy during induction showed statistically significant exposure-response relationships at Week 12 following 1,200 mg IV at Weeks 0, 4, and 8, in line with phase IIb results. Exposure-response analyses for maintenance demonstrated modest improvement in Week 52 efficacy when increasing the subcutaneous dose from 180 mg to 360 mg with largely overlapping confidence intervals. Exposure-response analyses for safety indicated no apparent exposure-dependent safety events over the induction or maintenance treatment. Based on these results, the recommended dosing regimen for risankizumab in UC patients is 1,200 mg IV at Weeks 0, 4, and 8, followed by 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter.

The Combined Anti-Aging Effect of Hydrolyzed Collagen Oligopeptides and Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells on Human Skin Fibroblasts.

Stem cell-derived exosomes (SC-Exos) are used as a source of regenerative medicine, but certain limitations hinder their uses. The effect of hydrolyzed collagen oligopeptides (HCOPs), a functional ingredient of SC-Exos is not widely known to the general public. We herein evaluated the combined anti-aging effects of HCOPs and exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exos) using a senescence model established on human skin fibroblasts (HSFs). This study discovered that cells treated with HucMSC-Exos + HCOPs enhanced their proliferative and migratory capabilities; reduced both reactive oxygen species production and senescence-associated ß-galactosidase activity; augmented type I and type III collagen expression; attenuated the expression of matrix-degrading metalloproteinases (MMP-1, MMP-3, and MMP-9), interleukin 1 beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α); and decreased the expression of p16, p21, and p53 as compared with the cells treated with HucMSC-Exos or HCOPs alone. These results suggest a possible strategy for enhancing the skin anti-aging ability of HucMSC-Exos with HCOPs.

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Risankizumab: Mechanism of action, clinical and translational science.

Risankizumab is a high-affinity neutralizing anti-interleukin (IL)-23 monoclonal antibody marketed in over 40 countries across the globe to treat several inflammatory diseases, such as plaque psoriasis (PsO), psoriatic arthritis (PsA), and Crohn's disease (CD). This paper reviews the regulatory approval, mechanism of action, pharmacokinetics (PKs)/pharmacodynamics, immunogenicity, and clinical efficacy and safety data for risankizumab, focusing on the three main approved indications. Risankizumab binds to the p19 subunit of IL-23 and inhibits IL-23 from interacting with the IL-23 receptor and subsequent signaling. Biomarker data obtained following treatment with risankizumab in multiple indications provided supportive evidence for downstream blockade of IL-23 signaling associated with disease pathology. The PKs of risankizumab is linear and time-independent, consistent with typical IgG1 monoclonal antibodies, across all evaluated indications. Risankizumab exhibited positive exposure-response relationships for efficacy with no apparent exposure-dependent worsening in safety. Immunogenicity to risankizumab had no major clinical consequences for either efficacy or safety. Efficacy and safety of risankizumab have been established in PsO, PsA, and CD in the pivotal clinical trials where superior benefit/risk profiles were demonstrated compared to placebo and/or active comparators. Moreover, safety evaluations in open-label extension studies following long-term treatment with risankizumab showed stable and favorable safety profiles consistent with shorter-term studies. These data formed the foundation for risankizumab's marketing approvals to treat multiple inflammatory diseases across the globe.

A first-in-human study of the novel immunology antibody-drug conjugate, ABBV-3373, in healthy participants.

AIMS: ABBV-3373, an immunology antibody-drug conjugate composed of adalimumab conjugated to a proprietary glucocorticoid receptor modulator (the small-molecule payload), has the potential to treat immune-mediated inflammatory diseases. This first-in-human study investigated the pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD) using a safety PD marker, and safety/tolerability of ABBV-3373 in healthy adults. METHODS: Fifty-five participants were randomly assigned to single-dose subcutaneous (SC; 30, 100 or 300 mg) or intravenous (IV; 30, 300 or 900 mg) ABBV-3373 or placebo. Eight additional participants received a single dose of 10 mg oral prednisone for evaluation of systemic glucocorticoid effects. Blood samples were collected for up to 85 days postdose for PK, anti-drug antibody and serum cortisol (safety PD marker) assessments. RESULTS: ABBV-3373 and total antibody displayed antibody-like SC/IV PK profiles and the unconjugated/free payload in circulation exhibited formation rate-limited kinetics with exposure several fold lower than ABBV-3373 or total antibody. Treatment-emergent anti-drug antibody incidence was 69%, with loss of exposure in 6% (SC) and 5% (IV) of participants, but without any impact on safety. ABBV-3373 up to 300 mg SC/IV had no apparent impact on serum cortisol, and only caused a transient decrease at 900 mg IV. Treatment-emergent adverse events were primarily mild in severity, and no pattern emerged with respect to dose or route of administration. CONCLUSIONS: ABBV-3373 had favourable PK profiles, manageable immunogenicity, and was generally well-tolerated. Except for a transient effect at 900 mg IV, there was no apparent impact on serum cortisol. Study results supported further clinical development of ABBV-3373.

Clinical Bridging From Prefilled Syringe to On-body Injector for Risankizumab in Crohn's Disease.

PURPOSE: This article describes the clinical development bridging strategy and key data to support the marketing application of the risankizumab on-body injection (OBI) system for the treatment of moderately to severely active Crohn's disease (CD), even though the OBI was not evaluated directly in the pivotal Phase III studies in CD. METHODS: Three studies were conducted as part of the clinical bridging strategy. The pilot pharmacokinetics (PK) study was a Phase I, single-dose, 4-arm, open-label, randomized, parallel-group exploratory PK and tolerability study that assessed the effect of rate and volume of administration on the bioavailability (BA) of risankizumab and the extent of injection site-related pain after subcutaneous (SC) administration in healthy subjects. The pivotal BA/bioequivalence (BE) study was a relative BA/BE bridging study in healthy subjects to assess the relative BA of the to-be-marketed risankizumab OBI compared with the prefilled syringe (PFS) used in the Phase III CD studies. The OBI adhesive study was a randomized, open-label, non-drug interventional study in healthy subjects to assess the OBI adhesive effectiveness and skin tolerability at 2 different locations (abdomen and upper thigh) over different periods of time (5 and 30 minutes). FINDINGS: The pilot PK study showed that risankizumab exposures were similar across different rates/volumes of SC administration in healthy subjects, thereby supporting further development of the OBI. Second, a pivotal BA/BE study showed comparability between the OBI and Phase III PFS with bioequivalent risankizumab AUCs and no clinically meaningful difference for Cmax based on the wide therapeutic window of risankizumab. In both studies, no new safety risks were identified. No impact of immunogenicity on PK profile or safety was observed for the OBI. Third, an adhesive OBI (without risankizumab) study showed that there were no differences in adhesion/skin tolerability observed over time (up to 30 minutes) or for location of adhesion, and the OBI device adhesion was well tolerated at both the abdomen and thigh locations. IMPLICATIONS: These results supported the risankizumab OBI presentation approval in CD.

Long-term safety and efficacy of risankizumab for the treatment of moderate-to-severe plaque psoriasis: Interim analysis of the LIMMitless open-label extension trial up to 5 years of follow-up.

BACKGROUND: Psoriasis is a chronic, inflammatory skin disease often requiring long-term therapy. OBJECTIVE: To evaluate the long-term safety and efficacy of risankizumab in patients with psoriasis. METHODS: LIMMitless is an ongoing phase 3, open-label extension study evaluating the long-term safety and efficacy of continuous risankizumab 150 mg every 12 weeks for adults with moderate-to-severe plaque psoriasis following multiple phase 2/3 base studies. This interim analysis assessed safety (ie, monitored treatment-emergent adverse events [TEAEs]) through 304 weeks. Efficacy assessments included determining the proportion of patients who achieved ≥90% or 100% improvement in Psoriasis Area and Severity Index (PASI 90/100), static Physician's Global Assessment of clear/almost clear (sPGA 0/1), and Dermatology Life Quality Index of no effect on patient's life (DLQI 0/1) through 256 weeks. RESULTS: Among 897 patients randomized to risankizumab in the base studies, 706 were still ongoing at data cutoff. Rates of TEAEs, TEAEs leading to discontinuation, and TEAEs of safety interest were low. At week 256, 85.1%/52.3% of patients achieved PASI 90/100, respectively, 85.8% achieved sPGA 0/1, and 76.4% achieved DLQI 0/1. LIMITATIONS: Open-label study with no placebo or active-comparator group. CONCLUSIONS: Long-term continuous risankizumab treatment for up to 5 years was well tolerated and demonstrated high and durable efficacy.

Efficacy, Safety, Patient Experience, and Tolerability of Risankizumab Administered by On-Body Injector for Moderate to Severe Crohn's Disease.

INTRODUCTION: In patients with moderate to severe Crohn's disease (CD), intravenous induction and subcutaneous maintenance dosing with risankizumab was efficacious and well tolerated. Long-term management of CD via self-administration of risankizumab using an on-body injector (OBI) may improve treatment adherence through convenience and ease of use. METHODS: Within the FORTIFY maintenance study, 46 patients from the United States (US) sites participated in an open-label extension Substudy and received 180 mg or 360 mg risankizumab delivered subcutaneously via OBI [360 mg (2.4 mL, 150 mg/mL) or 180 mg (1.2 mL, 150 mg/mL)]. At the Week 0 visit, patients were trained (pre-injection) by site staff, using Instructions for Use (IFU) and a training video, to self-administer risankizumab at Weeks 0 (on site), 8 (at home), and 16 (on site). Key objectives of the Substudy 4 were to assess OBI usability (observer rating of successful self-administration), hazard-free self-injection at Weeks 0 and 16, and patient rating of acceptability using the Self-Injection Assessment Questionnaire (SIAQ) at Weeks 0, 8, and 16. Additionally, the proportion of patients in clinical remission (CD Activity Index < 150) was collected at Weeks 0 and 16. RESULTS: All patients successfully self-administered risankizumab via OBI, including two patients who successfully self-administered with a second OBI (i.e., required two injection attempts). Acceptability of self-injection was high. Two patients (n = 2) experienced a use-related hazard. Stable clinical remission was observed with both risankizumab doses. Two patients experienced injection site reactions; neither was related to the OBI per investigator's assessment. Two device-related adverse events related to topical adhesive reactions were reported, both mild and resolved. No new safety risks were observed. CONCLUSION: The efficacy and safety of maintenance risankizumab delivered via OBI and OBI usability support the use of this device in patients with moderate to severe CD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03105102 (FORTIFY).

Efficacy and Safety of ABBV-3373, a Novel Anti-Tumor Necrosis Factor Glucocorticoid Receptor Modulator Antibody-Drug Conjugate, in Adults with Moderate-to-Severe Rheumatoid Arthritis Despite Methotrexate Therapy: A Randomized, Double-Blind, Active-Controlled Proof-of-Concept Phase IIa Trial.

OBJECTIVE: To assess the efficacy and safety of ABBV-3373, a novel antibody-drug conjugate (ADC) composed of the anti-tumor necrosis factor (anti-TNF) monoclonal antibody adalimumab linked to a glucocorticoid receptor modulator (GRM), compared to adalimumab, in patients with rheumatoid arthritis (RA). METHODS: In this randomized, double-blind, active-controlled, proof-of-concept trial (ClinicalTrials.gov identifier: NCT03823391), adults with moderate-to-severe RA receiving background methotrexate were administered intravenously (IV) ABBV-3373 100 mg every other week for 12 weeks, followed by placebo for 12 weeks, or subcutaneous adalimumab 80 mg every other week for 24 weeks. The primary end point was change from baseline in the Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) at week 12, with 2 prespecified primary comparisons of ABBV-3373 versus historical adalimumab (80 mg every other week or equivalent dose) and versus combined in-trial/historical adalimumab. Secondary end points included change from baseline in the Clinical Disease Activity Index, Simplified Disease Activity Index, and DAS28 using erythrocyte sedimentation rate, as well as the proportion of patients achieving a DAS28-CRP of ≤3.2 and the American College of Rheumatology 50% improvement criteria. RESULTS: Forty-eight patients were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). At week 12, ABBV-3373 demonstrated a reduction in DAS28-CRP compared to historical adalimumab (-2.65 versus -2.13; P = 0.022) and compared to combined in-trial/historical adalimumab (-2.65 versus -2.29; probability 89.9%), with numerically greater improvement than in-trial adalimumab (-2.51). For secondary end points, greater efficacy was observed with ABBV-3373 compared to historical adalimumab; ABBV-3373 was predicted with 79.3-99.5% probability to be more effective than adalimumab based on combined in-trial/historical adalimumab data. Of the ABBV-3373-treated patients who achieved DAS28-CRP ≤3.2 at week 12, 70.6% maintained this response at week 24 despite switching to placebo. Four serious adverse events (SAEs) were reported with ABBV-3373 (noncardiac chest pain, pneumonia, upper respiratory tract infection, and anaphylactic shock) and 2 SAEs with adalimumab (breast abscess and bronchitis). After increasing the duration of IV ABBV-3373 administration from 3 minutes to 15-30 minutes, no similar events of anaphylactic shock were reported. CONCLUSION: Data from this proof-of-concept trial support the continued development of a TNF-GRM ADC for the treatment of RA, with the potential to achieve superior outcomes compared to currently available therapies.

Population Pharmacokinetic and Exposure-Response Analyses for Efficacy and Safety of Risankizumab in Patients With Active Crohn's Disease.

The population pharmacokinetics (PK) of risankizumab and exposure-response relationships for efficacy and safety in patients with Crohn's disease (CD) were characterized using data from phase II and III studies to support dosing regimen selection. A two-compartment model with first-order absorption and first-order elimination adequately described risankizumab PK. Covariates including 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. Exposure-response analyses showed that exposures associated with the 600 mg intravenous (i.v.) induction dose at Weeks 0, 4, and 8 achieved a near maximal response for all efficacy end points evaluated, with negligible added benefit from the 1,200 mg i.v. regimen. By Week 52 of the maintenance treatment, trends of higher responses were observed for the exposure range associated with the 360 mg subcutaneous (s.c.) every-8-weeks (Q8W) regimen for most of the evaluated efficacy end points, particularly for the more stringent end points, such as endoscopic remission and ulcer-free endoscopy. Exposure-response analyses for safety did not identify any apparent relationship between exposure and safety. These results supported the final dose recommendation of 600 mg i.v. at Weeks 0, 4, and 8, followed by 360 mg s.c. at Week 12 and Q8W thereafter in patients with CD.

Population Pharmacokinetics and Exposure-Response Analyses for Risankizumab in Patients with Active Psoriatic Arthritis.

INTRODUCTION: Risankizumab is an anti-IL23 monoclonal antibody approved for the treatment of moderate to severe plaque psoriasis and active psoriatic arthritis (PsA). This work characterizes the pharmacokinetics of risankizumab in PsA compared with psoriasis and evaluates the efficacy and safety exposure-response relationships in PsA. METHODS: The population pharmacokinetic analyses included data from 1527 participants that originated from one phase 1 healthy participant study, one phase 2 dose-ranging study in patients with PsA with an open-label extension study, and two pivotal phase 3 studies in patients with PsA, where the clinical regimen of risankizumab 150 mg administered subcutaneously (SC) at weeks 0, 4, and every 12 weeks thereafter was compared with placebo. Pharmacokinetics were analyzed using nonlinear mixed-effects modeling. Simulation analyses using the final model were conducted to evaluate the impact of covariates on exposure. Data from 1407 patients with PsA from the phase 3 studies were included in the exposure-response analyses. Graphical analyses were used to evaluate efficacy and safety exposure-response relationships, and logistic regression was conducted for further assessment of efficacy exposure-response relationships. RESULTS: Risankizumab pharmacokinetics were well described by a two-compartment model with first-order SC absorption and elimination. None of the evaluated covariates showed clinically relevant impact on exposure. On the basis of the final model, systemic clearance, steady-state volume of distribution, and terminal phase elimination half-life were estimated to be ~ 0.31 L/day, 11.1 L, and 26.3 days, respectively, for a typical 90 kg patient with PsA. Absolute SC bioavailability was estimated to be 83.5%. Exposure-response quartile analyses suggested that exposures associated with the clinical regimen maximized efficacy across the endpoints evaluated. No exposure dependency was observed for key safety endpoints. CONCLUSIONS: Risankizumab exhibited linear and time-independent pharmacokinetics in patients with PsA and was comparable to patients with plaque psoriasis. Efficacy and safety exposure-response analyses support that the clinical regimen achieved robust efficacy with a favorable safety profile for patients with active PsA. CLINICAL TRIALS: NCT02596217, NCT02719171, NCT02986373, NCT03671148, and NCT03675308. CLINICAL TRIALS: NCT02596217, NCT02719171, NCT02986373, NCT03671148, and NCT03675308.

Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial.

BACKGROUND: There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy. METHODS: FORTIFY is a phase 3, multicentre, randomised, double-blind, placebo-controlled, maintenance withdrawal study across 273 clinical centres in 44 countries across North and South America, Europe, Oceania, Africa, and the Asia-Pacific region that enrolled participants with clinical response to risankizumab in the ADVANCE or MOTIVATE induction studies. Patients in ADVANCE or MOTIVATE were aged 16-80 years with moderately to severely active Crohn's disease. Patients in the FORTIFY substudy 1 were randomly assigned again (1:1:1) to receive either subcutaneous risankizumab 180 mg, subcutaneous risankizumab 360 mg, or withdrawal from risankizumab to receive subcutaneous placebo (herein referred to as withdrawal [subcutaneous placebo]). Treatment was given every 8 weeks. Patients were stratified by induction dose, post-induction endoscopic response, and clinical remission status. Patients, investigators, and study personnel were masked to treatment assignments. Week 52 co-primary endpoints were clinical remission (Crohn's disease activity index [CDAI] in the US protocol, or stool frequency and abdominal pain score in the non-US protocol) and endoscopic response in patients who received at least one dose of study drug during the 52-week maintenance period. Safety was assessed in patients receiving at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03105102. FINDINGS: 712 patients were initially assessed and, between April 9, 2018, and April 24, 2020, 542 patients were randomly assigned to either the risankizumab 180 mg group (n=179), the risankizumab 360 mg group (n=179), or the placebo group (n=184). Greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (CDAI clinical remission was reached in 74 (52%) of 141 patients vs 67 (41%) of 164 patients, adjusted difference 15% [95% CI 5-24]; stool frequency and abdominal pain score clinical remission was reached in 73 (52%) of 141 vs 65 (40%) of 164, adjusted difference 15% [5-25]; endoscopic response 66 (47%) of 141 patients vs 36 (22%) of 164 patients, adjusted difference 28% [19-37]). Higher rates of CDAI clinical remission and endoscopic response (but not stool frequency and abdominal pain score clinical remission [p=0·124]) were also reached with risankizumab 180 mg versus withdrawal (subcutaneous placebo; CDAI clinical remission reached in 87 [55%] of 157 patients, adjusted difference 15% [95% CI 5-24]; endoscopic response 74 [47%] of 157, adjusted difference 26% [17-35]). Results for more stringent endoscopic and composite endpoints and inflammatory biomarkers were consistent with a dose-response relationship. Maintenance treatment was well tolerated. Adverse event rates were similar among groups, and the most frequently reported adverse events in all treatment groups were worsening Crohn's disease, arthralgia, and headache. INTERPRETATION: Subcutaneous risankizumab is a safe and efficacious treatment for maintenance of remission in patients with moderately to severely active Crohn's disease and offers a new therapeutic option for a broad range of patients by meeting endpoints that might change the future course of disease. FUNDING: AbbVie.

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.

BACKGROUND: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. METHODS: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. FINDINGS: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. INTERPRETATION: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. FUNDING: AbbVie.

Long-Term Safety and Efficacy of Risankizumab Treatment in Patients with Crohn's Disease: Results from the Phase 2 Open-Label Extension Study.

BACKGROUND AND AIMS: Risankizumab, an interleukin-23 antibody, demonstrated efficacy and acceptable safety in a phase 2 study of patients with moderate-to-severe refractory Crohn's disease. This open-label extension investigated the long-term safety, pharmacokinetics, immunogenicity and efficacy of risankizumab in responders to risankizumab in the parent phase 2 study. METHODS: Enrolled patients had achieved clinical response [decrease in Crohn's Disease Activity Index from baseline ≥100] without clinical remission [Crohn's Disease Activity Index <150] at Week 26, or clinical response and/or remission at Week 52 in the parent phase 2 study and received open-label subcutaneous risankizumab 180 mg every 8 weeks. RESULTS: Sixty-five patients were enrolled, including four who had lost response in the parent study and were first reinduced with risankizumab 600 mg every 4 weeks [three infusions]. Patients received risankizumab for a median of 33 months [total: 167.0 patient-years]. The rate of serious adverse events was 24.6 events/100 patient-years; the majority were gastrointestinal in nature. Rates of serious infections, opportunistic infections and fungal infections were 4.2, 1.8, and 6.6 events/100 patient-years, respectively. No deaths, malignancies, adjudicated major adverse cardiovascular events, latent/active tuberculosis or herpes zoster were reported. Treatment-emergent anti-drug antibodies developed in eight patients [12.3%]; none were neutralizing. Efficacy outcomes were maintained during the study, including the proportions of patients [observed analysis] with clinical remission [>71%] and endoscopic remission [>42%]. CONCLUSIONS: Long-term maintenance treatment with subcutaneous risankizumab 180 mg every 8 weeks was well tolerated by patients with Crohn's disease, with no new safety signals. Clinical trial registration number: NCT02513459.

Pharmacokinetic Comparability of Risankizumab Formulations in Prefilled Syringe and Auto-injector for Subcutaneous Injection.

PURPOSE: Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that inhibits the p19 subunit of interleukin 23 from interacting with its receptor for the treatment of moderate to severe plaque psoriasis. The aim of this Phase I biopharmaceutics bridging study was to evaluate the pharmacokinetic comparability, immunogenicity, and tolerability of the risankizumab 90 mg/mL prefilled syringe (PFS) and the risankizumab 150 mg/mL PFS and auto-injector (AI) in healthy subjects. METHODS: Healthy subjects received one 150-mg dose of risankizumab in 1 of 3 ways (226 subjects randomized 3:3:1 to 3 treatment arms): 150 mg/mL by PFS × 1 SC injection, 90 mg/mL by PFS × 2 SC injections, or 150 mg/mL by AI × 1 SC injection, and were followed up for 140 days after dosing for the collection of pharmacokinetic, immunogenicity, and tolerability data. FINDINGS: Risankizumab concentration-time profiles overlapped with comparable pharmacokinetic parameters across all treatment arms, indicating similar pharmacokinetic characteristics. The CIs with both formulations and forms of administration were within the bioequivalence range of 0.80-1.25 across all measures of exposure. The prevalence of treatment-emergent anti-drug antibodies and the percentages of subjects who reported at least 1 treatment-emergent adverse event were comparable across all treatment arms. IMPLICATIONS: Bioequivalence was established between risankizumab 150 mg/mL PFS and 90 mg/mL PFS, and between 150 mg/mL PFS and AI, along with comparable immunogenicity profiles across all 3 treatment arms. Risankizumab 150 mg SC delivered by PFS or AI was well tolerated, with comparable safety profiles across all treatment arms, and no new safety risks were identified.

Vascular effects of serelaxin in patients with stable coronary artery disease: a randomized placebo-controlled trial.

AIMS: The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. CONCLUSION: In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

Clinical Pharmacokinetics and Pharmacodynamics of Risankizumab in Psoriasis Patients.

Risankizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody developed and approved for the treatment of moderate-to-severe plaque psoriasis at a dose of 150 mg administered subcutaneously at weeks 0 and 4, and every 12 weeks thereafter. Ongoing trials are investigating the use of risankizumab in other inflammatory autoimmune diseases. Risankizumab exhibits linear pharmacokinetics when administered intravenously (0.01 mg/kg-1200 mg) or subcutaneously (0.25 mg/kg-300 mg), with a long terminal half-life of approximately 28 days. Following subcutaneous administration, peak plasma concentration was reached approximately 3-14 days after dosing, with an estimated bioavailability of 89%. Population pharmacokinetic analyses identified bodyweight, high titers of antidrug antibodies occurring in < 2% of evaluated subjects, baseline serum albumin, baseline high-sensitivity C-reactive protein, and baseline serum creatinine to be statistically correlated with risankizumab clearance, but none of them had a clinically meaningful impact on risankizumab efficacy in psoriasis patients following the clinical dosing regimen. Exposure-response analyses in psoriasis patients demonstrated that the maximum efficacy was achieved with the clinically approved regimen and there was no apparent correlation between risankizumab exposure and safety. A dedicated drug interaction cocktail study in patients with psoriasis demonstrated a lack of therapeutic protein-drug interaction potentials for risankizumab and various cytochrome P450 substrates. In this article, we review the clinical pharmacology data available to date for risankizumab, which supported the clinical development program and ultimately regulatory approvals for risankizumab in the treatment of patients with moderate-to-severe plaque psoriasis.

Pharmacokinetics of Risankizumab in Asian Healthy Subjects and Patients With Moderate to Severe Plaque Psoriasis, Generalized Pustular Psoriasis, and Erythrodermic Psoriasis.

Risankizumab, a humanized monoclonal antibody that targets interleukin-23 p19 subunit, was developed for the treatment of psoriasis. This work characterizes risankizumab pharmacokinetics in Japanese and Chinese healthy subjects compared with white healthy subjects and in Japanese patients with moderate to severe plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis. A phase 1, single-dose study evaluated risankizumab pharmacokinetics and safety/tolerability in healthy white (18 and 300 mg subcutaneous [SC]), Japanese (18, 90, and 300 mg SC and 200, 600, and 1200 mg intravenous [IV]), and Chinese (18, 90, and 300 mg SC) subjects; pharmacokinetic data were analyzed using noncompartmental methods. Risankizumab pharmacokinetic data from phase 2/3 studies in Japanese patients with plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis following multiple SC doses of 75 mg or 150 mg were analyzed using a population pharmacokinetic approach along with data from the phase 1 and global phase 1 to 3 studies. Risankizumab plasma exposures (peak plasma concentration and area under the concentration-time curve) were approximately dose-proportional across 18- to 300-mg SC or 200- to 1200-mg IV doses. Risankizumab terminal elimination half-life (harmonic mean 27-34 days) was comparable across doses and ethnicities. Risankizumab exposures were approximately 20% to 30% higher in Japanese and Chinese healthy subjects compared with white healthy subjects or in Japanese patients compared with non-Japanese patients. After accounting for body-weight differences, risankizumab exposures were comparable across ethnicities. Overall, there was no ethnic impact on risankizumab pharmacokinetics, and the small difference in exposure due to body weight has no clinical relevance.

Population Pharmacokinetics of Risankizumab in Healthy Volunteers and Subjects with Moderate to Severe Plaque Psoriasis: Integrated Analyses of Phase I-III Clinical Trials.

BACKGROUND AND OBJECTIVE: Risankizumab is an anti-interleukin (IL)-23 monoclonal antibody being developed for treatment of moderate to severe plaque psoriasis. This study provided a comprehensive analysis of risankizumab pharmacokinetics in healthy subjects and patients with plaque psoriasis using data across phase I-III clinical trials. METHODS: Plasma pharmacokinetic data from 1899 subjects, including 13,123 observations, who received single or multiple intravenous or subcutaneous doses of risankizumab (0.01-5 mg/kg intravenous [IV], 200-1200 mg IV, 0.25-1 mg/kg subcutaneous [SC], and 18-300 mg SC) across the phase I-III clinical program were analyzed using a non-linear mixed-effects modeling approach. The developed model was qualified and the clinical relevance of covariates statistically correlated with risankizumab clearance (CL) was evaluated using simulation analyses. RESULTS: Risankizumab pharmacokinetics were best described using a two-compartment model with first-order absorption and elimination. Risankizumab CL, volume of distribution at steady state (Vss), and terminal-phase elimination half-life (t½) were estimated to be approximately 0.31 L/day, 11.2 L, and 28 days, respectively, for a typical 90 kg psoriatic subject, approaching steady-state plasma exposures by week 16 of dosing. Absolute SC bioavailability (F) was 89%. Bodyweight, anti-drug antibody (ADA) titers ≥ 128 (detected in only 1% of ADA-evaluable subjects in phase III studies), baseline serum albumin, high-sensitivity C-reactive protein (hs-CRP), and serum creatinine were statistically correlated with risankizumab CL; however, they had no clinically relevant impact on exposure. CONCLUSION: Risankizumab is characterized by dose-proportional, bi-exponential disposition with no difference in exposure between healthy subjects and patients with psoriasis. None of the covariates identified as being statistically correlated with risankizumab CL has a clinically meaningful impact on its exposure with the proposed psoriasis clinical regimen of 150 mg administered SC at weeks 0 and 4, and every 12 weeks thereafter. CLINICALTRIALS. GOV IDENTIFIERS: NCT01577550, NCT02054481, NCT02596217, NCT02684370, NCT02672852, NCT02684357, NCT02694523.

Colony-Stimulating Factor-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes.

The colony-stimulating factor-1 (CSF-1) receptor pathway has been implicated in a variety of diseases, and CSF-1-dependent mechanisms are also involved in bloodborne protein clearance. Lacnotuzumab is a novel, high-affinity, humanized, anti-CSF-1 monoclonal antibody that prevents CSF-1-mediated receptor activation. This phase 1, two-part, double-blind study in healthy volunteers assessed the safety and tolerability of lacnotuzumab and its pharmacokinetics (PK) and pharmacodynamic properties. Part A (n = 36) was a single, ascending-dose assessment of eight lacnotuzumab doses (0.01-20 mg/kg); in part B (n = 16), lacnotuzumab was administered at either 5 or 10 mg/kg. In each study cohort, individuals were randomized 3:1 to lacnotuzumab or placebo. Lacnotuzumab was generally well tolerated. At higher doses (10 and 20 mg/kg), creatine kinase (CK) elevations (>5× the upper limit of normal, but asymptomatic and reversible) and mild transient periorbital swelling were reported. Most adverse events (AEs) were low-grade, no unexpected or novel AEs were observed, and there were no discontinuations for AEs. Free, unbound lacnotuzumab serum concentration-time profiles showed nonlinear PK across doses from 0.01 to 20 mg/kg, with faster apparent elimination at lower doses or concentrations; this finding was consistent with apparent target-mediated drug disposition. Lacnotuzumab also showed dose-dependent, on-target effects on multiple downstream biomarkers. Preclinical investigations of the CK elevation and periorbital swelling observed after lacnotuzumab administration suggest that these are reversible, nonpathological events linked to inhibition of the CSF-1 pathway. These data support further evaluation of lacnotuzumab in clinical studies.