Steven John Padula

Anti–IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial

BACKGROUND IL-23 is associated with plaque psoriasis susceptibility and pathogenesis. BI 655066 is a fully human IgG1 mAb specific for the IL-23 p19 subunit. OBJECTIVE This first-in-human proof-of-concept study evaluated the clinical and biological effects of BI 655066 in patients with moderate-to-severe plaque psoriasis. METHODS We performed a single-rising-dose, multicenter, randomized, double-blind, placebo-controlled, within-dose cohort phase I trial. Patients received 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg BI 655066 intravenously, 0.25 or 1 mg/kg BI 655066 subcutaneously, or matched placebo. The primary objective was safety evaluation. RESULTS Thirty-nine patients received single-dose BI 655066 intravenously (n = 18) or subcutaneously (n = 13) or placebo (n = 8). Adverse events were reported with similar frequency in the BI 655066 and placebo groups. Four serious adverse events (not considered treatment related) were reported among BI 655066-treated patients. BI 655066 was associated with clinical improvement from week 2 and maintained for up to 66 weeks after treatment. At week 12, 75%, 90%, and 100% decreases in the Psoriasis Area and Severity Index were achieved by 87%, 58%, and 16% of BI 655066-treated patients (any dose), respectively, versus none receiving placebo. BI 655066 treatment resulted in reduced expression of lesional skin genes associated with IL-23/IL-17 signaling pathways and normalization of psoriatic lesion gene expression profiles to a profile approaching that of nonlesional skin. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed (r = 0.73, P = 2 × 10(-6)). CONCLUSIONS BI 655066 was well tolerated and associated with rapid, substantial, and durable clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.

Risankizumab versus Ustekinumab for Moderate-to-Severe Plaque Psoriasis

BACKGROUND Interleukin‐23 is thought to be critical to the pathogenesis of psoriasis. We compared risankizumab (BI 655066), a humanized IgG1 monoclonal antibody that inhibits interleukin‐23 by specifically targeting the p19 subunit and thus prevents interleukin‐23 signaling, and ustekinumab, an interleukin‐12 and interleukin‐23 inhibitor, in patients with moderate‐to‐severe plaque psoriasis. METHODS We randomly assigned a total of 166 patients to receive subcutaneous injections of risankizumab (a single 18‐mg dose at week 0 or 90‐mg or 180‐mg doses at weeks 0, 4, and 16) or ustekinumab (45 or 90 mg, according to body weight, at weeks 0, 4, and 16). The primary end point was a 90% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12. RESULTS At week 12, the percentage of patients with a 90% or greater reduction in the PASI score was 77% (64 of 83 patients) for risankizumab (90‐mg and 180‐mg groups, pooled), as compared with 40% (16 of 40 patients) for ustekinumab (P<0.001); the percentage of patients with a 100% reduction in the PASI score was 45% in the pooled 90‐mg and 180‐mg risankizumab groups, as compared with 18% in the ustekinumab group. Efficacy was generally maintained up to 20 weeks after the final dose of 90 or 180 mg of risankizumab. In the 18‐mg and 90‐mg risankizumab groups and the ustekinumab group, 5 patients (12%), 6 patients (15%), and 3 patients (8%), respectively, had serious adverse events, including two basal‐cell carcinomas and one major cardiovascular adverse event; there were no serious adverse events in the 180‐mg risankizumab group. CONCLUSIONS In this phase 2 trial, selective blockade of interleukin‐23 with risankizumab was associated with clinical responses superior to those associated with ustekinumab. This trial was not large enough or of long enough duration to draw conclusions about safety. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT02054481).

Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study.

BACKGROUND The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohns disease. We aimed to assess the efficacy and safety of risankizumab (BI 655066, Boehringer Ingelheim, Ingelheim, Germany), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23, in patients with moderately-to-severely active Crohns disease. METHODS In this randomised, double-blind, placebo-controlled phase 2 study, we enrolled patients at 36 referral sites in North America, Europe, and southeast Asia. Eligible patients were aged 18-75 years, with a diagnosis of Crohns disease for at least 3 months, assessed as moderate-to-severe Crohns disease at screening, defined as a Crohns Disease Activity Index (CDAI) of 220-450, with mucosal ulcers in the ileum or colon, or both, and a Crohns Disease Endoscopic Index of Severity (CDEIS) of at least 7 (≥4 for patients with isolated ileitis) on ileocolonoscopy scored by a masked central reader. Patients were randomised 1:1:1 using an interactive response system to a double-blind investigational product, and stratified by previous exposure to TNF antagonists (yes vs no). Patients received intravenous 200 mg risankizumab, 600 mg risankizumab, or placebo, at weeks 0, 4, and 8. The primary outcome was clinical remission (CDAI <150) at week 12 (intention-to-treat population). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02031276. FINDINGS Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 [79%]). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15·0%, 95% CI 0·1 to 30·1; p=0·0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9·0%, -8·3 to 26·2; p=0·31) and 15 (37%) of 41 who received the 600 mg dose (20·9%, 2·6 to 39·2; p=0·0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohns disease. No deaths occurred. INTERPRETATION In this short-term study, risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohns disease. Therefore, selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohns disease. FUNDING Boehringer Ingelheim.

Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study

Objectives To evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS). Methods A total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug. Results At week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was –2.5% (95% CI –21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups. Conclusions Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS. Trial registration number NCT02047110; Pre-results.

Risankizumab in patients with moderate to severe Crohn's disease: an open-label extension study

BACKGROUND Risankizumab, an anti-interleukin 23 antibody, was superior to placebo in achieving clinical and endoscopic remission at week 12 in a randomised, phase 2 induction study in patients with moderately to severely active Crohns disease. Here we aimed to assess the efficacy and safety of extended intravenous induction and subcutaneous maintenance therapy with risankizumab. METHODS All patients who completed the 12-week induction phase of the double-blind phase 2 induction study were included in this open-label extension study. Patients who did not achieve deep remission, defined as clinical remission (Crohns Disease Activity Index [CDAI] <150) and endoscopic remission (Crohns Disease Endoscopic Index of Severity [CDEIS] ≤4, or ≤2 for patients with isolated ileitis), at week 12 received open-label intravenous therapy with 600 mg risankizumab every 4 weeks for 12 weeks; patients in deep remission at week 12 entered a 12-week washout phase. Patients in clinical remission at week 26 were invited to participate in the maintenance phase of the study, in which they received open-label subcutaneous risankizumab (180 mg) every 8 weeks for 26 weeks. 26-week efficacy endpoints were the proportion of patients in clinical remission (CDAI <150), and the proportion of patients who achieved clinical response (either CDAI of <150 or a reduction from baseline of at least 100 points). 52-week efficacy endpoints were the proportion of patients achieving: clinical remission; clinical response; endoscopic response (>50% CDEIS reduction from baseline); endoscopic remission, as defined previously; mucosal healing; and deep remission. Safety was assessed in patients who received at least one dose of the study drug during the open-label phases of the study. This study is registered with ClinicalTrials.gov, number NCT02031276. FINDINGS Of the 108 patients who completed the 12-week double-blind induction trial, six patients were in deep remission and entered the 12-week washout phase. 102 patients were not in deep remission, 101 of whom received 12 weeks of 600 mg risankizumab (33 from the original placebo group, 34 from the 200 mg risankizumab group, and 34 from the 600 mg risankizumab group); the other patient declined to continue the study. At week 26, 54 (53%) of 101 patients treated with 600 mg rizankizumab were in clinical remission. Among patients included in the open-label extension trial, clinical remission rates at week 26 versus week 12 were: 18 (55%) versus six (18%) of 33 patients in the original placebo group; 20 (59%) versus seven (21%) of 34 patients in the original 200 mg risankizumab group; and 16 (47%) versus nine (26%) of 34 patients in the original 600 mg risankizumab group. 62 patients received risankizumab maintenance treatment, including the 54 patients who achieved clinical remission at week 26, the six patients who had achieved deep remission at week 12, and one patient because of a protocol violation. At week 52, clinical remission was maintained in 44 (71%) patients; 50 (81%) patients had a clinical response, 22 (35%) patients were in endoscopic remission, and 34 (55%) patients had an endoscopic response. 15 (24%) patients had mucosal healing and 18 (29%) patients achieved deep remission at week 52. Risankizumab was well tolerated with no new safety signals noted. The most frequent treatment-emergent adverse events were arthralgia (25 [22%] of 115 patients), headache (23 [20%]), abdominal pain (21 [18%]), nasopharyngitis (18 [16%]), nausea (18 [16%]), and pyrexia (15 [13%]). Most adverse events were mild or moderate and considered to be unrelated to study treatment. There were no treatment-related deaths. INTERPRETATION Extended induction treatment with open-label intravenous risankizumab was effective in increasing clinical response and remission rates at week 26. Open-label subcutaneous risankizumab maintained remission until week 52 in most patients who were in clinical remission at week 26. Selective blockade of interleukin 23 warrants further investigation as a treatment for Crohns disease. FUNDING Boehringer Ingelheim.

Selective IL-23 inhibition by risankizumab modulates the molecular profile in the colon and ileum of patients with active Crohn's disease: Results from a randomised phase II biopsy substudy.

Abstract Background and Aims We aimed to investigate the underlying mechanism of action of risankizumab, a monoclonal antibody targeting the IL-23 p19 subunit, previously reported to induce clinical and endoscopic remission in a randomised phase II study in patients with active Crohn’s disease. Methods Ileum and colon biopsies obtained at screening and Week 12 from a subgroup of patients [n = 106] in the risankizumab phase II study were analysed by transcriptome-wide RNA-Seq profiling. Univariate associations were assessed using linear modelling. Results By Week 12, risankizumab significantly decreased [p < 0.005] the expression of 1880 and 765 genes in the colon [false-discovery rate = 0.02] and ileum [false-discovery rate = 0.05], respectively. These genes were associated with the IL-23/IL-17 axis, Th1 pathway, innate immunity, and tissue turnover. Colonic transcriptomic profiles following risankizumab treatment reflected the transcriptomic changes observed in patients achieving endoscopic response and remission at Week 12 and were significantly different from placebo [p < 0.005]. The colonic transcriptomic profile, significantly modulated by risankizumab at Week 12, was indicative of suppression of pathways associated with epithelial biology. Furthermore, pathways associated with Crohn’s disease modulated by risankizumab treatment included second messenger-mediated signalling, immune response, lymphocyte and leucocyte activation, lymphocyte differentiation and cell–cell adhesion. Conclusions Endoscopic remission and response observed with risankizumab in patients with active Crohn’s disease was associated with significant transcriptomic changes in the colon, compared with placebo. Differentiated expression of genes associated with the IL-23/IL-17 axis was observed in the colon and ileum 12 weeks after risankizumab treatment.

Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Rising Doses of BI 655064, an Antagonistic Anti‐CD40 Antibody, in Healthy Subjects: A Potential Novel Treatment for Autoimmune Diseases

BI 655064 is a humanized antagonistic anti‐cluster of differentiation (CD) 40 monoclonal antibody that selectively blocks the CD40‐CD40L interaction. The CD40‐CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and lupus nephritis. The safety, tolerability, pharmacokinetics, and pharmacodynamics of repeated once‐weekly BI 655064 subcutaneous dosing over 4 weeks were evaluated in a multiple‐dose study in healthy subjects. Subjects (N = 40) were randomized 4:1 to four sequential BI 655064 dose groups (80, 120, 180, 240 mg) or to placebo. Safety and tolerability, plasma exposure, CD40 receptor occupancy, and CD40L‐induced CD54 upregulation were assessed over 64 and 78 days for the 80‐ to 180‐mg and 240‐mg dose groups, respectively. BI 655064 exposure increased in a supraproportional manner, due to target‐mediated drug clearance, for doses between 80 mg and 120 mg, but was near proportional for doses greater than 120 mg. Terminal half‐life ranged between 6 and 8 days. Dose‐dependent accumulation of BI 655064 supports the use of a loading dose in future clinical studies. Following 4 weeks of dosing, >90% CD40 receptor occupancy and inhibition of CD54 upregulation were observed at all dose levels, lasting for 17 days after the last dose. BI 655064 was generally well tolerated. There were no serious adverse events and the frequency and intensity of adverse events were similar for BI 655064 and placebo; no dose relationship or relevant signs of an acute immune reaction were observed. These findings support further investigation of BI 655064 as a potential treatment for autoimmune diseases.

THU0128 Evaluation of Safety, Pharmacokinetics and Pharmacodynamics of BI 638683, A Novel CCR1 Antagonist

Background Monocytes and macrophages play a major role in the pathogenesis of rheumatoid arthritis (RA). The chemokine receptor CCR1 regulates migration of these cells to synovial tissue and the bone. It is expected that sustained full antagonism of CCR1 will block trafficking of monocytes to the site of inflammation and will block the upregulation of cytokines, adhesion molecules and MMPs to slow the progression of joint damage in RA. Objectives This clinical study investigated safety, tolerability, pharmacokinetics and pharmacodynamics of the novel selective CCR1 antagonist BI 638683. Methods In a randomised, blinded, placebo-controlled trial, single rising doses from 1 to 700 mg BI 638683 or placebo were administered to 63 young healthy male volunteers (mean age 32 ± 9 years; mean BMI was 24.7 ± 2.4 kg/m2). Subjects were randomised in a 6:2 ratio to active or placebo per group. Two distinct mechanistic blood-based biomarker assays were used to establish a PK/PD relationship: 1. inhibition of MIP1α-induced CCR1 receptor internalization (RI) and 2. inhibition of RANTES-induced CCR1 dependent gene expression of CCL2, CLEC5A, RAB7B and PPARG Results All doses of BI 638683 were well tolerated. There were no serious adverse events (AE) and no AEs of severe intensity. There was no dose-relationship of AEs and no difference in the number or category of reported AEs in subjects treated with BI 638683 (7/47; 14.9%) compared to those treated with placebo (3/16; 18.8%). The most frequent AEs were GI disorders which were reported in 5/47 (10.6%) subjects treated with BI 638683 and 2/16 (12.5%) subjects treated with placebo. Only one event of nausea in the 700g mg dose group was rated as drug related. Plasma exposure of BI 638683 increased in a near dose-linear fashion, with a terminal t½ of 5-15 h. Two hours after dosing (the pharmacokinetic tmax), a dose of 150 mg BI 638683 inhibited RI by approximately 90%. The percentage of inhibition was directly related to the dose of BI 638683. At the 700 mg dose, an 83% inhibition of RI was measured at 24 h after dosing. Maximal inhibition of mRNA expression of the 4 CCR1 dependent marker genes was reached with a dose of 75 mg BI 638683 at the tmax. 24 h after dosing, ≥90% mean inhibition was still maintained for CCL2 and PPARG mRNAs by doses of 300 mg and higher, and for RAB7B mRNA by doses of 500 mg and higher. For CLEC5A, inhibition of 84% and 91% was achieved for the 500 and 700 mg dose, respectively. Conclusions Treatment with BI 636683 was well tolerated. The biomarker assays indicated substantial inhibition and demonstrated proof of mechanism for BI 638683 as a CCR1 inhibitor in early stage of clinical development, and the PK/PD data using these biomarkers can be used to determine appropriate dosing for this compound. Disclosure of Interest : P. Baum Employee of: Boehringer-Ingelheim, C. Schoelch Employee of: Boehringer-Ingelheim, H. Zimdahl-Gelling Employee of: Boehringer-Ingelheim, M. Brown Employee of: Boehringer-Ingelheim, D. Webb Employee of: Boehringer-Ingelheim, S. Padula Employee of: Boehringer-Ingelheim, J. Hilbert Employee of: Boehringer-Ingelheim, T. Giessmann Employee of: Boehringer-Ingelheim, J. Steffgen Employee of: Boehringer-Ingelheim DOI 10.1136/annrheumdis-2014-eular.2352