Stevan Shaw

First-in-human randomized study of bimekizumab, a humanized monoclonal antibody and selective dual inhibitor of IL-17A and IL-17F, in mild psoriasis

Aims To assess safety, pharmacokinetics (PK) and clinical efficacy of bimekizumab (formerly UCB4940), a novel humanized monoclonal antibody and dual inhibitor of interleukin (IL)‐17A and IL‐17F, in subjects with mild plaque psoriasis. Methods Randomized, double‐blind, first‐in‐human study of bimekizumab in 39 subjects who received single‐dose intravenous bimekizumab (8–640 mg) or placebo (NCT02529956). Results Bimekizumab demonstrated dose‐proportional linear PK and was tolerated across the dose range assessed. No subject discontinued due to treatment‐emergent adverse events and no severe adverse events were reported. Bimekizumab demonstrated fast onset of clinically‐meaningful effects on skin of patients with mild psoriasis as early as Week 2. Maximal improvements (100% or near 100% reductions from baseline) in all measures of disease activity were observed between Weeks 8–12 in subjects receiving 160–640 mg bimekizumab. The duration of effect at doses ≥160 mg was evident up to Weeks 12–20 after a single intravenous dose, dependent on endpoint. Conclusions This is the first study to demonstrate the safety, tolerability and clinical efficacy of a dual IL‐17A and IL‐17F inhibitor, in subjects with mild psoriasis. Bimekizumab showed fast onset of clinically‐meaningful efficacy by Week 2, with a maximal or near‐maximal magnitude of response that was maintained up to study Weeks 12–20. These findings support the continued clinical development of bimekizumab for diseases mediated by both IL‐17A and IL‐17F, including psoriasis.

Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling.

Interleukin-6 (IL-6) is a critical regulator of the immune system and has been widely implicated in autoimmune disease. Here, we describe the discovery and characterization of olokizumab, a humanized antibody to IL-6. Data from structural biology, cell biology and primate pharmacology demonstrate the therapeutic potential of targeting IL-6 at “Site 3”, blocking the interaction with the signaling co-receptor gp130.

Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation

Objective Interleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone. Methods Preclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease-relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated. Results IL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals. Conclusions These data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions. Trial registration number NCT02141763; Results.

OP0108 Bimekizumab, A Monoclonal Antibody That Inhibits both IL-17A and IL-17F, Produces A Profound Response in both Skin and Joints: Results of An Early-Phase, Proof-of-Concept Study in Psoriatic Arthritis

Background Bimekizumab (UCB4940) is a potent and selective monoclonal antibody inhibiting the activity of both IL-17A and IL-17F, which are key pro-inflammatory cytokines overexpressed in skin lesions of patients with psoriasis.1 Blocking both IL-17A and IL-17F may provide a therapeutic advantage. Objectives To study the safety/tolerability and efficacy of multiple-dose bimekizumab in patients with PsA with inadequate responses to at least 1 DMARD and/or 1 biologic DMARD (NCT02141763). Methods 52 patients were randomized to receive either bimekizumab (N=38) or PBO (N=14). Four active dose-level groups were studied using a single loading dose (80–560 mg bimekizumab) administered at wk 0; further doses (40–320 mg bimekizumab) were administered at wks 3 and 6. ACR and PASI scores were examined; safety and PK variables were also investigated. Results At baseline, patients had a mean SJC (66) of 12.6 and TJC (68) of 29.6, and mean baseline CRP of 12.5 mg/mL. For patients with skin involvement of >3% (N=23) a mean baseline PASI of 15.9 (SD=14.6) was observed. Onset of response was rapid for both skin and joints: by wk 8, an ACR20 RR of 80% was observed for the top 3 doses (N=32) compared with 17% in the PBO group (N=12). Clinically relevant responses in disease activity measures were observed to wk 20. A summary of results in skin and joints is presented in the table. Baseline Week 8 PBO Bimekizumab top 3 doses PBO Bimekizumab top 3 doses Joints:  ACR20 RR [95% CI] N/A N/A 17% [5%, 45%], 80% [63%, 91%], N=12 N=30  ACR50 RR [95% CI] N/A N/A 8% [2%, 35%], 40% [25%, 58%], N=12 N=30  Mean DAS(CRP) [95% CI] 5.1 [4.6, 5.6], 5.0 [4.6, 5.4], 3.9 [3.2, 4.6], 3.1 [2.7, 3.6], N=11 N=30 N=11 N=29 Skin:  PASI 90 RR [95% CI] N/A N/A 0% [0%, 43%], 87% [62%, 96%], N=5 N=15  Mean PASI [SD] 17.6 [18.0], 11.1 [9.2], 14.1 [17.9], 0.2 [0.6], N=5 N=15 N=5 N=15 Bayesian analysis on wk 8 data indicated a >99% probability that ACR score improvement, and ACR20 RR, were greater than PBO and exceed the pre-defined clinically relevant threshold (ACRntr: 0.31 and ACR20: 25%). Additionally, there was a high posterior probability of >99% that the bimekizumab ACR20 RR was greater than that reported for the current SOC biologic treatment, including anti-IL-17 therapies (59.7%) at wk 8.2,3 All doses of bimekizumab were well tolerated, with no unexpected safety findings. No patient discontinued due to treatment-emergent AEs. No treatment-related serious AEs were reported. Bimekizumab had a linear PK, with an expected half-life of ∼24 days. Conclusions In patients with PsA, bimekizumab demonstrated rapid onset, sustained and deep efficacy on disease activity in skin and joints, and within this limited patient and exposure set, was safe and well tolerated. Bayesian analysis indicated that bimekizumab ACR20 RR is greater than that reported for current therapies including anti-IL-17A. Results support that inhibition of both IL-17A and IL-17F could provide additional clinical benefit in IL-17-mediated diseases. References Johansen et al. Br J Dermatol 2009;160:319–24; McInnes et al. Lancet 2015;386:1137–46; McInnes et al. Lancet 2013;382:780–9 Acknowledgement This study was UCB Pharma funded. Disclosure of Interest S. Glatt Shareholder of: UCB, Employee of: UCB, F. Strimenopoulou Employee of: UCB, P. Vajjah Shareholder of: UCB, Employee of: UCB, S. Shaw Shareholder of: UCB, Employee of: UCB, L. Ionescu Employee of: UCB, S. Popa: None declared, D. Baeten Grant/research support from: AbbVie, Pfizer, MSD, UCB, Novartis, Boehringer Ingelheim, Consultant for: AbbVie, Pfizer, MSD, UCB, Novartis, Boehringer Ingelheim, Roche, Eli Lilly, BMS

Safety and pharmacokinetics of olokizumab, an anti‐IL‐6 monoclonal antibody, administered to healthy male volunteers: A randomized phase I study

Interleukin‐6 (IL‐6) is implicated in the pathophysiology of several inflammatory conditions. Olokizumab, a humanized anti‐IL‐6 monoclonal antibody, selectively blocks the final assembly of the IL‐6 signaling complex. A randomized, double‐blind, placebo‐controlled, phase I dose‐escalation study assessed the safety and tolerability of escalating single doses of olokizumab administered intravenously (iv) or subcutaneously (sc) to 67 healthy male volunteers. The pharmacokinetics, pharmacodynamics and immunogenicity of olokizumab were also assessed. Olokizumab was tolerated at doses up to 3.0 mg/kg sc and 10.0 mg/kg iv; the maximum tolerated dose was not reached. No serious adverse events or withdrawals as a result of treatment‐emergent adverse events were reported. Pharmacokinetic analysis showed that both maximum serum concentration and area under the concentration–time curve increased linearly with increasing dose. Mean terminal half‐life was 31.5 days (standard deviation 12.4 days). The bioavailability of the sc doses ranged from 84.2% to 92.5%. Rapid decreases in C‐reactive protein concentrations were observed, with no dose dependency.

Model-Based Optimal Design and Execution of the First-Inpatient Trial of the Anti-IL-6, Olokizumab.

The first‐in‐patient study for olokizumab (OKZ) employed model‐based, optimal design and adaptive execution to define the concentration–C‐reactive protein (CRP) suppression response. Modeling and exploratory statistics activities involved: reverse engineering of first‐in‐class (tocilizumab) pharmacokinetic/pharmacodynamic (PK/PD) models, adaptation of models to OKZ with a priori knowledge and preclinical data translation, application of multidimensional Desirability Index for optimal study design, sample size reestimation based on new information, optimization of second study part via Bayesian analysis of interim data, and interim and final analysis for PK/PD objective attainment. Design work defined a dose window (0.1–3 mg/kg) for CRP suppression exploration and suggested 72 patients in five single‐dose levels would suffice. During execution, new information resulted in reestimating the study size to half. Halting the first part and conducting interim analysis for second part optimization followed. Second interim and final analyses confirmed attainment of study objective, illustrating efficiency and optimality of the study.

THU0038 Bimekizumab dual inhibition of IL-17A and IL-17F provides evidence of IL-17F contribution to chronic inflammation in disease-relevant cells

Background IL-17A and IL-17F share structural homology and have similar biological function1. Although the contribution of IL-17A to immune-mediated inflammatory diseases has been widely reported1–3, the role of IL-17F is less well characterised in human tissue inflammation. Bimekizumab, a humanised monoclonal IgG1 antibody, was developed to neutralise both IL-17A and IL-17F potently and selectively, and is under clinical development as a treatment for psoriatic arthritis (PsA) and other immune-mediated conditions such as psoriasis. Objectives To assess the involvement of IL-17F in chronic inflammation in tissue from patients with PsA and disease-relevant cells, and to determine the effect of dual neutralisation of IL-17A and IL-17F in suppressing inflammation, compared with blockade of IL-17A. Methods Synovial and lesional skin tissue from patients with PsA was probed by immunostaining for expression of IL-17F protein. Normal dermal fibroblasts and synoviocytes, in the presence of TNFα, were stimulated with recombinant IL-17A and IL-17F to assess the inflammatory response. Using cytokine-specific blocking antibodies, the individual and combined effects of IL-17A and IL-17F were explored with: pro-inflammatory cytokine expression in a complex in vitro model (synoviocytes from patients with PsA and normal dermal fibroblasts were treated with pro-inflammatory mediators from supernatant [SN] of sorted Th17 cells), microarray and cell migration studies. Results IL-17F expression was observed in tissue biopsies from patients with PsA. In normal dermal fibroblasts, normal synoviocytes and synoviocytes from patients with PsA, stimulation with recombinant IL-17F promoted production of pro-inflammatory mediators, such as IL-6 and IL-8, though to a lesser extent than with recombinant IL-17A. Treatment of Th17 SN-stimulated synoviocytes from patients with PsA with bimekizumab (neutralising IL-17A and IL-17F) led to greater reductions of IL-6 (42% lower p<0.05) and IL-8 (35% lower p<0.05) production than IL-17A inhibition. Bimekizumab treatment of Th17 SN-stimulated normal dermal fibroblasts also reduced production of IL-6 (35% lower p<0.0001) and IL-8 (57% lower p<0.0001) more than IL-17A alone. Combining IL-17A + IL-17F monoclonal antibodies produced similar results to bimekizumab. Levels of expression of 27 inflammation-linked genes, including CXCL1, CXCL2, CXCL3 and IL-15RA, were lower with dual neutralisation of IL-17A and IL-17F by bimekizumab versus inhibition of IL-17A. Suppression of migration of neutrophils (Fig.) and monocytes, both involved in tissue destruction in immune-mediated diseases, was substantially greater with bimekizumab treatment than with single blockade of IL-17A. Conclusions Dual neutralisation of IL-17A and IL-17F provides evidence for the contribution of IL-17F to inflammation in joints and skin beyond IL-17A alone. As a result, dual inhibition of IL-17A and IL-17F by bimekizumab may provide an effective treatment for immune-mediated inflammatory diseases such as PsA. References C Johansen et al. Br J Dermatol 2009:160:319–24. AL Lima et al. Br J Dermatol 2016:174:514–21. C Doe et al. Chest 2010:138:1140–7. Disclosure of Interest A. Maroof Employee of: UCB Pharma, R. Okoye Employee of: UCB Pharma, T. Smallie Employee of: UCB Pharma, D. Baeten Grant/research support from: UCB Pharma, Consultant for: AbbVie, Pfizer, MSD, Roche, BMS, Novartis, Eli Lilly, Boehringer Ingelhaim and Glenmark, S. Archer Employee of: UCB Pharma, C. Simpson Employee of: UCB Pharma, M. Griffiths Consultant for: UCB Pharma, Employee of: UCB Pharma, S. Shaw Employee of: UCB Pharma

Efficacy of an Inhaled Interleukin-13 Antibody Fragment in a Model of Chronic Asthma.

Rationale: IL‐13 is an important cytokine implicated in the pathogenesis of allergic asthma and is an attractive target for an inhaled therapeutic. Objective: To investigate the efficacy of CDP7766, a nebulized inhaled anti‐IL‐13 monoclonal antibody Fab fragment, in a model of allergic asthma in cynomolgus macaques naturally sensitized to Ascaris suum. Methods: CDP7766 was nebulized using a vibrating‐membrane nebulizer on the basis of eFlow technology. The aerosol generated was analyzed to determine the particle size profile and the biophysical and functional properties of CDP7766. Nebulized CDP7766 (0.1‐60 mg/animal, once daily for 5 d) was delivered via the inhaled route. Measurements and Main Results: The investigational eFlow nebulizer used in this study generated a respirable aerosol of CDP7766 with no evidence of degradation, loss of potency, aggregation, or formation of particulates. Inhaled CDP7766 was well tolerated in the model (no adverse effects related to local irritation) and significantly inhibited BAL allergen‐induced cytokine and chemokine upregulation (60 mg vs. vehicle: eotaxin‐3, P < 0.0008; MIP [macrophage inflammatory protein]‐1&bgr;, IL‐8, IFN‐&ggr;, P ≤ 0.01). CDP7766 significantly inhibited the increase in pulmonary resistance stimulated by inhaled allergen, measured 15 minutes and 24 hours after allergen challenge. Conclusion: Inhaled CDP7766 potently inhibited the function of IL‐13 generated during the airway response to inhaled allergen in cynomolgus macaques, demonstrating the potential of inhaled anti‐IL‐13 therapeutics for the treatment of allergic asthma.

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration.

ABSTRACT Rozanolixizumab (UCB7665), a humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (IgG4P), has been developed to reduce pathogenic IgG in autoimmune and alloimmune diseases. We document the antibody isolation and compare rozanolixizumab with the same variable region expressed in various mono-, bi- and trivalent formats. We report activity data for rozanolixizumab and the different molecular formats in human cells, FcRn-transgenic mice, and cynomolgus monkeys. Rozanolixizumab, considered the most effective molecular format, dose-dependently and selectively reduced plasma IgG concentrations in an FcRn-transgenic mouse model (no effect on albumin). Intravenous (IV) rozanolixizumab dosing in cynomolgus monkeys demonstrated non-linear pharmacokinetics indicative of target-mediated drug disposition; single IV rozanolixizumab doses (30 mg/kg) in cynomolgus monkeys reduced plasma IgG concentration by 69% by Day 7 post-administration. Daily IV administration of rozanolixizumab (initial 30 mg/kg loading dose; 5 mg/kg daily thereafter) reduced plasma IgG concentrations in all cynomolgus monkeys, with low concentrations maintained throughout the treatment period (42 days). In a 13-week toxicology study in cynomolgus monkeys, supra-pharmacological subcutaneous and IV doses of rozanolixizumab (≤ 150 mg/kg every 3 days) were well tolerated, inducing sustained (but reversible) reductions in IgG concentrations by up to 85%, with no adverse events observed. We have demonstrated accelerated natural catabolism of IgG through inhibition of IgG:FcRn interactions in mice and cynomolgus monkeys. Inhibition of FcRn with rozanolixizumab may provide a novel therapeutic approach to reduce pathogenic IgG in human autoimmune disease. Rozanolixizumab is being investigated in patients with immune thrombocytopenia (NCT02718716) and myasthenia gravis (NCT03052751).

02.13 Il-17f contributes to human chronic inflammation in synovial tissue: Preclinical evidence with dual il-17a and il-17f inhibition with bimekizumab in psoriatic arthritis

Background IL-17A is an established target in several chronic immune-mediated inflammatory diseases; IL-17F, sharing significant structural homology and overlapping biological function with IL-17A,1 is a relatively understudied cytokine. Bimekizumab is a humanised monoclonal IgG1 antibody that potently and selectively neutralises the biological function of both IL-17A and IL-17F. Using preclinical human in vitro models we studied the contribution of IL-17F to inflammation, via stimulation and blocking assays, in joint cells from patients with psoriatic arthritis (PsA). Materials and methods Immunostaining was performed on synovial tissue from patients with PsA to probe for IL-17F. Recombinant IL-17A and IL-17F, with/without TNFα, were added to synoviocytes from patients with PsA, to examine their effect on inflammatory cytokine production. A complex in vitro assay was developed, using pro-inflammatory mediators from sorted Th17 cells, to explore the mechanism of action of bimekizumab and relative contributions of IL-17A and IL-17F to chronic disease. The Th17-cell supernatant profile had a complex mix of disease-relevant pro-inflammatory cytokines akin to those found elevated in joint tissue biopsies from patients with PsA. IL-17-isoform-specific blocking antibodies provided an overview of the individual and collective influence of IL-17A and IL-17F in regulating key disease-pathology-relevant cytokine and chemokine production. Results IL-17F protein was detected in inflamed synovium from patients with PsA. Stimulation of normal synoviocytes with recombinant IL-17A or IL-17F promoted qualitatively similar responses, notably induction of key pro-inflammatory mediators (eg, IL-8 and IL-6), albeit to a lesser extent with IL-17F than IL-17A. Similar results were obtained in synoviocytes from patients with PsA, stimulated in the presence of TNFα. When synoviocytes from patients with PsA were stimulated with Th17-cell supernatant, dual IL-17A and IL-17F inhibition with bimekizumab resulted in a greater downregulation of IL-6 (42% lower; p<0.05) and IL-8 (35.4% lower; p<0.05) expression than inhibition of IL-17A alone. Similar results were obtained using monospecific anti-IL-17A and anti-IL-17F antibodies. Conclusions Data support hypotheses that IL-17F contributes to human tissue inflammation in joints, beyond IL-17A alone, and that dual inhibition of IL-17A and IL-17F may be therapeutically beneficial in immune-mediated inflammatory diseases. Acknowledgements The authors thank the subjects and their caregivers in addition to the investigators and their teams who contributed to this study. This study was funded by UCB Pharma. The authors acknowledge the contributions of Tim Smallie, of UCB, Louise Healy, formerly of UCB, for their work on functional characterisation of bimekizumab. The authors also acknowledge the contribution of Catherine Simpson, of UCB, for flow cytometry cell sorting support, Remi Okoye, of UCB, for the immunohistochemistry work, and Iris Blijdorp of the Academic Medical Centre, Amsterdam, for work on blockade experiments in synoviocytes. The authors would like to acknowledge Ailsa Dermody, PhD, of iMed Comms, an Ashfield Company, part of UDG Healthcare plc, for editorial assistance that was funded by UCB Pharma. Reference Johansen C, Usher PA, Kjellerup RB, et al,.. Characterisation of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol 2009; 160(2): 319-24.