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Background The CD40/CD40L pathway is involved in the T-cell-dependent activation of B cells, which subsequently produce autoantibodies and inflammatory mediators that contribute to autoimmune disease pathology. MEDI4920 is an engineered fusion protein and antagonist of CD40L that lacks the fragment crystallisable (Fc) domain thought to be involved in thromboembolic events (TEs) previously reported with anti-CD40L agents containing an Fc domain. Objectives The primary objective of this Phase I, randomised, double-blind, placebo-controlled, single-ascending dose study was to evaluate the safety and tolerability of MEDI4920 in healthy subjects. Secondary objectives were to characterize T-cell-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) neoantigen, pharmacokinetics (PK), and anti-drug antibodies (ADAs) to MEDI4920. Methods Fifty-six healthy adult male subjects, aged 19–49 years, received a single intravenous dose of either MEDI4920 (3, 10, 30, 100, 300, 1000 or 3000 mg) or placebo. TDAR inhibition was analysed by measuring serum concentrations of IgG and IgM antibodies to KLH over time. A dose−response model was generated for TDAR inhibition. Blood samples were collected to evaluate PK, total soluble CD40L (sCD40L) and ADA concentrations. Results No deaths, TEs, severe or serious hypersensitivity reactions or infections or infusion-related reactions were observed in the study. One serious adverse event (fractured tibia) was reported in the placebo arm. MEDI4920 showed inhibition of the TDAR IgG response after the second administration of KLH on Day 15 at higher doses (≥300 mg; Figure 1A). An Emax model adequately characterised the TDAR dose−response at Day 43 (p Conclusions MEDI4920 demonstrated an acceptable safety and tolerability profile, and dose-dependent inhibition of TDAR. The dose-dependent increase in total sCD40L concentrations indicates binding of MEDI4920 to sCD40L and target engagement. The decreases in ADA incidence and ADA titres correlate with increasing MEDI4920 dose, consistent with the immunosuppressive mechanism of action of this molecule. These results support further exploration of MEDI4920 administration in subjects with autoimmune diseases where the CD40/CD40L pathway is activated. Acknowledgements Funded by MedImmune. Medical writing support: D. Trivedi, MedImmune LLC, Gaithersburg, MD, USA. Technical editing support: R. Plant, QXV Comms, an Ashfield company, which was funded by MedImmune. Disclosure of Interest M. Albulescu Shareholder of: MedImmune, Employee of: MedImmune, M. Gunsior Employee of: MedImmune, J. Li Employee of: MedImmune, J. Bush Employee of: Covance Clinical Research Unit Ltd (Co. contracted [and paid] by the sponsor to conduct the study), A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, R. Miday Employee of: MedImmune, E. Grant Shareholder of: AstraZeneca, Employee of: MedImmune, D. Howe Employee of: MedImmune, R. Faggioni Shareholder of: AstraZeneca, Employee of: MedImmune, L. Roskos Shareholder of: AstraZeneca, Employee of: AstraZeneca

Background RA is associated with pulmonary comorbidity and lung function decline over time, but longitudinal assessment of pulmonary abnormalities in the context of RA treatment needs further characterisation. Mavrilimumab, an investigational human monoclonal antibody, inhibits GM-CSF by binding to the GM-CSF receptor α subunit. Objectives To investigate the pulmonary safety of mavrilimumab because of the theoretical risk of inhibiting alveolar macrophage function and causing pulmonary alveolar proteinosis (PAP). Methods Pulmonary monitoring included standardised serial pulmonary function testing (spirometry and diffusing capacity of lung carbon monoxide [DLCO]), chest X-rays, assessments of dyspnoea and pulmonary adverse events (AEs) in two randomised, double-blind studies (NCT01706926; NCT01715896) where patients (pts) with moderate to severe RA received mavrilimumab 30, 100 or 150 mg every other week (eow), or placebo and mavrilimumab 100 mg eow or golimumab 50 mg every 4 weeks, respectively. Eligible pts transferred to the open-label extension study (NCT01712399) and received mavrilimumab 100 mg eow. All studies excluded pts with clinically significant uncontrolled pulmonary disease. An Independent Pulmonary Evaluation Committee (IPEC), blinded to treatment, adjudicated pulmonary AEs and lung function abnormalities. Results Mavrilimumab was received by 442 pts with cumulative safety data exposure of approximately 900 pt-yrs and a median (range) exposure time of 2.5 (0.1–3.3) yrs. Baseline (BL) characteristics are shown (Table). Mean dyspnoea (Table), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and DLCO were mostly maintained within 5% of BL values for pts treated with mavrilimumab during the clinical programme. Clinically relevant decreases in predicted FEV1 and FVC (>20% from BL and Conclusions We believe this is the most comprehensive longitudinal study of pulmonary function in a clinical RA programme. The BL pulmonary function profile indicates that this is not a normal population from a pulmonary health perspective. Mavrilimumab was not associated with substantial decline in pulmonary function or PAP in pts treated up to 3.3 years; its acceptable safety profile advocates initiation of Phase III studies with mavrilimumab. Further studies are now required to fully characterise pulmonary function over time in RA. Acknowledgements Funded by MedImmune. Medical writing support: R Plant, QXV Comms, an Ashfield company, funded by MedImmune. ^Senior author. Disclosure of Interest G. Burmester Consultant for: MedImmune, M. Michaels Employee of: MedImmune, D. Close Employee of: MedImmune, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, K. Middleton Employee of: MedImmune (contracted employment at time of study), P. Miranda Grant/research support from: Amgen, Medimmune, Janssen, Pfizer, Celltrion, Abbott, Sanofi, Actelion, Merck & Co, Boehringer, BMS, Consultant for: Pfizer [Etanecept: Fee less than USD5000], J. Vencovský Consultant for: Pfizer, Elli Lilly, MSD, Novartis, Speakers bureau: Biogen, Pfizer, MSD, Abbvie, Novartis, Boehringer, UCB, BMS, J. Kremer Shareholder of: Corrona, Grant/research support from: Abbvie, Amgen, Genentech, Lilly, Pfizer, Consultant for: Abbvie, Amgen, BMS, Genentech, Lilly, Pfizer, Employee of: Corrona, I. McInnes Grant/research support from: MedImmune [The University of Glasgow is a charity registered in Scotland, charity number SC004401 Grant/research support: Research award to University of Glasgow], Consultant for: MedImmune, M. Albulescu Shareholder of: MedImmune, Employee of: MedImmune, M. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience. Amgen, dxterity, Consultant for: MedImmune, Astra Zeneca, Amgen, Abbvie, BMS, Crescendo bioscience, Lilly, Pfizer, UCB, Roche, novartis