Objective: To assess the antiviral activity, pharmacokinetics, and safety of MK-6186 in HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI)-naïve, HIV-1-infected male participants. Design: Double-blind, randomized, two-panel study. Methods: In 2 sequential panels, 18 participants received MK-6186 (40 mg [Panel A] or 150 mg [Panel B]) or matching placebo once daily for 7 days. Plasma samples were collected for measurement of HIV-1 RNA levels and MK-6186 pharmacokinetics. Results: For the mean change from baseline in HIV-1 RNA (log10 copies/mL) at 24 h post Day 7 dose, the mean difference (90% confidence interval) between MK-6186 and placebo was -1.54 (-1.73, -1.34) in the 40-mg group and -1.28 (-1.81, -0.75) in the 150-mg group. One participant in the 150-mg group had viral rebound at 24 h after Day 6 dosing (Day 7 predose) associated with outgrowth of the V106A minority variant. Ultra-deep sequencing confirmed expansion of this predose minority variant from 0.26% to 63.67%. No outgrowth or rebound was seen in another participant in whom a V106A minority variant was also detected. MK-6186 was generally well tolerated. MK-6186 was rapidly absorbed with peak concentrations at 2 h followed by a biphasic decline. The effective t½ of MK-6186 was 43.9 to 48.7 h. Steady state was not achieved. Conclusions: Daily monotherapy with MK-6186 demonstrated robust antiviral activity with maximal antiviral activity at a dose of 40 mg. One participant in the 150-mg group exhibited viral rebound with outgrowth of the resistant V106A minority variant, demonstrating a risk of resistance development typical of NNRTIs. The reason for this outgrowth remains unclear as no outgrowth occurred in a participant in the 40-mg group in whom the V106A minority variant was also detected. MK-6186 may be an alternative next-generation NNRTI in combination therapy, in that combination antiretroviral therapy could prevent outgrowth of resistant minority variants.

To evaluate efficacy and safety of BGG492 (selurampanel; an orally active, competitive AMPA glutamate receptor antagonist) in patients with moderate-to-catastrophic chronic subjective tinnitus. Study (NCT01302873) enrolled patients with subjective tinnitus based on THI severity grade 3, 4 or 5 (moderate, severe or catastrophic), and those with chronic (> 6 and < 36 months) tinnitus. Primary endpoints were clinical status of tinnitus using TBF-12 and tinnitus loudness using VAS after multiple dose 2-week BGG492 treatment. Safety was assessed by recording all adverse events (AEs). After a single dose of BGG492 VAS scores for tinnitus loudness (P = 0.012) and tinnitus annoyance (P = 0.004) were significantly reduced vs placebo. After 2 weeks treatment a significantly greater proportion of patients showed improvement of ≥ 4 points from baseline in TBF-12 (stringent responder definition) with BGG492 vs placebo (26.7% [n = 23] vs 14% [n = 12], respectively; odds ratio [OR] (90% CI):2.30 (1.10, 4.83); P = 0.064), fulfilling proof-of-concept achievement criteria. No notable difference in proportion of responders to BGG492 vs placebo was observed as assessed using VAS (26.7% [n = 23] vs 27.6% [n = 24], respectively; OR (90% CI):0.94 (0.52, 1.67); P = 0.848). Dizziness was the most frequently reported AE in 50% [n = 21] and 31.5% [n = 17] patients on BGG492 100 and 50 mg TID, respectively vs 9.6% [n = 9] on placebo. In conclusion, BGG492 showed reduction of both tinnitus loudness and annoyance after a single dose and reduction of tinnitus handicap after 2 weeks of treatment in patients with chronic subjective tinnitus, thereby supporting further clinical investigation of AMPA receptor antagonists with an improved benefit/risk ratio. A dose of 100 mg TID BGG492 showed higher efficacy but somewhat lower tolerability compared to 50 mg TID.

Helicobacter pylori (Hp) eradication therapy alters gut microbiota, provoking gastrointestinal (GI) symptoms that could be improved by probiotics. The study aim was to assess the effect in Hp patients of a Test fermented milk containing yogurt and Lacticaseibacillus (L. paracasei CNCM I-1518 and I-3689, L. rhamnosus CNCM I-3690) strains on antibiotic associated diarrhea (AAD) (primary aim), GI-symptoms, gut microbiota, and metabolites. A randomised, double-blind, controlled trial was performed on 136 adults under 14-day Hp treatment, receiving the Test or Control product for 28 days. AAD and GI-symptoms were reported and feces analysed for relative and quantitative gut microbiome composition, short chain fatty acids (SCFA), and calprotectin concentrations, and viability of ingested strains. No effect of Test product was observed on AAD or GI-symptoms. Hp treatment induced a significant alteration in bacterial and fungal composition, a decrease of bacterial count and alpha-diversity, an increase of Candida and calprotectin, and a decrease of SCFA concentrations. Following Hp treatment, in the Test as compared to Control group, intra-subject beta-diversity distance from baseline was lower (padj = 0.02), some Enterobacteriaceae, including Escherichia-Shigella (padj = 0.0082) and Klebsiella (padj = 0.013), were less abundant, and concentrations of major SCFA (p = 0.035) and valerate (p = 0.045) were higher. Viable Lacticaseibacillus strains were detected during product consumption in feces. Results suggest that, in patients under Hp treatment, the consumption of a multi-strain fermented milk can induce a modest but significant faster recovery of the microbiota composition (beta-diversity) and of SCFA production and limit the increase of potentially pathogenic bacteria.

OBJECTIVES To apply serial ultrasound (US) assessments to show effects of ianalumab (anti-BAFF-R monoclonal antibody) on inflamed salivary glands of patients with primary Sjögren's syndrome (pSS). METHODS In a single-centre, 24-week double-blind study (NCT02149420), 27 pSS patients of moderate-to-severe activity were randomly assigned to receive a single i.v. dose of either 3 mg/kg or 10 mg/kg ianalumab, or placebo. Concurrent with clinical and laboratory outcomes, multi-modal US images were acquired of bilateral parotid glands (PG) and submandibular glands (SMG) at weeks 0, 6, 12, and 24. Applied US modalities included 1) B-mode echostructure scored by de Vita classification, 2) macrovascular blood flow by power Doppler, and in PG only 3) microvascularisation using contrast-enhanced US (area under the curve, time to peak or TTP) and 4) gland stiffness by sonoelastography. RESULTS Clinical study results were previously published. US data for PG differed from SMG but were comparable between respective left and right sides of these glands. Numerical improvements in salivary gland quality and declining tissue inflammation were observed in treated versus placebo groups, including more patients achieving ≥1-point reduction from baseline in De Vita score, together with trends towards decreased perfusion and stiffness. Correlations between clinical endpoints and US parameters were largely restricted to microvascular perfusion TTP and at the 12-week timepoint when ianalumab effects were predicted at maximal. CONCLUSIONS Early in vivo signs of salivary gland improvement in response to an effective intervention can be shown without need of biopsy by using a non-invasive, comprehensive, ultrasound-based approach over multiple time points.

OBJECTIVES:To evaluate the efficacy and safety of ianalumab (VAY736), a B cell-depleting, B cell activating factor receptor-blocking, monoclonal antibody, in patients with active primary Sjögren's syndrome (pSS) in a double-blind, placebo-controlled, phase II, single-centre study.METHODS:Patients with pSS, EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥6, were randomised to ianalumab single infusion at either 3 mg/kg (n=6), 10 mg/kg (n=12) or placebo (n=9). Outcomes were measured blinded at baseline and weeks 6, 12, 24, and unblinded at end of study (EoS) when B cell numbers had recovered. Clinical outcomes included ESSDAI, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), salivary flow rate, ocular staining score, physician global assessment and patient assessments of fatigue and general quality of life. Laboratory-based measures included circulating leucocyte subsets and markers of B cell activity.RESULTS:A similar trend showing positive therapeutic effect by ianalumab was observed across the primary clinical outcome (ESSDAI) and all secondary clinical outcomes (ESSPRI, Multidimensional Fatigue Inventory, Short Form-36, global assessments by physician and patient) versus the placebo-treated group. Rapid and profound B cell depletion of long-lasting duration occurred after a single infusion of ianalumab at either dose. Serum Ig light chains decreased, with return to baseline levels at EoS. Changes in some clinical outcomes persisted through to EoS in the higher dose group. Adverse effects were largely limited to mild to moderate infusion reactions within 24 hours of ianalumab administration.CONCLUSIONS:Overall results in this single-dose study suggest potent and sustained B cell depletion by ianalumab could provide therapeutic benefits in patients with pSS without major side effects.

AimsTo evaluate the safety, pharmacokinetics and pharmacodynamics of SAR425899, a novel polypeptide, active as an agonist at both the glucagon‐like peptide‐1 receptor (GLP‐1R) and the glucagon receptor (GCR), in healthy volunteers and in overweight/obese patients with type 2 diabetes (T2D).MethodsSubcutaneous administrations of SAR425899 were tested in two randomized, placebo‐controlled, double‐blind clinical trials. In the first trial, healthy overweight volunteers (body mass index [BMI] 25‐30 kg/m2; n = 32) received single‐ascending doses (0.01‐0.1 mg) of SAR425899 or placebo. In the second, a multiple‐ascending‐dose trial (NCT02411825), healthy normal‐ to overweight volunteers (BMI 20‐30 kg/m2; n = 40) and overweight/obese patients with T2D (BMI 28‐42 kg/m2; n = 36) received daily doses of SAR425899 or placebo over 21 or 28 days, respectively.ResultsThe most frequently reported adverse events were gastrointestinal; gastrointestinal side effects were less pronounced in patients with T2D compared with healthy volunteers. SAR425899 significantly reduced levels of fasting plasma glucose (P < 0.05 vs. placebo) and glycated haemoglobin (P < 0.001 versus placebo) in patients with T2D. Additionally, SAR425899 led to reductions in body weight, with a maximal reduction of 5.32 kg in healthy volunteers and 5.46 kg in patients with T2D (P < 0.001 vs. placebo) at end of treatment.ConclusionsSAR425899 was well tolerated and led to favourable glycaemic effects in patients with T2D and weight reduction in both healthy volunteers and patients. Whether dual GLP‐1R/GCR agonism represents a treatment method that is superior to pure GLP‐1R agonists for obesity and diabetes treatment remains to be confirmed.

The CD40–CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis. The safety, pharmacokinetics and pharmacodynamics of BI 655064, a novel humanised antagonistic anti-CD40 monoclonal antibody, were investigated in this first-in-human trial.

PURPOSE:Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. METHODS:These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. FINDINGS:Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants. IMPLICATIONS:The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose-response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002).

Objective: Tumor necrosis factor (TNF) and interleukin (IL)−17 independently contribute to the pathophysiology of rheumatoid arthritis (RA). ABT-122 is a novel dual variable domain immunoglobulin that selectively and simultaneously targets human TNF and IL-17A in an effort to evoke a greater clinical response than targeting either cytokine alone. This communication reports the pooled safety, tolerability, and exploratory pharmacodynamics of ABT-122 from two phase 1, placebo-controlled, multiple-dose studies in patients with primarily inactive RA. Methods: Patients (n=44) receiving stable methotrexate (2.5–25 mg/wk) were randomized to subcutaneous placebo, ABT-122 1 mg/kg every other week (4 doses), or ABT-122 0.5, 1.5, or 3 mg/kg weekly (8 doses) and were evaluated through 45 days after the last dose (day 92). Serum for inflammatory markers and chemokines was collected at baseline through day 92. A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. Results: No clinically significant safety findings were observed. Rates of treatment-emergent adverse events (TEAEs) were similar with ABT-122 and placebo. Only 1 serious AE, and no systemic hypersensitivity reactions or dose-limiting toxicities, were observed with ABT-122. Incidence of infections was similar between ABT-122 and placebo, with no serious infections reported. Chemokines C-X-C motif ligand 9 (CXCL9), CXCL10, C-C motif ligand 23 (CCL23) and soluble E-selectin were significantly decreased following ABT-122 treatment relative to placebo. Although patients had essentially inactive RA, exploratory clinical parameters suggested potential anti-inflammatory effects following treatment with ABT-122. Conclusion: These phase 1 results suggest that dual neutralization with ABT-122 has a profile acceptable for further exploration of therapeutic potential in TNFand IL-17A–driven immune-mediated inflammatory diseases. The introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) has greatly expanded treatment options for the management of rheumatoid arthritis (RA) (1, 2). In many patients, bDMARDs improve clinical symptoms, improve function, and slow disease progression (2). bDMARDs are recommended as add-on therapy to conventional synthetic DMARDs (csDMARDs) such as methotrexate (MTX) in patients who are incomplete responders to MTX (1, 3). Despite the availability of numerous bDMARDs, many patients with RA do not achieve the treatment goal of remission or even low disease activity, normalization of function, and inhibition of joint destruction (1, 2). One reason for not achieving these responses in most patients may be due to the complex pathophysiology of RA, which involves numerous proinflammatory cytokines and effector cells (2, 4). The multifaceted nature of RA presents opportunities for new therapeutic targets, including the inhibition of multiple pathways known to be involved in the pathogenesis of RA. Tumor necrosis factor (TNF) and interleukin (IL)−17 independently and cooperatively contribute to A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. the pathophysiology of RA (5, 6), while anti-TNF treatment increases IL-17 levels and T helper 17 cells (7, 8) For these reasons, it has been postulated that IL-17 may be an alternative or parallel mechanistic pathway that could be targeted in addition to TNF for effective disease control(6). This raises the question of whether dual neutralization of TNF and IL-17 can safely provide an opportunity to control inflammation in patients with RA not controlled with a TNF inhibitor alone. Multiple pathways and mediators contribute to joint pathology in RA (9). For example, C-XC motif ligand 9 (CXCL9)and CXCL10 recruit T and myeloid cells to sites of inflammation, increase synovial fibroblast invasion (10-12), and are elevated in the serum and synovial fluid of patients with RA (13, 14). CXCL10 also promotes expression of IL-17, which increases the production of E-selectin (13, 15). C-C motif ligand 23 (CCL23) recruits myeloid cells to sites of inflammation, is elevated in RA (16), and is correlated with higher 28-joint Disease Activity Score (DAS28) scores (17). Soluble E-selectin (sE-selectin) is a cell adhesion molecule that is released by endothelial cells (18) and promotes the migration of multiple immune cell types into inflamed tissues (19). sE-selectin is increased in RA, and is decreased with anti-TNF therapy (20). In a mouse collagen-induced arthritis model, combined administration of anti-TNF and anti−IL-17 antibodies produced a greater reduction in “arthritic” score than inhibition of either molecule alone (21). A mouse anti-TNF/IL-17 dual variable domain immunoglobulin (DVD-Ig) reduced inflammation and cartilage and bone destruction to a degree similar to that of combined anti-TNF and anti−IL-17 antibodies in a collagen-induced arthritis model, and more so than the use of either single antibody targeting one of these cytokines (22). Further, combined anti-TNF and anti−IL-17 treatment reduced levels of the inflammatory A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. mediators CXCL1 and CXCL5 in homogenized paw tissue, whereas the respective monotherapies had little effect. ABT-122 is a DVD-Ig (Figure 1) that targets both human TNF and IL-17; it is built on an adalimumab backbone with added IL-17 binding domains that had been identified with in vitro mRNA display technology and further refined to enhance affinity (23). Initial pharmacokinetic studies in healthy individuals and in patients with RA (24) demonstrated that ABT-122 displayed: (1) approximately dose-proportional exposure at subcutaneous (SC) doses >1 mg/kg, (2) approximately 50% bioavailability, (3) maximum serum concentrations after 3 to 4 days of dosing, and (4) half-lives of 10 to 18 days with dosing every other week (QOW) and every week (QW), respectively. Antidrug antibodies had minimal impact on the pharmacokinetics of ABT-122. Additionally, in an ex vivo assay in human fibroblast-like synoviocytes (FLS) derived from patients with RA, ABT-122 fully inhibited IL-6 release from FLS stimulated by the combination of TNF and IL-17, whereas individual monoclonal antibodies to TNF or IL-17 only partially inhibited IL-6 production (25). In this same assay, serum from patients receiving ABT-122 maintained the capability of simultaneous dual inhibition of TNF and IL-17 for up to 3 weeks after single-dose administration (25). ABT122 has been shown to have an acceptable safety profile in healthy individuals (25). Two phase 1 randomized, double-blind, placebo-controlled trials were conducted to evaluate the safety, tolerability, and pharmacodynamics of ABT-122 in patients with RA, with no requirement for active disease, who were receiving background MTX (24, 26). Pharmacodynamic effects of ABT-122 were assessed by measuring the levels of inflammatory markers and chemokines involved in the pathogenesis of RA. In addition, changes in DAS28 based on C-reactive protein (DAS28[CRP)]) were assessed as exploratory A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. endpoints as the trial was not designed to investigate the clinical efficacy of ABT-122. Preliminary data from these studies have been reported (26).

OBJECTIVE:Tumor necrosis factor (TNF) and interleukin-17 (IL-17) independently contribute to the pathophysiology of rheumatoid arthritis (RA). ABT-122 is a novel dual variable domain immunoglobulin that selectively and simultaneously targets human TNF and IL-17A. The aim of treatment with ABT-122 is to evoke a greater clinical response than that achieved by targeting either cytokine alone. This study was undertaken to present the pooled safety, tolerability, and exploratory pharmacodynamics of ABT-122 based on 2 phase I, placebo-controlled, multiple ascending-dose studies in patients with primarily inactive RA.METHODS:Patients (n = 44) receiving stable dosages of methotrexate (2.5-25 mg/week) were randomized to receive subcutaneous placebo, ABT-122 1 mg/kg every other week (4 doses), or ABT-122 0.5, 1.5, or 3 mg/kg weekly (8 doses) and were evaluated through 45 days after the last dose (day 92). Serum samples for the assessment of inflammation markers and chemokines were collected at baseline and on postdose days 3, 5, 8, 15, 29, 57, 64, 78, and 92.RESULTS:No clinically significant findings regarding the safety of ABT-122 were observed. The rates of treatment-emergent adverse events (AEs) were similar in patients receiving ABT-122 and those receiving placebo. Only 1 serious AE (and no systemic hypersensitivity reactions or dose-limiting toxicities) was observed in patients treated with ABT-122. The incidence of infections was similar between patients treated with ABT-122 and those receiving placebo, with no serious infection reported. The levels of CXCL9, CXCL10, CCL23, and soluble E-selectin were significantly decreased following ABT-122 treatment relative to placebo treatment. Although patients had essentially inactive RA, exploratory clinical parameters suggested potential antiinflammatory effects following treatment with ABT-122.CONCLUSION:The results of these phase I studies suggest that dual neutralization of TNF and IL-17 with ABT-122 has characteristics acceptable for further exploration of therapeutic potential in TNF- and IL-17A-driven immune-mediated inflammatory diseases.

Objective:To assess the antiviral activity, pharmacokinetics, and safety of doravirine in nonnucleoside reverse transcriptase inhibitor-naïve, HIV-infected men. Design:Double-blind, randomized, two-panel, dose-escalation study. Methods:In two sequential panels, 18 individuals received doravirine [25 mg (Panel A) or 200 mg (Panel B)] or matching placebo once daily for 7 days. Plasma samples were collected daily for measurement of HIV-1 RNA levels and doravirine pharmacokinetics. Results:For the mean change from baseline in HIV RNA (log10 copies/ml) at 24 h after the day 7 dose, the mean difference (90% confidence interval) between doravirine and placebo was –1.37 (–1.60, –1.14) in the 25-mg group and –1.26 (–1.51, –1.02) in the 200-mg group. None of the participants had viral breakthrough. Increases in mean AUC0–24 h, Cmax, and C24 h were slightly less than dose-proportional, with median Tmax of 1.0–2.0 h. Steady state was achieved after 3–5 days of once-daily dosing. At steady state, accumulation ratios (day 7/day 1) for AUC0–24 h, Cmax, and C24 h were 1.2–1.6. The calculated effective t1/2 (10–16 h) was similar to that in HIV-uninfected individuals. Adverse events were limited in number, transient, and generally mild to moderate in intensity. One participant had a serious adverse event of elevated liver enzymes (judged probably not drug related) in concurrence with a newly acquired hepatitis C infection. Conclusion:Doravirine monotherapy demonstrated robust antiviral activity at both dose levels, without evidence of viral resistance, and was generally well tolerated. Doravirine pharmacokinetics in HIV-infected individuals were similar to those in uninfected individuals receiving similar doses in prior studies.

Background TNF and IL-17 independently contribute to the pathophysiology of RA, synergistically inducing inflammatory mediators and joint destruction. Selective dual neutralization of TNF and IL-17 confers superior protection vs inhibition of either alone in mouse RA models. ABT-122 is a novel dual variable domain immunoglobulin (DVD-Ig™) targeting both human TNF and IL-17A and hypothesized to provide greater clinical responses in RA patients (pts). Objectives Investigate safety, tolerability, and exploratory pharmacodynamics of multiple doses of ABT-122 in pts with stable RA Methods Two phase 1, placebo (PBO)-controlled, multiple-dose studies randomized 43 pts with stable RA receiving stable methotrexate (7.5–25 mg/wk). Pts received subcutaneous PBO, ABT-122 1 mg/kg every other wk (4 doses), or ABT-122 0.5, 1.5, or 3 mg/kg weekly (8 doses), and were evaluated through 45 d after last dose. Serum for inflammation markers and chemokines, based on preclinical studies with dual TNF and IL-17 neutralization, was collected at baseline (BL) through d 92 and analyzed by multiplex assays. Results No clinically significant safety findings were observed. Rates of treatment-emergent AEs were similar in the ABT-122 and PBO groups, with no evidence of a dose response. There were no AE or serious AE trends, systemic hypersensitivity reactions, or dose-limiting toxicities with ABT-122. Infections were reported, as expected in RA, with no apparent patterns related to etiology, type, or dose with ABT-122 vs PBO, and no pt discontinued the study owing to infection. There were no clinically significant laboratory, vital sign, or ECG abnormalities. CXCL9 and CXCL10 decreased within 3 d of ABT-122 administration (−25% and −30% vs BL, respectively) relative to PBO. Maximal decreases occurred by d 15 (−60% and −45% for CXCL9 and CXCL10, respectively) and persisted through 14 d after last dose. CCL23 decreased following ABT-122, with maximal decreases (−30%) at d 64, and continued through d 92. Consistent with TNF inhibition, soluble E-selectin decreased following ABT-122, persisting through d 92 for the 3 mg/kg group. Conclusions ABT-122 demonstrated a well-tolerated safety profile in RA pts through 8 wk of dosing up to 3 mg/kg, consistent with the prior first-in-human study in healthy subjects. Because CXCL9, CXCL10, and CCL23 are involved in lymphocyte and myeloid cell recruitment into inflamed tissues, decreases in these chemokines indicate that ABT-122 rapidly modulates potential pathophysiologic pathways in RA pts, with evidence for persistent effects after cessation of dosing. These results suggest that dual neutralization of TNF and IL-17 may provide an opportunity to control inflammation and its clinical manifestations in RA and other immune-mediated inflammatory diseases. Acknowledgement The design, study conduct, analysis, and financial support of the clinical trials were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the content. All authors had access to all relevant data. Katherine Groschwitz and John Fincke of Complete Publication Solutions, LLC, provided medical writing support. ABT-122 is an investigational product. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Consultant for: AbbVie, F. Wagner: None declared, A. Kivitz Grant/research support from: AbbVie, H. Mansikka Shareholder of: AbbVie, Employee of: AbbVie, N. Khan Shareholder of: AbbVie, Employee of: AbbVie, J. Liu Shareholder of: AbbVie, Employee of: AbbVie, F. Hong Shareholder of: AbbVie, Employee of: AbbVie, M. Ruzek Shareholder of: AbbVie, Employee of: AbbVie, R. Padley Shareholder of: AbbVie, Employee of: AbbVie

Abstract Plant sterols (PS) lower LDL-cholesterol, an established risk factor for CHD. Endothelial dysfunction and low-grade inflammation are two important features in the development of atherosclerosis. Whether PS affect biomarkers of endothelial function and low-grade inflammation is not well studied. The aim of the present study was to investigate the effect of regular intake of PS on biomarkers of endothelial dysfunction and low-grade inflammation. In a double-blind, randomised, placebo-controlled, parallel-group study, which was primarily designed to investigate the effect of PS intake on vascular function (clinicaltrials.gov: NCT01803178), 240 hypercholesterolaemic but otherwise healthy men and women consumed a low-fat spread with added PS (3 g/d) or a placebo spread for 12 weeks. Endothelial dysfunction biomarkers (both vascular and intracellular adhesion molecules 1 and soluble endothelial-selectin) and low-grade inflammation biomarkers (C-reactive protein, serum amyloid A, IL-6, IL-8, TNF-α and soluble intercellular adhesion molecule-1) were measured using a multi-array detection system based on electrochemiluminescence technology. Biomarkers were combined using z-scores. Differences in changes from baseline between the PS and the placebo groups were assessed. The intake of PS did not significantly change the individual biomarkers of endothelial dysfunction and low-grade inflammation. The z-scores for endothelial dysfunction (−0·02; 95 % CI −0·15, 0·11) and low-grade inflammation (−0·04; 95 % CI −0·16, 0·07) were also not significantly changed after PS intake compared with placebo. In conclusion, biomarkers of endothelial dysfunction and low-grade inflammation were not affected by regular intake of 3 g/d PS for 12 weeks in hypercholesterolaemic men and women.

BACKGROUND AND AIMS:Plant sterols (PS) lower plasma LDL-cholesterol through partial inhibition of intestinal cholesterol absorption. Although PS themselves are poorly absorbed, increased intakes of PS result in elevated plasma concentrations. In this paper, we report time curves of changes in plasma PS during 12 weeks of PS intake. Furthermore, the impact of cholesterol synthesis and absorption on changes in plasma PS is explored.METHODS AND RESULTS:The study was a double-blind, randomized, placebo-controlled, parallel-group study with the main aim to investigate the effects of PS on vascular function (clinicaltrials.gov: NCT01803178). Hypercholesterolemic but otherwise healthy men and women (n = 240) consumed low-fat spreads without or with added PS (3 g/d) for 12 weeks after a 4-week run-in period. Blood sampling was performed at week 0, 4, 8 and 12. Basal cholesterol-standardized concentrations of lathosterol and sitosterol + campesterol were used as markers of cholesterol synthesis and absorption, respectively. In the PS group, plasma sitosterol and campesterol concentrations increased within the first 4 weeks of intervention by 69% (95%CI: 58; 82) starting at 7.2 μmol/L and by 28% (95%CI: 19; 39) starting at 11.4 μmol/L, respectively, and remained stable during the following 8 weeks. Placebo-corrected increases in plasma PS were not significantly different between high and low cholesterol synthesizers (P-values >0.05). Between high and low cholesterol absorbers, no significant differences were observed, except for the cholesterol-standardized sum of four major plasma PS (sitosterol, campesterol, brassicasterol and stigmasterol) showing larger increases in low absorbers (78.3% (95%CI: 51.7; 109.5)) compared to high absorbers (40.8% (95%CI: 19.9; 65.5)).CONCLUSIONS:Increases in plasma PS stabilize within 4 weeks of PS intake and do not seem impacted by basal cholesterol synthesis or absorption efficiency. This study was registered at clinicaltrials.gov (NCT01803178).

Background VAY736 is a novel, defucosylated, human IgG1 mAb targeting the receptor for B cell activating Factor of the TNF family (BAFF-R), providing both enhanced antibody-dependent cellular cytotoxicity (ADCC)-mediated depletion of B cells and blockade of BAFF:BAFF-R signaling that drives B cell differentiation, proliferation and survival. Objectives To clinically evaluate the clinical efficacy of the dual mechanisms of action of VAY736 in patients with pSS, a highly BAFF-driven, systemic autoimmune disease involving lymphocytic infiltration and progressive dysfunction of exocrine glands along with various extra-glandular manifestations. Methods A single center, randomized, parallel group, double-blind, placebo-controlled trial recruited 27 seropositive pSS patients with EULAR Sjögren9s Syndrome Disease Activity Index (ESSDAI) ≥6 and residual salivary flow over a 10-month period and randomized for treatment with intravenous VAY736 at either a single high dose, (n=12), a single lower dose (n=6), or with placebo (n=9). Outcomes were measured at baseline and at weeks 6, 12 and 24. The primary outcome was change in ESSDAI at week 12. Secondary outcomes included the EULAR Sjögren9s Syndrome Patient Reported Index (ESSPRI), Short Form-36 (SF-36), Multidimensional Fatigue Inventory (MFI) and global VAS assessments. Additional outcomes included salivary flow rates, Ocular Staining Score (OSS), high resolution salivary gland ultrasound (US) de Vita scores, serum markers of B cell hyperactivity and flow cytometry-determined lymphocyte subsets. Results Data analyses included all patients. VAY736 was safe and well-tolerated with no drug-related SAE, drop outs or discontinuations. Mean age was 50.5 years with 4 males, 2 in placebo and 1 in each treated arm. Baseline mean ESSDAI scores (range) were 11.5 (6–18), 14.5 (6–31) and 11.1 (6–19) in the high dose, lower dose and placebo arms, respectively. Rapid, profound depletion of circulating B cells was observed in all VAY736-treated patients. The primary endpoint of ESSDAI was reduced within 12 weeks but did not reach clinical or statistical significance. Improvements in VAY736-treated subjects were seen across the clinical secondary outcome measures, particularly for scores of patient and physician global assessments and SF-36 physical. Of note, the higher dose group had more sustained effects on clinical outcomes (e.g., ESSPRI, MFI) at weeks 6 and 12, while maximal effects in the lower dose group were more evident at the earlier week 6 time point, suggesting reduced VAY736 tissue exposure in some patients by week 12. PD measurements (serum BAFF levels, circulating B cells) confirmed target engagement. A trend in improvement of US scores occurred in the high dose group. There were no consistent changes in salivary flow rate or OSS. Analyses of additional biomarkers are pending. Conclusions Despite a limited, single infusion, VAY736 achieved in this early phase trial trends in the primary outcome and across all secondary outcomes. Thus, this treatment was safe and suggests a positive therapeutic effect for this dual mechanisms of action in pSS that warrant further evaluation. Disclosure of Interest T. Dörner: None declared, M. Posch: None declared, F. Wagner: None declared, A. Hüser: None declared, T. Fischer: None declared, L. Mooney Employee of: Novartis Pharma AG, O. Petricoul Employee of: Novartis Pharma AG, P. Maguire Employee of: Novartis Pharma AG, P. Pal Employee of: Novartis Pharma AG, J. Doucet Employee of: Novartis Pharma AG, M. Cabanski Employee of: Novartis Pharma AG, E. Kamphausen Employee of: Novartis Pharma AG, S. Oliver Employee of: Novartis Pharma AG

Background TNF and IL-17 independently contribute to the pathophysiology of RA, synergistically inducing inflammatory mediators and joint destruction. Selective dual neutralization of TNF and IL-17 confers superior protection vs inhibition of either alone in mouse RA models. ABT-122 is a novel dual variable domain immunoglobulin (DVD-Ig™) targeting both human TNF and IL-17A and hypothesized to provide greater clinical responses in RA patients (pts). Objectives Investigate safety, tolerability, and exploratory pharmacodynamics of multiple doses of ABT-122 in pts with stable RA Methods Two phase 1, placebo (PBO)-controlled, multiple-dose studies randomized 43 pts with stable RA receiving stable methotrexate (7.5–25 mg/wk). Pts received subcutaneous PBO, ABT-122 1 mg/kg every other wk (4 doses), or ABT-122 0.5, 1.5, or 3 mg/kg weekly (8 doses), and were evaluated through 45 d after last dose. Serum for inflammation markers and chemokines, based on preclinical studies with dual TNF and IL-17 neutralization, was collected at baseline (BL) through d 92 and analyzed by multiplex assays. Results No clinically significant safety findings were observed. Rates of treatment-emergent AEs were similar in the ABT-122 and PBO groups, with no evidence of a dose response. There were no AE or serious AE trends, systemic hypersensitivity reactions, or dose-limiting toxicities with ABT-122. Infections were reported, as expected in RA, with no apparent patterns related to etiology, type, or dose with ABT-122 vs PBO, and no pt discontinued the study owing to infection. There were no clinically significant laboratory, vital sign, or ECG abnormalities. CXCL9 and CXCL10 decreased within 3 d of ABT-122 administration (−25% and −30% vs BL, respectively) relative to PBO. Maximal decreases occurred by d 15 (−60% and −45% for CXCL9 and CXCL10, respectively) and persisted through 14 d after last dose. CCL23 decreased following ABT-122, with maximal decreases (−30%) at d 64, and continued through d 92. Consistent with TNF inhibition, soluble E-selectin decreased following ABT-122, persisting through d 92 for the 3 mg/kg group. Conclusions ABT-122 demonstrated a well-tolerated safety profile in RA pts through 8 wk of dosing up to 3 mg/kg, consistent with the prior first-in-human study in healthy subjects. Because CXCL9, CXCL10, and CCL23 are involved in lymphocyte and myeloid cell recruitment into inflamed tissues, decreases in these chemokines indicate that ABT-122 rapidly modulates potential pathophysiologic pathways in RA pts, with evidence for persistent effects after cessation of dosing. These results suggest that dual neutralization of TNF and IL-17 may provide an opportunity to control inflammation and its clinical manifestations in RA and other immune-mediated inflammatory diseases. Acknowledgement The design, study conduct, analysis, and financial support of the clinical trials were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the content. All authors had access to all relevant data. Katherine Groschwitz and John Fincke of Complete Publication Solutions, LLC, provided medical writing support. ABT-122 is an investigational product. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Consultant for: AbbVie, F. Wagner: None declared, A. Kivitz Grant/research support from: AbbVie, H. Mansikka Shareholder of: AbbVie, Employee of: AbbVie, N. Khan Shareholder of: AbbVie, Employee of: AbbVie, J. Liu Shareholder of: AbbVie, Employee of: AbbVie, F. Hong Shareholder of: AbbVie, Employee of: AbbVie, M. Ruzek Shareholder of: AbbVie, Employee of: AbbVie, R. Padley Shareholder of: AbbVie, Employee of: AbbVie

Background: Plant sterols (PSs) lower LDL cholesterol, an established risk factor for coronary artery disease (CAD). No direct evidence is available supporting a reduced risk of CAD for foods with added PSs. Endothelial dysfunction is seen as an early indicator of atherosclerotic damage. Objectives: This study was primarily designed to investigate the effect of a low-fat spread with added PSs on brachial artery endothelial function as measured by flow-mediated dilation (FMD). Second, effects on arterial stiffness, blood pressure, serum lipids, and plasma PS concentrations were investigated. We hypothesized that PSs would not worsen FMD but would rather modestly improve FMD. Design: This study had a double-blind, randomized, placebo-controlled, parallel design. After a 4-wk run-in period, 240 hypercholesterolemic but otherwise healthy men and women consumed 20 g/d of low-fat spread without (control) or with added PSs (3 g/d) during 12 wk. Pre- and postintervention, vascular function measurements and blood sampling were performed. Results: In total, 232 participants completed the study period. For the primary endpoint FMD, 199 participants were included in the statistical analysis. PS intake did not affect FMD (+0.01 percentage points; 95% CI: −0.73, 0.75) compared with control. Measures of arterial stiffness (pulse wave velocity and augmentation index) and blood pressure were also not significantly changed compared with control. After PS intervention, LDL cholesterol significantly decreased on average by 0.26 mmol/L (95% CI: −0.40, −0.12) or 6.7% compared with control. Plasma sitosterol and campesterol concentrations significantly increased in the PS group up to on average 11.5 μmol/L and 13.9 μmol/L (expressed as geometric means), respectively. Conclusions: The intake of a low-fat spread with added PSs neither improved nor worsened FMD or other vascular function markers in hypercholesterolemic men and women. As expected, serum LDL cholesterol decreased, whereas plasma PSs increased after PS intake. This study was registered at clinicaltrials.gov as NCT01803178.