Publikationen

The potential risk that bacteria, might become resistant to antibacterial medicines, has been already acknowledged by the pioneers of antibiotic research. In the 21st century, antimicrobial resistance has become a global public health problem - a silent pandemic that threatens mankind. In 2019, bacterial infections were associated with 7.7 million deaths, of which almost 1.27 million were directly attributable to antimicrobial drug resistance. In the same year, the WHO declared Antimicrobial Resistance as one of ten threats to global health.

Factors contributing to the antibiotic crisis are a low outcome of new antibiotic principles, infeasible trial conduct standards and economic limitations. As a consequence, big pharma divested own research and development over the last 20 years. Efforts to identify new active ingredients and mechanisms to overcome antimicrobial resistance have since been driven primarily by small and medium-sized companies. Recent R&D incentives in Europe and national efforts of scientists and regulatory bodies seek to tackle this big challenge.

The recent update (2024) of the WHO Bacterial Priority Pathogens includes 15 families of antibiotic resistant pathogens. Future development strategies should focus on antibiotics that are active against multidrug-resistant (especially carbapenem resistant) Gram-negative bacteria and tuberculosis. Particularly important antibiotic classes for the treatment of bacterial infections, whose efficacy must be maintained at all costs include 3rd to 5th generation cephalosporins and macrolides.

The current antibacterial clinical drug pipeline continues to be dominated by combinations of β-lactam antibiotics with ß-lactamase inhibitors and bacteriophages targeting WHO priority pathogens. Among the innovative agents there are two novel boronate-based serine ß-lactamase inhibitors (taniborbactam and xeruborbactam) which target also metallo-ß-lactamases which continue to grow in prevalence. As part of the national ‘Phage4Cure’ project, the clinical development of a bacteriophage-cocktail consisting of three phages directed against multidrug-resistant Pseudomonas aeruginosa was recently started at the Charité Research Organisation (Berlin, Germany).

Background and Objective

MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and  has demonstrated efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370.

Methods

This was a phase 1, randomised, placebo-controlled study conducted in three parts. In part A, participants received (3:1) a single ascending dose (SAD) of 1, 3, 10, 20, 40, 80, 160, 320, 640 and 1000 mg MHV370 or placebo. In part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200 and 400 mg MHV370 twice daily (b.i.d) or placebo for 14 days. In part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, pharmacokinetic and pharmacodynamic parameters were evaluated.

Results

MHV370 was well tolerated, and no safety signal was observed in the study. No dose-limiting adverse events occurred across the dose range evaluated. Plasma concentrations of MHV370 increased with dose (mean [SD] maximum plasma concentrations ranged from 0.97 [0.48] to 1670 [861.0] ng/mL for SAD of 3–1000 mg, 29.5 [7.98] to 759 [325.0] ng/mL for MAD of 25–400 mg b.i.d. on day 1). The intake of food did not have a relevant impact on the pharmacokinetics of MHV370. Pharmacodynamic data indicated time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells (100% inhibition at 24 h post-dose starting from SAD 160 mg and MAD 50 mg b.i.d.) and TLR8-mediated TNF release after ex vivo stimulation (>90% inhibition at 24 h post-dose starting from SAD 320 mg and MAD 100 mg b.i.d.).

Conclusion

The safety, pharmacokinetic and pharmacodynamic data support the further development of MHV370 in systemic autoimmune diseases driven by the overactivation of TLR7 and TLR8.

When 2019 the world community was unexpectedly overrun by a new coronavirus called SARS-CoV-2, the acute symptom-oriented treatment of the patients concerned as well as the containment of the virus-spread were in the foreground of activities. The underlying mechanism(s) of the diverse organ infestations was unclear and is still subject of research today. The first emerging virus variant was very aggressive and caused organ failure resulting in deaths, too many deaths.

Three years later, we are facing a multifaceted population that has been completely or partially vaccinated, experienced the illness one or more times or never had contact with the virus. Apparently the clinic copes with the acute symptoms of the infection today, the currently circulating virus variants seem to be more harmless. However, the initial concern that infection with the SARS-CoV-2 virus may lead to sustained or recurrent multi-organ symptoms and even failures is becoming more and more evident. Many patients experience extended COVID-19 symptomatology over weeks to months that is called post-acute COVID-19 syndrome or more commonly as Long-COVID.

There is currently no approved drug for the treatment of Long-COVID: The research for Long-COVID treatments has started mostly with small pilot studies, observations or case reports, mainly using marketed products to improve clinical symptoms of Long-COVID that are common in similar conditions such as the post-infectious myalgic-encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, more targeted interventions for Long-COVID based on evidence in controlled clinical trials are urgently required.

In this Review we discuss the current knowledge on Long-COVID. We describe how the pharmaceutical industry, medical device companies as well as academic research are now increasing their efforts to gain knowledge of risk factors and pathogenic triggers of Long-COVID with the scope to develop efficient and safe medicines to prevent and /or treat this burdensome disease.

Objective

Inhibiting sodium–glucose cotransporters (SGLTs) improves glycemic and cardiovascular outcomes in patients with type 2 diabetes (T2D). We investigated the differential impact of selective SGLT2 inhibition and dual inhibition of SGLT1 and SGLT2 on multiple parameters.

Research Design and Methods

Using a double-blind, parallel-group design, we randomized 40 patients with T2D and hypertension to receive the dual SGLT1 and SGLT2 inhibitor sotagliflozin 400 mg or the selective SGLT2 inhibitor empagliflozin 25 mg, with preexisting antihypertensive treatment, for 8 weeks. In an in-house testing site, mixed-meal tolerance tests (MMTTs) and other laboratory and clinical evaluations were used to study metabolic, intestinal, cardiovascular, and urinary parameters over 24 h.

Results

Changes from baseline in glycemic and blood pressure control; intestinal, urine, and metabolic parameters; and cardiovascular biomarkers were generally similar with sotagliflozin and empagliflozin. During the breakfast MMTT, sotagliflozin significantly reduced incremental area under the curve (AUC) values for postprandial glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) and significantly increased incremental AUCs for postprandial glucagon-like peptide 1 (GLP-1) relative to empagliflozin, consistent with sotagliflozin-mediated inhibition of intestinal SGLT1. These changes waned during lunch and dinner MMTTs. Both treatments significantly lowered GIP incremental AUCs relative to baseline over the 14 h MMTT interval; the most vigorous effect was seen with sotagliflozin soon after start of the first meal of the day. No serious or severe adverse events were observed.

Conclusions

Changes from baseline in glycemic and blood pressure control, cardiovascular biomarkers, and other parameters were comparable between sotagliflozin and empagliflozin. However, sotagliflozin but not empagliflozin inhibited intestinal SGLT1 after breakfast as shown by larger changes in postprandial glucose, insulin, GIP, and GLP-1 AUCs, particularly after breakfast. Additional study is warranted to assess the clinical relevance of transient SGLT1 inhibition and differences in incretin responses (NCT03462069).

Abstract

This prospective longitudinal epidemiological study was aimed at investigating the occupational SARS-CoV-2 infection risk of long distance train services in Germany. Three different employee groups (train attendants, train drivers and maintenance workers) within the workforce of the German railway carrier Deutsche Bahn Fernverkehr AG were studied based on their contact frequency with passengers and colleagues. Approximately 1100 employees were tested by PCR for acute infections and by antibody detection for past infections in June 2020, October 2020 and February 2021. Cumulative incidence (acute and past infections) after the third (final) test series in February 2021 was 8.5% (95% interval CI 6.8–10.4): 8.5% (95% CI 6.2–11.2) for train attendants, 5.5% (95% CI 2.9–9.5) for train drivers and 11.8% (95% CI 7.6–17.2) for maintenance workers. Between June 2020 and October 2020, the incidence was 1.2% (95% CI 0.6–2.3): 1.2% (95% CI 0.4–2.7) for train attendants, 1.1% (95% CI 0.1–3.9) for train drivers and 1.4% (95% CI 0.17–5.10) for maintenance workers. Between October 2020 and February 2021, it was 5.1% (95% CI 3.6–6.8): 5.2% (95% CI 3.3–7.8) for train attendants, 1.6% (95% CI 0.3–4.5) for train drivers and 8.8% (95% CI 4.9–14.3) for maintenance workers. Thus, contrary to expectation our exploratory data did not show train attendants to be at the highest risk of SARS-CoV-2 infections among the employee groups. In line with expectations, train drivers, representing the low contact group, seemed at lowest occupational risk.

Abstract

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity.
This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066:TRPCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066: TRPCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066:TRPCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066:TRPCB [MAXI]: 026; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066:TRPCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.

Indacaterol (IND), is co-formulated with glycopyrronium (GLY), and mometasone furoate (MF) as a once-daily (o.d.) inhaled fixed-dose combination (IND/GLY/MF) delivered via the Breezhaler® device for maintenance treatment of asthma. We evaluated the steady state plasma pharmacokinetics (PK) of IND, GLY and MF following inhalation of IND/GLY/MF or as monotherapies.

This was a randomized, open-label, four-way crossover study. Subjects received IND/GLY/MF 150/50/160 μg (high-dose), IND 150 μg, GLY 50 μg or MF 190 μg (in vitro fine particle mass comparable to 160 μg MF in IND/GLY/MF) via the Breezhaler® device, o.d. for 14 days in each period, with a washout of at least 7 days. PK was characterized on Day 14, up to 24 h post-dose.

In total, 36 healthy subjects were randomized. For IND, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.922 (0.878, 0.969) and 1.02 (0.967, 1.08), respectively for the IND/GLY/MF versus IND monotherapy comparison. For GLY, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.986 (0.944, 1.03) and 1.21 (1.09, 1.34), respectively for the IND/GLY/MF versus GLY comparison. For MF, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 1.16 (1.09, 1.24) and 1.17 (1.09, 1.25), respectively for IND/GLY/MF versus MF comparison. Similar systemic exposure was noted for IND/GLY/MF versus monotherapy for all three mono-components, indicating a lack of PK interaction. Multiple inhaled doses of IND, GLY and MF were safe and well tolerated, when administered alone or in combination.

There was no clinically relevant pharmacokinetic interaction between IND, GLY and MF when administered as IND/GLY/MF.

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 time point 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.

Aims

Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.

Methods and results

We studied the effects of danicamtiv on LV and LA function in non‐clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double‐blind, single‐ and multiple‐dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment‐emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to −1.0%, P < 0.05) and circumferential strain (up to −3.3%, P < 0.01), decreased LA minimal volume index (up to −2.4 mL/m2, P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo.

Conclusions

Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre‐clinical findings of direct activation of LA contractility.

Context

Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity.

Objective

To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects.

Design/setting

Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites.

Patients

Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs.

Intervention

Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50-300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2).

Main outcome measures

Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC0-4h]) post-mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2).

Results

Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0-4h post MMTT (least squares mean [90% CI], -21.52% [-25.68, -17.37] vs 6.32% [0.45, 12.20]; P < 0.001) and body weight (-3.41% [-4.37, -2.44] vs -0.08% [-1.45, 1.28]; P = 0.002). A significant increase in insulin AUC0-4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs -42.9 minutes; P = 0.0392).

Conclusion

These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying.

Background

Primary Sjögren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjögren's syndrome have shown efficacy. CD40–CD154-mediated T cell–B cell interactions in primary Sjögren's syndrome contribute to aberrant lymphocyte activation in inflamed tissue, leading to sialadenitis and other tissue injury. Therefore, we investigated the safety and preliminary efficacy of iscalimab (CFZ533), a novel anti-CD40 monoclonal antibody, in patients with primary Sjögren's syndrome.

Methods

This multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study took place at ten investigational sites across Europe (UK, n=4; Germany, Switzerland, and Hungary, n=1 each) and the USA (n=3). Eligible patients were aged 18–75 years and fulfilled the 2002 American European consensus group diagnostic classification criteria for primary Sjögren's syndrome. In the double-blind phase of the trial, patients were randomly assigned (2:1) via computer-generated unique randomisation numbers to receive subcutaneous iscalimab (3 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 1) or intravenous iscalimab (10 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 2). Randomisation was stratified according to baseline intake of oral corticosteroids. At week 12, patients in both cohorts received open-label iscalimab (same dose and route) for 12 weeks. The primary objectives of the study were to assess the safety, tolerability, and efficacy of multiple doses of iscalimab in the two sequential dose cohorts. Safety and tolerability were assessed by adverse events and efficacy of iscalimab versus placebo was assessed by clinical disease activity, as measured by the change in European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI) score after 12 weeks of treatment. Analyses were done on a per-protocol basis.

Findings

Between Oct 22, 2014, and June 28, 2016, we assessed 82 patients for eligibility (25 for cohort 1 and 57 for cohort 2). 38 patients were excluded because of ineligibility. In cohort 1, 12 patients were randomly assigned to receive either 3 mg/kg doses of iscalimab (n=8) or placebo (n=4), and in cohort 2, 32 patients were randomly assigned to receive either intravenous 10 mg/kg doses of iscalimab (n=21) or placebo (n=11). Adverse events were similar between iscalimab treatment groups and placebo groups, with adverse events occurring in all patients in cohort 1, and in 52% and 64% of the iscalimab and placebo groups, respectively, in cohort 2. Two serious adverse events were reported (one case of bacterial conjunctivitis in cohort 1 and one case of atrial fibrillation in cohort 2), which were unrelated to treatment with iscalimab. Intravenous treatment with iscalimab resulted in a mean reduction of 5·21 points (95% CI 0·96–9·46; one-sided p=0·0090) in ESSDAI score compared with placebo. There was no signficiant difference in ESSDAI score between subcutaneous iscalimab and placebo.

Interpretation

To our knowledge, this is the first randomised, placebo-controlled proof-of-concept study of a new investigational drug for primary Sjögren's syndrome that indicates preliminary efficacy. Our data suggest a role of CD40–CD154 interactions in primary Sjögren's syndrome pathology and the therapeutic potential for CD40 blockade in this disease should be investigated further.

Background

Islatravir (also known as ISL and MK-8591) is a unique nucleoside reverse transcriptase translocation inhibitor in clinical development for treatment of people with HIV-1 infection. In preclinical studies, intracellular islatravir-triphosphate exhibits a long half-life and prolonged virological effects. In this study, we aimed to assess islatravir safety, pharmacokinetics, and antiretroviral activity in treatment-naive adults with HIV-1 infection.

Methods

This open-label, consecutive-panel, phase 1b trial was done at Charité Research Organisation (Berlin, Germany) and included men and women (aged 18–60 years, inclusive) with HIV-1 infection who were ART naive. Participants were required to have plasma HIV-1 RNA counts of at least 10 000 copies per mL within 30 days before the trial treatment phase, without evidence of resistance to nucleoside reverse transcriptase inhibitors. Participants were enrolled in one of five consecutive dosing panels, receiving a single oral dose of islatravir (0·5–30 mg). The primary outcomes were safety and tolerability of islatravir and change from baseline in HIV-1 plasma RNA; secondary outcomes were islatravir plasma and islatravir-triphosphate intracellular pharmacokinetics. We obtained descriptive safety and pharmacokinetics statistics, and estimated efficacy results from a longitudinal data analysis model. This study is registered with ClinicalTrials.gov, NCT02217904, and EudraCT, 2014-002192-28.

Findings

Between Sept 17, 2015, and May 11, 2017, we enrolled 30 participants (six per panel). Islatravir was generally well tolerated. 27 (90%) participants had 60 adverse events after receipt of drug, of which 21 (35%) were deemed to be drug related. The most common (n>1) drug-related adverse events were headache (in nine [30%] participants) and diarrhoea (in two [7%]). No serious adverse events were reported, and no participants discontinued due to an adverse event. Plasma islatravir pharmacokinetics and intracellular islatravir-triphosphate pharmacokinetics were approximately dose proportional. The islatravir-triphosphate intracellular half-life was 78·5–128·0 h. Least-squares mean HIV-1 RNA at 7 days after dose decreased from 1·67 log 10 copies per mL (95% CI 1·42–1·92) at 10 mg dose to 1·20 log 10 copies per mL (0·95–1·46) at 0·5 mg dose. No genetic changes consistent with development of viral resistance were detected.

Interpretation

Single doses of islatravir as low as 0·5 mg significantly suppressed HIV-1 RNA by more than 1·0 log at day 7 in treatment-naive adults with HIV-1 infection and were generally well tolerated, supporting the further development of islatravir as a flexible-dose treatment for individuals with HIV-1 infection.

Background

Indacaterol (IND [LABA]), is co-formulated with glycopyrronium (GLY [LAMA]), and mometasone furoate (MF [ICS]) as a once daily (o.d.) fixed dose combination (IND/GLY/MF) delivered with the Breezhaler® device for maintenance treatment of asthma. We evaluated the steady-state plasma pharmacokinetics (PK) of IND, GLY and MF following inhalation of IND/GLY/MF o.d.

Methods

This was a randomised, open-label, four-way crossover study. Subjects received IND/GLY/MF 150/50/160 μg (high-dose ICS), IND 150 µg, GLY 50 µg or MF 190 µg (in vitro fine particle mass comparable to 160 μg MF in IND/GLY/MF) via the Breezhaler® device, o.d. for 14 days in each period, with a washout of at least 7 days. PK was characterised on Day 14 up to 24h post-dose.

Results

In total 36 healthy subjects were randomised. For IND, the geometric mean ratios (GMR) [90% CI] for AUC0-24h, ss and Cmax, ss were 0.922 [0.878, 0.969] and 1.02 [0.967, 1.08], respectively, for IND/GLY/MF vs IND monotherapy. For GLY, the GMR [90% CI] for AUC0-24h, ss and Cmax, ss were 0.986 [0.944, 1.03] and 1.21 [1.09, 1.34], respectively for IND/GLY/MF vs. GLY. For MF, the GMR [90% CI] for AUC0-24h, ss and Cmax, ss were 1.16 [1.09, 1.24] and 1.17 [1.09, 1.25], respectively for IND/GLY/MF vs. MF. Similar systemic exposure was noted for IND/GLY/MF vs. monotherapy comparison for all monocomponents, indicating a lack of PK interaction. Multiple inhaled doses of IND, GLY and MF were safe and well tolerated, when administered alone or in combination.

Conclusion

There was no clinically relevant pharmacokinetic interaction between IND, GLY and MF when administered as IND/GLY/MF.

Background 

The aetiology of dilated cardiomyopathy (DCM) is highly heterogeneous including genetic and/or acquired (infective, toxic, immune, endocrine, and nutritional) factors. The major part of acquired DCM in developed countries is caused by either viral or autoimmune myocarditis. It is believed that the activation of the T-lymphocyte cell system is the major pathomechanism underlying autoimmune myocarditis and inflammatory DCM (DCMi). However, in the hearts of a subset of patients, a significant number of CD20+ B-lymphocytes can be detected too. Limited information exists on the role of B-cell-dependent mechanisms in the progression of DCMi. Particularly CD20+ B-lymphocytes, which can be targeted by anti-CD20+ B-lymphocytes antibodies or inhibitors, might contribute to the pathogenesis of myocardial damage beyond antibody production.

Case summary 

Here, we present a case series of six patients with subacute and chronic endomyocardial biopsy-proven CD20+ B-lymphocyte-associated DCMi, where symptomatic heart failure therapy, with or without combined immunosuppressive therapy with steroid-based treatment regime, was insufficient to improve cardiac function. Five patients improved clinically several weeks after a standard infusion protocol with rituximab, a chimeric monoclonal antibody against the pan-B-cell surface molecule CD20.

Discussion 

Our case series shows that CD20+ B-lymphocyte persistence can play a pathophysiologic role in a subset of DCMi patients and highlights the potential of targeting CD20+ B cells in patients with prominent CD20+ B-lymphocyte persistence.

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.

Objective

The objective of this study was to characterize the effects of risankizumab on the in vivo activity of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in psoriasis patients using a cocktail approach.

Methods

Patients with moderate to severe chronic plaque psoriasis (n = 21) received single oral doses of sensitive probe substrates for CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) on day 1, followed by 12 weeks of subcutaneous risankizumab treatment of 150 mg once every 4 weeks from day 8 to day 92, and again the same cocktail of substrates on day 98. Serial blood samples were collected for determination of the CYP probe drugs and metabolites with and without risankizumab. Trough samples were collected for risankizumab.

Results

The 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞) ratios for the CYP probe substrates administered with risankizumab versus without risankizumab were within the default 0.8-1.25 equivalence bounds. Similar results were observed for maximum plasma concentration (Cmax), except for omeprazole, for which the lower bound of the 90% CI for Cmax (0.73) extended slightly below the default equivalence limit. No differences were observed in metabolite-to-parent drug Cmax or AUC ratios with risankizumab versus without risankizumab. Risankizumab trough plasma concentrations significantly exceeded those of the phase III regimen of risankizumab in psoriasis (150 mg subcutaneously at weeks 0 and 4 and every 12 weeks thereafter).

Conclusions

Risankizumab did not affect the in vivo activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A enzymes in patients with moderate or severe plaque psoriasis and therefore has no potential for drug interactions through these enzymes.

Objective

Hybrid Fc-fused rhGH (GX-H9) is a long-acting recombinant human growth hormone (GH) under clinical development for both adults and children with GH deficiency (GHD). We compared the safety, pharmacokinetics and pharmacodynamics of weekly and every other week (EOW) dosages of GX-H9 with those of daily GH administration in adult GHD (AGHD) patients.

Design

This was a randomized, open-label, active-controlled and dose-escalation study conducted in 16 endocrinology centers in Europe and Korea.

Methods

Forty-five AGHD patients with or without prior GH treatment were enrolled. Patients with prior GH treatments were required to have received the last GH administration at least 1 month prior to randomization. Subjects were sequentially assigned to treatment groups. Fifteen subjects were enrolled to each treatment group and randomly assigned to receive either GX-H9 or Genotropin (4:1 ratio). GX-H9 dosage regimens for Groups 1, 2 and 3 were 0.1 mg/kg weekly, 0.3 mg/kg EOW and 0.2 mg/kg EOW, respectively. All Genotropin-assigned subjects received 6 µg/kg Genotropin, regardless of treatment group. Main outcome analyses included measurements of serum insulin-like growth factor 1 (IGF-I), safety, pharmacokinetics, pharmacodynamics and immunogenicity.

Results

Mean GX-H9 peak and total exposure increased with an increase in dose after a single-dose administration. The mean IGF-I response was sustained above baseline over the intended dose interval of 168 h for the weekly and 336 h for the EOW GX-H9 groups. Safety profiles and immunogenicity were not different across the treatment groups and with Genotropin.

Conclusions

GX-H9 has the potential for up to twice-monthly administration.

Aims

To evaluate the safety, pharmacokinetics, and pharmacodynamics of SAR425899, a novel polypeptide active as an agonist at both the glucagon-like peptide-1 receptor (GLP-1 R) and the glucagon receptor, in healthy volunteers and in patients with overweight/obesity and type 2 diabetes.

Methods

Subcutaneous administrations of SAR425899 were tested in two randomized, placebo-controlled, double-blind clinical trials. In the first trial, healthy overweight volunteers (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 patients with overweight/obesity and type 2 diabetes (BMI: 28─42 kg/m2 ; n = 36) received daily doses of SAR425899 or placebo over 21 or 28 days, respectively.

Results

Adverse events reported most frequently were gastrointestinal; gastrointestinal side effects were less pronounced in patients compared with healthy volunteers. SAR425899 significantly reduced levels of fasting plasma glucose (P < .05 versus placebo) and glycated haemoglobin (P < .001 versus placebo) in patients. 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 (P < .001 versus placebo) at end of treatment.

Conclusions

SAR425899 was well tolerated and led to favourable glycaemic effects in patients with type 2 diabetes and weight reduction in both healthy volunteers and patients. Whether dual GLP-1 R/glucagon receptor agonism represents a treatment modality superior to pure GLP-1 R agonists for obesity and diabetes treatment remains to be confirmed.

Background

Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes.

Methods

This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18-65 years with controlled type 2 diabetes (glycated haemoglobin A1c [HbA1c] levels of 6·5-8·5% at screening) and a body-mass index between 27 kg/m2 and 40 kg/m2. An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2:1 in cohorts A-C and 3:1 in cohorts D and E in the MAD portion of the study, and 1:1 in the phase 2a portion. Randomisation was done by a contracted third-party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 μg for 22 days or less in the MAD portion of the study, and a dose of no more than 200 μg for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0-4 h (AUC0-4 h) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02548585.

Findings

Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC0-4 h post MMTT decreased significantly with MEDI0382 versus placebo (least squares [LS] mean -32·78% [90% CI -36·98 to -28·57] vs -10·16% [-14·10 to -6·21], and the mean difference was -22·62% [-28·40 to -16·85]; p<0·0001). In the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean -3·84 kg [90% CI -4·55 to -3·12] vs -1·70 kg [-2·40 to -1·01] and mean difference of 2·14 kg [-3·13 to -1·31]; p=0·0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 [88%] of 25 in the MEDI0382 group vs 23 [88%] of 26 in the placebo group); gastrointestinal disorders (18 [72%] vs 13 [40%]) and decreased appetite (five [20%] vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two [8%] in the placebo group).

Interpretion

MEDI0382 has the potential to deliver clinically meaningful reductions in blood glucose and bodyweight in obese or overweight individuals with type 2 diabetes.

Funding

MedImmune

Aims

MEDI0382 is a balanced glucagon-like peptide-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus and non-alcoholic steatohepatitis. The primary objective was to assess the safety of MEDI0382 in healthy subjects.

Methods

In this placebo-controlled, double-blind, phase 1 study, healthy subjects (aged 18-45 years) were randomised (3:1) to receive a single subcutaneous dose of MEDI0382 or placebo after ≥8 hours of fasting. The study consisted of six cohorts that received study drug at 5 μg, 10 μg, 30 μg, 100 μg, 150 μg, or 300 μg. The primary objective was safety and tolerability. Secondary endpoints included assessments of pharmacokinetics and immunogenicity. All subjects were followed for up to 28 days.

Results

A total of 36 subjects received MEDI0382 (n = 6 per cohort) and 12 subjects received placebo (n = 2 per cohort). Treatment-emergent adverse events (TEAEs) occurred more frequently with MEDI0382 vs placebo, which was mostly due to an increased occurrence at MEDI0382 doses ≥150 μg. All TEAEs were mild or moderate in severity. The most common TEAEs were vomiting, nausea, and dizziness. There appeared to be a dose-dependent increase in heart rate with MEDI0382 treatment. MEDI0382 showed linear pharmacokinetic profile (time to maximum plasma concentration: 4.50-9.00 hours; elimination half-life: 9.54-12.07 hours). No immunogenicity was observed in the study.

Conclusions

In this single-dose, phase 1 study in healthy subjects, the safety and pharmacokinetic profiles of MEDI0382 support once-daily dosing and further clinical development of MEDI0382.

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. 

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.

Aims

Progressive aortic stiffening eventually leads to left ventricular (LV) hypertrophy and heart failure if left untreated. Anti-hypertensive agents have been shown to reverse this to some extent. The effects of sacubitril/valsartan (LCZ696), a dual-action angiotensin receptor blocker (ARB), and neprilysin inhibitor, on arterial stiffness and LV remodelling have not been investigated.

Methods and results

This was a randomized, multi-centre, double-blind, double-dummy, active-controlled, parallel group, study to compare the effects on cardiovascular remodelling of sacubitril/valsartan with those of olmesartan in patients with hypertension and elevated pulse pressure. Magnetic resonance imaging scans were used to assess LV mass and local aortic distensibility, at baseline and at 12 and 52 weeks after initiation of treatment. Central pulse and systolic pressure were determined using a SphymoCor® XCEL device at each time point. A total of 114 patients were included, with 57 in each treatment group. The mean age was 59.8 years, and 67.5% were male. Demographic characteristics did not vary between the two sets of patients. Left ventricular mass index decreased to a greater extent in the sacubitril/valsartan group compared to the olmesartan group from baseline to 12 weeks (-6.36 vs. -2.32 g/m2; P = 0.039) and from baseline to 52 weeks (-6.83 vs. -3.55 g/m2; P = 0.029). These differences remained significant after adjustment for systolic blood pressure (SBP) at follow-up (P = 0.036 and 0.019 at 12 and 52 weeks, respectively) and similar signals (though formally non-significant) were observed after adjusting for changes in SBP (P = 0.0612 and P = 0.0529, respectively). There were no significant differences in local distensibility changes from baseline to 12 or 52 weeks between the two groups; however, there was a larger reduction in central pulse pressure for the sacubitril/valsartan group compared to the olmesartan group (P = 0.010).

Conclusion

Since LV mass change correlates with cardiovascular prognosis, the greater reductions in LV mass indicate valuable advantages of sacubitril/valsartan compared to olmesartan. The finding that LV mass index decrease might be to some extent independent of SBP suggests that the effect of the dual-acting agent may go beyond those due to its BP-lowering ability.

Purpose

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.

Methods

Healthy male subjects (n = 72) were randomised 3:1, within each BI 655064 dose group, to single intravenous (IV; 0.2-120 mg) or subcutaneous (SC; 40-120 mg) doses of BI 655064 or placebo. Safety, plasma exposure, CD40 receptor occupancy and CD40L-induced CD54 upregulation were assessed over 12 weeks.

Results

Adverse events (AEs) were reported in 43% of subjects (n = 31). Frequency and intensity of AEs were generally similar between BI 655064 and placebo and showed no dose relationship. The most frequent AEs were headache and nasopharyngitis. One mild rash and one local reaction occurred with SC BI 655064; two serious AEs were reported, both judged unrelated to BI 655064. Pharmacokinetic evaluation demonstrated a more than proportional increase in plasma exposure relative to BI 655064 dose, with a terminal half-life between 4 h and 4 days IV and approximately 5 days SC; doses ≥ 20 mg IV and 120 mg SC showed > 90% CD40 receptor occupancy and inhibition of CD54 upregulation, which lasted 7 days in the 120 mg IV and SC groups.

Conclusions

Single doses up to 120 mg BI 655064 IV and SC were well tolerated and showed a high potential to block the CD40-CD40L pathway, supporting further clinical development of BI 655064 in patients with autoimmune disease.

Background/Purpose

Primary Sjogren’s syndrome (pSS) is a systemic, progressive autoimmune disease characterized by formation of ectopic germinal centers in exocrine glands and secretory gland dysfunction. A subset of patients also develops extraglandular manifestations. CFZ533 is a novel monoclonal antibody that potently and selectively blocks CD40, a co-stimulatory pathway receptor essential for germinal center reactions and other immune mediated functions implicated in pSS pathogenesis. We conducted a randomized, double–blind, placebo-controlled, multi-centric, partial cross-over Phase IIa Proof of Concept (PoC) study to evaluate the safety, tolerability and efficacy of CFZ533 in patients with pSS.

Methods

Clinically active (EULAR Sjögren’s Syndrome Disease Activity Index [ESSDAI]≥6) pSS patients were randomized to receive four doses of 3 mg/kg s.c. CFZ533 or placebo (2:1, Cohort 1) or 10 mg/kg i.v. CFZ533 or placebo (2:1, Cohort 2) over 12 weeks in Period 1. Four additional doses of 3 mg/kg s.c. CFZ533 or 10 mg/kg i.v. CFZ533, respectively, were administered in an open label extension (Period 2) for 12 weeks. Key outcomes included safety and efficacy as assessed by change in ESSDAI after 12 weeks treatment. In addition, measurements of pharmacokinetics and pharmacodynamics (PK/PD) of CFZ533, EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), Multi-dimensional Fatigue Inventory (MFI), Physician’s Global Assessment, Patient’s Global Assessment, SF-36, and biomarkers of pSS were monitored.

Results

Forty-four patients were enrolled: 8 patients received 3 mg/kg s.c. CFZ533 and 4 placebo in Cohort 1 and 21 received 10 mg/kg i.v. CFZ533 and 11 placebo in Cohort 2. While PK/PD was as expected in the CFZ533 10 mg/kg i.v. cohort based on healthy volunteer data from the first in human trial, CFZ533 exposure appeared lower than expected in the 3 mg/kg s.c. cohort, likely due to target mediated disposition. Overall, CFZ533 was safe and well tolerated, and the majority of AEs were mild or moderate. There was a single serious AE (bacterial conjunctivitis) in the 3 mg/kg s.c. cohort that was not related to study drug. In Cohort 1, ESSDAI was observed to improve by approximately 2 points from mean baseline scores of approximately 12 in both placebo and 3 mg/kg s.c. groups, with therefore no evidence of treatment difference (ΔESSDAI=0.68, 95% CI = -4.71 – 6.46). However in Cohort 2, the improvement in ESSDAI from mean baselines of approximately 11 was observed to be 6.35 in the 10 mg/kg i.v. group compared to 1.27 in the placebo group, with the modelled difference between groups of ΔESSDAI=5.64 (95% CI=1.02 – 10.58) strongly favoring the CFZ533 i.v. treatment. Improvements in other measures such as ESSPRI, MFI, Physician’s Global Assessment, and Patient’s Global Assessment and decreases in the germinal center-related serum biomarker CXCL13 were also observed in the 10 mg/kg i.v. CFZ533 group.

Conclusion

In this proof of concept study, testing a blocking, non-depleting anti-CD40 antibody for the first time in primary Sjögren`s syndrome, results suggest that CFZ533 may offer a new treatment modality in clinically active pSS.

Objective

The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus.

Methods

A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18–65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials).

Results

All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets.

Conclusions

Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells.

Registration

ClinicalTrials.gov: NCT01686555.

Objective

This first-in-human, randomized, double-blind, placebo-controlled trial assessed the safety of NNC0114-0005, a human recombinant anti interleukin (IL)-21 monoclonal antibody, for the treatment of rheumatoid arthritis (RA).

Methods and Materials

Healthy male subjects (HS (n = 44)) and patients with active RA treated with methotrexate (n = 20) were randomized 3 : 1 to single IV or SC doses of NNC0114-0005 (0.0025 - 25 mg/kg) or placebo. Safety endpoints, pharmacokinetics, and pharmacodynamics were assessed over 12 weeks.

Results

All study participants were analyzed. 37 AEs were reported in 21 NNC0114-0005-treated participants (44%) and 18 AEs in 10 placebo-treated participants (63%), with no dose-dependency. The most common AEs were headache and nasopharyngitis; there were no injection-site reactions Linear pharmacokinetics of NNC0114-0005 were indicated (mean terminal half-life, 2 - 3 weeks). Dose-dependent total IL-21 (free IL-21 and IL-21‒NNC0114-0005 complexes) accumulation was observed. Preliminary signs of reduced RA activity were observed with 25 mg/kg NNC0114-0005.

Conclusions

Single doses of NNC0114-0005 (≤ 25 mg/kg IV; ≤ 4 mg/kg SC) were well tolerated in HS and patients with RA. Accumulation of IL-21-containing complexes suggests neutralization of the target cytokine. Based< on this trial, further trials to explore the efficacy of anti-IL-21 were initiated.

Background and objective

Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects.

Methods

Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25).

Results

Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related.

Conclusions

No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications.

Background

GSK3532795 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor that targets HIV-1 Gag, inhibiting the final protease cleavage between capsid protein p24 and spacer protein-1, producing immature, noninfectious virions.

Methods

This was a phase 2a, randomized, dose-ranging multipart trial. In part A, subtype B-infected subjects received 5-120 mg GSK3532795 (or placebo) once daily for 10 days. In part B, subtype B-infected subjects received 40 mg or 80 mg GSK3532795 once daily with atazanavir (ATV) with or without (±) ritonavir (RTV) or standard of care (SOC) (tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and ATV/RTV 300 mg/100 mg) for 28 days. In part C, subtype C-infected subjects received 40 mg or 120 mg GSK3532795 once daily (or placebo) for 10 days. Endpoints included change in HIV-1 RNA from baseline on day 11 (parts A/C) or day 29 (part B).

Results

A >1 log10 median decline in HIV-1 RNA was achieved by day 11 in parts A and C and day 29 in part B at GSK3532795 doses ≥40 mg; part B subjects receiving GSK3532795 and ATV ± RTV achieved similar declines to those receiving SOC. Median of the maximum declines in HIV-1 RNA were similar for the 40-120 mg once-daily dose groups regardless of baseline Gag polymorphisms. There were no deaths, adverse events leading to discontinuation, or serious adverse events.

Conclusions

GSK3532795 demonstrated potent antiviral activity against subtype B (monotherapy or with ATV ± RTV) and subtype C, and was generally well tolerated, which supported continued development of GSK3532795 in subjects with HIV-1 subtype B or subtype C.

Clinical Trial Registration

NCT01803074

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 Sjögren's 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 Sjögren's 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.

GLP-1 agonists are well-established treatments to achieve glycemic control associated with weight loss in type 2 diabetes mellitus (T2DM) patients. Early clinical experimentation with the endogenous dual GLP-1/glucagon receptor agonist oxyntomodulin suggests superior weight loss is achievable trough this combination. SAR425899 is a novel entity with agonistic activity on both receptors. Clinical development started in 2014 with a single ascending dose (SAD) study in healthy subjects and a combined multiple ascending dose study in healthy subjects (MAD-1) and T2DM patients (MAD-2, NCT02411825). Studies were placebo controlled, randomized and double blind. SAD: 32 subjects were randomized to receive sequentially one out of five SAR425899 doses (0.01, 0.03, 0.05, 0.075 and 0.1 mg, subcutaneously) or placebo. Drug exposure and C increased roughly dose proportionally, half-life was around 15 hours. Glucose levels following a mixed meal test were lowered by SAR425899 at doses >0.03mg. Adverse events (AE) related to gastrointestinal disorders (GI) were reported most often. Heart rate increased at doses > 0.05 mg. MAD-1: 40 subjects were treated with one out of five dose regimens (0.025 - 0.05 - 0.075, 0.05 - 0.075 - 0.01, 0.05 - 0.1 - 0.15, 0.05 - 0.1 - 0.2 and 0.06 - 0.12 - 0.18 mg SAR425899) over 21 days including two uptitration steps. FPG, PPG and body weight were lowered at all doses with maximal weight loss at highest dose. Dose-dependent GI AEs were observed most frequently and increased heart rate and a few cases of mild plasma level elevations of lipase were noted for all dose groups. MAD-2: 36 overweight to obese subjects with T2DM were included to receive one out of two dose regimens, 0.03 - 0.06 - 0.09 or 0.06 - 0.12 - 0.18 mg SAR425899, over 28 days with uptitration after day 7 and 14. The pattern of AEs was similar to those observed in healthy subjects while heart rate elevation and loss of body weight was less pronounced.

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

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 BI655066 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 BI655066-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.

Objectives

To determine the safety, pharmacokinetics (PK), and immunogenicity of the recombinant human monoclonal antibody MOR103 to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with multiple sclerosis (MS) with clinical or MRI activity.

Methods

In this 20-week, randomized, double-blind, placebo-controlled phase 1b dose-escalation trial (registration number NCT01517282), adults with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) received an IV infusion of placebo (n = 6) or MOR103 0.5 (n = 8), 1.0 (n = 8), or 2.0 (n = 9) mg/kg every 2 weeks for 10 weeks. Patients had to have ≤10 gadolinium (Gd)-enhancing brain lesions on T1-weighted MRI at baseline. The primary objective was safety.

Results

Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The most frequent was nasopharyngitis. Between-group differences in TEAE numbers were small. There were no TEAE-related trial discontinuations, infusion-related reactions, or deaths. Nine patients experienced MS exacerbations: 3, 5, 1, and 0 patient(s) in the placebo, 0.5, 1.0, and 2.0 mg/kg groups, respectively. A few T1 Gd-enhancing lesions and/or new or enlarging T2 lesions indicative of inflammation were observed in all treatment groups. No clinically significant changes were observed in other clinical assessments or laboratory safety assessments. No anti-MOR103 antibodies were detected. PK evaluations indicated dose linearity with low/no drug accumulation over time.

Conclusions

MOR103 was generally well-tolerated in patients with RRMS or SPMS. No evidence of immunogenicity was found.

Classification of evidence

This phase 1b study provides Class I evidence that MOR103 has acceptable tolerability in patients with MS.

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, bloodpressure, 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 vascularfunction 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.

Objective

The objective of this paper is to investigate the safety, pharmacokinetics (PK) and immunogenicity of CDP7657, a PEGylated anti-CD40L antibody fragment, in healthy individuals and patients with systemic lupus erythematosus (SLE).

Methods

This randomized, double-blind, single-dose, dose-escalation phase I study consisted of two parts. In part 1, 28 healthy individuals received CDP7657 IV (0.004-5 mg/kg) or placebo. In part 2, 17 patients with SLE received CDP7657 IV (5-60 mg/kg) or placebo. The CDP7657:placebo ratio was 3:1.

Results

Adverse events (AEs) were reported by 76% of healthy individuals and 100% of patients with SLE treated with CDP7657; most were mild or moderate in intensity. Two healthy individuals reported serious AEs (SAEs), one of which was considered treatment related (infusion-related reaction; 5 mg/kg cohort). One patient with SLE (60 mg/kg cohort) experienced three SAEs, one of which was considered treatment related (herpes zoster infection). No thromboembolic events were reported. CPD7657 exposure increased in a dose-proportional manner. Low anti-CDP7657 antibody titres were detected in the majority of CDP7657-treated participants with no apparent impact on the PK of CDP7657.

Conclusion

Single doses of CDP7657 showed predictable PK in healthy individuals and patients with SLE and were well tolerated, with no safety signals of concern. These findings support further investigation of CDP7657 as a therapy for SLE.

Aim

Fingolimod, a sphingosine 1-phosphate receptor modulator, is the first oral disease modifying therapy approved for the treatment of relapsing multiple sclerosis. The aim of this double-blind, placebo-controlled study was to evaluate the effect of fingolimod on cerebral blood flow, platelet function and macular thickness in healthy volunteers.

Methods

The study included 88 healthy volunteers who received fingolimod 0.5 mg or 1.25 mg or matched placebo over a period of 4 weeks. Transcranial colour coded sonography was performed to measure mean blood flow velocities, the platelet function was measured by the PFA-100® assay using a collagen/epinephrine cartridge and macularthickness was measured using optical coherence tomography. An assessment of non-inferiority of fingolimod vs. placebo was performed against a reference value (20% of the overall baseline value).

Results

All 88 randomized participants completed the study. At day 28 compared with baseline value, for 0.5 mg, 1.25 mg and placebo treatments, the mean middle cerebral artery blood flow velocity decreased by 4, 1 and 3.7 cm s(-1), respectively. The platelet function analyzer closure time increase was not significant (7.8, 7.5 and 10.4 s, respectively). The mean percentage change in the central foveal thickness from baseline for both eyes was below 3% for all groups. The safety profile of fingolimod in this study was found consistent with the previous reports.

Conclusions

In healthy volunteers, the changes seen with both fingolimod doses were found to be within normal variability, non-inferior and comparable with those observed with placebo for all the pharmacodynamic parameters assessed.

Aims

The PDY6797 study evaluated efficacy, safety and pharmacodynamics of lixisenatide in Japanese and Caucasianpatients with type 2 diabetes mellitus (T2DM) insufficiently controlled with sulphonylureas with/without metformin.

Methods

This randomized, double-blind, placebo-controlled trial comprised a single-dose assessment of lixisenatide 5 and 10 µg, and a 5- to 6-week repeated dose-escalation assessment of lixisenatide 5 to 30 µg once (QD) or twice daily (BID). The primary endpoint was change in postprandial plasma glucose (PPG) area under the curve (AUC)[0:29-4:30 h] after a standardized breakfast at the highest tolerated lixisenatide dose. Change from baseline in glycated haemoglobin (HbA1c), 2-h PPG and fasting plasma glucose (FPG) were assessed, as were adverse events.

Results

Change from baseline in PPG AUC[0:29-4:30 h] with lixisenatide QD and BID was significantly greater than placebo (p < 0.0001 for all study populations), with particularly prominent effects in Japanese patients. Greater reductions in PPG AUC[0:29-4:30 h] were seen with lixisenatide QD versus BID, while the totality of evidence suggested that the lixisenatide 20 µg dose was optimal. In the overall population, changes from baseline for 2-h PPG, HbA1c and FPG were significant with lixisenatide QD and BID versus placebo (p < 0.01 for all). Lixisenatide was well tolerated.

Conclusions

Lixisenatide significantly reduced PPG AUC[0:29-4:30 h] versus placebo at the highest well-tolerated dose in patients with T2DM treated with sulphonylureas with/without metformin and had a good safety and tolerability profile. Japanese patients experienced particular benefits with lixisenatide in terms of reductions in PPG excursions.

In order to evaluate the potential for CYP3A4 induction by moxidectin, midazolam pharmacokinetic (PK) parameters were compared before and after moxidectin administration. Healthy subjects received a single 8 mg dose of moxidectin and 3 single 7.5 mg doses of midazolam 3 days before, and 7 and 89 days after the moxidectin. Blood samples were taken for 24 hours to measure midazolam and metabolites in plasma, and for 89 days to measure moxidectin in plasma after dose administration. Noncompartmental PK analyses were performed for each analyte. Analysis of variance was performed on log-transformed midazolam parameters with treatment day as a fixed effect. Adverse events were recorded and laboratory tests, physical examinations, pulse oximetry monitoring, vital sign measurement, and electrocardiograms performed. Thirty-nine subjects were enrolled in the study; PK data were available for 37 subjects. Moxidectin PK parameters were similar to previous studies. There were no significant changes in PK for midazolam or its metabolites 7 or 89 days after moxidectin administration. Adverse events were generally mild and there were no relevant changes in safety assessments. Thus, 8 mg moxidectin does not induce CYP3A4 activity and other CYP3A4 substrates are unlikely to be affected by moxidectin co-administration.

Dabigatran, a specific, reversible direct thrombin inhibitor, is used to prevent ischaemic and haemorrhagic strokes in patients with atrial fibrillation. As with every anticoagulant, there is a need to rapidly reverse its effects in emergency situations. In an open-label, single-centre phase I study with two fixed multiple dosing periods, we investigated the pharmacokinetics, pharmacodynamics and safety of dabigatran before, during and after 4 hour haemodialysis sessions with either 200 or 400 ml/min targeted blood flow in seven end-stage renal disease patients without atrial fibrillation. Dabigatran was administered over three days in a regimen designed to achieve peak plasma concentrations comparable to those observed in atrial fibrillation patients receiving 150 mg b.i.d. and to attain adequate distribution of dabigatran in the central and peripheral compartments. Plasma concentration-time profiles were similar in both periods on Day 3 (Cmax: 176 and 159 ng/ml). Four hours of haemodialysis removed 48.8% and 59.3% of total dabigatran from the central compartment with 200 and 400 ml/minute targeted blood flow, respectively. The anticoagulant activity of dabigatran was linearly related to its plasma levels. There was a minor redistribution of dabigatran (<16%) after the end of the haemodialysis session. In conclusion, a 4 hour haemodialysis session can rapidly eliminate a substantial amount of dabigatran from the central compartment with a concomitant marked reduction in its anticoagulant activity. There was a clinically negligible redistribution of dabigatran after haemodialysis. These results demonstrate that haemodialysis can be a suitable approach to eliminate dabigatran in emergency situations.

Background

Allergen-specific TH2 responses contribute to the development of allergic asthma. Their increase may be due to a reduced early exposure to environmental pathogens, which induces a TH1 response, and thereby suppresses the allergic TH2 response. QbG10 (bacteriophage Qbeta-derived virus-like particle with CpG-motif G10 inside), a novel Toll-like receptor 9 agonist packaged into virus-like particles, was designed to stimulate the immune system toward a TH1-mediated protective response.

Objective

We examined clinical efficacy, safety, and tolerability of QbG10 with patient-reported and objective clinicaloutcome parameters in patients with mild-to-moderate persistent allergic asthma.

Methods

In this proof-of-concept parallel-group, double-blind, randomized trial, 63 asthmatic patients followed conversion to a standardized inhaled steroid and were treated with 7 injections of either QbG10 or placebo. Incorporating a controlled steroid withdrawal, the effects on patient-reported (day- and nighttime asthma symptoms, salbutamol usage, and 7-item-Asthma Control Questionnaire scores) and objective clinical outcome measures (FEV1, fraction of exhaled nitric oxide, and blood eosinophils) were assessed over 12 weeks (ClinicalTrials.gov number, NCT00890734).

Results

All patient-reported parameters improved overall between week 0 and 12 in QbG10-treated patients (n = 33) despite steroid withdrawal, compared with deteriorations observed under placebo (n = 30, P < .05). At week 12, two thirds of the QbG10-treated patients had their asthma "well controlled" (Asthma Control Questionnaire score ≤0.75) compared with one third under placebo. FEV1 had worsened to a clinically significant extent in patients on placebo, while it remained stable in QbG10 patients. Adverse events were mostly injection site reactions occurring after QbG10administration.

Conclusion

Treatment with QbG10 may contribute to continued asthma control during steroid reduction in patients on moderate or high-dose inhaled steroids.

Background

Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE) ≤700 IU/ml. To extend current dosing tables, we evaluated the potential of high omalizumab doses to block allergen-induced bronchoconstriction in patients with higher IgE levels.

Methods

Asthmatic adults (18-65 years; body weight 40-150 kg) were divided into groups according to screening IgE (group 1: 30-300 IU/ml; group 2: 700-2,000 IU/ml) and randomized 2:1 to omalizumab/placebo every 2 or 4 weeks for 12-14 weeks. Allergen bronchoprovocation (ABP) testing was performed before treatment and at weeks 8 and 16. The primary efficacy endpoint, the early-phase allergic response (EAR), was defined as the maximum percentage drop in forced expiratory volume in 1 s during the first 30 min after ABP. Serum free IgE was determined as a pharmacodynamic endpoint, and the exhaled fractional concentration of nitric oxide (FE(NO)) was an exploratory endpoint.

Results

Fifty patients were included in the study. Omalizumab improved EAR; at week 8, EAR was 23.1% for placebo, 9.3% in group 1 (p = 0.018 versus placebo) and 5.6% in group 2 (p < 0.001). At week 16, EAR was 20%, 11.8% (p = 0.087) and 5.1% (p < 0.001), respectively. Free IgE decreased in groups 1 and 2 and remained <50 ng/ml in all patients during weeks 6-16. Omalizumab completely suppressed FE(NO) increases after ABP in both groups.

Conclusions

Omalizumab blocked early asthmatic responses over a broad range of IgE/body weight combinations. Extending the dosing tables enables omalizumab to benefit a wider range of patients.

Objectives

The aim of this study was to compare the single-dose effects of thiazide-type diuretics cicletanine and hydrochlorothiazide (HCTZ), on natriuresis and kaliuresis in prehypertensive and treatment-naïve, stage 1 hypertensivepatients and to explore the impact of GRK4 gene polymorphisms on thiazide-induced urinary electrolyte excretion.

Methods

The study was a randomized, double-blind, placebo-controlled, three-period, four-treatment, balanced incomplete block, cross-over study in male patients assigned to treatment sequences consisting of placebo, cicletanine50 mg, cicletanine 150 mg, and HCTZ 25 mg, doses used to treat hypertension. Cumulative urine samples were collected predosing and over 24 h after dosing in each period to compare urine electrolyte excretion profiles of potassium (UKV), sodium (UNaV), magnesium, calcium, phosphate, chloride, and pH among groups. Each treatment was administered to 18 different patients in each period, and an equal number of patients had less than and at least three GRK4 allele variants.

Results

Compared with placebo, mean UKV was significantly increased with HCTZ 25 mg (12.7 mmol/day; P ≤ 0.001), cicletanine 50 mg (4.6 mmol/day; P = 0.026), and cicletanine 150 mg (5.5 mmol/day; P = 0.011), and mean UNaV was significantly increased with HCTZ 25 mg (102.2 mmol/day; P ≤ 0.001), cicletanine 50 mg (21.7 mmol/day; P = 0.005), and cicletanine 150 mg (57.9 mmol/day; P ≤ 0.001).

Conclusion

All treatments had more natriuresis, diuresis, and kaliuresis than placebo, and both doses of cicletaninehad less kaliuresis than HCTZ. These findings suggest that cicletanine is a favorable and well tolerated option for the treatment of hypertension with an improved safety profile compared with HCTZ.

Introduction 

MK-5172 is a novel, HCV NS3/4A protease inhibitor with potent activity against multiple genotypes (GT) in development for the treatment of chronic HCV infection. In a combined single and multiple ascending-dose study in healthy subjects, MK-5172 was shown to be well-tolerated and exhibited a pharmacokinetic (PK) profile supportive of once-daily (QD) dosing. The pharmacokinetics and pharmacodynamics (i.e., anti-viral efficacy) following QD administration of MK-5172 monotherapy to patients with chronic GT1 or GT3 HCV infection were assessed in a placebo-controlled study.

Methods

HCV-infected patients were enrolled in an 11-panel study (6 GT1 panels, 5 GT3 panels). In each panel, male patients were administered oral QD doses of MK-5172 or matching placebo for 7 days. Blood samples for MK-5172 concentration determination were collected on Days 1-12. Pharmacodynamic (PD) samples were collected on Days 1-15 and at select times up to 2 months. An Emax model was used to characterize the PK/PD relationship in HCV GT3 patients.

Results 

QD administration of MK-5172 to GT1 and GT3 patients resulted in a median Tmax of 2-4 hours and biphasic elimination with a mean terminal half-life of ~22-33 hours. Steady-state was achieved within 7 days of dosing. Mean steady-state AUC0-24hr and Cmax in GT1 and GT3 patients increased in a greater than dose proportional manner, which is consistent with single- and multiple-dose pharmacokinetics in healthy subjects. PK exposure is comparable between GT1 and GT3 patients for 100-600 mg QD doses, with a GT1/GT3 geometric mean ratio (GMR) of ~0.4-1.8 for AUC0-24hr and Cmax. HCV patients have moderately increased exposures compared to healthy subjects, with a steady-state GT1/healthy GMR of ~1.2-2.1 for AUC(0-24hr) and Cmax. The Emax model used to characterize the PK/PD relationship for patients suggests that steady-state AUC(0-24hr) of ~5 uM*hr and C24hr of ~30 nM would result in a 3-log reduction in viral load in GT3 patients. The PK/PD relationship for GT1 patients is not yet established since there is a limited dose-response in GT1 patients (a mean viral load reduction of ~4-5 log for all doses studied).

Conclusions

MK-5172 plasma PK is comparable between GT1 and GT3 patients and exhibits a PK profile supportive of once daily dosing in HCV patients. The extent and rate of absorption are moderately increased in patients compared to healthy subjects, which may be attributed to hepatic dysfunction in patients or differences in transporter-mediated disposition. The PK/PD relationship is well-characterized by an Emax model, which estimates the plasma PK required to achieve the target efficacy in HCV patients.

Indacaterol is a novel, inhaled once-daily ultra long-acting β2-agonist for the treatment of COPD. This randomised, double-blind, placebo-controlled, two-period crossover study evaluated the effect of two-week treatment with indacaterol300 μg on peak and isotime exercise inspiratory capacity (IC) in patients with COPD. Patients (40-80 years) with post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 70%, percent predicted FEV1 ≥ 40% and ≤ 80%, smoking history ≥ 20 pack-years and functional residual capacity > 120% of predicted normal were randomised to receive indacaterol 300 μg or placebo once-daily via a single-dose dry powder inhaler. Following 14 days of treatment, IC at peak and isotime during constant-load (80% of maximum workload) cycle ergometry was analysed using linear mixed-effects models. Safety and tolerability were also monitored. Twenty-seven patients (67% male; mean age, 61.3 years) were randomised; 24 completed the study. On Day 14, indacaterol showed statistically significant improvements over placebo in peak (317 mL [95% CI: 118-517]; p < 0.01) and isotime IC (268 mL [95% CI: 104-432]; p < 0.01). Statistically significant improvements were observed with indacaterol versus placebo on Day 14 for the following secondary endpoints: resting IC, trough FEV1, dyspnoea (BDI/TDI and Borg CR10 scale at isotime) and exercise endurance time. Indacaterol was well tolerated, with no serious adverse events or deaths. In conclusion, indacaterol 300 μg administered once-daily showed a clinically relevant increase in IC after 14 days of treatment, reflecting a reduction in dynamic hyperinflation.

More effective and better-tolerated therapies are needed for chronic hepatitis C virus (HCV) infection. Among the direct-acting anti-HCV agents in development is the nonstructural 5B protein (NS5B polymerase) non-nucleoside inhibitorfilibuvir. We investigated the antiviral activity, pharmacokinetics, safety, and tolerability of multiple doses of filibuvir in treatment-naive and treatment-experienced patients who were chronically infected with HCV genotype 1 in two phase 1b clinical studies (study 1 was a randomized, placebo-controlled dose escalation study and study 2 was a nonrandomized, open-label study). The filibuvir doses evaluated ranged from 200-1400 mg daily, and the duration of dosing ranged from 3-10 days. Genotypic changes in the NS5B nucleotide sequence following short-term filibuvir therapy were also assessed. Filibuvir potently inhibited viral replication in a dose-dependent manner. Mean maximum HCV RNA change from baseline ranged from -0.97 log(10) IU/mL with filibuvir given at 100 mg twice daily to -2.30 log(10) IU/mL with filibuvir given at 700 mg twice daily in treatment-naive patients. In treatment-experienced patients, an HCV RNA reduction of 2.20 log(10) IU/mL was achieved with filibuvir given at 450 mg twice daily. Filibuvir was well tolerated in both studies. Adverse events were mild or moderate in severity. No discontinuations, serious adverse events, or deaths were reported. NS5B sequencing identified residue 423 as the predominant site of mutation after filibuvir dosing.

Conclusion

Filibuvir administration resulted in significant reductions in HCV RNA concentrations at doses that were well tolerated in patients infected with HCV genotype 1. Filibuvir is currently being evaluated in combination with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients.

Casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) lower bloodpressure (BP) in long-term clinical studies. Their acute effects on BP and vascular function, important for daily dosing scheme, were studied in a placebo-controlled double-blind crossover study using a single oral dose of a fermented milkproduct containing Ile-Pro-Pro and Val-Pro-Pro as well as plant sterols. Twenty-five subjects with untreated mild hypertension received in random order 250 g of study product (25 mg peptides and 2 g plant sterols) or placebo. Ambulatory BP was monitored for 8 h post-dose and arterial stiffness measured by pulse wave analysis at 2, 4, and 8 h. Blood and urine samples were analyzed for markers of the renin-angiotensin system (RAS) and endothelial function. Baseline adjusted treatment effect for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial BP was -2.1 mmHg (95% CI: -4.1 to -0.1, p = 0.045), -1.6 mmHg (95% CI: -3.1 to -0.1, p = 0.03), and -1,9 mmHg (95% CI: -3-3 to -0.4, p = 0.0093), respectively, in favor of the active treatment for 8 h post- dose. No significant differences between the treatments were seen in brachial or aortic augmentation index, pulse wave velocity, or markers of RAS. Urinary excretion of cGMP, the second messenger of endothelial nitric oxide, was higher in the active group vs. placebo (p = 0.01). The results indicate that a single dose of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Proand plant sterols acutely lowers brachial SBP and DBP in mildly hypertensive subjects.

In cardiac transplantation postoperative right ventricular dysfunction is a major cause of morbidity and mortality. Recipients with pulmonary hypertension due to end-stage heart failure and a donor heart, fragile because of ischemia-reperfusion injury, and not previously adapted to an elevated pulmonary resistance are the causes of right ventricular dysfunction, that unless aggressively treated may progress to overt right ventricular failure. Dysfunctional pulmonary vascular endothelium with diminished release of NO and increased expression of endothelin-1 is considered to be the primary pathophysiology that induces pulmonary hypertension. New therapeutic approaches are aimed at ameliorating endothelial dysfunction. How extensively pulmonary hypertension has to be treated depends on the degree of functional impairment of the right ventricle resulting from the acute increase of right ventricular afterload at heart transplantation. Mainstays in the treatment of pulmonary hypertension are optimizing right ventricular preload, increasing contractility, lowering right ventricular afterload, improving coronary perfusion and failing these therapeutic interventions mechanical circulatory support. Judicious use of volume therapy is mandatory to avoid volume overload in the postoperative setting. As a general rule to explore right ventricular preload reserve volume should only be carefully administered by observing filling pressures up to a maximum of a central venous pressure of 10 mm Hg. Volume administration is not indicated if it only increases right atrial filling pressure without subsequently increasing cardiac output. In most cases relative volume overload is the clinical problem and not hypovolemia. In this situation aggressive diuretic therapy and in cases of acute renal failure renal replacement therapy is mandatory. Positive inotropic therapy is indicated to treat consecutive right ventricular dysfunction. Dobutamine may be a choice in the presence of a low cardiac index but preserved systemic pressures and epinephrine in cases of low cardiac output syndrome and systemic hypotension. A useful adjunct to catecholamine therapy is phosphodiesterase-III-inhibitors in the absence of arterial hypotension. Most importantly, pulmonary arterial pressures and right ventricular afterload have to be lowered in pulmonary hypertension compromising right ventricular function. Systemic vasodilators to treat pulmonary hypertension are non-selective and may induce arterial hypotension.This also applies to intravenously administered prostanoids. Inhaled NO in therapeutic doses selectively dilates the pulmonary vasculature without inducing systemic hypotension. To prevent a rebound phenomenon, inhaled NO therapy has to be slowly weaned. To account for the individually different response to inhaled NO, dose titration is recommended with doses of 10–50 ppm NO to lower pulmonary arterial pressures. Inhaled NO has been successfully used for all indications in the treatment of pulmonary hypertension in cardiac surgery. It has proved to be especially effective after implantation of left ventricular assist devices and following heart transplantations. As an alternative therapy, inhalation of aerosolized prostanoids similar to inhaled NO selectively decreases pulmonary arterial pressures. In recent years there has been growing evidence that the orally available phosphodiesterase 5 inhibitor sildenafil may be a useful adjunct to therapy in right ventricular failure. Inhibition of posphodiesterase 5 by sildenafil selectively induces pulmonary vasodilatation without deleterious effects on the systemic circulation. It can also be employed to facilitate weaning heart transplant recipients of inhaled NO, catecholamines and mechanical ventilator support. It has also been reported to have synergistic effects with inhaled NO and may be a treatment option in refractory cases. Potential drug interactions with immunosuppressive drugs have to be accounted for. Although clinical data are still limited administration of the calcium sensitizer levosimendan with reported inotropic effects and at the same time decreasing pulmonary pressures may be an attractive treatment option in patients after heart transplantation presenting with right ventricular dysfunction. Endothelin antagonists are effective in the treatment of moderate to severe pulmonary hypertension, but their future role still has to be determined in further studies. Supportive therapeutic measures in acute pulmonary hypertension are the use of 100% oxygen, moderate hyperventilation and correction of acidosis. If right ventricular failure progresses to a low cardiac output syndrome, implantation of an intraaortic balloon pump has to be considered to improve coronary perfusion. In refractive pulmonary hypertension and frank right ventricular failure implantation of a right ventricular assist device remains the last resort for treatment.

GM-CSF is thought to play a significant role in RA. Elevated levels of GM-CSF have been shown in tissue biopsies and synovial fluid from arthritic patients. Furthermore, recombinant GM-CSF has shown to exacerbate disease in RA patients undergoing treatment for neutropenia (1). Using phage display we developed a human monoclonal antibody (CAM-3001) to the GM-CSFR alpha chain that neutralizes GM-CSF activity. We describe the results of a Phase I single ascending dose of CAM-3001 in RA. 
 

Purpose 

The primary objective was to assess the safety and tolerability of CAM-3001 in patients with RA. Other objectives included the pharmacokinetics of CAM-3001 and the effect on biomarkers of systemic inflammation. 
 

Method 

Thirty-two subjects with mild or inactive RA (DAS28 ≤4.8) on stable methotrexate (≥3 months) received single i.v. doses of CAM-3001 or placebo in ascending doses of 0.01 and 0.03, 0.1, 0.3, 1, 3, or 10 mg/kg. Safety was assessed throughout the study by evaluation of clinical and laboratory parameters. 
 

Results

Adverse events were generally mild or moderate, and balanced between placebo and active treatments with no dose-relationship. There were two treatment-emergent serious adverse events (bilateral hernia, and breast cancer), neither of which was considered related to study drug. Mild transient neutropenia was seen in two subjects, and mild transient elevation of hepatic enzymes was also seen in two subjects. One subject experienced moderate urticaria of the face and neck during the infusion. Pulmonary function was also monitored and showed no clinically significant changes over the study period. Although the study was not designed to demonstrate clinical efficacy, post-hoc analysis of individual subjects with elevated CRP (>5mg/L) and ESR (>20mm/hr) at baseline showed reductions in CRP or normalization of ESR within the first 3 weeks post infusion, suggesting a potential benefit in RA. The pharmacodynamic activity of CAM-3001 pre and post dosing was also confirmed using an ex vivo GM-CSF-induced SOCS3 RT-PCR assay.
 

Conclusion

This is the first reported clinical study of a monoclonal antibody targeting the GM-CSF pathway in patients with rheumatoid arthritis. In this study, we show that CAM-3001 has an acceptable safety profile. Furthermore, the effects observed on acute phase reactants following single infusion of CAM-3001 suggest a potential effect on disease activity. This will be formally investigated in future clinical studies.

Background

PF-00868554 is a novel, potent, non-nucleoside inhibitor of the HCV polymerase. PF-00868554 inhibits genotype 1a and 1b replicons in vitro, with an overall mean EC50 of 0.059 _M. The safety and tolerability of PF 00868554 has been demonstrated in healthy volunteers administered PF-00868554 up to 300 mg TID for 14 days. The objectives of this study were to evaluate the safety, tolerability, pharmacokinetics (PK) and antiviral activity of PF-00868554 in HCV-infected subjects.
 
Methods

This was a randomized, double-blind, placebo-controlled, sequential group study. Subjects eligible for participation were those naïve to previous interferon-based HCV therapy and infected with a genotype 1 strain of the virus. Four cohorts of eight subjects were randomized (6:2) to receive oral doses of PF-00868554 (100, 300 and 450 mg BID and 300 mg TID) or placebo, for 8 days.
 
Results 

Of the 32 subjects randomized, the majority were male (84%) and Caucasian (97%). Mean baseline HCV RNA levels ranged from 5.8 to 6.1 log10 IU/mL. All doses of PF-00868554 were well tolerated. The most frequently reported all-causality adverse events (AEs ) were headache, flatulence, and fatigue. All AEs were mild or moderate in severity. There were no dose-limiting AEs, Grade 3 or 4 laboratory abnormalities, withdrawals due to AEs, serious AEs, or deaths. The half life of PF-00868554 in this study ranged from 8 to 12 hours. All doses achieved plasma concentrations that exceeded the median protein binding adjusted in vitro EC50 value for genotype 1 HCV throughout the duration of the dosing interval. 
 
The mean maximum reduction (log10) in HCV RNA achieved with PF-00868554 100, 300 or 450 mg BID or 300 mg TID was -0.97, -1.84, -1.74, and -2.13, respectively. The mean reduction in HCV RNA at the end of PF-00868554 treatment on Day 8 was -0.68, -1.26, -1.21, and -1.95, respectively. HCV RNA decreased rapidly during the first 48 hours of PF-00868554 treatment. Following this first phase of viral suppression, most subjects experienced a plateau or rebound in HCV RNA; however, some subjects' HCV RNA continued to decline through the completion of dosing on Day 8.
 
Conclusions

Results from this study indicate that PF-00868554 was well tolerated at all dose levels. PF-00868554 potently inhibited viral replication in HCV-infected, treatment-naïve subjects, with mean maximum reductions in HCV RNA ranging from -0.97 to -2.13. Results from the present study support the further evaluation of PF-00868554, and a study investigating PF-00868554 in combination with pegylated interferon alpha-2a and ribavirin in treatment-naïve subjects is currently underway.

Background

Hypertension can be controlled adequately with existing drugs such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Nevertheless, treatment success is often restricted by patients not adhering to treatment. Immunisation against angiotensin II could solve this problem. We investigated the safety and efficacy of CYT006-AngQb-a vaccine based on a virus-like particle-that targets angiotensin II to reduce ambulatory blood pressure.

Methods

In this multicentre, double-blind, randomised, placebo-controlled phase IIa trial, 72 patients with mild-to-moderate hypertension were randomly assigned with a computer-generated randomisation list to receive subcutaneous injections of either 100 mug CYT006-AngQb (n=24), 300 mug CYT006-AngQb (24), or placebo (24), at weeks 0, 4, and 12. 24-h ambulatory blood pressure was measured before treatment and at week 14. The primary outcomes were safety and tolerability. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00500786.

Findings

Two patients in the 100 mug group, three in the 300 mug group, and none in the placebo group discontinued study treatment. All patients were included in safety analyses; efficacy analyses did not include the five dropouts, for whom no data were available at week 14. Five serious adverse events were reported (two in the 100 mug group, two in the 300 mug group, and one in the placebo group); none were deemed to be treatment related. Most side-effects were mild, transient reactions at the injection site. Mild, transient influenza-like symptoms were seen in three patients in the 100 mug group, seven in the 300 mug group, and none in the placebo group. In the 300 mug group, there was a reduction from baseline in mean ambulatory daytime blood pressure at week 14 by -9.0/-4.0 mm Hg compared with placebo (p=0.015 for systolic and 0.064 for diastolic). The 300 mug dose reduced the early morning blood-pressuresurge compared with placebo (change at 0800 h -25/-13 mm Hg; p<0.0001 for systolic, p=0.0035 for diastolic).

Interpretation

Immunisation with CYT006-AngQb was associated with no serious adverse events; most observed adverse events were consistent with local or systemic responses similar to those seen with other vaccines. The 300 mug dose reduced blood pressure in patients with mild-to-moderate hypertension during the daytime, especially in the early morning.

Funding

Cytos Biotechnology AG.

Abstract

Immunisation against angiotensin II may offer a valuable alternative to conventional drugs for the treatment of hypertension by tackling the main limitation to successful therapy: the patients’ inconsistent drug intake. CYT006-AngQb, a virus-like-particle based conjugate vaccine targeting angiotensin II (Ang II), was shown to induce antibodies against Ang II and to reduce day-time ambulatory systolic blood pressure (SBP) in a multicenter, double blind, randomized, placebo-controlled phase IIa trial in 72 mild-to-moderate hypertensive patients. The vaccine was safe and well tolerated. Three injections of either 100 or 300 μg of AngQb, or placebo (Pbo), formulated in the adjuvant aluminum hydroxide, were administered on weeks 0, 4 and 12. Ambulatory blood pressure was determined at baseline and at week 14. Plasma active renin was measured at weeks 0, 6 and 14. A strong antibody response against Ang II was raised in all vaccinated patients. This was evident even after the first injection, and could be boosted. The antibody response was significantly higher in the 300 μg than the 100 μg group (P=0.01), and was relatively long-lived with a half-life of about 4 months. In the 300 μg group, ambulatory day-time SBP and diastolic blood pressure (DBP) were reduced at week 14 compared to baseline by 5.6 (P=0.007) and 2.8 mm Hg (P=0.034), respectively. The reduction in SBP was also significant in comparison to Pbo, with a baseline-corrected difference of -5.4 mm Hg (P=0.0498). Moreover, for the 300 μg group, the morning surge in blood pressure was blunted between 5 and 8 AM (P=0.0032 / 0.022, SBP / DBP), with a baseline-corrected difference from Pbo at 8 AM of -26 / -11 mm Hg (SBP / DBP, P=0.0002 / 0.009). Plasma active renin was only slightly increased from baseline on week 14 in the 300 μg group (from 5.1 to 6.3 pg/ml, P=0.02). CYT006-AngQb reduced blood pressure in situations where the renin-angiotensin-aldosterone system is stimulated, and was particularly effective in the morning hours when most cardiovascular events occur. These effects were dependent upon the dose of vaccine and antibody levels. Furthermore, the antibody response was long-lived and reversible. These findings support further testing of the vaccine with an optimized dose regimen.

Background & aims

SCH 503034 is a novel and potent oral hepatitis C virus (HCV) protease inhibitor. In this phase Ib study, we assessed safety parameters and virologic response of combination of SCH 503034 plus pegylated (PEG) interferon (IFN) alpha-2b in patients with HCV genotype 1 infections who were previously nonresponders to PEG-IFN-alpha-2b +/- ribavirin therapy.

Methods

This was a multicenter, open-label, 2-dose level, 3-way crossover, randomized (to crossover sequence) study carried out in 3 medical centers in Europe. Adult patients received SCH 503034 200 mg (n = 14) or 400 mg (n = 12) 3 times daily orally and PEG-IFN-alpha-2b 1.5 microg/kg subcutaneously once each week. Patients received SCH503034 as monotherapy for 1 week, PEG-IFN-alpha-2b as monotherapy for 2 weeks, and combination therapy for 2 weeks with washout periods between each treatment period.

Results

Combination therapy with SCH 503034 and PEG-IFN-alpha-2b was well tolerated, with no clinically significant changes in safety parameters. Mean maximum log(10) changes in HCV RNA were -2.45 +/- 0.22 and -2.88 +/- 0.22 for PEG-IFN-alpha-2b plus 200 mg and 400 mg SCH 503034, respectively, compared with -1.08 +/- 0.22 and -1.61 +/- 0.21 for SCH 503034 200 mg and 400 mg, respectively, and -1.08 +/- 0.22 and -1.26 +/- 0.20 for PEG-IFN-alpha-2b alone in the 200 mg and 400 mg SCH 503034 groups, respectively.

Conclusions

SCH 503034 plus PEG-IFN-alpha-2b was well tolerated in patients with HCV genotype 1nonresponders to PEG-IFN-alpha-2b +/- ribavirin. These preliminary results of antiviral activity of the combination suggest a potential new therapeutic option for this hard-to-treat, nonresponder patient population.

Rationale

This phase I study assessed the absolute bioavailability and tolerability of subcutaneous (SC) versus intravenous (IV) administration of Icatibant in healthy volunteers.

Methods

A total of 24 healthy males aged 18-50 years entered this single-centre study. Subjects received 0.4 mg/kg Icatibant IV (as a 1 mg/ml solution, for 30 min) or SC (as a 10 or 20 mg/ml solution) in an open-label crossover design.

Results

At a dose of 0.4 mg/kg, the mean absolute bioavailability (AUC0-N) for SC Icatibant was 96.1% (95% confidence interval [CI]: 86.7, 106.4) for the 10 mg/ml formulation, and 83.4% (95% CI: 70.9, 98.2) for 20 mg/ml. AUC0-inf values were comparable for SC (3114 and 2615 h*ng/ml, for 10 and 20 mg/ml, respectively) and IV (3208 h*ng/ ml) Icatibant. Mean Cmax values were 1429 ng/mL for the 10 mg/mL SC injection, 1149 ng/mL for the 20 mg/mL SC injection, and 2971 ng/mL for the IV infusion. Regardless of administration route or Icatibant concentration, Cmax was reached by approximately 0.5 h. Elimination half life (1.2-1.5 h) was similar for SC and IV administration. All adverse events were mild, and local site reactions usually resolved spontaneously within 1 h. There were no serious adverse events. Laboratory parameters, vital signs and ECG did not show relevant changes during the study.

Conclusions

Bioavailability of Icatibant is similar for SC and IV administration routes. Icatibant was safe and well tolerated at the dose of 0.4 mg/kg. 

Background

Despite the availability of efficacious drugs, the success of treating hypertension is limited by patients' inconsistent drug intake. Immunization against angiotensin II may offer a valuable alternative to conventional drugs for the treatment of hypertension, because vaccines induce relatively long-lasting effects and do not require daily dosing. Here we describe the preclinical development and the phase I clinical trial testing of a virus-like particle (VLP)-basedantihypertensive vaccine.

Methods and results

An angiotensin II-derived peptide was conjugated to the VLP Qbeta (AngQb). AngQb was highly immunogenic in mice and rats. To test for efficacy, spontaneously hypertensive rats (SHR) were immunized with 400 microg AngQb or VLP alone. Group mean systolic blood pressure (SBP) was reduced by up to 21 mmHg (159 +/- 2 versus 180 +/- 5 mmHg, P < 0.001), and total angiotensin II levels (antibody-bound and free) were increased ninefold (85 +/- 20 versus 9 +/- 1 pmol/l, P = 0.002) compared with VLP controls. SHR treated with the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg per day by mouth) reached an SBP of 155 +/- 2 mmHg. Twelve healthy volunteers of a placebo-controlled randomized phase I trial were injected once with 100 microg AngQb. Angiotensin II-specific antibodies were raised in all subjects (100% responder rate) and AngQb was well tolerated.

Conclusions

AngQb reduces blood pressure in SHR to levels obtained with an ACE inhibitor, and is immunogenic and well tolerated in humans. Therefore, vaccination against angiotensin II has the potential to become a useful antihypertensive treatment providing long-lasting effects and improving patient compliance.

Background

The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA).

Methods

We conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmaticresponses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1).

Results

After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P=0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P=0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo.

Conclusions

Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses. (Funded by Sterna Biologicals and the German Federal Ministry of Education and Research; ClinicalTrials.gov number, NCT01743768.).