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Journal
Diabetes Obes Metab.
Publication date
Authors
Tillner J, Posch MG, Wagner F, Teichert L, Hijazi Y, Einig C, Keil S, Haack T, Wagner M, Bossart M, Larsen PJ.
Abstract

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.

Journal
Lancet
Publication date
Authors
Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, Tsai LF, Robertson D, Jain M, Petrone M, Rondinone C, Hirshberg B, Jermutus L
Abstract

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

Journal
Br J Clin Pharmacol
Publication date
Keywords
diabetes, drug safety, pharmacokinetics-pharmacodynamics, phase 1, randomised controlled trial
Authors
Ambery PD, Klammt S, Posch MG, Petrone M, Pu W, Rondinone C, Jermutus L, Hirshberg B
Abstract

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.

Journal
Clin Ther
Publication date
Keywords
elbasvir, genotype 1, genotype 3, grazoprevir, hepatitis C virus, monotherapy
Authors
Yeh WW, Fraser IP, Jumes P, Petry A, Lepeleire I, Robberechts M, Reitmann C, Van Dyck K, Huang X, Guo Z, Panebianco D, Nachbar RB, O'Mara E, Wagner JA, Butterton JR, Dutko FJ, Moiseev V, Kobalava Z, Hüser A, Visan S, Schwabe C, Gane E, Popa S
Ghicavii N, Uhle M, Wagner F
Abstract

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. 

Journal
Arthritis & Rheumatology
Publication date
Authors
Fleischmann RM, Wagner F, Kivitz AJ, Mansikka HT, Khan N, Othman AA, Khatri A, Hong F, Jiang P, Ruzek M, Padley RJ
Abstract

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.

Journal
Eur Heart
Publication date
Keywords
Angiotensin, Arterial stiffness, Heart failure, Hypertension, Left ventricular hypertrophy, Neprilysin
Authors
Schmieder RE, Wagner F, Mayr M, Delles C, Ott C, Keicher C, Hrabak-Paar M, Heye T, Aichner S, Khder Y, Yates D, Albrecht D, Langenickel T, Freyhardt P, Janka R, Bremerich J
Abstract

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.

Journal
European Journal of Clinical Pharmacology
Publication date
Keywords
Anti-CD40, First-in-human trial, Lupus nephritis, Monoclonal antibody, Rheumatoid arthritis, Systemic lupus erythematosus
Authors
Albach FN, Wagner F, Hüser A, Igel J, Joseph D, Hilbert J, Schoelch C, Padula SJ, Steffgen J.
Abstract

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.

Journal
Arthritis Rheumatol.
Publication date
Keywords
Sjogren's syndrome, clinical research
Authors
Fisher B, Zeher M, Ng WF, Bombardieri M, Posch M, Papas AS, Farag AM, Daikeler T, Bannert B, Kivitz AJ, Carsons SE, Isenberg DA, Barone F, Bowman S, Espie P, Wieczorek G, Moulin P, Floch D, Dupuy C, Ren X, Faerber P, Wright AM, Hockey HU, Rotte M, Rush JS
Abstract

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.

Journal
Int. Journal of Clinical Pharmacology and Therapeutics
Publication date
Keywords
rheumatoid arthritis, dose-escalation trial, interleukin-21, monoclonal antibody, first-in-human trial
Authors
Ignatenko S, Skrumsager BK, Mouritzen U
Abstract

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.

Journal
Clin Pharmacokinet
Publication date
Authors
Hausner H, Derving Karsbøl J, Holst AG, Jacobsen JB, Wagner FD, Golor G, Anderson TW
Abstract

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.

Journal
Annals of the Rheumatic Diseases
Publication date
Authors
Dörner T, Posch M, Wagner F, Hüser A, Fischer T, Mooney L, Petricoul O, Maguire P, Pal P, Doucet J, Cabanski M, Kamphausen E, Oliver SJ
Abstract

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.

Publication date
Authors
Tillner J, Posch MG, Hüser A, Teichert L, Einig C, Bergmann K, Keil S, Rimbault M, Larsen PJ, Lorenz M
Abstract

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.

Journal
AIDS
Publication date
Authors
Schürmann D, Sobotha C, Gilmartin J, Robberechts M, De Lepeleire I, Yee KL, Guo Y, Liu R, Wagner F, Wagner JA, Butterton JR, Anderson MS
Abstract

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.

Journal
J Allergy Clin Immunol
Publication date
Keywords
IL-23A, biomarkers, mAb, pharmacokinetics, psoriasis, randomized, single dose
Authors
Krueger JG, Ferris LK, Menter A, Wagner F, White A, Visvanathan S, Lalovic B, Aslanyan S, Wang EE, Hall D, Solinger A, Padula S, Scholl P.
Abstract

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.

Journal
Neurol Neuroimmunol Neuroinflamm
Publication date
Authors
Constantinescu CS, Asher A, Fryze W, Kozubski W, Wagner F, Aram J, Tanasescu R, Korolkiewicz RP, Dirnberger-Hertweck M, Steidl S, Libretto SE, Sprenger T, Radue EW
Abstract

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.

Journal
Am J Clin Nutr
Publication date
Keywords
cholesterol, flow-mediated dilation plant sterols, randomized controlled trial, vascular function
Authors
Ras RT, Fuchs D, Koppenol WP, Garczarek U, Greyling A, Keicher C, Verhoeven C, Bouzamondo H, Wagner F, Trautwein EA.
Abstract

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.

Journal
Lupus
Publication date
Keywords
CDP7657, anti-CD40L, lupus, systemic lupus erythematosus
Authors
Tocoian A, Buchan P, Kirby H, Soranson J, Zamacona M, Walley R, Mitchell N, Esfandiari E, Wagner F, Oliver R
Abstract

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.

Journal
Br J Clin Pharmacol
Publication date
Keywords
cerebral blood flow; fingolimod; healthy volunteers; macular thickness; platelet function; sphingosine 1-phosphate
Authors
Ocwieja M, Meiser K, David OJ, Valencia J, Wagner F, Schreiber SJ, Pleyer U, Ziemer S, Schmouder R
Abstract

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.

Journal
Diabetes Obes Metab
Publication date
Keywords
Caucasian, Japanese, lixisenatide, prandial, type 2 diabetes mellitus
Authors
Seino Y, Takami A, Boka G, Niemoeller E, Raccah D; PDY6797 investigators
Abstract

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.

Journal
Clin Pharmacol Drug Dev
Publication date
Keywords
CYP3A4, drug interaction, midazolam, moxidectin, onchocerciasis
Authors
Korth-Bradley JM, Parks V, Wagner F, Chalon S, Gourley I, Matschke K, Gossart S, Ripp SL, Fleckenstein L
Abstract

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.

Journal
Thromb Haemost
Publication date
Keywords
Pharmacokinetics, dabigatran etexilate, direct thrombin inhibitor, DTI, elimination, haemodialysis
Authors
Khadzhynov D, Wagner F, Formella S, Wiegert E, Moschetti V, Slowinski T, Neumayer HH, Liesenfeld KH, Lehr T, Härtter S, Friedman J, Peters H, Clemens A
Abstract

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.

Journal
J Allergy Clin Immunol
Publication date
Keywords
Persistent allergic asthma, Toll-like receptor 9, virus-like particle, immune modulator, clinical trial
Authors
Beeh KM, Kanniess F, Wagner F, Schilder C, Naudts I, Hammann-Haenni A, Willers J, Stocker H, Mueller P, Bachmann MF, Renner WA
Abstract

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.

Journal
Int Arch Allergy Immunol
Publication date
Keywords
Allergen, allergic asthma, bronchoconstriction, immunoglobulin E, omalizumab
Authors
Zielen S, Lieb A, De La Motte S, Wagner F, de Monchy J, Fuhr R, Munzu C, Koehne-Voss S, Rivière GJ, Kaiser G, Erpenbeck VJ
Abstract

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.

Journal
J Hypertens
Publication date
Authors
Wagner F, Malice MP, Wiegert E, McGrath HE, Gildea J, Mitta S, Van Dyck K, De Lepeleire I, Johnson-Levonas AO, Sisk CM, Fernandez R, Greenwalt DM, Beals C, Carey RM, Nunes I
Abstract

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.

Journal
J Hepatol 51
Publication date
Authors
Caro L, Anderson M, Du L, Palcza, Han L, vanDyck K, Robberechts M, de Lepiere I, Petry A, Young MB, Fraser I, O'Mara E, Moissev V, Kobalava Z, Wagner F
Abstract

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.

Journal
COPD
Publication date
Keywords
Indacaterol, COPD, Inspiratory capacity, Dyspnoea, Bronchodilator, FEV
Authors
Beeh KM, Wagner F, Khindri S, Drollmann AF
Abstract

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.

Journal
Hepatology
Publication date
Authors
Wagner F, Thompson R, Kantaridis C, Simpson P, Troke PJ, Jagannatha S, Neelakantan S, Purohit VS, Hammond JL
Abstract

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.

Journal
Clin Exp Hypertens
Publication date
Keywords
bioactive milk peptides, Ile-Pro-Pro, Val-Pro-Pro, blood pressure, vascular function, human
Authors
Turpeinen AM, Ehlers PI, Kivimäki AS, Järvenpää S, Filler I, Wiegert E, Jähnchen E, Vapaatalo H, Korpela R, Wagner F
Abstract

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.

Journal
Transplantationsmedizin
Publication date
Keywords
right ventricular function, heart transplantation, donor heart
Authors
Wagner F
Abstract

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.

Journal
Ann Rheum Dis
Publication date
Keywords
rheumatoid arthritis
Authors
Burmester G, Feist E, Wagner F, Sleeman M, Grove G, White B
Abstract

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.

Journal
J Hepatol. 48, Suppl 1, 267A
Publication date
Authors
Hammond JL, Rosario MC, Wagner F, Mazur D, Kantaridis C, Purohit VS, Durham LK, Jagannatha S, DeBruin MF
Abstract

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.

Journal
Lancet
Publication date
Authors
Tissot AC, Maurer P, Nussberger J, Sabat R, Pfister T, Ignatenko S, Volk HD, Stocker H, Müller P, Jennings GT, Wagner F, Bachmann MF
Abstract

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.

Journal
Circulation
Publication date
Authors
Tissot AC, Nussberger J, Maurer P, Stocker H, Pfister T, Wagner F, Müller P, Jennings GT, Bachmann MF
Abstract

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.

Journal
Gastroenterology
Publication date
Authors
Sarrazin C, Rouzier R, Wagner F, Forestier N, Larrey D, Gupta SK, Hussain M, Shah A, Cutler D, Zhang J, Zeuzem S
Abstract

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.

Journal
J Allergy Clin Immunol
Publication date
Authors
Wagner F, Rosenkranz B, Knolle J
Abstract

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. 

Journal
J Hypertens
Publication date
Authors
Ambühl PM, Tissot AC, Fulurija A, Maurer P, Nussberger J, Sabat R, Nief V, Schellekens C, Sladko K, Roubicek K, Pfister T, Rettenbacher M, Volk HD, Wagner F, Müller P, Jennings GT, Bachmann MF
Abstract

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.

Journal
N Engl J Med
Publication date
Authors
Norbert Krug, M.D., Jens M. Hohlfeld, M.D., Anne-Marie Kirsten, M.D., Oliver Kornmann, M.D., Kai M. Beeh, M.D., Dominik Kappeler, M.D., Stephanie Korn, M.D., Stanislav Ignatenko, M.D., Wolfgang Timmer, M.D., Cordelia Rogon, Dipl.-Stat., Jana Zeitvogel, Ph
Abstract

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.).