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Polo-like kinase 1 (PLK1) regulates mitotic checkpoints and cell division. PLK1 overexpression is reported in numerous cancers, including acute myeloid leukemia (AML), and is associated with poor prognosis. Volasertib is a selective, potent cell-cycle kinase inhibitor that targets PLK to induce mitotic arrest and apoptosis. This phase 1 trial investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of volasertib in combination with decitabine in AML patients aged ≥ 65 years. Thirteen patients were treated with escalating volasertib doses (3 + 3 design; 300 mg, 350 mg, and 400 mg) plus standard-dose decitabine. Dose-limiting toxicity was reported in one patient in cycle 1; the MTD of volasertib in combination with decitabine was determined as 400 mg. The most common treatment-emergent adverse events were febrile neutropenia, pneumonia, and decreased appetite. Objective response rate was 23%. The combination was well tolerated, and the adverse event profile was in line with previous findings.

Background and Aims In patients (pts) with SLE, activation of the CD40–CD40L pathway results in stimulation and proliferation of B cells and other inflammatory cell types. The subsequent generation of autoantibodies and their deposition in the kidney, as well as activation of myeloid and resident kidney cells, result in local inflammation and eventually, kidney injury. Thus, CD40 is an appealing therapeutic target in lupus nephritis (LN). BI 655064 is a humanised anti-CD40 monoclonal antibody that blocks the CD40 pathway in a nanomolar range and downregulates activated B cells. This study assessed the efficacy and safety over 52 weeks (wks) of three doses of subcutaneous BI 655064 compared with placebo, as add-on to mycophenolate and steroids, in pts with active proliferative LN (ClinicalTrials.gov number: NCT02770170). Method Overall, 121 pts with LN were randomised, double blind, in a 2:1:1:2 ratio to placebo or BI 655064 120 mg, 180 mg or 240 mg, and received a weekly loading dose for the first 3 wks, followed by dosing every 2 wks for the 120 and 180 mg doses, and weekly (120 mg) for the 240 mg group. Key inclusion criteria included an active ISN/RPS class III or IV (±V) renal biopsy within 3 months prior to screening and a screening protein/creatinine ratio of ≥1 mg/mg. Randomisation was stratified based on race (Asian vs non-Asian) and screening protein/creatine (UP/UC) ratio ( Results The placebo response in this trial was higher than expected (48.3%; Table 1); none of the BI 655064 doses increased rates of CRR at Wk 52 compared with placebo. However, CRR at Wk 52 based on creatinine-adjusted proteinuria, assessed using spot urine, showed a better response in the 180 mg group (50%) vs placebo (42.5%), and the 180 mg dose showed a greater change from baseline over time vs placebo from Wk 4. Time to CRR was shorter in the 180 mg group (17.3 wks) vs placebo (20.4 wks). The 180 mg group also showed improvement vs placebo in total SLEDAI (SELENA) and its subscores. The unexpected high placebo response prompted a post hoc analysis evaluating confirmed CRR (cCRR), whereby confirmation of the endpoint was required at both Wks 46 (penultimate visit on treatment) and 52. A 15.2% higher cCRR in the 180 mg group (44.3%) vs placebo (29.1%) was observed (p=0.26). While based on a small sample size, there were more reports of infection-related severe and serious adverse events and neutropenia in the 240 mg group compared with placebo. Of note, in those who experienced neutropenia, a clinical impact (e.g. increase in infections) was not established. Aside from these observations, safety data were comparable across treatment groups. Larger decreases from baseline were observed in the percentage of CD27−IgD−CD95+, CD27−IgD+CD95+, CD27+IgD+CD95+ and CD27+IgD−CD95+ B-cell subsets in the 180 and 240 mg groups compared with placebo. Treatment-emergent anti-drug antibodies (ADAs) were detected in five pts treated with BI 655054, all at low titre, and in one who received placebo; ADAs had no impact on pharmacokinetics or safety. Conclusion The trial did not meet its primary CRR endpoint. However, when confirmation of CRR was required at both Wks 46 and 52, the resultant decrease in the placebo response generated an effect size of 15.2% and 9.1% in favour of 180 mg and 240 mg BI 655064, respectively.

Background:In patients with SLE, activation of the CD40–CD40L pathway results in stimulation and proliferation of B cells and other inflammatory cell types. The subsequent generation of autoantibodies and their deposition in the kidney, as well as activation of myeloid and resident kidney cells, result in local inflammation and eventually, kidney injury. Thus, CD40 is an appealing therapeutic target in lupus nephritis (LN). BI 655064 is a humanised anti-CD40 monoclonal antibody that blocks the CD40 pathway in a nanomolar range and downregulates activated B cells.Objectives:To assess the efficacy and safety over 52 weeks of three doses of subcutaneous BI 655064 compared with placebo, as add-on to mycophenolate and steroids, in patients with active proliferative LN (ClinicalTrials.gov number: NCT02770170).Methods:Overall, 121 patients with LN were randomised, double blind, in a 2:1:1:2 ratio to placebo or BI 655064 120 mg, 180 mg or 240 mg, and received a weekly loading dose for the first 3 weeks, followed by dosing every 2 weeks for the 120 and 180 mg doses, and weekly (120 mg) for the 240 mg group. Key inclusion criteria included an active ISN/RPS class III or IV (±V) renal biopsy within 3 months prior to screening and a screening protein/creatinine ratio of ≥1 mg/mg. Randomisation was stratified based on race (Asian vs non-Asian) and screening protein/creatine (UP/UC) ratio (Results:The placebo response in this trial was higher than expected (48.3%; Table 1); none of theBI 655064 doses increased rates of CRR at Week 52 compared with placebo. However, CRR at Week 52 based on creatinine-adjusted proteinuria, assessed using spot urine, showed a better response in the 180 mg group (50%) vs placebo (42.5%), and the 180 mg dose showed a greater change from baseline over time vs placebo from Week 4. Time to CRR was shorter in the 180 mg group (17.3 weeks) vs placebo (20.4 weeks). The 180 mg group also showed improvement vs placebo in total SLEDAI (SELENA) and its subscores.The unexpected high placebo response prompted a post hoc analysis evaluating confirmed CRR (cCRR), whereby confirmation of the endpoint was required at both Weeks 46 (penultimate visit on treatment) and 52. A 15.2% higher cCRR in the 180 mg group (44.3%) vs placebo (29.1%) was observed (p=0.26).While based on a small sample size, there were more reports of infection-related severe and serious adverse events and neutropenia in the 240 mg group compared with placebo. Of note, in those who experienced neutropenia, a clinical impact (e.g. increase in infections) was not established. Aside from these observations, safety data were comparable across treatment groups.Larger decreases from baseline were observed in the percentage of CD27−IgD−CD95+, CD27−IgD+CD95+, CD27+IgD+CD95+ and CD27+IgD−CD95+ B-cell subsets in the 180 and 240 mg groups compared with placebo.Treatment-emergent anti-drug antibodies (ADAs) were detected in five patients treated with BI 655054, all at low titre, and in one who received placebo; ADAs had no impact on pharmacokinetics or safety.Conclusion:The trial did not meet its primary CRR endpoint. However, when confirmation of CRR was required at both Weeks 46 and 52, the resultant decrease in the placebo response generated an effect size of 15.2% and 9.1% in favour of 180 mg and 240 mg BI 655064, respectively.Table 1.Efficacy endpoints at Week 52Placebo (n=40)BI 655064120 mg (n=21)180 mg (n=20)240 mg (n=40)Observed CRR, n208918Adjusted* CRR, %48.338.34544.6Observed cCRR, n135916Adjusted* cCRR, %29.122.544.338.2Mean change from baseline in SLEDAITotal score−6.5−6.1−9.7−8.2Non-renal score−1.4−3.0−2.8−3.1Renal score−5.1−3.7−6.8−5.0Clinical score−5.7−3.9−7.9−6.5CRR based on 24 h proteinuria; cCRR based on UP/UC (spot urine) at Weeks 46 and 52. *Logistic regression model including treatment and the covariates race and proteinuria at screening.Disclosure of Interests:David Jayne Consultant of: DRJ has received consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline Research & Development Ltd, Novartis, and Roche, Juergen Steffgen Employee of: JS is employed by Boehringer Ingelheim., Juanita Romero-Diaz Consultant of: JRD has received research consulting fees from Boehringer Ingelheim, Hirofumi Amano Grant/research support from: HA has received research grants from Boehringer Ingelheim, Kajohnsak Noppakun Consultant of: KN has received honoraria from Boehringer Ingelheim, Novartis, Roche, Jansen, AstraZeneca, Otsuka Pharmaceuticals, Astellas Pharma, Abbott, Sanofi and Novo Nordisk, Grant/research support from: KN has received research grants from Boehringer Ingelheim, GlaxoSmithKline Research & Development Ltd, Visterra Inc., Kalbe Genexine Biologics, Aurinia Pharmaceuticals Inc., and Omeros Corporation., Harold Michael Gomez Speakers bureau: HMG has received speaker’s fees for Pfizer, MSD, Unilab, Astellas Pharma, AstraZeneca, GlaxoSmithKline Research & Development Ltd, and Aurinia Pharmaceuticals Inc., Rhona Recto: None declared, Valérie Belsack Employee of: Boehringer Ingelheim, Nora Fagan Employee of: Boehringer Ingelheim, Steven Padula Employee of: Boehringer Ingelheim, Ivette Revollo Employee of: Boehringer Ingelheim, Jing Wu Employee of: Boehringer Ingelheim, Sudha Visvanathan Employee of: Boehringer Ingelheim, Richard Furie Consultant of: RF has received research consulting fees, Grant/research support from: RF has received clinical trial support

Background.Parkinson’s disease (PD) progressively affects dopaminergic neurotransmission and may affect retinal dopaminergic functions and structures.Objective.This 2-year randomized, open-label, parallel-group, flexible-dose study,NCT00144300, evaluated ophthalmologic safety profiles of immediate-release (IR) pramipexole and ropinirole in patients with early idiopathic PD with ≤6 months’ prior dopamine agonist exposure and without preexisting major eye disorders.Methods.Patients received labeled IR regimens of pramipexole (n=121) or ropinirole (n=125) for 2 years. Comprehensive ophthalmologic assessments (COA) included corrected acuity, Roth 28-color test, slit-lamp biomicroscopy, intraocular pressure, computerized visual field test, fundus photography, and electroretinography.Results.At baseline, we observed retinal pigmentary epithelium (RPE) hypopigmentation not previously reported in PD patients. The estimated relative risk of 2-year COA worsening with pramipexole versus ropinirole was 1.07 (95% CI: 0.71–1.60). Mean changes from baseline in Unified Parkinson’s Disease Rating System parts II+III total scores (pramipexole: 1 year, −4.1±8.9, and 2 years, −0.7±10.1, and ropinirole: 1 year, −3.7±8.2, and 2 years, −1.7±10.5) and Hoehn–Yahr stage distribution showed therapeutic effects on PD symptoms. Safety profiles were consistent with labeling.Conclusions.The risk of retinal deterioration did not differ in early idiopathic PD patients receiving pramipexole versus ropinirole. RPE hypopigmentation at baseline was not previously reported in this population. This trial is registered withNCT00144300.

Introduction: Ipratropium bromide (IB) is an established and effective first-line maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). A new IB metered-dose inhaler (MDI) using hydrofluoroalkane 134a propellant (IB HFA) has been developed as an alternative to the MDI containing chlorofluorocarbon (IB CFC). Objective: To compare the long-term safety and efficacy of IB HFA and IB CFC in patients with COPD. Study design: This was a randomised, open-label, parallel-group, 1-year, multi-centre trial. Primary endpoints included adverse events (AEs) and vital signs. Secondary endpoints included therapeutic response (>15% increase in forced expiratory volume in 1 second [FEV1] peak change from baseline), FEV1 area under the response-time curve (AUC). Patients and interventions: Patients (n = 456) with moderate-to-severe COPD, who received either IB HFA (n = 305) or IB CFC (n = 151 ), both 42µg four times daily. Results: There were no significant differences in the incidences of individual AEs between groups over the short and long term; respiratory disorders were the most common. The incidence of anticholinergic AEs possibly related to treatment was low (1.3% IB HFA, 0.7% IB CFC). Serious AEs occurred in 19.0% and 20.5%, and discontinuations due to AEs in 7.2% and 7.3%, of patients receiving IB HFA and IB CFC, respectively. Therapeutic bronchodilatory responses were achieved in 76–81% and 72–84% of patients, and AUC ranged from 0.117–0.148L and 0.117–0.174L, in patients receiving IB HFA and IB CFC, respectively. Conclusions: IB HFA had similar efficacy and tolerability to IB CFC over 1 year, supporting a seamless transition from the CFC MDI to the HFA MDI in both short- and long-term treatment.

Background We recently reported improved glycemic control with reduced insulin dose in subjects with type 1 diabetes treated with the sodium glucose co-transporter-2 inhibitor empagliflozin. To further characterize the effects, we analyzed diurnal glycemic patterns by continuous glucose monitoring (CGM). Methods In an 8-week single-arm open-label pilot study of empagliflozin, we compared ambulatory glucose profiles produced from CGM data during 2-week intervals in a placebo run-in baseline period, end-of-treatment, and post-treatment. Change in glycemic exposure was evaluated by area under the median curve according to time of day (AUCTOTAL 12:00am-11:55pm; AUCDAY 7:05am-10:55pm, AUCNIGHT 11:00pm-7:00am), as well as glycemic variability, glycemic stability and time-in-target (≥70 to ≤140mg/dL). Results The 40 patients (26 on insulin pump) were aged 24±5 years and BMI 24.5±3.2 kg/m2. Consistent with the observed HbA1c decrease (8.0±0.9% to 7.6±0.9%, p

OBJECTIVE Adjunctive-to-insulin therapy with sodium-glucose cotransporter 2 (SGLT2) inhibition may improve glycemic control in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS We evaluated the glycemic efficacy and safety of empagliflozin 25 mg daily in 40 patients treated for 8 weeks in a single-arm open-label proof-of-concept trial (NCT01392560). RESULTS Mean A1C decreased from 8.0 ± 0.9% (64 ± 10 mmol/mol) to 7.6 ± 0.9% (60 ± 10 mmol/mol) (P < 0.0001), fasting glucose from 9.0 ± 4.3 to 7.0 ± 3.2 mmol/L (P = 0.008), symptomatic hypoglycemia ( CONCLUSIONS This proof-of-concept study strongly supports a randomized clinical trial of adjunctive-to-insulin empagliflozin in patients with T1D.

Background— The primary objective of this mechanistic open-label, stratified clinical trial was to determine the effect of 8 weeks’ sodium glucose cotransporter 2 inhibition with empagliflozin 25 mg QD on renal hyperfiltration in subjects with type 1 diabetes mellitus (T1D). Methods and Results— Inulin (glomerular filtration rate; GFR) and paraaminohippurate (effective renal plasma flow) clearances were measured in individuals stratified based on having hyperfiltration (T1D-H, GFR ≥ 135 mL/min/1.73m 2 , n=27) or normal GFR (T1D-N, GFR 90–134 mL/min/1.73m 2 , n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4–6 mmol/L) and hyperglycemic (9–11 mmol/L) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by −33 mL/min/1.73m 2 with empagliflozin in T1D-H, (GFR 172±23–139±25 mL/min/1.73 m 2 , P P P ≤0.04). Conclusions— In conclusion, short-term treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin attenuated renal hyperfiltration in subjects with T1D, likely by affecting tubular-glomerular feedback mechanisms. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01392560.

Study objective To compare the efficacy and safety of ipratropium bromide reformulated with the chlorofluorocarbon (CFC)-free propellant hydrofluoroalkane (HFA)-134a (ipratropium bromide HFA) to that of the marketed ipratropium bromide inhalation aerosol (containing CFC) in patients with COPD. Design This was a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial. The primary efficacy parameter was acute bronchodilator response. The primary end points were peak change in FEV 1 from baseline and area under the response-time curve. Setting Thirty-one clinical centers in the United States participated in this project. Patients A total of 507 patients with moderate-to-severe COPD were randomized, and 444 patients completed the trial. Interventions Twelve weeks of treatment four times daily with one of the following: ipratropium bromide HFA, 42 μg; ipratropium bromide HFA, 84 μg; HFA placebo; ipratropium bromide inhalation aerosol, 42 μg; or CFC placebo. Measurements and results Patients in all active treatment groups had significant bronchodilator responses as shown by increases in mean FEV 1 from baseline of at least 15%. Bronchodilator response in all active treatment groups was also significantly more than their respective placebo treatments based on FEV 1 , area under the time-response curve from 0 to 6 h, and peak response. FVC results were similar to those seen with FEV 1 . There were no significant differences in adverse events, laboratory findings, or ECG findings among the treatment groups. Conclusions Ipratropium bromide HFA, 42 μg, provided bronchodilation comparable to the marketed ipratropium bromide CFC, 42 μg, over 12 weeks of regular use.

Background Individuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity. Methods Blood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4–6 mmol/L) and hyperglycaemia (blood glucose 9–11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily). Results In response to empagliflozin during clamped euglycaemia, systolic blood pressure (111 ± 9 to 109 ± 9 mmHg, p = 0.02) and augmentation indices at the radial (-52% ± 16 to -57% ± 17, p = 0.0001), carotid (+1.3 ± 1 7.0 to -5.7 ± 17.0%, p