Licogliflozin versus placebo in women with polycystic ovary syndrome: A randomized, double-blind, phase 2 trial.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066 :TRPCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066 :TRPCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066 :TRPCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066 :TRPCB [MAXI]: 0·26; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066 :TRPCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate following once-daily inhalation as a combination in healthy subjects.

Indacaterol (IND), is co-formulated with glycopyrronium (GLY), and mometasone furoate (MF) as a once-daily (o.d.) inhaled fixed-dose combination (IND/GLY/MF) delivered via the Breezhaler® device for maintenance treatment of asthma. We evaluated the steady state plasma pharmacokinetics (PK) of IND, GLY and MF following inhalation of IND/GLY/MF or as monotherapies. This was a randomized, open-label, four-way crossover study. Subjects received IND/GLY/MF 150/50/160 µg (high-dose), IND 150 µg, GLY 50 µg or MF 190 µg (in vitro fine particle mass comparable to 160 µg MF in IND/GLY/MF) via the Breezhaler® device, o.d. for 14 days in each period, with a washout of at least 7 days. PK was characterized on Day 14, up to 24 h post-dose. In total, 36 healthy subjects were randomized. For IND, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.922 (0.878, 0.969) and 1.02 (0.967, 1.08), respectively for the IND/GLY/MF versus IND monotherapy comparison. For GLY, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.986 (0.944, 1.03) and 1.21 (1.09, 1.34), respectively for the IND/GLY/MF versus GLY comparison. For MF, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 1.16 (1.09, 1.24) and 1.17 (1.09, 1.25), respectively for IND/GLY/MF versus MF comparison. Similar systemic exposure was noted for IND/GLY/MF versus monotherapy for all three mono-components, indicating a lack of PK interaction. Multiple inhaled doses of IND, GLY and MF were safe and well tolerated, when administered alone or in combination. There was no clinically relevant pharmacokinetic interaction between IND, GLY and MF when administered as IND/GLY/MF.

Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme.

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 asthmatic responses 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.).

Safety, PK, and PD of recombinant anti-interleukin-21 monoclonal antibody in a first-in-human trial.

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.

The Effect of Various Degrees of Renal or Hepatic Impairment on the Pharmacokinetic Properties of Once-Weekly Insulin Icodec.

BACKGROUND AND OBJECTIVE: Icodec is a once-weekly insulin being developed to provide basal insulin coverage in diabetes mellitus. This study evaluated the effects of renal or hepatic impairment on icodec pharmacokinetics. METHODS: Two open-label, parallel-group, single-dose (1.5 U/kg subcutaneously) trials were conducted. In a renal impairment trial, 58 individuals were allocated to normal renal function (measured glomerular filtration rate ≥ 90 mL/min), mild (60 to < 90 mL/min), moderate (30 to < 60 mL/min) or severe (< 30 mL/min) renal impairment or end-stage renal disease. In a hepatic impairment trial, 25 individuals were allocated to normal hepatic function or mild (Child-Pugh Classification grade A), moderate (grade B) or severe (grade C) hepatic impairment. Blood was sampled frequently for a pharmacokinetic analysis until 35 days post-dose. RESULTS: The shape of the icodec pharmacokinetic profile was not affected by renal or hepatic impairment. Total icodec exposure was greater for mild (estimated ratio [95% confidence interval]: 1.12 [1.01; 1.24]), moderate (1.24 [1.12; 1.37]) and severe (1.28 [1.16; 1.42]) renal impairment, and for end-stage renal disease (1.14 [1.03; 1.28]), compared with normal renal function. It was also greater for mild (1.13 [1.00; 1.28]) and moderate (1.15 [1.02; 1.29]) hepatic impairment versus normal hepatic function. There was no statistically significant difference between severe hepatic impairment and normal hepatic function. Serum albumin levels (range 2.7-5.1 g/dL) did not statistically significantly influence icodec exposure. CONCLUSIONS: The clinical relevance of the slightly higher icodec exposure with renal or hepatic impairment is limited as icodec should be dosed according to individual need. No specific icodec dose adjustment is required in renal or hepatic impairment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03723785 and NCT04597697.

A randomized, double-blind phase 1b study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of the NLRP3 inhibitor selnoflast in patients with moderate to severe active ulcerative colitis.

BACKGROUND: The NLRP3 inflammasome drives release of pro-inflammatory cytokines including interleukin (IL)-1ß and IL-18 and is a potential target for ulcerative colitis (UC). Selnoflast (RO7486967) is an orally active, potent, selective and reversible small molecule NLRP3 inhibitor. We conducted a randomized, placebo-controlled Phase 1b study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selnoflast. METHODS: Nineteen adults with previous diagnosis of UC and current active moderate to severe disease were randomized 2:1 to selnoflast or placebo for 7 days. A dose of 450 mg QD (once daily) was selected to achieve 90% IL-1ß inhibition in plasma and colon tissue. Consecutive blood, sigmoid colon biopsies and stool samples were analyzed for a variety of PD markers. Safety and PK were also evaluated. RESULTS: Selnoflast was well-tolerated. Plasma concentrations increased rapidly after oral administration, reaching Tmax 1 h post-dose. Mean plasma concentrations stayed above the IL-1ß IC90 level throughout the dosing interval (mean Ctrough on Day 1 and Day 5: 2.55 µg/mL and 2.66 µg/mL, respectively). At steady state, post-dose selnoflast concentrations in sigmoid colon (5-20 µg/g) were above the IC90 . Production of IL-1ß was reduced in whole blood following ex vivo stimulation with lipopolysaccharide (LPS) (in the selnoflast arm). No changes were observed in plasma IL-18 levels. There were no meaningful differences in the expression of an IL-1-related gene signature in sigmoid colon tissue, and no differences in the expression of stool biomarkers. CONCLUSIONS: Selnoflast was safe and well-tolerated. Selnoflast 450 mg QD achieved plasma and tissue exposure predicted to maintain IL-1ß IC90 over the dosing interval. However, PD biomarker results showed no robust differences between treatment arms, suggesting no major therapeutic effects are to be expected in UC. The limitations of this study are its small sample size and indirect assessment of the effect on IL-1ß in tissue. TRIAL REGISTRATION: ISRCTN16847938.

Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study.

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-pressure surge 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.

Lack of Effect of 12-Week Treatment with Risankizumab on the Pharmacokinetics of Cytochrome P450 Probe Substrates in Patients with Moderate to Severe Chronic Plaque Psoriasis.

OBJECTIVE: The objective of this study was to characterize the effects of risankizumab on the in vivo activity of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in psoriasis patients using a cocktail approach. METHODS: Patients with moderate to severe chronic plaque psoriasis (n = 21) received single oral doses of sensitive probe substrates for CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) on day 1, followed by 12 weeks of subcutaneous risankizumab treatment of 150 mg once every 4 weeks from day 8 to day 92, and again the same cocktail of substrates on day 98. Serial blood samples were collected for determination of the CYP probe drugs and metabolites with and without risankizumab. Trough samples were collected for risankizumab. RESULTS: The 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞) ratios for the CYP probe substrates administered with risankizumab versus without risankizumab were within the default 0.8-1.25 equivalence bounds. Similar results were observed for maximum plasma concentration (Cmax), except for omeprazole, for which the lower bound of the 90% CI for Cmax (0.73) extended slightly below the default equivalence limit. No differences were observed in metabolite-to-parent drug Cmax or AUC ratios with risankizumab versus without risankizumab. Risankizumab trough plasma concentrations significantly exceeded those of the phase III regimen of risankizumab in psoriasis (150 mg subcutaneously at weeks 0 and 4 and every 12 weeks thereafter). CONCLUSIONS: Risankizumab did not affect the in vivo activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A enzymes in patients with moderate or severe plaque psoriasis and therefore has no potential for drug interactions through these enzymes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02772601.

Long-acting FC-fusion rhGH (GX-H9) shows potential for up to twice-monthly administration in GH-deficient adults.

OBJECTIVE: Hybrid Fc-fused rhGH (GX-H9) is a long-acting recombinant human growth hormone (GH) under clinical development for both adults and children with GH deficiency (GHD). We compared the safety, pharmacokinetics and pharmacodynamics of weekly and every other week (EOW) dosages of GX-H9 with those of daily GH administration in adult GHD (AGHD) patients. DESIGN: This was a randomized, open-label, active-controlled and dose-escalation study conducted in 16 endocrinology centers in Europe and Korea. METHODS: Forty-five AGHD patients with or without prior GH treatment were enrolled. Patients with prior GH treatments were required to have received the last GH administration at least 1 month prior to randomization. Subjects were sequentially assigned to treatment groups. Fifteen subjects were enrolled to each treatment group and randomly assigned to receive either GX-H9 or Genotropin (4:1 ratio). GX-H9 dosage regimens for Groups 1, 2 and 3 were 0.1 mg/kg weekly, 0.3 mg/kg EOW and 0.2 mg/kg EOW, respectively. All Genotropin-assigned subjects received 6 µg/kg Genotropin, regardless of treatment group. Main outcome analyses included measurements of serum insulin-like growth factor 1 (IGF-I), safety, pharmacokinetics, pharmacodynamics and immunogenicity. RESULTS: Mean GX-H9 peak and total exposure increased with an increase in dose after a single-dose administration. The mean IGF-I response was sustained above baseline over the intended dose interval of 168 h for the weekly and 336 h for the EOW GX-H9 groups. Safety profiles and immunogenicity were not different across the treatment groups and with Genotropin. CONCLUSIONS: GX-H9 has the potential for up to twice-monthly administration.

Clinical significance of PlA polymorphism of platelet GP IIb/IIIa receptors during long-term VAD support.

BACKGROUND: Although bleeding and thromboembolism remain major complications after implantation of ventricular assist devices (VADs), no standard anticoagulation protocols are available. Genetic polymorphism of platelet glycoprotein IIb/IIIa may contribute to the development of complications. The present study demonstrates a relationship between the PlA genotype and postoperative complications in patients implanted with pulsatile and axial flow VADs. METHODS: The PlA genotype was determined in 41 consecutive patients treated with a VAD who received anticoagulation with phenprocoumon and aspirin. Pulsatile Novacor (Novacor Corp, Oakland, CA) and Berlin Heart VADs (Berlin Heart, Berlin, Germany) were implanted in 28 patients and the axial flow MicroMed DeBakey VAD (MicroMed Technology, Inc, Houston, TX) in 13. The relationship between the PlA genotype, the anticoagulation regime, and bleeding and thromboembolic events was analyzed. RESULTS: There were no differences between patients with the A1A1 and A1A2 genotype regarding demographic characteristics, weight, or infection episodes. The international normalized ratio (INR), platelet activation tests, and doses of aspirin and dipyridamol before events were similar in both groups. Patients with the A1A1 genotype developed more bleeding complications (39% vs 0%, p = 0.021), while patients with the A1A2 genotype showed a tendency toward more thromboembolic events (13% vs 30%, p = 0.33). With regard to different types of VAD, patients with the axial flow DeBakey VAD and the A1A1 genotype developed significantly more bleeding complications (70% vs 0%, p = 0.033). CONCLUSIONS: In patients with a long-term VAD determination of PlA polymorphism and subsequent adjustment of the anticoagulation regime may lead to a reduction of bleeding and thromboembolic complications.