Bimekizumab for the treatment of moderate-to-severe plaque psoriasis: efficacy, safety, pharmacokinetics, pharmacodynamics and transcriptomics from a phase IIa, randomized, double-blind multicentre study.

BACKGROUND: Bimekizumab is a monoclonal antibody that selectively inhibits both interleukin (IL)-17A and IL-17F, which is currently under investigation for treatment of moderate-to-severe plaque psoriasis. Maintenance dosing every 4 weeks is well established with IL-17 inhibitors for psoriasis. OBJECTIVES: To investigate the possible dosing interval during bimekizumab maintenance therapy to maintain clear skin, to inform phase III studies. METHODS: Forty-nine patients with moderate-to-severe plaque psoriasis received bimekizumab 320 mg at weeks 0/4, followed at week 16 by bimekizumab 320 mg (n = 17) or placebo (n = 32). Efficacy, safety, pharmacokinetics, immunogenicity and biopsy transcriptomic analyses were assessed to week 28. RESULTS: At week 8, 47% of patients achieved a 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 100), increasing to 57% at week 12 (8 weeks after the second dose) before decreasing. In those who received bimekizumab at week 16, PASI 100 rate increased to comparable peak levels at week 20, but reduced by week 28 to 41% (12 weeks after the third dose). The week 8 transcriptional signature observed in lesional psoriatic skin rapidly normalized to levels consistent with nonlesional skin, resulting in molecular remission. Keratinocyte-related gene products such as CXCL1 (C-X-C motif chemokine ligand 1), IL-8 (encoded by the CXCL8 gene), CCL20 (C-C motif chemokine 20), IL-36γ and IL-17C were profoundly normalized to levels associated with nonlesional skin. CONCLUSIONS: Here, inhibition of IL-17F in addition to IL-17A resulted in rapid, deep clinical responses. Additionally, profound normalization of keratinocyte biology and the psoriatic transcriptome was observed, including normalization of both IL17 and IL23 gene expression by week 8. These data provide evidence to support evaluation of bimekizumab maintenance dosing both every 8 and every 4 weeks in phase III clinical trials.

Pharmacokinetic comparisons of three nasal fentanyl formulations; pectin, chitosan and chitosan-poloxamer 188.

OBJECTIVES: To optimize the absorption profile and reduce C(max), three new fentanyl nasal spray formulations have been developed: fentanyl pectin (FPNS), fentanyl chitosan (FChNS) and fentanyl in chitosan-poloxamer 188 (FChPNS). The venous pharmacokinetic profiles and tolerability of these formulations were assessed and compared with oral transmucosal fentanyl citrate (OTFC) lozenge. SUBJECTS AND METHODS: This randomized, open-label, crossover study was conducted in opioid-naïve, healthy adult volunteers. Subjects were dosed under naltrexone blockade on four occasions with three nasal sprays (100 microg in 100 microl) and OTFC 200 microg. Fentanyl venous plasma concentrations were measured up to 24 h post-dose. Tolerability was assessed by clinical nasal assessments and a nasal reactogenicity questionnaire. RESULTS: 18 subjects were enrolled and completed the study. The mean dose-normalized AUC(0-infinity) for each nasal formulation was significantly higher (p < 0.05) compared with OTFC. Bioavailability compared with OTFC was significantly greater for all nasal fentanyl formulations (FPNS 132.4%, FChNS 154.1%, FChPNS 122.3%). Median tmax (FPNS 0.33 h, FChNS 0.17 h, FChPNS 0.26 h) were significantly (p < 0.001) reduced (OTFC 1.5 h) and mean C(max) significantly increased with all nasal formulations compared with OTFC. Nasal reactogenicity symptom incidence was lowest for the FPNS formulation (FPNS 2, FChNS 28 and FChPNS 45). CONCLUSIONS: All nasal formulations demonstrated significantly increased systemic exposure and reduced times to peak plasma values compared with OTFC. The FPNS formulation exhibited the most favorable nasal and general tolerability profiles. It appears suitable for further investigation in breakthrough cancer pain management.

Pharmacokinetics and relative bioavailability of fentanyl pectin nasal spray 100 - 800 µg in healthy volunteers.

OBJECTIVES: Fentanyl pectin nasal spray (FPNS) is formulated as a solution utilizing PecSys®; pectin based enabling technology (Archimedes). On contact with the nasal mucosa the formulation will gel and modulate fentanyl absorption while limiting nasal drip or runoff. This single-dose volunteer study compared the pharmacokinetics of FPNS 100, 200, 400, and 800 µg doses and assessed bioavailability relative to oral transmucosal fentanyl (OTFC) 200 µg. Safety and dose proportionality were also examined. SUBJECTS AND METHODS: 16, opioid-naïve subjects were dosed on five separate visits under naltrexone block. FPNS doses were administered using a Pfeiffer device delivering 100 µl. Devices were filled with either 1.57 mg/ml (100 and 200 µg dosing) or 6.28 mg/ml fentanyl citrate (400 and 800 µg). Venous blood samples were collected up to 48 h after dosing and plasma fentanyl concentrations measured. RESULTS: Median tmax values for FPNS ranged from 15 to 21 min post-dose and were dose-independent. At 200 µg Cmax values were 2.3-fold higher for FPNS compared with OTFC. Mean relative bioavailability of FPNS to OTFC ranged from 103% to 163%. Dose proportionality for Cmax and AUC0-1 across the FPNS range was statistically confirmed. Drug absorption also increased in a close to dose-proportional manner for AUC0-inf. CONCLUSIONS: FPNS has a shorter tmax, higher Cmax and greater bioavailability than OTFC and is well tolerated. The dose proportionality of Cmax and AUC0-1 was demonstrated. It is concluded that the pharmacokinetic profile of FPNS suggests this product is suitable for clinical investigation in breakthrough pain in cancer patients.

A critical threshold of exercise capacity in the ventilatory response to exercise in heart failure.

During exercise patients with chronic left heart failure ventilate more than normal individuals at the same workload; the ratio of minute ventilation to minute production of carbon dioxide (VE/VCO2) is increased. The relation between increased VE/VCO2, severity of heart failure, and exercise capacity has not been defined. VE/VCO2 was measured in 47 patients with chronic left heart failure (New York Heart Association grades II and III) and in 1009 healthy controls. Exercise capacity was assessed by peak oxygen consumption (VO2max) during progressive exercise. In the controls VO2max ranged from 25 to 93 ml/kg/min; VE/VCO2 was 17-36 and did not correlate with VO2max. In chronic left heart failure the VO2max ranged from 9 to 29 ml/kg/min; VE/VCO2 was 22-42 and correlated strongly with VO2max. End tidal carbon dioxide and respiratory rate at peak exercise were similar in the controls and patients with chronic left heart failure. The increase in VE/VCO2 on exercise in chronic left heart failure indicates increased physiological dead space, presumably caused by a ventilation-perfusion mismatch. In the controls and patients with chronic left heart failure the relation of VE/VCO2 to VO2max was curvilinear with a threshold of VO2max below which VE/VCO2 started to rise above the normal range. This point of inflection may be explained by the existence of a critical level of cardiac function necessary to perfuse adequately all lung zones on exercise.

Brief exercise induces an immediate and a delayed leucocytosis.

Haematological profiles were measured: (1) before and for 5 h 30 min after 30 min sports (squash, swimming, jogging); and (2) before, during and for 2 h 30 min after 30 min cycle ergometry at workloads which required rates of oxygen consumption that were between 48% and 84% of maximal. In both instances exercise induced an immediate leucocytosis (owing to rises in both neutrophils and lymphocytes) which subsided rapidly at the finish of exercise and was followed by a delayed neutrophilia of greater magnitude which peaked at approximately 3 h after the start of exercise. Changes in plasma catecholamines and cortisol recorded during and after exercise (cycle ergometry only) support the hypothesis that the immediate leucocytosis during brief exercise is attributable to elevated catecholamine levels, whereas the delayed neutrophilia is due to raised cortisol levels.

Studies on the immediate and delayed leucocytosis elicited by brief (30-min) strenuous exercise.

Eight healthy male volunteers exercised for two 30-min sessions starting 3 h apart on an electronically braked cycle ergometer at a work load (mean 155.9 W, SD 33.4 W) which required an oxygen consumption that was 70% of their maximal rate of oxygen uptake. Venous blood samples were taken through an indwelling cannula over a period of 6 h beginning shortly before the first bout of exercise and were analysed for routine haematological parameters and for lactate, noradrenaline, adrenaline and cortisol. Both bouts of exercise induced an immediate leucocytosis due to rises in lymphocytes and neutrophils but only the first exercise bout induced a substantial delayed neutrophilia. In at least five subjects, changes in lymphocyte and platelet numbers were correlated (Spearman's rank procedure, P less than 0.05) with simultaneous changes in the plasma concentrations of lactate, noradrenaline and adrenaline over the 6-h period studied. Increases in the plasma concentration of cortisol due to exercise correlated positively with the percentage changes in neutrophil numbers at 3 h and 6 h. These results are consistent with the suggestion that the immediate and delayed leucocytosis induced by exercise are mediated respectively by catecholamine and by cortisol.