Pharmacokinetics,safety and tolerability of the novel,selective mineralocorticoid receptor antagonist finerenone – results from first‐in‐man and relative bioavailability studies

The safety, tolerability and pharmacokinetics of the selective nonsteroidal mineralocorticoid receptor antagonist finerenone were evaluated in healthy male volunteers in two randomized, single‐centre studies. Study 1 was a first‐in‐man, single‐blinded, placebo‐controlled, parallel‐group, dose‐escalation study. Fasted participants (n = 45) received single oral doses of finerenone 1–40 mg polyethylene glycol (PEG) solution or placebo. Study 2 was a relative bioavailability study comparing a finerenone 10 mg immediate‐release (IR) tablet with finerenone 10 mg PEG solution in the fasted state, investigating the effect of a high‐fat/high‐calorie meal on the pharmacokinetics of the IR tablet and assessing a further dose escalation to finerenone 80 mg (eight × finerenone 10 mg IR tablets), in an open‐label, fourfold crossover design (n = 15). Finerenone was rapidly absorbed from PEG solution (median time to maximum plasma concentration [t_max]: 0.500–1.00 h), exhibited dose‐linear pharmacokinetics and was rapidly eliminated from plasma (geometric mean terminal half‐life [t_½]: 1.70–2.83 h). Finerenone IR tablets demonstrated similar pharmacokinetics (median t_max: 0.750–2.50 h; geometric mean t_½: 1.89–4.29 h) with, however, enhanced bioavailability versus PEG solution (least‐squares mean tablet/solution ratio of 187% for area under the plasma–concentration curve [AUC] and maximum plasma concentration [C_max]). High‐fat/high‐calorie food affected the rate but not the extent of finerenone absorption. Finerenone was well tolerated and did not influence clinical laboratory parameters, blood pressure, heart rate, urinary electrolytes or neurohormones, including serum aldosterone and angiotensin II. In conclusion, finerenone has favourable pharmacokinetics and tolerability in healthy men, and is suitable for dosing independent of food intake.     

A first‐in‐human study of KMRC011, a potential treatment for acute radiation syndrome,to explore tolerability,pharmacokinetics, and pharmacodynamics

KMRC011 is a novel Toll‐like receptor 5 agonist under development as a treatment for acute radiation syndrome (ARS). The aim of this first‐in‐human study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of a single intramuscular dose of KMRC011 in healthy subjects. A randomized, single‐blind, placebo‐controlled, single dose‐escalation study was conducted with the starting dose of 5 μg. Eight (4 only for 5 μg cohort) subjects per cohort were randomly assigned to KMRC011 or placebo in a 3:1 ratio. Dose‐limiting toxicity (DLT) was assessed throughout the study. Serum concentrations of KMRC011, granulocyte colony‐stimulating factor (G‐CSF), and interleukin‐6 (IL‐6) were measured up to 48 h postdose. Based on safety review, the dose of KMRC011 escalated up to 20 μg, and consequently, a total of 4 dose levels (5, 10, 15, and 20 μg) were explored. The most common adverse event was injection site reaction, showing no dose‐related trend. Three DLTs (2 cases of hepatic enzyme increased and 1 of pyrexia) were observed; 1 in the 15 μg cohort and 2 in the 20 μg cohort. A developed method could not detect any KMRC011 in serum. KMRC011 15 μg and 20 μg showed significant increases of G‐CSF, IL‐6, and absolute neutrophil counts, compared with the placebo. A single intramuscular administration of KMRC011 ranging from 5 to 15 μg was tolerated in healthy subjects. Doses of KMRC011 equal to or greater than 15 μg exerted TLR5 agonist‐like activities by increasing serum G‐CSF and IL‐6. It suggests that KMRC011 has the potential for a treatment for ARS.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Toll‐like receptor 5 (TLR5) can be a target for acute radiation syndrome (ARS), and KMRC011 is a novel TLR5 agonist being developed as a treatment for ARS. In animal models of irradiation, TLR5 agonists showed radioprotective and radiomitigative effect, and granulocyte colony‐stimulating factor (G‐CSF) and interleukin‐6 (IL‐6) have been proposed as efficacy biomarkers for TLR5 agonists. For further development, properties of KMRC011 including tolerability in humans need to be evaluated.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does KMRC011, a novel TLR5 agonist, show acceptable safety profiles and clinically meaningful changes in efficacy biomarkers in healthy humans?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A single intramuscular administration of KMRC011 was tolerated in healthy humans. In addition, KMRC011 exerted TLR5 agonist‐like activities by increasing the levels of serum G‐CSF and IL‐6. As a result, KMRC011 demonstrates acceptable tolerability and preliminary activity in humans as well as animal models, and thus, KMRC011 may have the potential for a treatment for ARS.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our first‐in‐human study provided new clinical pharmacology information, such as safety and pharmacodynamics (PDs) of KMRC011 in humans. These findings are expected to be integrated with previous animal PD data, translate animal efficacy to humans, and ultimately contribute to the drug approval under the Animal Rule.     

Pharmacokinetics,safety, and tolerability of sulcardine sulfate: an open‐label,single‐dose,randomized study in healthy Chinese subjects

Sulcardine sulfate (Sul) is a novel anti‐arrhythmic agent as a potential treatment for atrial fibrillation and ventricular arrhythmias. This study was conducted to investigate the pharmacokinetic profile, safety, and tolerability of Sul in healthy Chinese subjects. In this open‐label, single‐dose, randomized study, 10 healthy subjects were assigned to receive Sul doses of 200, 400, and 800 mg under fasting conditions (Cohorts A, B, and C, respectively) or 400 mg under fed conditions (Cohort D). The study incorporated a crossover design, separated by a seven‐day washout period. Blood samples were collected before treatment and at successive time intervals up to 48 h after treatment. Sul concentrations in plasma samples were determined using a validated LC‐MS/MS method. Tolerability was determined by clinical evaluation and adverse event (AE) monitoring. Pharmacokinetic results demonstrated that C_max and AUC_(0–t) of Sul increased with an increasing dose. The mean t_1/2 values for Cohorts A, B, and C were 16.85, 17.66, and 11.87 h, respectively. No statistically significant differences were observed between men and women for the main pharmacokinetic parameters, with the exception of t_1/2 in Cohorts B and C. No significant differences were observed in the absorption and bioavailability of Sul between the fed and fasted states (P > 0.05). Four subjects reported mild AEs during the study. No serious AEs were reported. Sul was shown to be safe and well tolerated in healthy Chinese subjects. Pharmacokinetics studies demonstrated that Sul has adequate oral absorption and bioavailability properties.     

Safety,tolerability, pharmacokinetics,and pharmacodynamics of HBM9161, a novel FcRn inhibitor,in a phase I study for healthy Chinese volunteers

Blockade of the binding between neonatal Fc receptor and IgG‐Fc reduces circulating IgG, and thus emerges as a potential therapy for IgG‐mediated autoimmune conditions. This was a double blind, randomized, single ascending dose study to evaluate the safety, pharmacokinetics, and pharmacodynamics of HBM9161 (a fully humanized Fc receptor monoclonal antibody) in healthy Chinese volunteers. Subjects were randomized to receive a single s.c. dose of HBM9161 or placebo in a 3:1 ratio in 3 dosing cohorts (340 mg, 510 mg, or 680 mg, respectively), and then followed up for 85 days. Study end points included incidence of adverse event (AE), serum drug concentration, IgG and its subclasses, and anti‐drug antibodies (ADAs). Twenty‐four subjects were randomized. Dose‐dependent reduction of total IgG occurred rapidly from baseline to reach nadir at day 11, then recovered steadily from day 11 to day 85. The mean maximum percentage reductions from baseline total IgG were 21.0 ± 9.3%, 39.8 ± 5.13%, and 41.2 ± 10.4% for subjects receiving HBM9161 340 mg, 510 mg, and 680 mg, respectively. The exposure of HBM9161 (areas under the curve [AUCs] and peak plasma concentration [C_max]) increased in a more than dose‐proportional manner at the dose examined. All reported AEs were mild in severity. The most reported AEs in the HBM9161 groups were influenza‐like illness and rash. Two subjects developed ADA during the study period. A single s.c. dose of HBM9161 results in sustained and dose‐dependent IgG reduction, and was well‐tolerated at a dose up to 680 mg in Chinese subjects. The data warrant further investigation of its effects in IgG‐mediated autoimmune disorders.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Animal studies and recent human data from White populations showed that treatment with neonatal Fc receptor (FcRn) inhibitor reduces circulating IgG levels and is well‐tolerated. Data of FcRn inhibitors in Asians is relatively limited.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety profile of HBM9161 (an FcRn inhibitor) in healthy Chinese volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Subcutaneous HBM9161 is safe and effective in IgG reduction in Chinese subjects. The PKs, PDs, and safety characteristics in Chinese are similar to the first‐in‐human study in the White population.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

HBM9161 can be a potential treatment for IgG‐mediated autoimmune disorders and organ transplant rejection.     

First‐in‐human study of the safety,tolerability, pharmacokinetics,and pharmacodynamics of ALPN‐101, a dual CD28/ICOS antagonist,in healthy adult subjects

ALPN‐101 (ICOSL vIgD‐Fc) is an Fc fusion protein of a human inducible T cell costimulatory ligand (ICOSL) variant immunoglobulin domain (vIgD) designed to inhibit the cluster of differentiation 28 (CD28) and inducible T cell costimulator (ICOS) pathways simultaneously. A first‐in‐human study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN‐101 in healthy adult subjects. ALPN‐101 was generally well‐tolerated with no evidence of cytokine release, clinically significant immunogenicity, or severe adverse events following single subcutaneous (SC) doses up to 3 mg/kg or single intravenous (IV) doses up to 10 mg/kg or up to 4 weekly IV doses of up to 1 mg/kg. ALPN‐101 exhibited a dose‐dependent increase in exposure with an estimated terminal half‐life of 4.3–8.6 days and SC bioavailability of 60.6% at 3 mg/kg. Minimal to modest accumulation in exposure was observed with repeated IV dosing. ALPN‐101 resulted in a dose‐dependent increase in maximum target saturation and duration of high‐level target saturation. Consistent with its mechanism of action, ALPN‐101 inhibited cytokine production in whole blood stimulated by Staphylococcus aureus enterotoxin B ex vivo, as well as antibody responses to keyhole limpet hemocyanin immunization, reflecting immunomodulatory effects upon T cell and T‐dependent B cell responses, respectively. In conclusion, ALPN‐101 was well‐tolerated in healthy subjects with dose‐dependent PK and PD consistent with the known biology of the CD28 and ICOS costimulatory pathways. Further clinical development of ALPN‐101 in inflammatory and/or autoimmune diseases is therefore warranted.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

ALPN‐101 is an Fc fusion protein of a human inducible T cell costimulatory ligand variant immunoglobulin domain designed to block the cluster of differentiation 28 CD28) and inducible T cell costimulator (ICOS) simultaneously, thereby inhibiting two key costimulatory pathways in T lymphocytes. Although inhibitors of each pathway alone have been studied in humans, this is the first assessment of a dual antagonist in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This first‐in‐human study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN‐101 in healthy subjects. The PK‐PD relationship was evaluated.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

ALPN‐101 demonstrated favorable safety and tolerability profiles and dose‐dependent PK and PD in healthy subjects. The dose‐PK‐PD analysis showed that the target saturation of ALPN‐101 can be well‐predicted based on PK data and the observed PD effects are consistent with the known biology of the CD28 and ICOS pathways.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The results support further clinical development of ALPN‐101 and the PK‐PD relationship will guide dosing regimens in autoimmune and inflammatory diseases.     

Safety, tolerability and pharmacokinetics of BIBN 4096 BS, the first selective small molecule calcitonin gene-related peptide receptor antagonist, following single intravenous administration in healthy volunteers

BIBN 4096 BS ([R-(R*,S*)]-N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-,1-piperidinecarboxamide) is the first selective, highly potent, small molecule, nonpeptide calcitonin gene-related peptide (CGRP) receptor antagonist, which has been developed for the treatment of acute migraine. The objective of this study was to obtain information on the safety, tolerability and pharmacokinetics of BIBN 4096 BS following single intravenous administration of rising doses (0.1, 0.25, 0.5, 1, 2.5, 5 and 10 mg) in 55 healthy male and female volunteers. The study was of single-centre, double-blind (within dose levels), placebo-controlled, randomized, single rising dose design. Blood pressure, pulse rate, respiratory rate, ECG, laboratory tests and forearm blood flow did not reveal any clinically relevant, drug-induced changes. Sixteen adverse events (AEs) were reported by eight of 41 volunteers after BIBN 4096 BS compared to five AEs reported by four of 14 volunteers after placebo. Approximately two-thirds of all AEs related to active treatment occurred at the highest dose of 10 mg. At this dose level, all AEs were confined to the three BIBN 4096 BS-treated females, and consisted mainly of transient and mild paresthesias. Paresthesias were the single most frequent AE, whereas fatigue was the AE which occurred in the highest number of subjects. Only two AEs were of moderate intensity, all remaining AEs were of mild intensity. No serious AEs were reported. The local tolerability after intravenous administration was good. In summary, intravenously administered BIBN 4096 BS revealed a very favourable safety profile over the dose range tested in both genders. Generally well tolerated at all dose levels, it was of satisfactory tolerability in female subjects at the highest dose of 10 mg. The plasma concentration-time courses of BIBN 4096 BS showed multicompartmental disposition characteristics. Mean maximum concentration (Cmax) values appeared to be dose-proportional. Based on the results from the two high dose levels (5 and 10 mg) with sufficient individual subject data, BIBN 4096 BS exhibited a total plasma clearance (CL) of approximately 12 l/h and an apparent volume of distribution at steady state (Vss) of approximately 20 l, resulting in a terminal half-life (t1/2) of approximately 2.5 h. Inter-individual variability was moderate with a coefficient of variation of approximately 45% based on the area under the plasma concentration-time curve (AUC) values. The mean renal clearance (CLR) was approximately 2 l/h, suggesting that renal excretion plays only a minor role in the elimination of unchanged BIBN 4096 BS.     

Recombinant human tissue factor pathway inhibitor exerts anticoagulant,anti‐inflammatory and antimicrobial effects in murine pneumococcal pneumonia

See also Maroney SA, Mast AE. Tissue factor pathway inhibitor and bacterial infection. This issue, pp 119–21. Summary. Background: Streptococcus (S.) pneumoniae is the most common causative pathogen in community‐acquired pneumonia and a major cause of sepsis. Recombinant human tissue factor pathway inhibitor (rh‐TFPI) attenuates sepsis‐induced coagulation and has been evaluated in clinical trials involving patients with sepsis and community‐acquired pneumonia. Objective: To examine the effect of rh‐TFPI on coagulation, inflammation and bacterial outgrowth in S. pneumoniae pneumonia in mice, with or without concurrent antibiotic treatment. Methods: Pneumonia was induced by intranasal inoculation with S. pneumoniae. Mice were treated with placebo, rh‐TFPI, ceftriaxone or rh‐TFPI combined with ceftriaxone. Early (8 h) and late (24 h) initiated treatments were evaluated. Samples were obtained 24 or 48 h after infection, for early and late initiated treatment, respectively. In vitro, placebo or rh‐TFPI was added to a suspension of S. pneumoniae. Results: Rh‐TFPI reduced pneumonia‐induced coagulation; rh‐TFPI with ceftriaxone further attenuated coagulation relative to ceftriaxone alone. Rh‐TFPI inhibited accumulation of neutrophils in lung tissue and reduced the levels of several cytokines and chemokines in lungs and plasma in mice not treated with antibiotics; in these animals, rh‐TFPI initiated 24 h after infection decreased pulmonary bacterial loads. In vitro, rh‐TFPI also inhibited growth of S. pneumoniae. Conclusions: Therapeutic rh‐TFPI attenuates coagulation, inflammation and bacterial growth during pneumococcal pneumonia, whereby the latter two effects only become apparent in the absence of concurrent antibiotic treatment.