Safety,tolerability, pharmacokinetic,and pharmacodynamic characteristics of vutiglabridin: A first‐in‐class,first‐in‐human study

This study aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of vutiglabridin, a potential anti‐obesity treatment under development, for the first time in humans. A randomized, placebo‐controlled, single‐ and multiple‐ascending dose study (SAD and MAD, respectively) was performed in healthy Koreans and Whites. Subjects randomly received a single oral dose of 30–720 mg vutiglabridin or placebo at a ratio of 8:2 in the SAD study or 240–480 mg vutiglabridin or placebo once daily for 14 days in the MAD study. Food effect was also evaluated in 240 mg single dose group. Pharmacokinetics were evaluated through plasma concentrations, and pharmacodynamic biomarkers related to obesity or inflammation were analyzed. Safety and tolerability were assessed throughout the study. Single and multiple doses of vutiglabridin were generally well‐tolerated. The pharmacokinetic parameters show less than dose‐proportionality increase, and plasma concentrations increased more than two‐fold after multiple administrations. The mean half‐life of Koreans and Whites in the MAD study was 110 and 73 h, respectively. The systemic exposure of vutiglabridin was significantly increased when taken with a high‐fat meal, and the systemic exposure was lower in Whites than in Koreans. Vutiglabridin was well‐tolerated in healthy Koreans and Whites. The plasma concentration increased less than the dose‐proportionality manner. These results justify further investigation of vutiglabridin in patients with obesity.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

A treatment with multifunctional effects is needed for obesity. Because the chronic inflammation caused by obesity plays an essential role in the progression of metabolic disorders, suppressing inflammatory pathways may be another important treatment goal.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What is the safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics of vutiglabridin, a novel anti‐obesity agent, in healthy Korean and White individuals?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Vutiglabridin was well‐tolerated in both Korean and White individuals. The pharmacokinetic parameters of vutiglabridin did not show dose‐proportionality, and after multiple administrations, vutiglabridin showed accumulation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides safety, pharmacokinetic, and pharmacodynamic information about vutiglabridin, which will be used for further trials for the treatment of obesity.     

The safety and tolerability of levodopa eye drops for the treatment of ocular disorders: A randomized first‐in‐human study

Myopia is the leading cause of low vision worldwide and can lead to significant pathological complications. Therefore, to improve patient outcomes, the field continues to develop novel interventions for this visual disorder. Accordingly, this first‐in‐human study reports on the safety profile of a novel dopamine‐based ophthalmic treatment for myopia, levodopa/carbidopa eye drops. This phase I, first‐in‐human, monocenter, placebo‐controlled, double‐blind, paired‐eye, multidose, randomized clinical trial was undertaken in healthy adult males aged 18–30 years (mean age 24.9 ± 2.7) at the University of Canberra Eye Clinic, Australia. Participants were randomly assigned to receive either a low (1.4 levodopa:0.34 carbidopa [μmoles/day], n = 14) or standard dose (2.7 levodopa:0.68 carbidopa [μmoles/day], n = 15) of levodopa/carbidopa eye drops in one eye and placebo in the fellow eye once daily for 4 weeks (28 days). Over this 4‐week trial, and after a 4‐month follow‐up visit, levodopa/carbidopa treatment had no significant effect on ocular tolerability and anterior surface integrity, visual function, ocular health, refraction/ocular biometry, and did not induce any non‐ocular adverse events. These results indicate that topical levodopa/carbidopa is safe and tolerable to the eye, paving the way for future studies on the efficacy of this novel ophthalmic formulation in the treatment of human myopia. The findings of this study have implications not only for the treatment of myopia, but in a number of other visual disorders (i.e., amblyopia, diabetic retinopathy, and age‐related macular degeneration) in which levodopa has been identified as a potential clinical intervention.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Preclinical data indicate that levodopa/carbidopa eye drops can safely inhibit the development of experimental myopia in animal models.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated whether levodopa/carbidopa eye drops are safe and tolerable to the human eye.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In this phase I, first‐in‐human, monocenter, randomized, double‐blind, placebo‐controlled, multidose trial, levodopa/carbidopa eye drops were found to be safe and well tolerated in healthy adult males over a 4‐week period. Furthermore, no non‐ocular adverse events were reported.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

As topical administration of levodopa/carbidopa eye drops is well tolerated in humans, the efficacy of this novel ophthalmic treatment at inhibiting the development of myopia in patient populations can now be assessed. If found to be effective, this will provide a powerful new method for inhibiting the onset and development of the leading cause of low vision worldwide. This topical formulation may also provide a valuable tool in the treatment of other visual disorders shown to be responsive to levodopa therapy (i.e., amblyopia, diabetic retinopathy, and age‐related macular degeneration).     

Pharmacokinetics and pharmacodynamics of itepekimab in healthy adults and patients with asthma: Phase I first‐in‐human and first‐in‐patient trials

Itepekimab is a monoclonal antibody that targets interleukin (IL‐33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single‐ascending and multiple‐ascending doses of itepekimab in two randomized, double‐blind, placebo‐controlled phase I studies. Healthy adults (N = 40) were randomized to the single‐dose study and patients with moderate asthma (N = 23) to the multiple‐dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single‐dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple‐dose study. Itepekimab exhibited linear PKs across studies and dose‐proportional increases in mean maximum concentration in serum and area under the concentration–time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59–73% and a long terminal half‐life (30.0–31.6 days). IL‐33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL‐33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well‐tolerated in both studies with no detection of treatment‐emergent anti‐drug antibody responses.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Preclinical data suggest that itepekimab, a monoclonal antibody targeting IL‐33, may benefit patients with chronic inflammatory airway diseases by blocking IL‐33–mediated pathologic inflammation. Neither the pharmacokinetic (PK) profile of itepekimab nor its safety has been fully elucidated in first‐in‐human or first‐in‐patient studies.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study evaluated the initial safety of itepekimab, and its PK and pharmacodynamic activity in healthy adults and patients with asthma.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Itepekimab demonstrated linear and dose‐proportional PKs in our studies and was well‐tolerated, with no evidence of immunogenicity. These findings have facilitated dose and regimen selection for subsequent clinical studies in patients with asthma and chronic obstructive pulmonary disease.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Itepekimab is one of a few anti‐alarmin biologics under development; if successful, it may provide an alternative mechanism of action with which to target chronic inflammatory airway diseases, alone or in combination with other targeted therapies.     

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.     

A first‐in‐human study of the safety,tolerability, pharmacokinetics and pharmacodynamics of PF‐06741086, an anti‐tissue factor pathway inhibitor mAb,in healthy volunteers

Essentials

• Tissue factor pathway inhibitor (TFPI) is an antagonist of FXa and the TF‐FVIIa complex.
• PF‐06741086 is an IgG₁ monoclonal antibody that targets the Kunitz‐2 domain of TFPI.
• Single doses of PF‐06741086 were evaluated in a phase 1 study in healthy volunteers.
• Data from this study support further investigation of PF‐06741086 in individuals with hemophilia.

Summary

Background

Tissue factor pathway inhibitor (TFPI) is a protease inhibitor of the tissue factor–activated factor VII complex and activated FX. PF‐06741086 is a mAb that targets TFPI to increase clotting activity.

Objectives

This study was a randomized, double‐blind, sponsor‐open, placebo‐controlled, single intravenous or subcutaneous dose escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of PF‐06741086.

Patients/Methods

Volunteers who provided written informed consent were assigned to cohorts with escalating dose levels. Safety endpoints included treatment‐emergent adverse events (TEAEs), infusion/injection site reactions, vital signs, electrocardiogram, and coagulation and hematology laboratory parameters. Pharmacokinetic (PK) and pharmacodynamic (PD) endpoints included exposures of PF‐06741086 in plasma and measures of PF‐06741086 pharmacology, respectively.

Results

Forty‐one male volunteers were recruited overall. Thirty‐two were dosed with PF‐06741086 from 30 mg subcutaneously to 440 mg intravenously. All doses were safe and well tolerated. TEAEs were mild or moderate in severity, laboratory abnormalities were transient, there were no serious adverse events, there were no infusion/injection site reactions, and no dose escalation stopping criteria were met. Plasma exposures of PF‐06741086 increased greater than proportionally with dose under the same dosing route. Coagulation pharmacology was demonstrated via total TFPI, dilute prothrombin time, D‐dimer, prothrombin fragment 1 + 2 and thrombin generation assay parameters.

Conclusions

Single doses of PF‐06741086 at multiple dose levels were safe and well tolerated in a healthy adult male population. The safety, PK and PD data from this study support progression to a multiple‐dose study in hemophilic patients.

     

A phase I,first‐in‐human,randomized dose‐escalation study of anti‐activated factor XII monoclonal antibody garadacimab

Factor XII (FXII) is the principal initiator of the plasma contact system and has proinflammatory and prothrombotic activities. This single‐center, first‐in‐human phase I study aimed to assess the safety and tolerability of single escalating doses of garadacimab, a monoclonal antibody that specifically inhibits activated FXII (FXIIa), in healthy male volunteers. Volunteers were randomized to eight cohorts, with intravenous (i.v.) doses of 0.1, 0.3, 1, 3, and 10 mg/kg and subcutaneous (s.c.) doses of 1, 3, and 10 mg/kg. Six volunteers in each cohort received garadacimab or placebo in a ratio of 2:1. Follow‐up for safety lasted 85 days after dosing. Blood samples were collected throughout for pharmacokinetic/pharmacodynamic analysis. Forty‐eight volunteers were enrolled: 32 received garadacimab and 16 received placebo. Most volunteers experienced at least one treatment‐emergent adverse event (TEAE), predominantly grade 1. No serious TEAEs, deaths, or TEAEs leading to discontinuation were reported. No volunteers tested positive for garadacimab antidrug antibodies. Garadacimab plasma concentrations increased in a dose‐dependent manner. Sustained inhibition of FXIIa‐mediated kallikrein activity beyond day 28 resulted from 3 and 10 mg/kg garadacimab (i.v. and s.c.). A dose‐dependent increase in activated partial thromboplastin time with no change in prothrombin time was demonstrated. Garadacimab (single‐dose i.v. and s.c.) was well‐tolerated in healthy volunteers. Dose‐dependent increases in plasma concentration and pharmacodynamic effects in relevant kinin and coagulation pathways were observed. These results support the clinical development of garadacimab, including in phase II studies in hereditary angioedema and coronavirus disease 2019 (COVID‐19).

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Plasma protein factor XII (FXII) is the principal initiator of the contact system. Activated FXII (FXIIa) leads to the production of the proinflammatory mediator bradykinin via the kallikrein–kinin system. The production of bradykinin results in increased vascular permeability, vasodilation, and chemotaxis. FXIIa is being investigated as a potential target in hereditary angioedema. Garadacimab is a fully human recombinant antibody that specifically inhibits FXIIa. Preclinical in vitro and in vivo studies of garadacimab showed it to inhibit FXIIa, produce anti‐inflammatory effects, and prevent the formation of bradykinin as well as effectively reduce edema and block proinflammatory cytokine production.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This phase I, single‐center study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating doses of garadacimab after a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The data in this study show that s.c. and i.v. administration of garadacimab in healthy male volunteers is well‐tolerated with no serious treatment‐emergent adverse events (TEAEs) reported during the study, and no discontinuations of garadacimab due to TEAEs. Moreover, the data show that garadacimab plasma concentrations and inhibition of FXII‐mediated kallikrein activity were increased in a dose‐dependent manner. A dose‐dependent increase in activated partial thromboplastin time with no change in prothrombin time and no associated bleeding was also observed.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides the first evidence of the safety and pharmacodynamic impact in FXIIa blockade in humans using a monoclonal antibody. These results support the investigation of garadacimab in a variety of disease states.     

Phase I study in healthy participants to evaluate safety,tolerability, and pharmacokinetics of inhaled nezulcitinib,a potential treatment for COVID‐19

Nezulcitinib (TD‐0903), a lung‐selective pan–Janus‐associated kinase (JAK) inhibitor designed for inhaled delivery, is under development for treatment of acute lung injury associated with coronavirus disease 2019 (COVID‐19). This two‐part, double‐blind, randomized, placebo‐controlled, single ascending dose (part A) and multiple ascending dose (part B) phase I study evaluated the safety, tolerability, and pharmacokinetics (PK) of nezulcitinib in healthy participants. Part A included three cohorts randomized 6:2 to receive a single inhaled dose of nezulcitinib (1, 3, or 10 mg) or matching placebo. Part B included three cohorts randomized 8:2 to receive inhaled nezulcitinib (1, 3, or 10 mg) or matching placebo for 7 days. The primary outcome was nezulcitinib safety and tolerability assessed from treatment‐emergent adverse events (TEAEs). The secondary outcome was nezulcitinib PK. All participants completed the study. All TEAEs were mild or moderate in severity, and none led to treatment discontinuation. Overall (area under the plasma concentration‐time curve) and peak (maximal plasma concentration) plasma exposures of nezulcitinib were low and increased in a dose‐proportional manner from 1 to 10 mg in both parts, with no suggestion of clinically meaningful drug accumulation. Maximal plasma exposures were below levels expected to result in systemic target engagement, consistent with a lung‐selective profile. No reductions in natural killer cell counts were observed, consistent with the lack of a systemic pharmacological effect and the observed PK. In summary, single and multiple doses of inhaled nezulcitinib at 1, 3, and 10 mg were well‐tolerated in healthy participants, with dose‐proportional PK supporting once‐daily administration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

There are a number of investigations of orally delivered Janus‐associated kinase (JAK) inhibitors for the treatment of coronavirus disease 2019 (COVID‐19)–associated cytokine storm. The systemic JAK inhibitor baricitinib appears to be effective for treatment of COVID‐19. An inhaled pan‐JAK inhibitor for local delivery to the lung, nezulcitinib, was in preclinical development at the start of the COVID‐19 pandemic but had not yet been tested in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This first‐in‐human study addresses the safety and pharmacokinetics (PK) of nezulcitinib in healthy participants, and the appropriateness to move nezulcitinib forward in clinical trials in patients with COVID‐19 infection.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Nezulcitinib was generally well‐tolerated in healthy participants; adverse events were mild or moderate in severity, and none resulted in study discontinuation. The PK of nezulcitinib were consistent with preclinical results suggesting a lung‐selective profile and support once‐daily dosing.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results informed an ongoing phase II clinical trial of nezulcitinib for treatment of acute lung injury associated with COVID‐19 in symptomatic patients ({"type":"clinical-trial","attrs":{"text":"NCT04402866","term_id":"NCT04402866"}}NCT04402866).     

Translational findings for odronextamab: From preclinical research to a first‐in‐human study in patients with CD20+ B‐cell malignancies

Odronextamab is a fully‐human IgG4‐based CD20xCD3 bispecific antibody that binds to CD3 on T cells and CD20 on B cells, triggering T‐cell‐mediated cytotoxicity independent of T‐cell‐receptor recognition. Adequate safety, tolerability, and encouraging durable complete responses have been observed in an ongoing first‐in‐human (FIH) study of odronextamab in patients with relapsed/refractory (R/R) B‐cell non‐Hodgkin lymphoma (B‐NHL; {"type":"clinical-trial","attrs":{"text":"NCT02290951","term_id":"NCT02290951"}}NCT02290951). We retrospectively evaluated the pharmacokinetic, pharmacodynamic, and antitumor characteristics of odronextamab in a series of in vitro/in vivo preclinical experiments, to assess their translational value to inform dose escalation for the FIH study. Half‐maximal effective concentration values from in vitro cytokine release assays (range: 0.05–0.08 mg/L) provided a reasonable estimate of odronextamab concentrations in patients associated with cytokine release at a 0.5 mg dose (maximum serum concentration: 0.081 mg/L) on week 1/day 1, which could therefore be used to determine the week 1 clinical dose. Odronextamab concentrations resulting in 100% inhibition of tumor growth in a Raji xenograft tumor mouse model (1–10 mg/L) were useful to predict efficacious concentrations in patients and inform dose‐escalation strategy. Although predicted human pharmacokinetic parameters derived from monkey data overestimated projected odronextamab exposure, they provided a conservative estimate for FIH starting doses. With step‐up dosing, the highest‐tested weekly odronextamab dose in patients (320 mg) exceeded the 1 mg/kg single dose in monkeys without step‐up dosing. In conclusion, combination of odronextamab in vitro cytokine data, efficacious concentration data from mouse tumor models, and pharmacokinetic evaluations in monkeys has translational value to inform odronextamab FIH study design in patients with R/R B‐NHL.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Odronextamab is an IgG4‐based CD20xCD3‐targeting bispecific antibody being evaluated in a first‐in‐human (FIH) study in patients with relapsed/refractory (R/R) B‐cell non‐Hodgkin lymphoma (B‐NHL). Preliminary clinical data indicate adequate safety and tolerability, and encouraging response rates.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This retrospective analysis assessed the translational value of odronextamab preclinical data to inform FIH study design.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In vitro cytokine data, efficacious concentration data in Raji xenograft tumor mouse models, and pharmacokinetic evaluations in cynomolgus monkeys have translational value to inform the odronextamab starting dose and dose escalation strategy, but not the projected target dose, for the FIH study in patients with R/R B‐NHL.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These data demonstrate the value of odronextamab preclinical data to aid efficient FIH clinical study design, some aspects of which may be generalized qualitatively to other bispecific antibodies.     

Phase I studies of the safety,tolerability, pharmacokinetics,and pharmacodynamics of DS‐1211, a tissue‐nonspecific alkaline phosphatase inhibitor

Tissue‐nonspecific alkaline phosphatase (TNAP) hydrolyzes and inactivates inorganic pyrophosphate (PPi), a potent inhibitor of calcification; therefore, TNAP inhibition is a potential target to treat ectopic calcification. These two first‐in‐human studies evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single (SAD) and multiple‐ascending doses (MAD) of DS‐1211, a TNAP inhibitor. Healthy adults were randomized 6:2 to DS‐1211 or placebo, eight subjects per dose cohort. SAD study subjects received one dose of DS‐1211 (range, 3–3000 mg) or placebo, whereas MAD study subjects received DS‐1211 (range, 10–300 mg) once daily, 150 mg twice daily (b.i.d.), or placebo for 10 days. Primary end points were safety and tolerability. PK and PD assessments included plasma concentrations of DS‐1211, alkaline phosphatase (ALP) activity, and TNAP substrates (PPi, pyridoxal 5′‐phosphate [PLP], and phosphoethanolamine [PEA]). A total of 56 (DS‐1211: n = 42; placebo: n = 14) and 40 (DS‐1211: n = 30; placebo: n = 10) subjects enrolled in the SAD and MAD studies, respectively. In both studies, adverse events were mild or moderate and did not increase with dose. PKs of DS‐1211 were linear up to 100 mg administered as a single dose and 150 mg b.i.d. administered as a multiple‐dose regimen. In multiple dosing, there was minimal accumulation of DS‐1211. Increased DS‐1211 exposure correlated with dose‐dependent ALP inhibition and concomitant increases in PPi, PLP, and PEA. In two phase I studies, DS‐1211 appeared safe and well‐tolerated. Post‐treatment PD assessments were consistent with exposure‐dependent TNAP inhibition. These data support further evaluation of DS‐1211 for ectopic calcification diseases.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

In preclinical studies, successful inhibition of tissue‐nonspecific alkaline phosphatase (TNAP) decreased soft‐tissue calcification. However, TNAP inhibition is untested in humans, and the safety and pharmacological effects are unknown.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What are the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) effects of TNAP‐specific inhibitor DS‐1211?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

TNAP inhibition mediated by orally administered DS‐1211 appears to be safe and well‐tolerated in humans. The PD effects of DS‐1211 on alkaline phosphatase, inorganic pyrophosphate, pyridoxal 5′‐phosphate, and phosphoethanolamine suggest it can inhibit TNAP in humans. This is the first clinical trial with a TNAP‐specific inhibitor; its safety over 10 days and PK‐dependent profiles of TNAP inhibition were established.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Ectopic calcification lacks a direct and safe treatment. TNAP inhibition with DS‐1211 may provide a novel targeted therapy for excess soft‐tissue calcification.     

Model‐based dose selection to inform translational clinical oncology development of WNT974, a first‐in‐class Porcupine inhibitor

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. A phase I clinical trial is being conducted in patients with advanced solid tumors. During the dose‐escalation part, various dosing regimens, including once or twice daily continuous and intermittent dosing at a dose range of 5–45 mg WNT974 were studied, however, the protocol‐defined maximum tolerated dose (MTD) was not established based on dose‐limiting toxicity. To assist in the selection of the recommended dose for expansion (RDE), a model‐based approach was utilized. It integrated population pharmacokinetic (PK) modeling and exposure–response analyses of a target‐inhibition biomarker, skin AXIN2 mRNA expression, and the occurrence of the adverse event, dysgeusia. The target exposure range of WNT974 that would provide a balance between target inhibition and tolerability was estimated based on exposure–response analyses. The dose that was predicted to yield an exposure within the target exposure range was selected as RDE. This model‐based approach integrated PK, biomarker, and safety data to determine the RDE and represented an alternative as opposed to the conventional MTD approach for selecting an optimal biological dose. The strategy can be broadly applied to select doses in early oncology trials and inform translational clinical oncology drug development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. The conventional approach for dose selection in small‐molecule oncology trials is based on the maximum tolerated dose (MTD).

• WHAT QUESTION DID THIS STUDY ADDRESS?

How to inform the clinical development path and selection of the recommended dose for expansion (RDE) for a first‐in‐class oncology molecule.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A model‐based approach can be effectively used to integrate pharmacokinetic (PK), pharmacodynamic and safety data and inform RDE selection in oncology drug development.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This model‐based approach integrated population PK and exposure–response analyses of biomarker and safety to determine the RDE, rather than the conventional MTD approach. The strategy can be applied to support translational clinical oncology development, and dose selection in early oncology trials to inform later phase clinical development and study design.     

Safety,tolerability, and pharmacokinetics of oral baicalein tablets in healthy Chinese subjects: A single‐center,randomized, double‐blind,placebo‐controlled multiple‐ascending‐dose study

Baicalein is a biologically important flavonoid in extracted from the Scutellaria baicalensis Georgi, which can effectively inhibit the influenza virus. This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials. In this multiple‐ascending‐dose placebo‐controlled trial, 36 healthy subjects were randomized to receive 200, 400, and 600 mg of baicalein tablet or placebo once daily on day 1 and day 10, 3 times daily on days 4–9. All groups were intended to produce safety and tolerability outcomes (lowest dose first). Blood and urine samples were collected from subjects in the 600 mg group for baicalein PK analysis. Our study had shown that Baicalein tablet was generally safe and well‐tolerated. All adverse events were mild and resolved without any intervention except one case of fever reported in the 600 mg group, which was considered as moderate but not related with baicalein as judged by the investigator. Oral baicalein tablets were rapidly absorbed with peak plasma levels being reached within 2 h after multiple administration. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many studies have shown that baicalin has an anti‐influenza effect in cell and animal experiments. The primary mechanism of action is that baicalein has a strong inhibitory effect on the sialidase of the influenza virus.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our study results have shown that baicalein tablets were administered multiple times within the studied dose range were safe and well‐tolerated in healthy Chinese subjects with no serious or severe adverse effects. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend. Oral baicalein tablets were rapidly absorbed with peak plasma levels reached within 2 h after multiple administration.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our study addresses the safety outcomes of baicalein tablets and emphasizes the PKs of baicalein, which provides a better understanding and a scientific basis of the clinical application of baicalein for further evaluation.     

First‐in‐human study of milvexian,an oral,direct, small molecule factor XIa inhibitor

Milvexian (BMS‐986177/JNJ‐70033093) is a small molecule, active‐site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two‐part, double‐blind, placebo‐controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200‐ and 500‐mg panels investigated the pharmacokinetic impact of a high‐fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once‐ or twice‐daily) or placebo for 14 days. All milvexian dosing regimens were safe and well‐tolerated, with only mild treatment‐emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half‐life (T_1/2) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose‐proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose‐dependent fashion. In MAD panels, steady‐state milvexian plasma concentration was reached within 3 and 6 dosing days with once‐ and twice‐daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Factor XI (FXI) amplifies thrombin generation and has a limited role in hemostasis. Targeted FXI inhibition may reduce the burden of vascular and thromboembolic diseases while preserving hemostasis.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the selective, direct, small molecule FXIa inhibitor milvexian.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Single and multiple ascending doses of milvexian up to 500 mg were generally safe and well‐tolerated, with no clinically significant bleeding events. Milvexian plasma concentration was dose proportional at doses up to 200 mg q.d. The milvexian half‐life is suitable for q.d. or b.i.d. dosing. Milvexian exhibited low renal excretion and low overall variability in PK and PD parameters.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results can inform the future clinical development of milvexian.     

A phase I,randomized, double‐blind,placebo‐controlled,single‐ and multiple dose escalation study evaluating the safety,pharmacokinetics and pharmacodynamics of VX‐128, a highly selective Nav1.8 inhibitor,in healthy adults

Selective inhibition of certain voltage‐gated sodium channels (Na_vs), such as Na_v1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX‐128 is a highly potent and selective Na_v1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX‐128 in healthy subjects in a single‐ and multiple‐ascending dose (MAD) first‐in‐human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX‐128 up to 300 mg were well‐tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX‐128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily [q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX‐128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor‐ and pressure pain, which was dose‐dependent for the latter. VX‐128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half‐life of ~80 h at 10 mg q.d., and approximately two‐fold accumulation ratio after 10 and 30 mg q.d. Although VX‐128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Na_v1.8 inhibitors as pain treatments.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Selective sodium channel (Na_v) inhibitors have been proposed as an alternative to opioids for pain management. Their potential, however, has yet to be confirmed, as none of the multiple selective Na_v inhibitors that have been investigated for pain management has reached the market.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We investigated the safety, tolerability, and initial analgesic effects of VX‐128, a novel and highly selective Na_v1.8 inhibitor, in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This is the first study to describe clinical data obtained on the highly selective Na_v1.8 inhibitor VX‐128, and the first to report analgesic effects of this selective Na_v inhibitor in humans. VX‐128 administered as a single dose was well‐tolerated, but dose‐limiting skin rashes occurred after multiple doses resulting in a premature study halt. Although the study had a parallel design and was not necessarily powered to detect pharmacodynamic effects, nociceptive test results suggest that VX‐128 leads to dose‐dependent analgesic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our findings substantiate research that is performed on evaluating selective Na_v1.8 inhibitors as treatment for pain, and suggests that the cold pressor‐ and pressure pain models are suitable to evaluate selective Na_v1.8 inhibitors.     

Pharmacokinetic/pharmacodynamic modeling for dose selection for the first‐in‐human trial of the activated Factor XII inhibitor garadacimab (CSL312)

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein–kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first‐in‐class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first‐in‐human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose‐related PD effects were observed (e.g., a mechanism‐based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically‐based pharmacokinetic (mPBPK) models with target‐mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (<10%) of FXIIa with a starting dose of 0.1 mg/kg garadacimab and a near maximal inhibition (>95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa‐mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Models based on physiology and mechanisms of action can be highly useful in translating pharmacokinetic/pharmacodynamic (PK/PD) data from animal studies to expectations in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This analysis sought to select doses for investigation in a phase I, first‐in‐human trial of garadacimab (CSL312), a first‐in‐class, fully human, immunoglobulin G4 monoclonal antibody that targets FXIIa.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This analysis demonstrated how a mechanism‐based PK/PD model describing the relationship between drug administration and pharmacologic response observed in cynomolgus monkeys was generated and extrapolated to select doses for investigation in a phase I, first‐in‐human trial of garadacimab. The detailed explanation of the modeling and extrapolation methodology used in this study provides guidance to future researchers selecting doses for phase I, first‐in‐human trials of monoclonal antibodies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study highlights the importance and utility of insightful, physiologic, and mechanistic mathematical modeling in conjunction with robust animal data for translation of PK/PD and accurate prediction of first‐in‐human dosing for clinical trials.     

Safety,tolerability, and pharmacokinetics of single‐ and multiple‐dose administration of islatravir (MK‐8591) in adults without HIV

Islatravir (MK‐8591) is a nucleoside analogue in development for the treatment and prevention of HIV‐1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18–60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir‐triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participants, assigned to 1 of 3 panels, received alternating single doses of islatravir in a fasted state from 5 mg to 400 mg, or placebo, over 3 dosing periods; a 30 mg dose was additionally assessed following a high‐fat meal. In Study 2, 8 participants per dose received 3 once‐weekly doses of 10, 30, or 100 mg islatravir or placebo in a fasted state. For each panel in both trials, 6 participants received active drug and 2 received placebo. Islatravir was generally well‐tolerated, with no serious adverse events or discontinuations due to adverse events. Islatravir was rapidly absorbed (median time to maximum plasma concentration 0.5 hours); plasma half‐life was 49–61 h; intracellular islatravir‐triphosphate half‐life was 118–171 h. Plasma exposure increased in an approximately dose‐proportional manner; there was no meaningful food effect. There was a modest degree of intracellular islatravir‐triphosphate accumulation after multiple weekly dosing. After single oral doses of islatravir greater than or equal to 5 mg, intracellular islatravir‐triphosphate levels were comparable to levels associated with efficacy in preclinical studies. These results warrant continued clinical investigation of islatravir.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

​Current HIV treatment and prevention strategies have limitations, and novel agents that offer improved safety and tolerability, a high barrier to HIV resistance, and more convenient dosing regimens are required.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Two phase 1 studies in participants without HIV assessed safety and pharmacokinetics of rising single and multiple doses of oral islatravir, a nucleoside analogue, to support continued development for the treatment and prevention of HIV‐1 infection.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Islatravir was generally well‐tolerated at single doses up to 400 mg. Oral doses of islatravir greater than or equal to 10 mg resulted in intracellular peripheral blood mononuclear cell levels of the active form, islatravir‐triphosphate, comparable to those associated with antiviral efficacy in preclinical studies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These studies provide important safety and pharmacokinetic information about islatravir in adults without HIV, which will be used to support further clinical investigation of islatravir for the treatment and prevention of HIV‐1 infection.     

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.     

A phase I study to evaluate safety,pharmacokinetics, and pharmacodynamics of respiratory syncytial virus neutralizing monoclonal antibody MK‐1654 in healthy Japanese adults

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among all infants worldwide and remains a significant cause of morbidity and mortality. To address this unmet medical need, MK‐1654, a half‐life extended RSV neutralizing monoclonal antibody, is in clinical development for the prevention of RSV disease in infants. This was a phase I, randomized, placebo‐controlled, single‐site, double‐blind trial of MK‐1654 in 44 healthy Japanese adults. The safety, tolerability, pharmacokinetics, antidrug antibodies (ADAs), and serum neutralizing antibody (SNA) titers against RSV were evaluated for 1 year after a single intramuscular (i.m.) or intravenous (i.v.) dose of MK‐1654 or placebo in five groups (100 mg i.m., 300 mg i.m., 300 mg i.v., 1000 mg i.v., or placebo). MK‐1654 was generally well‐tolerated in Japanese adults. There were no serious drug‐related adverse events (AEs) reported in any MK‐1654 recipient and no discontinuations due to any AEs in the study. The half‐life of MK‐1654 ranged from 76 to 91 days across dosing groups. Estimated bioavailability was 86% for 100 mg i.m. and 77% for 300 mg i.m. One participant out of 33 (3.0%) developed detectable ADA with no apparent associated AEs. The RSV SNA titers increased in a dose‐dependent manner among participants who received MK‐1654. These data support the development of MK‐1654 for use in Japanese infants.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

MK‐1654 is a half‐life extended human monoclonal antibody against respiratory syncytial virus that is being developed for the prevention of infection in infants.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the safety, tolerability, pharmacokinetics (PKs), neutralization activity, and immunogenicity of MK‐1654 in healthy Japanese adults as a surrogate population.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

MK‐1654 was well‐tolerated with a low incidence of treatment emergent antidrug antibodies (ADAs; 3.0%). An extended elimination half‐life (76–91 days) resulted in sustained exposure and pharmacodynamic activity (respiratory syncytial virus serum neutralizing antibody) in healthy Japanese male adults. There was a remarkable increase in SNA following single dose administration of MK‐1654 in Japanese healthy adults (compared to placebo). There was no apparent racial difference in the PKs and PDs of MK‐1654 between Japanese and non‐Japanese adults (historical data) across all dosing regimens.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The results of this study provide a scientific rationale to initiate a global program for MK‐1654 involving Japanese and non‐Japanese infants without dose adjustment.     

Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety,tolerability, pharmacokinetics,and pharmacodynamics of nivolumab

Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis. Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters. Twelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase. In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any ‘cytokine storm’. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. NCT02960854.     

A randomized,placebo‐controlled study to evaluate safety and pharmacokinetics of inhaled ribavirin

Ribavirin is an inosine monophosphate dehydrogenase inhibitor. Studies suggest ribavirin aerosol could be a safe and efficacious treatment option in the fight against coronaviruses. However, current treatment is long (12–18 h per day, 3–7 days), limiting clinical utility. A reduction in treatment time would reduce treatment burden. We aimed to evaluate safety and pharmacokinetics (PK) of four, single‐dose regimens of ribavirin aerosol in healthy volunteers. Thirty‐two subjects were randomized, to four cohorts of aerosolized ribavirin (active) or placebo. Cohort 1 received 50 mg/ml ribavirin/placebo (10 ml total volume); cohort 2, 50 mg/ml ribavirin/placebo (20 ml total volume); cohort 3, 100 mg/ml ribavirin/placebo (10 ml total volume); and cohort 4, 100 mg/ml ribavirin/placebo (20 ml total volume). Intense safety monitoring and PK sampling took place on days 1, 2, 3, and 40. Subjects were (mean ± SD, active vs. placebo) aged 57 ± 4.5 vs. 60 ± 2.5 years; 83% vs. 88% were female; and 75% vs. 50% were Caucasian. Some 12.5% (3/24) and 25% (2/8) experienced at least one treatment‐emergent adverse event (TEAE) (two moderate; five mild) in the active and placebo groups, respectively. No clinically significant safety concerns were reported. Mean maximum observed concentration (C _max) and area under the curve (AUC) values were higher in cohort 4, whereas cohorts 2 and 3 showed similar PK values. Ribavirin absorption reached C _max within 2 h across cohorts. Four single‐dose regimens of ribavirin aerosol demonstrated systemic exposure with minimal systemic effects. Results support continued clinical development of ribavirin aerosol as a treatment option in patients with coronaviruses.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Ribavirin is an inosine monophosphate dehydrogenase inhibitor, an enzyme in the synthesis of purine nucleotides, and a broad‐spectrum antiviral agent. It is approved in the USA and Canada for the treatment of lower respiratory tract infections in hospitalized infants and children due to the respiratory syncytial virus (RSV). Early data suggest that ribavirin is safe and effective in the treatment of COVID‐19. However, RSV treatment procedures are lengthy (12–18 h per day for 3−7 days), limiting wider clinical utility. A shorter treatment time, while maintaining safety and efficacy, is required for ribavirin to become a practical treatment option for coronaviruses.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We performed this study to evaluate the safety and pharmacokinetics (PK) of four, single‐dose, clinically relevant regimens of ribavirin aerosol in healthy volunteers. Doses ranged from 50 to 100 mg/ml, delivered in a single inhalation of either 20 or 40 min duration.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results showed that four single‐dose regimens of ribavirin aerosol were safe and well‐tolerated, without dose‐limiting toxicities, and a comparable safety profile to placebo. The PK were linear and well‐tolerated across the four single‐dose regimens, demonstrating systemic exposure with minimal systemic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

In the context of coronaviruses, delivery of drug directly to the site of infection (the respiratory tract) is key. As such, these results support the continued clinical development of ribavirin aerosol as a new treatment option in patients with coronaviruses.