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.     

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 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.     

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.     

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.     

Evaluation of the pharmacokinetics of trazpiroben (TAK‐906) in the presence and absence of the proton pump inhibitor esomeprazole

Trazpiroben, a dopamine D₂/D₃ receptor antagonist under development to treat gastroparesis, displays decreasing solubility with increasing pH. This single‐sequence, open‐label, two‐period, crossover study evaluated the effect of esomeprazole, a proton pump inhibitor that raises gastric pH, on the single‐dose pharmacokinetics, safety, and tolerability of trazpiroben in healthy adults ({"type":"clinical-trial","attrs":{"text":"NCT03849690","term_id":"NCT03849690"}}NCT03849690). In total, 12 participants were enrolled and entered period 1 (days 1–3), receiving a single oral dose of trazpiroben 25 mg on day 1. After a 4‐day washout, participants then entered period 2 (days 8–13) and received esomeprazole 40 mg once daily on days 8–12, with a single oral dose of trazpiroben 25 mg co‐administered 1 h post esomeprazole dosing on day 11. Geometric mean area under the curve from time 0 extrapolated to infinity (AUC_∞) and maximum plasma concentration (C_max) values were generally similar when trazpiroben was administered alone versus alongside esomeprazole (AUC_∞, 44.03 vs. 38.85 ng h/ml; C_max, 19.76 vs. 17.24 ng/ml). Additionally, the associated geometric mean ratio (GMR; co‐administration: administration alone) 90% confidence intervals (CIs) suggested no clinically meaningful difference between treatment groups (AUC_∞, GMR 0.88, 90% CI 0.78–1.00; C_max, 0.87, 90% CI 0.70–1.09). Mean apparent first‐order terminal elimination half‐life values were similar between treatments, illustrating co‐administration with esomeprazole had minimal effect on trazpiroben elimination. Trazpiroben was well‐tolerated in healthy adults following administration alone and alongside esomeprazole, with no clinically relevant adverse events reported. The lack of evidence of any clinically meaningful drug–drug interaction supports the co‐administration of esomeprazole with trazpiroben.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Gastroparesis is a gastric motility disorder typified by delayed gastric emptying without mechanical obstruction, with affected patients experiencing a range of gastrointestinal symptoms. Patients with gastroparesis may experience symptom overlap with, or comorbid, gastroesophageal reflux disease. Proton pump inhibitors (PPIs), which raise gastric pH, are frequently used to provide symptomatic relief. Trazpiroben is a dopamine D₂/D₃ receptor antagonist under development to treat gastroparesis. Given that trazpiroben displays decreasing solubility with increasing pH, the potential for a drug–drug interaction (DDI) with a PPI was evaluated.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of the PPI esomeprazole on the single‐dose pharmacokinetics, safety, and tolerability of trazpiroben in healthy adults.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The results of this study demonstrated no evidence of any clinically meaningful DDI between trazpiroben and esomeprazole. Trazpiroben was well‐tolerated following administration alone and alongside esomeprazole, with no clinically relevant adverse events reported.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The current treatment landscape for gastroparesis is limited, with use of available therapies restricted by safety concerns. Our findings support the potential co‐administration of trazpiroben and esomeprazole, indicating that trazpiroben could represent a promising treatment option for patients with gastroparesis who are receiving PPI therapy.     

Pharmacokinetics of daridorexant,a dual orexin receptor antagonist,are not affected by renal impairment

The aim of this study was to evaluate the impact of renal impairment on the pharmacokinetics (PKs), safety, and tolerability of daridorexant, a dual orexin receptor antagonist intended for the treatment of insomnia. A single‐center, open‐label study evaluated the PKs of daridorexant in patients with severe renal function impairment (SRFI; determined by creatinine clearance using the Cockcroft‐Gault equation; N = 8) not on dialysis, and in matched control subjects (based on sex, age, and body weight; N = 7). A single oral dose of daridorexant 25 mg was orally administered in the morning. Blood samples were collected up to 72 h postdose for PK assessments of daridorexant. In patients with SRFI, maximum plasma concentrations (C_max; geometric mean ratio [GMR] and 90% confidence interval [CI]: 0.94 [0.60–1.46]), time to reach C_max (T _max; median difference [90% CI] of −0.25 h [−0.75 to 0.25]), and half‐life (GMR [90% CI] of 0.99 [0.66–1.48]), were virtually unchanged. Exposure (area under the plasma concentration‐time profile) to daridorexant was slightly higher in patients with SRFI than in control subjects with the GMR (90% CI) being 1.16 (0.63–2.12). No safety issue of concern was detected as all adverse events were transient and of mild or moderate intensity, and no treatment‐related effects on vital signs, clinical laboratory, or electrocardiogram variables were observed following daridorexant administration in patients with SRFI and control subjects. Based on these observations, PK alterations of daridorexant due to renal function impairment are not considered of clinical relevance and no dose adjustment is necessary in these patients.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Daridorexant, a potent and selective dual orexin receptor antagonist being developed to treat insomnia, has been shown to have significant effects on sleep onset and sleep maintenance, and improves the impaired daytime functioning of patients with insomnia. Daridorexant has recently been submitted for marketing authorization (in the United States and the European Union).

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study compared the pharmacokinetics (PKs), safety, and tolerability of daridorexant between patients with severe renal function impairment (SRFI) and control subjects.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Similar PK profiles and no tolerability issues were observed in patients with SRFI and control subjects following single‐dose administration of 25 mg daridorexant.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

In clinical practice, the same dose of daridorexant can be administered to patients with insomnia with or without any degree of renal function impairment.     

Pharmacogenetic testing among patients with depression in a US managed care population

Actionable drug–gene pairs relevant to depression treatment include CYP2D6 and CYP2C19 with specific antidepressants. While clinical use of pharmacogenetic testing is growing, little is known about pharmacogenetic testing for depression treatment in managed care. We determined the incidence of single‐gene CYP2D6 and CYP2C19 testing following a new depression episode among US managed care patients, and described characteristics and antidepressant use of patients receiving tests. We used paid medical and pharmacy claims for patients from commercial health plans in the US. For adult patients with a new depression episode from January 1, 2013 to June 30, 2018, we identified covered claims for single‐gene CYP2D6 and CYP2C19 pharmacogenetic tests and antidepressant fills. Fewer than 1% (n = 1795) of the depressed cohort (n = 438,534) received a single‐gene CYP2D6 or CYP2C19 test through their insurance within 365 days of their earliest depression episode. The percentage of patients who received a test nearly tripled from 0.2% in 2013 to 0.5% in 2014 before plateauing at 0.4% from 2014 to 2017. Among the patients who received a single‐gene CYP2D6 or CYP2C19 test and filled an antidepressant within 365 days of their depression diagnosis, up to 30% may have had their initial antidepressant informed by the test result. Our findings describe the use of antidepressants before and after pharmacogenetic testing, which is clinically relevant as pharmacogenomic testing becomes more common in clinical practice. Our study also emphasizes the need for procedure and billing codes that capture multiple‐gene panel tests to be more widely implemented in administrative databases.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Major depressive disorder is common and many patients do not respond to first‐line treatment. Examples of actionable drug–gene pairs relevant to antidepressants include CYP2D6 and CYP2C19, yet little is known about the extent of pharmacogenetic testing for depression treatment in managed care.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study sought to address the incidence of single‐gene pharmacogenetic testing following a depression episode among a managed care population, and the characteristics of antidepressant use before and after testing is received.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Single‐gene CYP2D6 or CYP2C19 testing through insurance was rare. However, among patients who received a single‐gene CYP2D6 or CYP2C19 test and filled an antidepressant after their depression diagnosis, up to 30% may have had their initial antidepressant informed by the test result.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

As precision medicine research in the mental health field continues to evolve, these findings illustrate how real‐world insurance claims data can be leveraged to answer important questions about the clinical utility of pharmacogenetic testing in depression.     

The pharmacokinetic,safety, and tolerability profiles of eslicarbazepine acetate are comparable between Korean and White subjects

Eslicarbazepine acetate (ESL) is a prodrug antiseizure medication for the treatment of focal seizures. ESL shows a well‐established pharmacokinetic (PK)‐pharmacodynamic relationship and has similar extrinsic epilepsy‐related factors across ethnicities. This study evaluated and compared ESL safety, tolerability, and PK characteristics between Korean and White subjects. A randomized, double‐blind, placebo‐controlled, single‐ and multiple‐dose escalation study was conducted in healthy Korean and White adults. Participants randomly received a single dose and multiple oral doses of ESL (400–1600 mg) or placebo once daily for 11 days at a ratio of 8:2. Serial blood samples were collected to determine the plasma concentration of ESL and its metabolites (eslicarbazepine, [R‐licarbazepine and oxcarbazepine). Safety and tolerability were assessed throughout the study. A total of 29 Korean and 20 White subjects completed the study. The PK profiles of the metabolites of ESL were similar between Korean and White subjects. The geometric mean ratio (90% confidence interval) of Korean to White subjects for the area under the concentration–time curve within a dosing interval of eslicarbazepine was 1.06 (0.97–1.17) and 0.96 (0.87–1.06) after multiple oral doses of 400 and 1600 mg ESL, respectively. Other PK parameters were also similar between the two ethnic groups. ESL was well‐tolerated in healthy Korean and White subjects, and its PK characteristics were similar between the two ethnic groups. The results of this study support to use the same dosage regimen of ESL in both White and Korean patients with seizures.

Eslicarbazepine acetate (ESL) is an anti‐epileptic drug for monotherapy or adjunctive therapy for partial‐onset seizures. There are little clinical data of ESL for Koreans patients, although the sensitivity of ESL to ethnic factors is assessed to be low.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated pharmacokinetics (PKs), safety, and tolerability of ESL after single and multiple dose administration in healthy Korean and White subjects.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The PKs of ESL and its active metabolites were similar between Korean and White subjects. In addition, ESL was well‐tolerated in healthy Korean subjects. The efficacy and safety data from White patients with epilepsy can be extrapolated to Korean patients.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE

This study demonstrated that there was no difference in ESL PKs between healthy Korean and White subjects. The dosage regimen of ESL can be extrapolated to Korean patients according to the results of this bridging accumulating data in respect of ethnic differences.     

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.     

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.     

Propsective evaluation of high‐dose methotrexate pharmacokinetics in adult patients with lymphoma using novel determinants of kidney function

High‐dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single‐center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7‐hydroxy‐MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine‐ or cystatin C‐based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2–75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8–11.3) grams. Median clearance was similar across three dosing levels at 4.5–5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFR_cys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4‐h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C‐based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Methotrexate (MTX) clearance has a relationship with glomerular filtration rate (GFR), which is often calculated using serum creatinine as a surrogate marker of renal clearance; however, kidney function estimation derived from serum creatinine‐based GFR formulas has several known limitations, particularly in patients with cancer.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study attempts to answer the question of which estimated GFR (eGFR) equation has the strongest correlation with MTX clearance.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Results of this study suggest that, when high‐dose MTX is administered, cystatin C based eGFR equations more strongly correlate with MTX clearance than eGFR equations based on serum creatinine alone.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Incorporating cystatin C into baseline evaluation when estimating kidney function has potential to improve MTX safety and optimize MTX exposure.     

An evaluation of a supratherapeutic dose of inclisiran on cardiac repolarization in healthy volunteers: A phase I,randomized study

Inclisiran is a small interfering RNA molecule that has been shown to provide an effective and sustained reduction in low‐density lipoprotein cholesterol levels. This study aimed to determine whether a supratherapeutic dose of inclisiran affects cardiac repolarization and conduction in healthy volunteers. A phase I, randomized, double‐blind, double‐dummy, placebo‐ and positive‐controlled, three‐way crossover study was performed in 48 healthy volunteers. Volunteers were assigned to three treatments in a randomized sequence: a supratherapeutic dose of inclisiran sodium (900 mg), placebo, or moxifloxacin 400 mg as a positive control, with a minimum 7‐day washout period between treatments. Continuous electrocardiogram monitoring was performed from >60 min before dosing until 48 h after dosing. Pharmacokinetics, pharmacodynamics, and safety were also assessed. Inclisiran, at a supratherapeutic dose, did not show a clinically significant effect on the QT interval (Fridericia correction formula [QTcF]; maximal placebo‐ and baseline‐corrected change: 2.5 ms [90% confidence interval: 0.6, 4.5]) near the maximal plasma concentrations at 4 h. In addition, inclisiran did not show any effects on other electrocardiogram intervals or ST‐ and T‐wave morphology. The positive control, moxifloxacin, demonstrated the expected changes in QTcF interval, validating the adequate sensitivity of the study. A supratherapeutic dose of inclisiran sodium (900 mg) had no effect on the QTcF interval or other electrocardiogram parameters, providing additional insight and reassurance regarding the safety profile of inclisiran.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Inclisiran is a novel siRNA therapeutic agent that specifically targets the liver and has been shown to effectively, sustainably, and safely lower low‐density lipoprotein cholesterol levels, a proven risk factor for atherosclerotic cardiovascular disease. Prolongation of cardiac repolarization can result in life‐threatening arrhythmias; therefore, a thorough characterization of the effects of inclisiran on the QT/corrected QT interval is a premarketing requirement for this therapeutic agent. This is the first clinical study investigating the potential effects of an siRNA therapy on QT intervals to our best knowledge.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addressed whether or not a supratherapeutic dose of inclisiran had any effects on cardiac repolarization based on the corrected QT interval or other electrocardiogram parameters in healthy participants.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A supratherapeutic dose of inclisiran sodium (900 mg) was generally safe and well‐tolerated and did not show a clinically relevant effect on the QT interval. Other electrocardiogram intervals and ST‐ and T‐wave morphology were also unaltered by a supratherapeutic dose of inclisiran.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study demonstrated that a supratherapeutic dose of inclisiran sodium (900 mg), a novel siRNA therapeutic agent, does not affect cardiac repolarization, providing additional reassurance regarding the safety profile of inclisiran. This is the first QT clinical study investigating the effects of a novel siRNA therapeutic agent.     

Pharmacokinetics and tolerability of apremilast in healthy Korean adult men

We performed a two‐part study to evaluate the pharmacokinetics, safety, and tolerability of oral apremilast, a phosphodiesterase 4 inhibitor indicated for the treatment of psoriasis, in healthy Korean adult men. In part 1, there were 12 subjects who randomly received a single oral dose of apremilast at 20, 30, or 40 mg in each of 3 periods in a crossover fashion. In part 2, there were 16 subjects who randomly received 30 mg of apremilast or its matching placebo in a ratio of 3:1 twice daily for 14 days. Apremilast was rapidly absorbed (maximum concentration: ~2–3 h postdose), and eliminated according to a monoexponential pattern with a terminal‐phase elimination half‐life of 8–9 h. The exposure to apremilast increased in a dose‐proportional manner and accumulation was 1.6‐fold at steady‐state. Apremilast was well‐tolerated after a single oral administration and multiple oral administrations in Korean adult men; all of the treatment‐emergent adverse events were mild and recovered without sequelae. In conclusion, apremilast was safe and well‐tolerated in healthy Korean adult men when administered single oral doses of 20, 30, or 40 mg or when administered multiple oral doses of 30 mg b.i.d. for 14 days. Overall exposures increased in an approximate dose proportional manner in healthy Korean adult men.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Apremilast, a phosphodiesterase 4 inhibitor, has been approved to treat patients with psoriasis in many countries, including the United States, Canada, and Japan. Although apremilast has shown a linear pharmacokinetic (PK) profile and little ethnic sensitivity, apremilast has never been studied specifically in Koreans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This two‐part study evaluated differences in PKs and tolerability of apremilast between healthy Korean adult men and previously studied ethnic populations.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results clearly showed that apremilast was safe and well‐tolerated after single and multiple oral administrations in healthy Korean adult men. Linear PK profiles of apremilast were consistently observed in healthy Korean adult men.

• HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?

Our results support the notion that recommended apremilast dose of 30 mg b.i.d., after a first week of titration, would be also appropriate in Koreans.     

Dose‐dependent inactivation of airway tryptase with a novel dissociating anti‐tryptase antibody (MTPS9579A) in healthy participants: A randomized trial

Tryptase is the most abundant secretory granule protein in human lung mast cells and plays an important role in asthma pathogenesis. MTPS9579A is a novel monoclonal antibody that selectively inhibits tryptase activity by dissociating active tetramers into inactive monomers. The safety, tolerability, pharmacokinetics (PKs), and systemic and airway pharmacodynamics (PDs) of MTPS9579A were assessed in healthy participants. In this phase I single‐center, randomized, observer‐blinded, and placebo‐controlled study, single and multiple ascending doses of MTPS9579A were administered subcutaneously (s.c.) or intravenously (i.v.) in healthy participants. In addition to monitoring safety and tolerability, the concentrations of MTPS9579A, total tryptase, and active tryptase were quantified. This study included 106 healthy participants (82 on active treatment). Overall, MTPS9579A was well‐tolerated with no serious or severe adverse events. Serum MTPS9579A showed a dose‐proportional increase in maximum serum concentration (C_max) values at high doses, and a nonlinear increase in area under the curve (AUC) values at low concentrations consistent with target‐mediated clearance were observed. Rapid and dose‐dependent reduction in nasosorption active tryptase was observed postdose, confirming activity and the PK/PD relationship of MTPS9579A in the airway. A novel biomarker assay was used to demonstrate for the first time that an investigative antibody therapeutic (MTPS9579A) can inhibit tryptase activity in the upper airway. A favorable safety and tolerability profile supports further assessment of MTPS9579A in asthma. Understanding the exposure‐response relationships using the novel PD biomarker will help inform clinical development, such as dose selection or defining patient subgroups.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

MTPS9579A is a novel monoclonal antibody that selectively inhibits tryptase activity by dissociating active tetramers into inactive monomers. In preclinical studies, MTPS9579A inhibited tryptase activity in the airway.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This phase I study reports the safety and tolerability, pharmacokinetics (PKs), pharmacodynamics, and dose response of MTPS9579A in healthy human participants.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

MTPS9579A was well‐tolerated at all tested dose levels and had linear PKs at high concentrations. MTPS9579A is pharmacologically active and inhibits the target (active tryptase) in the upper airway of healthy participants.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results allow further exploration into the clinical efficacy and optimization of doses for MTSP9579A in treating patients with asthma and other mast cell‐related diseases.     

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.     

Effects of sevelamer carbonate versus calcium acetate on vascular calcification,inflammation, and endothelial dysfunction in chronic kidney disease

Hyperphosphatemia is present in most patients with end‐stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium‐based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL‐cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF‐23 levels and there was no change with CA treatment. The inflammatory markers IL‐8, IFN‐γ, and TNFα decreased with response to both treatments. The levels of IL‐6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti‐inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Non‐calcium‐based phosphate binders are effective in the patients with end stage kidney disease for lowering serum phosphorus and have demonstrated anti‐inflammatory effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study demonstrates a favorable reduction in systemic, vascular, and bone‐related inflammatory markers from treatment with sevelamer carbonate (SC) in the patients with chronic kidney disease (CKD) not on dialysis with normal serum phosphorus levels.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study suggests that patients with CKD not on dialysis may benefit from SC phosphate binders despite having a normal serum phosphorus level.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study offers insight to the role phosphates binder may play in lowering inflammation and vascular calcification in patients with CKD not on dialysis.     

Safety and clinical efficacy of the double switch from originator infliximab to biosimilars CT‐P13 and SB2 in patients with inflammatory bowel diseases (SCESICS): A multicenter cohort study

Data regarding double switching from originator infliximab (IFX) to IFX biosimilars in inflammatory bowel diseases (IBDs) are lacking. The purpose of this study was to evaluate the safety and efficacy of switching from originator IFX to CT‐P13 and subsequently to SB2 (double switch) in patients with IBD. Patients undergoing IFX‐double switch in eight Centers in Lombardy (Italy) from November 2018 to May 2019 were retrospectively analyzed. The IFX discontinuation rate, incidence and type of adverse events (AEs), and clinical remission rate were recorded. A comparison with a control group of patients with IBD single‐switched from originator IFX to CT‐P13 was performed, before and after an inverse probability of treatment weighting (IPTW)‐based propensity score analysis. Fifty‐two double‐switched patients with IBD were enrolled. The 24‐ and 52‐week proportions of patients continuing on IFX therapy following the second switch (CTP13 → SB2) were 98% (95% confidence interval [CI] 94%–100%) and 90% (95% CI 81%–99%), respectively. Four patients experienced a total of five AEs, all graded 1–3 according to Common Terminology Criteria for Adverse Events (CTCAE). No infusion reactions were observed. The 24‐week and follow‐up end clinical remission rates following the second switch were 94% and 88%, respectively. No differences were observed in the safety and efficacy outcomes by comparing the double‐switch group with a single‐switch group of 66 patients with IBD; all these results were confirmed by IPTW‐adjusted analysis. The study suggests both the safety and efficacy of the double switch from originator IFX to CT‐P13 and SB2 in patients with IBD is maintained. This strategy may be associated with potential cost implications.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Biosimilars reduce the direct costs of therapy and facilitate access to high‐cost therapies to patients. Data show that switching from originator infliximab to infliximab biosimilars (CT‐P13 or SB2) is safe and effective. Few data are available on the outcomes of double switch (from biological originator to a first biosimilar and then to a second biosimilar), and caution has been expressed by the European Crohn’s and Colitis Organization (ECCO) and the Italian Group for the study of inflammatory bowel disease (IBD; IG‐IBD).

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study was aimed to compare the effectiveness and safety of single and double switch of infliximab (IFX) in patients with IBDs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

No differences were found in clinical response and remission as well as adverse events between either single or double IFX switch. Data were consistent with the safety profile of IFX.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Double switch strategy is safe and effective in IBD. These data assume high relevance in terms of cost‐savings strategies.     

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.     

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.