A randomized,double‐blind,placebo‐ and positive‐controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects

Durlobactam (formerly ETX2514) is a diazabicyclooctane β‐lactamase inhibitor that inhibits class A, C, and D β‐lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem‐ and colistin‐resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo‐ and active‐controlled, single‐infusion, three‐way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3‐h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3‐h i.v. infusion of placebo, and a single 3‐h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open‐label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post‐start of infusion. For the primary ECG end point, placebo‐corrected change‐from‐baseline corrected QT Fridericia’s formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration‐QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug‐induced prolongation of the QT interval has the potential to cause severe, potentially fatal ventricular arrhythmias. A number of antimicrobial agents, including fluoroquinolones and macrolides, are associated with a low, but clinically significant increased risk of QT prolongation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval in healthy subjects to determine if there were any potentials for proarrhythmic effects.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study found that durlobactam had a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Because durlobactam had a low risk for prolonging the QT interval alone and when co‐administered with sulbactam, clinicians should be confident in administering the combination without risk for proarrhythmic effects.     

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.     

A phase I randomized,double‐blind,single subcutaneous dose escalation study to determine the safety,tolerability, and pharmacokinetics of rezafungin in healthy adult subjects

Rezafungin is a novel echinocandin being developed for the treatment and prevention of invasive fungal infections. The objectives of this randomized, double‐blind study in healthy adults were to determine the safety, tolerability, and pharmacokinetics of rezafungin after subcutaneous (s.c.) administration. The study design consisted of six sequential cohorts of eight subjects, except for the first cohort with four subjects. The subjects were randomized in a 3:1 ratio of rezafungin to placebo and were to receive a single dose of 1, 10, 30, 60, 100, or 200 mg. The most common adverse events (AEs) were increased alanine aminotransferase and sinus bradycardia (unsolicited) and erythema at the injection site (solicited). Unsolicited AEs were generally mild to moderate and not rezafungin‐related. Although the study was terminated after the 10 mg dose cohort due to concerns of potential increased severity of injection site reactions, no predetermined dose escalation halting criteria were met. Following the 10 mg single s.c. dose of rezafungin (n = 6), the geometric mean (GM) maximum concentration (C _max) was 105.0 ng/ml and the median time to C _max was 144 h. The GM area under the concentration‐time curve was 32,770 ng*h/ml. The median estimated terminal half‐life was 193 h. The GM apparent oral clearance was 0.255 L/h and the GM apparent volume of distribution was 68.5 L. This study demonstrates that a single s.c. dose of rezafungin in healthy adult subjects: (1) did not result in serious AEs, death, or withdrawal from the study due to an AE; and (2) produced a pharmacokinetic profile with long exposure period postadministration. In an effort to reduce the occurrence of injection site reactions, a re‐evaluation of the rezafungin s.c. formulation could be considered in the future.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Currently marketed antifungal agents of the echinocandin class are dosed by i.v. once daily and are therefore not practical for prolonged or outpatient prophylaxis. Rezafungin is an investigational echinocandin (currently in phase III trials studying once‐weekly i.v. administration) that has excellent activity against clinically relevant Candida and Aspergillus spp. and Pneumocystis jirovecii, a prolonged half‐life allowing for longer dosing intervals, and a stability/solubility profile that allows for the possibility of subcutaneous (s.c.) dosing.

• WHAT QUESTION DID THE STUDY ADDRESS?

The objectives of this randomized, double‐blind study in healthy adults were to determine the safety, tolerability, and pharmacokinetics (PKs) of rezafungin after s.c. administration.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study provided safety data regarding s.c. administration of rezafungin. Despite common solicited injection site reactions, s.c. administration of 10 mg of rezafungin did not result in serious adverse event (AEs), death, or withdrawals due to an AE in healthy adult subjects. The study also showed that rezafungin had a PK profile with a long exposure period.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

In an effort to reduce the occurrence of injection site reactions, these findings may lead to a future re‐evaluation of the s.c. formulation of rezafungin.     

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.     

First‐in‐human,randomized, double‐blind,placebo‐controlled,dose escalation trial of the anti‐herpes simplex virus monoclonal antibody HDIT101 in healthy volunteers

HDIT101 is a first‐in‐class humanized monoclonal antibody recognizing a conserved epitope in glycoprotein B, a target present on the surface of herpes simplex virus 1 (HSV‐1) and HSV‐2 particles as well as on virus‐infected cells. This was a first‐in‐human, single‐center, double‐blind, placebo‐controlled trial in 24 healthy volunteers, randomized 3:1 (placebo:active) in each of the six dose levels with escalating doses up to 12,150 mg HDIT101. HDIT101 was administered intravenously, to study safety, pharmacokinetics (PKs), and immunogenicity. HDIT101 was well‐tolerated in all recipients and no serious or severe adverse events, no infusion‐related reactions, and no events suggestive of dose limiting off‐target toxicity occurred. The mean serum exposure (area under the curve from zero to infinity [AUC_0‐∞]) of HDIT101 showed a linear increase from 4340 h*μg/ml at a dose of 50 mg to 1,122,247 h*μg/ml at a dose of 12,150 mg. No immunogenic effects following HDIT101 exposure were observed at any of the applied doses. HDIT101 demonstrated the expected PK properties of a monoclonal antibody was well‐tolerated, and could be safely administered even at excessively high doses that may be required for treatment of patients with septical HSV spread.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Herpes simplex virus (HSV‐1) and HSV‐2 are a global disease burden with significant morbidity and serious consequences for patients mainly in immunocompromised settings. There is a need for new drugs that reduce symptoms, recurrences, and effectively suppress viral shedding. WHAT QUESTION DID THIS STUDY ADDRESS? How safe is the administration of HDIT101, a first‐in‐class humanized monoclonal antibody recognizing the exclusively viral target glycoprotein B? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? HDIT101 is the first clinically tested monoclonal antibody against HSV. It was well tolerated by healthy volunteers and could be safely administered up to very high doses. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Our findings pave the way for efficacy trials in patients to evaluate the promising first‐in‐class therapeutic antibody for patients suffering from HSV‐related diseases.     

Muscle velocity recovery cycles as pharmacodynamic biomarker: Effects of mexiletine in a randomized double‐blind placebo‐controlled cross‐over study

Measuring muscle velocity recovery cycles (MVRCs) is a method to obtain information on muscle cell excitability, independent of neuromuscular transmission. The goal was to validate MVRC as a pharmacodynamic (PD) biomarker for drugs targeting muscle excitability. As proof‐of‐concept, sensitivity of MVRC to detect effects of mexiletine, a voltage‐gated sodium channel (Na_v) blocker, was assessed. In a randomized, double‐blind, two‐way crossover study, effects of a single pharmacologically active oral dose of 333 mg mexiletine was compared to placebo in 15 healthy male subjects. MVRC was performed predose, and 3‐ and 5‐h postdose using QTrac. Effects of mexiletine versus placebo were calculated using a mixed effects model with baseline as covariate. Mexiletine had significant effects on MVRC when compared to placebo. Early supernormality after five conditioning stimuli was decreased by mexiletine (estimated difference −2.78% [95% confidence interval: −4.16, −1.40]; p value = 0.0003). Moreover, mexiletine decreased the difference in late supernormality after five versus one conditioning stimuli (5XLSN; ED −1.46% [−2.26, −0.65]; p = 0.001). These results indicate that mexiletine decreases the percentage increase in velocity of the muscle fiber action potential after five conditioning stimuli, at long and short interstimulus intervals, which corresponds to a decrease in muscle membrane excitability. This is in line with the pharmacological activity of mexiletine, which leads to use‐dependent Na_V1.4 blockade affecting muscle membrane potentials. This study shows that effects of mexiletine can be detected using MVRC in healthy subjects, thereby indicating that MVRC can be used as a tool to demonstrate PD effects of drugs targeting muscle excitability in early phase drug development.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Muscle velocity recovery cycles (MVRC) is a method to obtain information on muscle excitability, independent of neuromuscular transmission. MVRC has been used to distinguish various neuromuscular diseases from healthy controls. WHAT QUESTION DID THIS STUDY ADDRESS? Can MVRC be a valuable pharmacodynamic (PD) biomarker for drugs targeting muscle excitability? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? As proof‐of‐concept, we evaluated effects of mexiletine—a sodium channel blocker expected to decrease muscle excitability—on MVRC in a double‐blind, placebo‐controlled study in healthy subjects. We demonstrated significant effects of mexiletine on MVRC, indicating reduced muscle excitability, in line with the pharmacological mechanism of action. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Our results encourage use of MVRC as a tool to demonstrate PD effects in the development of drugs targeting muscle excitability. This biomarker may be used to demonstrate target engagement in early clinical drug development. Furthermore, it could be of interest as a biomarker in the translation from preclinical to clinical studies, and from healthy subjects to patients with neuromuscular disease.     

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.     

Effect of difelikefalin,a selective kappa opioid receptor agonist,on respiratory depression: A randomized,double‐blind,placebo‐controlled trial

Difelikefalin, a selective kappa opioid receptor agonist designed to limit central nervous system (CNS) penetration, is under development for the treatment of pruritus. Its hydrophilic, small‐peptidic structure limits CNS entry, minimizing potential CNS‐mediated adverse events (AEs). This study assessed the effect of difelikefalin on key relevant measures of respiratory depression in healthy volunteers. This single‐center, randomized, double‐blind, placebo‐controlled, three‐way crossover study enrolled healthy, nonsmoking volunteers. Subjects were randomized to 1 of 3 treatment sequences of difelikefalin (1.0 or 5.0 mcg/kg i.v.) or placebo on sequential days with an intervening 24 (±2) h washout period. The primary end points included incidence of increased end‐tidal carbon dioxide (ETCO₂) greater than or equal to 10 mm Hg versus baseline or a level greater than 50 mm Hg sustained greater than or equal to 30 seconds, and incidence of reduction in saturation of peripheral oxygen (SpO₂) to less than 92% sustained greater than or equal to 30 seconds. Secondary end points included incidence of reduced respiratory rate and other safety assessments. Fifteen subjects were randomized and completed the study. No subject on placebo or difelikefalin met the increased ETCO₂ or reduced SpO₂ primary end point criteria for respiratory depression. All respiratory measures in each group remained near baseline values during 4‐h postdose observations. No subject met the reduced respiratory rate criterion or experienced clinically significant changes in ETCO₂, SpO₂, or respiratory rate. The most commonly reported treatment‐emergent AEs (TEAEs; ≥20% of subjects) were paresthesia, hypoesthesia, and somnolence in the difelikefalin arms. All TEAEs were mild and resolved without intervention. Difelikefalin 1.0 and 5.0 mcg/kg i.v. did not produce respiratory depression.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Severe respiratory depression is a life‐threatening complication of inappropriate use of mu opioid receptor agonists. Difelikefalin, a peripherally restricted kappa opioid receptor (KOR) agonist, has not demonstrated evidence of compromised respiratory safety.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated whether difelikefalin, a selective and potent KOR agonist, induces respiratory depression.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study helps to expand on the safety profile for difelikefalin. Difelikefalin did not produce respiratory depression in healthy volunteers at doses that were 2 to 10 times higher than those observed to be therapeutically effective in clinical trials of patients with chronic kidney disease–associated pruritus.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

KOR agonists may be potentially safe and effective therapeutics. Difelikefalin is currently being evaluated for chronic kidney disease‐associated pruritus and other chronic pruritic conditions.     

Safety,pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized,placebo‐controlled,double‐blind phase I/Ib studies in healthy subjects and patients

RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)–penetrant, small‐molecule, reversible inhibitor of RIPK1. In three early‐stage clinical trials in healthy subjects and patients with AD or ALS ({"type":"clinical-trial","attrs":{"text":"NCT03757325","term_id":"NCT03757325"}}NCT03757325 and {"type":"clinical-trial","attrs":{"text":"NCT03757351","term_id":"NCT03757351"}}NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well‐tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof‐of‐mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long‐term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early‐stage clinical trials. The dose‐limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1‐inhibitors, suggesting that these toxicities are compound‐specific (related to SAR443060) rather than RIPK1 pathway‐specific.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases, including for Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS).

• WHAT QUESTION DID THIS STUDY ADDRESS?

Three early‐stage clinical trials evaluating a central nervous system (CNS) penetrant small molecule RIPK1 inhibitor in healthy subjects and patients with AD or ALS suggest central RIPK1 inhibition is safe and pharmacokinetic and peripheral target engagement can be reliably measured.WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?RIPK1 inhibition by SAR443060 was safe and well‐tolerated for up to 28 days in patients with AD and ALS. SAR443060 distributed into the cerebrospinal fluid CSF after oral administration and demonstrated median peripheral target engagement (pRIPK1‐inhibition in peripheral blood mononuclear cells) at steady‐state trough of 81.83% and 65.92% at a 50 mg b.i.d. dose level in patients with AD and ALS.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The combination of CSF‐distribution and robust peripheral target engagement offers an encouraging proof‐of‐mechanism that therapeutic modulation of RIPK1 in the CNS may be possible and further studies should be pursued.     

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

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

Savor the flavor: A randomized double‐blind study assessing taste‐enhanced placebo analgesia in healthy volunteers

Placebo effects substantially contribute to analgesic treatment outcomes and might be leveraged to enhance gold‐standard treatments. The taste of oral medications has been proposed to boost placebo effects. Here, we aimed at estimating how far the taste of an oral medication enhances placebo analgesia. We conducted a randomized, double‐blind, between‐group, single‐visit study, with pre‐treatment baseline. Over the course of three substudies, 318 healthy volunteers (297 included) were tested in a clinical trial setting. Participants were subjected to experimental tonic cold water pain (cold pressor test) before and after receiving taste‐neutral (water), or bitter (quinine), or sweet (saccharin), or no placebo drops. Pre‐ versus post‐treatment changes in area under the pain rating curve, the main outcome, indicated that placebo treatment showed a small analgesic effect versus no treatment. Added taste induced placebo enhancement in the very small effect size range, but accounted for a substantial portion of the overall placebo effect. No noteworthy advantage of sweet over bitter placebo was observed. An exploration of heart rate (HR) recordings indicated that placebo treatments were associated with an increase in peak HR‐response to cold water, but these were not associated with placebo analgesia at an individual level. Placebo treatments were associated with minimal side effects. These results indicate that added taste may be an easy‐to‐implement, cost‐effective, and safe way to optimize treatment outcomes and that taste‐neutral preparations may reduce placebo‐related outcome variance in clinical trials. Further studies are needed to test if these findings can be translated into clinical scenarios.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Taste is a prominent characteristic of any oral medication and has been suggested to drive placebo effects, yet surprisingly few data are available to support this claim.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We performed a randomized, double‐blind study in a total of 318 healthy volunteers to estimate: How much stronger is placebo analgesia induced by bitter‐ and sweet‐flavored placebo drops versus neutral placebo and no treatment?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Overall, the study found that placebo effects were in the small to very small range, but bitter and sweet placebo drops were approximately 1.8 and 2.5 times more effective in reducing pain than neutral placebo. Placebo treatment caused minimal adverse effects, regardless of taste. Placebo treatments, especially the bitter placebo, enhanced the cardiac response to cold pressor stress.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our results indicate that added taste may be an easy‐to‐implement, cost‐effective, and safe way to optimize analgesic treatment outcomes, but confirmation in patients and clinical settings is needed. Further, these data suggest that using taste‐neutral preparations may be key to reducing placebo‐related outcome variance in clinical trials.     

Safety, tolerability, and pharmacokinetics of TAS-108 in normal healthy post-menopausal female subjects: a phase I study on single oral dose

OBJECTIVES: The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of TAS-108 after ascending single oral doses and to analyse preliminarily the effect of food on the pharmacokinetics of TAS-108 in normal healthy post-menopausal female subjects. METHODS: Twelve healthy subjects participated in an open-label, ascending single-dose, alternating group, safety, tolerance, and pharmacokinetic study of TAS-108 administered orally to two groups of the subjects, one given alternating doses of 10, 40, 120 mg (group A) and the other of 20, 80, 160 mg (group B), in the fasting state. In addition, six subjects (group A) were administered an additional dose at 120 mg TAS-108 after food consumption. Plasma and urine samples for measurement of TAS-108 were analysed by validated analytical procedures using a liquid chromatographic method with tandem mass spectrometric detection (LC/MS/MS). RESULTS: There was no dose-dependent increase in any adverse events (AEs), and there were no serious AEs or deaths. TAS-108 was readily absorbed following oral administration of the 80-, 120- and 160-mg doses. Plasma TAS-108 levels steadily declined, generally in a mono-exponential manner, with overall mean t(1/2) values ranging from 3.04 to 4.43 h in the fasting groups. Administration of TAS-108 after a high-fat meal markedly increased the bioavailability of the drug. The mean C(max) and AUC(0--t) values increased after a high-fat breakfast by 182 and 191% compared with the fasting value respectively. CONCLUSIONS: In this escalating dose study of TAS-108, the drug was well tolerated by the participants. The maximum and systemic exposure to TAS-108 tended to increase with increasing dose and its bioavailability markedly increased after high-fat food intake.     

Managing endothelial dysfunction in COVID‐19 with statins,beta blockers,nicorandil, and oral supplements: A pilot,double‐blind,placebo‐controlled,randomized clinical trial

Coronavirus disease 2019 (COVID‐19) is associated with endothelial dysfunction. Pharmacologically targeting the different mechanisms of endothelial dysfunction may improve clinical outcomes and lead to reduced morbidity and mortality. In this pilot, double‐blind, placebo‐controlled, randomized clinical trial, we assigned patients who were admitted to the hospital with mild, moderate, or severe COVID‐19 infection to receive, on top of optimal medical therapy, either an endothelial protocol consisting of (Nicorandil, L‐arginine, folate, Nebivolol, and atorvastatin) or placebo for up to 14 days. The primary outcome was time to recovery, measured by an eight category ordinal scale and defined by the time to being discharged from the hospital or hospitalized for infection‐control or other nonmedical reasons. Secondary outcomes included the composite outcome of intensive care unit (ICU) admission or the need for mechanical ventilation, all‐cause mortality, and the occurrence of side effects. Of 42 randomized patients, 37 were included in the primary analysis. The mean age of the patients was 57 years; the mean body mass index of study participants was 29.14. History of hypertension was present in 27% of the patients, obesity in 45%, and diabetes mellitus in 21.6%. The median (interquartile range) time to recovery was not significantly different between the endothelial protocol group (6 [4–12] days) and the placebo group (6 [5–8] days; p value = 0.854). Furthermore, there were no statistically significant differences in the need for mechanical ventilation or ICU admission, all‐cause mortality, or the occurrence of side effects between the endothelial protocol group and the placebo group. Among patients hospitalized with mild, moderate, or severe COVID‐19 infection, targeting endothelial dysfunction by administering Nicorandil, L‐arginine, Folate, Nebivolol, and Atorvastatin on top of optimal medical therapy did not decrease time to recovery. Based on this study’s findings, targeting endothelial dysfunction did not result in a clinically significant improvement in outcome and, as such, larger trials targeting this pathway are not recommended.     

Single‐ and multiple‐dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects

Chemoattractant receptor‐homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G‐protein‐coupled receptor for prostaglandin D₂ (PGD₂), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study, we investigated the single‐ and multiple‐dose tolerability and pharmacokinetics (PKs) of setipiprant, an orally active, potent, and selective CRTH2 antagonist. This randomized, double‐blind, placebo‐controlled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of eight subjects each. Additionally, the impact of food on the PKs was investigated in one‐dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables and plasma and urine levels of setipiprant were determined. Setipiprant was well tolerated after single‐ and multiple‐dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single‐ and multiple‐dose administration, setipiprant was rapidly absorbed and followed a biphasic elimination pattern with an elimination half‐life between 10 and 18 h. Steady‐state conditions were reached after 2–3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose. In this entry‐into‐human study, setipiprant showed good tolerability and a favorable PK profile, thus warranting its development in the treatment of inflammatory disorders.     

Phase I,randomized, double‐blind,placebo‐controlled,single‐dose escalation study of the recombinant factor VIIa variant BAY 86‐6150 in hemophilia

Summary. Background: BAY 86‐6150 is a new human recombinant factor VIIa variant developed for high procoagulant activity and longer action in people with hemophilia with inhibitors. Objectives: To investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and immunogenicity of BAY 86‐6150 in non‐bleeding hemophilia subjects. Methods: The study included non‐bleeding men (18–65 years of age) with moderate or severe hemophilia A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY 86‐6150 (6.5, 20, 50 or 90 μg kg^?1 [n = 3 per cohort]) or placebo (n = 1 per cohort); an independent data‐monitoring committee reviewed previous cohort data before the next dose escalation. Blood sampling was performed predose and postdose; subjects were monitored for 50 days postdose. Results: At the tested doses, BAY 86‐6150 was not associated with clinically significant adverse events or dose‐limiting toxicities. BAY 86‐6150 pharmacokinetics exhibited a linear dose response, with a half‐life of 5–7 h. Subjects demonstrated consistent, dose‐dependent thrombin generation ex vivo in platelet‐poor plasma (PPP) (mean peak effect, 26–237 nm thrombin from 6.5 to 90 μg kg^?1). Peak thrombin levels over time paralleled BAY 86‐6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY 86‐6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de novo anti‐BAY 86‐6150 neutralizing antibodies during the 50‐day follow‐up. Conclusions: In this first‐in‐human, multicenter, randomized, double‐blind, placebo‐controlled, single‐dose escalation study, BAY 86‐6150 was tolerated at the highest dose (90 μg kg^?1), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies.     

Lack of efficacy of alpha‐lipoic acid in burning mouth syndrome: A double‐blind,randomized, placebo‐controlled study

Background: A systematic review from the Cochrane Collaboration stated that alpha‐lipoic acid (ALA) may help in the management of burning mouth syndrome (BMS). Because all of the data on ALA came from a single group, it has been stressed that its effectiveness should be reproduced in other populations. Aim: A double‐blind, randomized, placebo‐controlled study, including two test groups (Group A and Group B) and one control group (Group C), was carried out to evaluate the efficacy of systemic ALA (400mg) and ALA (400mg) plus vitamins in the treatment of BMS. Methods: Sixty‐six patients (54 females and 12 males) were included in an 8‐week trial. Symptoms were evaluated by using a visual analogue scale (VAS) and the McGill Pain Questionnaire (MPQ) at 0, 2, 4, 8 and 16 weeks. Results: Fifty‐two patients (43 females and 9 males, aged 67.3±11.9 years) completed the study. All three groups had significant reductions in the VAS score and in the mixed affective/evaluative subscale of the MPQ; the responders’ rate (at least 50% improvement in the VAS score) was about 30%. No significant differences were observed among the groups either in the response rate or in the mean latency of the therapeutic effect. Conclusions: The fairly high placebo effect observed is very similar to data obtained from patients affected by atypical facial pain. This study failed to support a role for ALA in the treatment of BMS, and further investigations are needed to identify the cause of BMS in order to develop efficacious therapies.     

Topiramate for the management of methamphetamine dependence: a pilot randomized,double‐blind,placebo‐controlled trial

To date, no medication has been approved as an effective treatment for methamphetamine dependence. Topiramate has attracted considerable attention as a treatment for the dependence on alcohol and stimulants. Therefore, this study aimed to evaluate the effect of topiramate for methamphetamine dependence. This study was a double‐blind, randomized, placebo‐controlled trial. In the present investigation, 62 methamphetamine‐dependent adults were enrolled and randomized into two groups, and received topiramate or a placebo for 10 weeks in escalating doses from 50 mg/day to the target maintenance dose of 200 mg/day. Addiction severity index (ASI) and craving scores were registered every week. The Beck questionnaire was also given to each participant at baseline and every 2 weeks during the treatment. Urine samples were collected at baseline and every 2 weeks during the treatment. Fifty‐seven patients completed 10 weeks of the trial. There was no significant difference between both groups in the mean percentage of prescribed capsules taken by the participants. At week six, the topiramate group showed a significantly lower proportion of methamphetamine‐positive urine tests in comparison with the placebo group (P = 0.01). In addition, there were significantly lower scores in the topiramate group in comparison with the placebo group in two domains of ASI: drug use severity (P < 0.001) and drug need (P < 0.001). Furthermore, the craving score (duration) significantly declined in the topiramate patients compared to those receiving the placebo. In conclusion, the results of this trial suggest that topiramate may be beneficial for the treatment of methamphetamine dependence.