Single Ascending Dose Study Research Articles

A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder.

BackgroundAnxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder.MethodsTwenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes.ResultsTwenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score.ConclusionsOur study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted.The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519).

A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis.

ObjectiveThe objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22).MethodsSeventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months.ResultsrHIgM22 was well tolerated with no clinically significant safety signals. Noncompartmental PK modeling demonstrated linear dose-proportionality both of Cmax and AUC0–Last. The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort.ConclusionsSingle doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.

Phase 1, Randomized, Double‐Blind, Placebo‐Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers

Naldemedine (S-297995) is a peripherally acting μ-opioid receptor antagonist for the treatment of opioid-induced constipation, a common side effect of opioid therapy. We determined the safety, tolerability, and pharmacokinetic profiles of oral naldemedine in healthy volunteers in 2 randomized, double-blind, placebo-controlled, phase 1 studies. In the single ascending dose study, subjects received a single dose of naldemedine (0.1-100 mg; n = 42) or placebo (n = 14). In the multiple ascending dose study, subjects received once-daily naldemedine (3-30 mg; n = 27) or placebo (n = 9) for 10 days. On day 1 of the single ascending dose studies and day 10 of the multiple ascending dose studies, respectively, the maximum plasma concentration levels of naldemedine were 1.98 to 2510 ng/mL and 73.8 to 700 ng/mL, peaked at 0.5 hours and 0.5 to 0.75 hours, and the fraction excreted in urine was 15.9% to 20.5% and 19.7% to 19.1%. There were no major safety or tolerability concerns even at naldemedine doses 150 to 500 times the therapeutic dose of 0.2 mg. The incidence of adverse events was not dose dependent. Gastrointestinal adverse events occurred more frequently with naldemedine vs placebo, and all of these were considered treatment related. Overall, naldemedine was rapidly absorbed, and no safety or tolerability issues were noted at the doses evaluated.

Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a single ascending dose study in opioid-naïve healthy volunteers

Objective: Fentanyl sublingual spray offers rapid pain relief in opioid-tolerant cancer patients, and may be useful in acute or post-operative pain. Both opioid-naïve and non-tolerant patients are likely to receive opioids in these settings. Understanding the relationship between systemic exposure of fentanyl sublingual spray and effects on respiratory function in opioid-naïve or non-tolerant populations is important to ensure patient safety. This study evaluated single-dose fentanyl sublingual spray in opioid-naïve participants.Research design: Participants were randomized to receive single-dose fentanyl sublingual spray (100, 200, 400, 600, 800 mcg) or fentanyl citrate IV in one of five cohorts. Dosing occurred following a 10-h fast, with fasting continuing for 4 h post-dose. Dose proportionality was assessed using analysis of variance and linear regression techniques. PK assessments and safety monitoring were performed through 24 h post-dose. Safety assessments, including adverse event (AE) monitoring, occurred from dosing through Day 7.Results: Fifty participants (19−53 years) received fentanyl sublingual spray or fentanyl citrate IV. Mean maximum plasma concentrations were reached between 0.27–0.60 h post-dose for fentanyl sublingual spray. Peak (Cmax) and total (AUC0–t, AUC0–∞) fentanyl exposures increased in a linear, but more than dose-proportional manner, with higher doses. The most common AEs were somnolence, nausea, and vomiting. All AEs were mild or moderate in severity. Doses at 400, 600, and 800 mcg were associated with nausea and vomiting, requiring pharmacologic intervention. Hypoxia episodes requiring nasal cannula oxygenation were observed with 600mcg and 800mcg doses.Conclusions: Overall, single-dose fentanyl sublingual spray (100–800 mcg) was generally well tolerated, with greater incidences of AEs (e.g. nausea, vomiting, hypoxia) at higher doses. Doses up to 200 mcg may be safely administered to healthy opioid-naïve individuals with routine monitoring; doses between 400–800 mcg may be administered in settings with nasal cannula oxygenation.

TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS IN HEALTHY SUBJECTS OF SINGLE DOSES OF LY2599666, AN ANTIGEN BINDING FRAGMENT (FAB) OF A MONOCLONAL ANTIBODY THAT TARGETS SOLUBLE MONOMER Aβ LINKED TO A POLY(ETHYLENE GLYCOL) MOLECULE

Amyloid-beta (Aβ) antibody antigen-binding fragment (Fab)-polyethylene glycol (PEG), LY2599666, is a humanized, affinity-optimized monoclonal antibody Fab linked to a PEG molecule that targets soluble Aβ monomers. LY2599666 is engineered to support once-weekly (QW) subcutaneous (SC) dosing as a passive immunization therapy for Alzheimer's disease by attaching a 20 kDa PEG to the Fab to increase the half-life relative to the naked Fab. This first-in-human, subject- and investigator-blinded, placebo-controlled, single ascending dose study (NCT02614131) assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) effects of 10- to 200-mg SC doses of LY2599666 in healthy subjects. Four sequential cohorts of 10–11 subjects each, aged ≥ 20 years, were administered single doses of 10mg, 25mg, 100mg or 200mg LY2599666, respectively or matching placebo. Adverse events, vital signs, electrocardiograms, clinical laboratory tests, physical examinations, plasma PK, and plasma PD (plasma total Aβ) were assessed throughout the study and for up to 28 days after dosing. Forty-three heathy subjects received a SC dose of LY2599666 or placebo. Treatment-emergent adverse events reported regardless of treatment included injection-site erythema (5 subjects); dizziness (3 subjects); and contusion, headache, and upper respiratory tract infection (2 subjects each). Plasma free LY2599666 concentrations and Aβ concentrations (total Aβ 40 and total Aβ 42) will be presented. LY2599666 was generally well tolerated by healthy subjects after a single SC administration over a dose range of 10 to 200 mg.

SUVN-G3031, A SELECTIVE H3 RECEPTOR INVERSE AGONIST: ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS

SUVN-G3031, a potent and selective histamine H3 receptor inverse agonist is being developed for the treatment of cognitive deficits associated with Alzheimer's disease. SUVN-G3031 demonstrated cognitive enhancement and relevant neurochemical modulation without affecting the sleep in rodent models. SUVN-G3031 was studied in a single-center, multi-faceted, phase 1 clinical study (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single and multiple ascending doses in healthy adult subjects. For single dose evaluation, subjects dosed with 0.1 mg to 20 mg of SUVN-G3031 tablets. For multiple ascending dose evaluation, once daily doses of 1 mg to 6 mg were administered for 14 days. Effect of food on pharmacokinetics was evaluated under fed and fasted conditions in healthy adult male subjects. For evaluation of gender and age effect, SUVN-G3031 was administered under fasted conditions in healthy female and elderly subjects. SUVN-G3031 was quantified in plasma using a validated LC-MS/MS method. Safety and tolerability was assessed throughout the study by incidence and severity of AEs, abnormalities in vital signs, ECG and clinical laboratory assessments. SUVN-G3031 was well tolerated up to the highest tested dose of 20 mg single dose or 12 mg/ day repeated dose in healthy adult subjects. During single ascending dose studies, exposures were observed to be dose-proportional at the tested doses between 0.1 mg to 20 mg. During multiple ascending dose studies, SUVN-G3031 has shown an excellent pharmacokinetic profile. SUVN-G3031 achieved the projected efficacy concentrations and attained steady state on day 6. At a tested dose of 6 mg, food, gender and age had no effect on human pharmacokinetics of SUVN-G3031. SUVN-G3031 was well tolerated and there were no clinically relevant or serious adverse events observed in different population. SUVN-G3031 has excellent safety and pharmacokinetic profile in healthy human volunteers after single and multiple dose administration for 14 days. Food, gender and age had no effect on SUVN-G3031 pharmacokinetics in human. Long term safety studies are completed and SUVN-G3031 is ready for phase-2 clinical evaluation.

SUVN-D4010: A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST— ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS

SUVN-D4010 is a potent, selective and orally bioavailable 5-HT4 receptor partial agonist being developed for the treatment of Alzheimer's disease (AD). SUVN-D4010 has shown to improve the memory in preclinical animal models. SUVN-D4010 also produced significant increase in the brain acetylcholine levels and cortical sAPPα with simultaneous decrease in amyloid-β protein levels. SUVN-D4010 was studied in a single-center, multi-faceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single or multiple ascending doses in healthy male subjects. For single dose evaluation, subjects were dosed with 5 mg, 15 mg, 30 mg or 45 mg of SUVN-D4010 tablets, once. For multiple ascending dose evaluation, the once daily doses of 10, 25 and 40 mg SUVN-D4010 were administered for 14 days. SUVN-D4010 was administered at a dose of 25 mg for evaluation of food, gender and age effect. Effect of food on SUVN-D4010 pharmacokinetics was evaluated under fed and fasted conditions in healthy adult male subjects. For evaluation of gender and age effect, SUVN-D4010 was administered under fasted conditions in healthy female and elderly subjects. SUVN-D4010 was quantified in plasma using a validated LC-MS/MS method. Safety and tolerability was assessed by incidence and severity of AEs, abnormalities in vital signs, ECG and laboratory assessments. SUVN-D4010 was well tolerated up to the highest tested dose of 45 mg single dose or 40 mg/day multiple doses in healthy male subjects. There were no clinically relevant or serious adverse events reported. During single ascending dose studies, the absorption of SUVN-D4010 was rapid and exposures (Cmax and AUC) were dose proportional. During multiple ascending dose studies, SUVN-D4010 achieved steady state on day 3 in the tested population. SUVN-D4010 has excellent safety and pharmacokinetic profile following single or multiple dose administration for 14 days in healthy male subjects. Projected efficacy concentrations of SUVN-D4010 achieved during multiple ascending dose studies. SUVN-D4010 is currently being evaluated for long term safety in animal models.

40 QR-010 via inhalation is safe, well-tolerated, and achieves systemic concentrations in a single ascending dose study in subjects with cystic fibrosis homozygous for the F508del CFTR mutation

40 QR-010 via inhalation is safe, well-tolerated, and achieves systemic concentrations in a single ascending dose study in subjects with cystic fibrosis homozygous for the F508del CFTR mutation

A neutralizing anti-G-CSFR antibody blocks G-CSF-induced neutrophilia without inducing neutropenia in nonhuman primates.

Neutrophils are the most abundant WBCs and have an essential role in the clearance of pathogens. Tight regulation of neutrophil numbers and their recruitment to sites of inflammation is critical in maintaining a balanced immune response. In various inflammatory conditions, such as rheumatoid arthritis, vasculitis, cystic fibrosis, and inflammatory bowel disease, increased serum G-CSF correlates with neutrophilia and enhanced neutrophil infiltration into inflamed tissues. We describe a fully human therapeutic anti-G-CSFR antibody (CSL324) that is safe and well tolerated when administered via i.v. infusion to cynomolgus macaques. CSL324 was effective in controlling G-CSF-mediated neutrophilia when administered either before or after G-CSF. A single ascending-dose study showed CSL324 did not alter steady-state neutrophil numbers, even at doses sufficient to completely prevent G-CSF-mediated neutrophilia. Weekly infusions of CSL324 (≤10 mg/kg) for 3 wk completely neutralized G-CSF-mediated pSTAT3 phosphorylation without neutropenia. Moreover, repeat dosing up to 100 mg/kg for 12 wk did not result in neutropenia at any point, including the 12-wk follow-up after the last infusion. In addition, CSL324 had no observable effect on basic neutrophil functions, such as phagocytosis and oxidative burst. These data suggest that targeting G-CSFR may provide a safe and effective means of controlling G-CSF-mediated neutrophilia as observed in various inflammatory diseases.

Next-generation neuroactive steroid SAGE-217 in a single-ascending dose study (P6.017)

Next-generation neuroactive steroid SAGE-217 in a single-ascending dose study (P6.017)

Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects.

ObjectiveDA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5) in the plasma and urine after administration of a single oral dose in healthy male subjects.MethodsA dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP) enzymes on the pharmacokinetics of DA-8031 was evaluated.ResultsAfter a single dose, plasma DA-8031 reached the maximum concentration at a median of 2–3 h and was eliminated with terminal elimination half-life of 17.9–28.7 h. The mean renal clearance was 3.7–5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20–80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized Cmax and AUC0–t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported.ConclusionIn conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20–80 mg. Genetic polymorphisms of CYP2D6 had an effect on the systemic exposure of DA-8031. DA-8031 was well tolerated after single doses of 80 mg or less.

Multiple Ascending Dose Safety, Tolerability, and Pharmacokinetics of KBP-7072, a Novel Third-generation Tetracycline

KBP-7072 is a novel aminomethylcycline exhibiting broad-spectrum activity against Gram+ and Gram- multidrug-resistant bacterial isolates and strains. KBP-7072 has previously been studied in a single ascending dose study up to 300 mg in healthy adults. This was a randomized, single-blind, placebo-controlled, sequential parallel-group, multiple ascending dose study to evaluate the safety, tolerability, and pharmacokinetics (PK) of KBP-7072 in healthy adults. Four cohorts were planned with 8 subjects (6 KBP-7072, 2 placebo) in each cohort to evaluate KBP-7072 100 mg QD, 200 mg QD, 300 mg QD, and 200 mg BID for 10 days. Dose escalation stopped following completion of the 200 mg QD cohort. Safety, tolerability, and PK were evaluated for each cohort. 16 subjects (male: 87.5%; 18–55 years of age) were enrolled including 8 in each of the 2 dose escalation cohorts (100 mg QD and 200 mg QD). After the results of the first two cohorts (100 mg QD and 200 mg QD) were analyzed, it was determined that the therapeutic dose of KBP-7072 was likely to be less than 200 mg/day. All treatment-emergent adverse events (TEAEs) were of mild intensity, resolved without intervention, and most TEAEs were assessed as either unrelated or probably unrelated to treatment. No serious adverse events were reported. Elevated alanine aminotransferase was reported in 4 subjects (all in the 200 mg QD cohort) who were asymptomatic and recovered without intervention. PK data included in the table below suggests that exposure is approximately dose proportional. KBP-7072 Plasma PK Parameters by Treatment at Day 10 – PK Population KBP-7072 Plasma PK Parameters by Treatment at Day 10 – PK Population This study demonstrated that KBP-7072 was safe and generally well-tolerated at doses up to and including 200 mg QD. F. Yang, KBP Biosciences Co., Ltd.: Employee, Salary. Y. Wang, KBP Biosciences USA Inc.: Employee, Salary. P. Wang, KBP Biosciences Co., Ltd.: Employee, Salary. M. Hong, KBP Biosciences: Employee, Salary. V. Benn, KBP Biosciences USA Inc.: Employee, Salary.

A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-CC5) Targeting Complement C5 for Treatment of PNH and Complement-Mediated Diseases: Preliminary Phase 1/2 Study Results in Patients with PNH

▪Background:Uncontrolled complement activation plays a pivotal role in a variety of disorders such as paroxysmal nocturnal hemoglobinuria (PNH). Challenges to be addressed with eculizumab therapy include inter-individual variation in clearance of eculizumab, economic burden, and improvements in the current biweekly intravenous infusion maintenance schedule. ALN-CC5 is a subcutaneous (SC) investigational RNA interference (RNAi) therapeutic targeting hepatic complement C5 (C5) synthesis. Previously presented data from our ongoing Phase 1/2 study showed that ALN-CC5 was generally well tolerated and exhibited a clamped C5 knockdown and complement activity inhibition in healthy volunteers (Hill et al. Haematologica 2016; 101, Suppl 1). The aim of this abstract is to report updated tolerability and clinical activity of ALN-CC5 in patients with PNH.Methods: A phase 1/2 single-ascending dose (Part A) and multiple-ascending dose study (Part B) of ALN-CC5 was conducted in healthy adult volunteers and in patients with PNH (Part C). In Part C, patients with PNH received weekly doses of 200 mg or 400 mg of ALN-CC5 for 2 to 16 weeks; ALN-CC5 is administered subcutaneously at a concentration of 200 mg/mL. The primary endpoints are safety and tolerability and secondary endpoints include: pharmacokinetics (PK), reduction of circulating C5 and complement activity, as measured by CAP/CCP Wieslab ELISA assays and sheep erythrocyte hemolysis assay, as well as reduction in LDH.Results: Part C included 6 patients with PNH (treatment naïve n=3; patients receiving eculizumab n=3), including 1 patient who was experiencing breakthrough hemolysis despite receiving 1200mg eculizumab q2wk. ALN-CC5 was generally well tolerated in patients with PNH after multiple doses with the majority of adverse events (AEs) being mild or moderate in severity. There were no serious AEs or discontinuations due to AEs. One patient, who was also taking eculizumab, cyclosporine and anabolic steroids as concomitant medications, experienced a transient asymptomatic grade 3 elevation of liver transaminases that was deemed possibly related to study drug. In eculizumab naïve patients (n=3), ALN-CC5 monotherapy achieved a mean maximum C5 knockdown of 98.2% ± 0.3%, residual C5 levels of 0.9 mcg/mL and a mean maximum CCP inhibition of 94.2 ± 1.7%. During treatment with ALN-CC5, maximum reduction in LDH was 37% and 50% in 2 patients who received 17 doses of ALN-CC5 but remained above the goal of less than 1.5 times the ULN. In the remaining eculizumab naïve patient, LDH lowering was not observed following 8 doses of ALN-CC5. After completion of ALN-CC5 dosing and in the setting of ongoing >95% ALN-CC5-mediated KD of serum C5, treatment naïve patients received a single 600 mg dose of eculizumab (labeled induction dose is 600 mg weekly x 4) for the treatment of residual hemolysis followed by close clinical monitoring. An exploratory analysis was conducted to understand the potential for ALN-CC5 to reduce eculizumab dose and frequency. All 3 patients achieved sustained lowering of LDH <1.5 ULN for out to 4 weeks. In patients entering the study on a stable dose of eculizumab (n=3), ALN-CC5 was also able to achieve a robust C5 KD (mean max 86.7% ± 5.6%) with residual complement activity of <2% as measured by CCP assay from day 21 onward. The addition of ALN-CC5 resulted in LDH lowering to within reference range by day 35 post treatment (maintained out to Day 112) in an inadequate response patient who entered the study on higher than labeled dose of eculizumab. As a result, this patient’s subsequent dosing of eculizumab was lowered from 1200mg q2wk to 900mg q2wk. Updated safety, pharmacodynamics (PD) and clinical activity for all 6 patients with PNH in Part C of this ongoing Phase 1/2 study will be presented.Conclusion: ALN-CC5 was shown to be generally well tolerated in patients with PNH. The PD effects of ALN-CC5 were found to be durable, with clamped C5 knockdown and complement activity inhibition. Collectively, the data suggest that clamped inhibition of hepatic C5 synthesis may provide the foundation to potentially reduce the dose and frequency of eculizumab administration for patients with PNH, and to improve disease control in patients with inadequate response to eculizumab. DisclosuresHill:Alnylam Pharmaceuticals: Consultancy, Honoraria. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference support. Munir:Alexion pharmaceuticals: Honoraria. Borodovsky:Alnylam Pharmaceuticals: Employment, Equity Ownership. Kawahata:Alnylam Pharmaceuticals: Employment, Equity Ownership. Mclean:Alnylam Pharmaceuticals: Employment, Equity Ownership. Shi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Partisano:Alnylam: Employment, Equity Ownership. Kim:Alnylam Pharmaceuticals: Employment, Equity Ownership. Najafian:Alnylam Pharmaceuticals: Employment, Equity Ownership.

Pharmacokinetics, pharmacodynamics and safety of CKD-519, a CETP inhibitor, in healthy subjects.

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of dyslipidemia to raise high-density lipoprotein cholesterol. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of CKD-519 in healthy adult subjects. A randomized, double-blinded, placebo-controlled, single ascending dose study was performed. Eight healthy subjects were enrolled in each CKD-519 dose group (25, 50, 100, 200, or 400 mg) and randomized to CKD-519 (n=6) or matching placebo (n=2). CKD-519 reached the maximum plasma concentration (Cmax) at 5–6 h post-dose, and had a long terminal half-life ranging between 40–70 h. The area under the plasma concentration–time curve (AUC) and Cmax increased with the dose, however, Cmax and AUC normalized by dose decreased with each incremental dose. CETP activity decreased with dose, and the maximum decrease (63%–83%) was observed at 6–8 h post-dose. A sigmoid Emax model best described the relationship between CKD-519 plasma concentrations and CETP activity with an EC50 of 17.3 ng/mL. Overall, 11 adverse events (AEs) were observed. All AEs were mild or moderate in intensity, and resolved without any complications. There were no clinically significant effects on blood pressure. In conclusion, single doses of CKD-519 up to 400 mg were well tolerated and showed potent inhibition of CETP activity.

Supratherapeutic dose evaluation and effect of lesinurad on cardiac repolarization: a thorough QT/QTc study.

IntroductionLesinurad is a selective uric acid reabsorption inhibitor approved in the United States and Europe for treatment of gout in combination with a xanthine oxidase inhibitor. A maximum tolerated dose study was conducted to determine the lesinurad supratherapeutic dose, followed by a thorough QTc study to characterize the effect of lesinurad on cardiac repolarization.MethodsThe maximum tolerated dose study was a randomized, double-blind, placebo-controlled, single-ascending dose study that enrolled 35 healthy men and women. Lesinurad plasma exposure (maximum observed plasma concentration and area under the plasma concentration versus time curve) was determined at doses of 800 mg, 1,200 mg, and 1,600 mg. The thorough QTc study was a double-blind, four-period, placebo-controlled crossover study with 54 healthy men and women who received single doses of lesinurad 1,600 mg (supratherapeutic dose), lesinurad 400 mg, moxifloxacin 400 mg, and placebo in randomized sequence. Digital 12-lead electrocardiograms were recorded at eleven time points over 24 hours in each treatment period. QT intervals were corrected for heart rate using an individual-specific correction factor (QTcI).ResultsThe upper bound of the one-sided 95% confidence interval for time-matched, placebo-subtracted, baseline-adjusted QTcI intervals (ΔΔQTcI) was <10 ms for both the lesinurad 400 mg and 1,600 mg doses. ΔΔQTcI was independent of lesinurad concentrations. No QTcI thresholds >480 ms or QTcI increases >30 ms were observed. Moxifloxacin mean QTcI intervals were >5 ms, and the lower bounds of the 90% confidence interval were >5 ms at 2 hours, 3 hours, and 4 hours, confirming assay sensitivity.ConclusionLesinurad, at supratherapeutic doses, does not have a significant effect on the QT interval in healthy male or female subjects.

229 A Phase 1, Open-Label, Randomized, Single Ascending Dose Study to Evaluate the Pharmacokinetics and Safety of Fentanyl Sublingual Spray and Fentanyl Citrate Intravenous in Adult Opioid Naive Subjects

229 A Phase 1, Open-Label, Randomized, Single Ascending Dose Study to Evaluate the Pharmacokinetics and Safety of Fentanyl Sublingual Spray and Fentanyl Citrate Intravenous in Adult Opioid Naive Subjects

Exposure-response analysis to assess the concentration-QTc relationship of CC-122.

CC-122 hydrochloride is a novel pleiotropic pathway modifier compound that binds cereblon, a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex. CC-122 has multiple activities including modulation of immune cells, antiproliferative activity of multiple myeloma and lymphoma cells, and antiangiogenic activity. CC-122 is being developed as an oncology treatment for hematologic malignancies and advanced solid tumors. Cardiovascular and vital sign assessments of CC-122 have been conducted in hERG assays in vitro and in a 28-day good laboratory practice monkey study with negative signals. To assess the potential concentration–QTc relationship in humans and to ascertain or exclude a small QT effect by CC-122, a plasma concentration exposure- and ΔQTcF-response model of CC-122 was developed. Intensive CC-122 concentration and paired triplicate electrocardiogram data from a single ascending dose study were included in the analysis. The parameters included in the final linear exposure-response model are intercept, slope, and treatment effect. The slope estimate of 0.0201 with 90% CI of (0.009, 0.035) indicates a weak relationship between ΔQTcF and CC-122 concentration. The upper bounds of the 90% CI of the model-predicted ΔΔQTcF effect at Cmax from the 4 mg clinical dose and the supratherapeutic dose of 15 mg (1.18 ms and 8.76 ms, respectively) are <10 ms threshold, suggesting that the risk of CC-122 QT prolongation effect at the relevant therapeutic dose range from 1 mg to 4 mg is low.

Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus.

AimTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD‐6972, in healthy subjects and subjects with type 2 diabetes (T2DM).MethodsIn the single ascending dose study, LGD‐6972 (2‐480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD‐6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD‐6972 daily for 14 days.Results LGD‐6972 had linear plasma pharmacokinetics consistent with once‐daily dosing that was comparable in healthy and T2DM subjects. Dose‐dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD‐6972 also reduced plasma glucose in the postprandial state. Dose‐dependent increases in fasting plasma glucagon were observed, but glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD‐6972 was well tolerated at the doses tested without dose‐related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycaemia.ConclusionInhibition of glucagon action by LGD‐6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycaemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD‐6972 after 14 days of dosing supports continued clinical development.

First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer's disease

IntroductionAducanumab (BIIB037), a human monoclonal antibody selective for aggregated forms of amyloid beta, is being investigated as a disease-modifying treatment for Alzheimer's disease (AD). MethodsThis randomized, double-blind, placebo-controlled single ascending-dose study investigated the safety, tolerability, and pharmacokinetics (PK) of aducanumab in patients with mild-to-moderate AD. Eligible patients were sequentially randomized 6:2 to aducanumab (0.3, 1, 3, 10, 20, 30, and 60 mg/kg) or placebo. ResultsThe primary outcome was safety and tolerability. Doses ≤30 mg/kg were generally well tolerated with no severe or serious adverse events (SAEs). All three patients who received 60 mg/kg aducanumab developed SAEs of symptomatic amyloid-related imaging abnormalities, which completely resolved by weeks 8–15. Aducanumab Cmax, AUC0–last, and AUCinf increased in a dose-proportional manner. DiscussionIn this single-dose study, aducanumab demonstrated an acceptable safety and tolerability profile and linear PK at doses ≤30 mg/kg (clinicaltrials.govNCT01397539).

Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, After Single and Multiple Doses in Healthy Subjects.

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once‐weekly DPP‐4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single‐dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP‐4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once‐weekly doses over the dose range studied. Omarigliptin resulted in ∼2‐fold increases in weighted average postprandial active GLP‐1. Omarigliptin acts by stabilizing active GLP‐1, which is consistent with its mechanism of action as a DPP‐4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once‐weekly dosing. A model‐based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.