Single Ascending Dose Study Research Articles

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.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study.

BackgroundHMS5552, a novel fourth-generation glucokinase (GK) activator, has demonstrated promising effects on glycemic control in preclinical models of type 2 diabetes. This single ascending dose study was conducted to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HMS5552 during its first-in-human exposure.MethodsSixty healthy subjects were enrolled. In each of six dose-cohorts (5, 10, 15, 25, 35, and 50 mg), ten subjects were randomized with eight subjects receiving the same cohort-dose of HMS5552 and two receiving placebo. Plasma HMS5552 exposure, glucose, and insulin were measured repeatedly during fasting and after a standardized meal. Assessment included safety, PK, and PD endpoints.ResultsHMS5552 showed dose-proportional increases in area under the curve 0 to the last quantifiable concentration (AUC0–t) and maximum plasma concentration (Cmax). Slopes estimated by linear regression for AUC0–t and Cmax were ~1.0 (0.932 and 0.933, respectively). Geometric mean elimination half-life ranged from 4.48 to 7.51 hours and apparent clearance ranged from 11.5 to 13.1 L/h across all doses. No significant sex effect was observed in PK parameters. HMS5552 also demonstrated dose-related PD responses in terms of maximum glucose change from baseline (%) and mean glucose area under effect curve 0–4 hours change from baseline (%) (P<0.001). Fifteen adverse events were reported by nine subjects (ten with HMS5552 and five with the placebo). All adverse events were mild in intensity and resolved without any treatment.ConclusionThis first-in-human single ascending dose study provided predicted PK of HMS5552 with dose-proportional increases in AUC0–t and Cmax, as well as dose-related glucose-lowering effects over the range of 5–50 mg in healthy subjects. HMS5552 at doses up to 50 mg in healthy subjects was safe and well-tolerated.

Efficacy and Safety of Alirocumab in Japanese Subjects (Phase 1 and 2 Studies)

We assessed the safety and tolerability of ascending single doses of alirocumab in healthy Japanese subjects and evaluated the effect of alirocumab at 3 doses (50, 75, 150mg) on low-density lipoprotein cholesterol (LDL-C) reduction in patients with primary hypercholesterolemia on atorvastatin. A randomized, single ascending-dose study of alirocumab (100, 150, 250, or 300mg) or placebo (3:1 ratio), administered subcutaneously, was conducted in 32 healthy Japanese men. The phase 2, randomized, double-blind, placebo-controlled, parallel-group study was performed in patients with primary hypercholesterolemia (defined as calculated LDL-C ≥100mg/dl [2.6mmol/l]) who were on a stable dose of atorvastatin (5to 20mg). Patients were randomized to alirocumab (50, 75, or 150mg) or placebo (in single 1.0-ml injection volumes) administered every 2weeks (Q2W) for 12weeks; the primary outcome was the mean percent change in calculated LDL-C from baseline to week 12. Single subcutaneous administration of alirocumab in healthy subjects was well tolerated over 15weeks and resulted in highest mean percent reductions in LDL-C from baseline of approximately 40% to 60%. In the multiple-dose study, least-square mean (SE) changes in calculated LDL-C concentrations from baseline to week 12 were-54.8% (3.1%) for alirocumab 50mg,-62.3% (3.1%) for alirocumab 75mg, and-71.7% (3.1%) for alirocumab 150mg, with a least-square mean (SE) difference versus placebo of-52.2% (4.3%),-59.6% (4.3%), and-69.1% (4.3%), respectively (all p <0.0001). In conclusion, alirocumab was well tolerated and significantly reduced LDL-C concentrations in Japanese patients with primary hypercholesterolemia on atorvastatin.

(405) A single ascending-dose study of mirogabalin in healthy subjects: safety, tolerability, pharmacokinetic, and pharmacodynamic results

Mirogabalin is a preferentially selective a2d-1 ligand being developed for the treatment of pain associated with fibromyalgia and neuropathic pain. A randomized, double-blind, placebo-controlled, single ascending-dose study was conducted in healthy subjects to assess mirogabalin pharmacokinetics, pharmacodynamics, safety, and tolerability. Six mirogabalin doses (3, 5, 10, 30, 50, and 75mg) were administered, with 8 subjects enrolled per dose cohort and randomly assigned (3:1) to mirogabalin or placebo. Serial blood and urine samples were collected to measure pharmacokinetic parameters. Pharmacodynamic variables included sedation, attention, dizziness, and ataxia. Safety was evaluated based on treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, physical examinations, and vital sign measurements. All 48 subjects (mirogabalin, 36; placebo, 12) completed the study. Following oral administration, mirogabalin was rapidly absorbed and rapidly eliminated (61%–72% via urinary excretion). Mirogabalin exposure increased approximately linearly from 3 to 75mg, with tmax of 1h and t½ values ranging from 2.96h to 4.94h. Mean CL/F and Vz/F were comparable across all dose levels. Subjects in the highest dose cohorts had greater levels of sedation (75mg), reduced attention (50 and 75mg), and ataxia (50 and 75mg) than those in other dose cohorts. Dizziness was apparent at 7h postdose in the 50-mg cohort and within 2h of dosing in the 75-mg cohort. Most TEAEs were reported in the 50- and 75-mg dose cohorts. The most common TEAEs were somnolence (25%) and dizziness (22%). In summary, mirogabalin was rapidly absorbed and rapidly excreted through urine, with exposure proportional to dose. Subjects receiving the highest mirogabalin doses (50 and 75mg) showed greater impairment in PD assessments and higher rates of TEAEs than subjects receiving 3 to 30mg. TEAEs of dizziness and somnolence were expected based on mirogabalin’s mechanism of action. Overall, mirogabalin was well tolerated at doses ranging from 3 to 30mg. Supported by Daiichi Sankyo, Inc.

(479) A phase 2a, randomized, double-blind, placebo-controlled, single ascending-dose study to evaluate the safety and efficacy of naldemedine in patients with chronic non-cancer pain and opioid-induced bowel dysfunction

(479) A phase 2a, randomized, double-blind, placebo-controlled, single ascending-dose study to evaluate the safety and efficacy of naldemedine in patients with chronic non-cancer pain and opioid-induced bowel dysfunction

Ascending Single‐Dose, Double‐Blind, Placebo‐Controlled Safety Study of Noribogaine in Opioid‐Dependent Patients

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and Cmax and was slowly eliminated (mean t1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues.

Safety and Upper Respiratory Pharmacokinetics of the Hemagglutinin Stalk-Binding Antibody VIS410 Support Treatment and Prophylaxis Based on Population Modeling of Seasonal Influenza A Outbreaks

BackgroundSeasonal influenza is a major public health concern in vulnerable populations. Here we investigated the safety, tolerability, and pharmacokinetics of a broadly neutralizing monoclonal antibody (VIS410) against Influenza A in a Phase 1 clinical trial. Based on these results and preclinical data, we implemented a mathematical modeling approach to investigate whether VIS410 could be used prophylactically to lessen the burden of a seasonal influenza epidemic and to protect at-risk groups from associated complications. MethodsUsing a single-ascending dose study (n=41) at dose levels from 2mg/kg–50mg/kg we evaluated the safety as well as the serum and upper respiratory pharmacokinetics of a broadly-neutralizing antibody (VIS410) against influenza A (ClinicalTrials.gov identifier NCT02045472). Our primary endpoints were safety and tolerability of VIS410 compared to placebo. We developed an epidemic microsimulation model testing the ability of VIS410 to mitigate attack rates and severe disease in at risk-populations. FindingsVIS410 was found to be generally safe and well-tolerated at all dose levels, from 2–50mg/kg. Overall, 27 of 41 subjects (65.9%) reported a total of 67 treatment emergent adverse events (TEAEs). TEAEs were reported by 20 of 30 subjects (66.7%) who received VIS410 and by 7 of 11 subjects (63.6%) who received placebo. 14 of 16 TEAEs related to study drug were considered mild (Grade 1) and 2 were moderate (Grade 2). Two subjects (1 subject who received 30mg/kg VIS410 and 1 subject who received placebo) experienced serious AEs (Grade 3 or 4 TEAEs) that were not related to study drug. VIS410 exposure was approximately dose-proportional with a mean half-life of 12.9days. Mean VIS410 Cmax levels in the upper respiratory tract were 20.0 and 25.3μg/ml at the 30mg/kg and 50mg/kg doses, respectively, with corresponding serum Cmax levels of 980.5 and 1316μg/mL. Using these pharmacokinetic data, a microsimulation model showed that median attack rate reductions ranged from 8.6% (interquartile range (IQR): 4.7%–11.0%) for 2% coverage to 22.6% (IQR: 12.7–30.0%) for 6% coverage. The overall benefits to the elderly, a vulnerable subgroup, are largest when VIS410 is distributed exclusively to elderly individuals, resulting in reductions in hospitalization rates between 11.4% (IQR: 8.2%–13.3%) for 2% coverage and 30.9% (IQR: 24.8%–35.1%) for 6% coverage among those more than 65years of age. InterpretationVIS410 was generally safe and well tolerated and had good relative exposure in both serum and upper respiratory tract, supporting its use as either a single-dose therapeutic or prophylactic for influenza A. Including VIS410 prophylaxis among the public health interventions for seasonal influenza has the potential to lower attack rates and substantially reduce hospitalizations in individuals over the age of 65. FundingVisterra, Inc.

Andexanet alfa for reversal of factor Xa inhibitors induced-anticoagulation in nonclinical and clinical studies

Andexanet alfa for reversal of factor Xa inhibitors induced-anticoagulation in nonclinical and clinical studies

FRI-355 - NDI-010976, A Potent, Liver-Directed, Oral Inhibitor of Acetyl Coa Carboxylase for Non-Alcoholic Steatohepatitis: A Phase 1 Single Ascending Dose Study in Healthy Volunteers

FRI-355 - NDI-010976, A Potent, Liver-Directed, Oral Inhibitor of Acetyl Coa Carboxylase for Non-Alcoholic Steatohepatitis: A Phase 1 Single Ascending Dose Study in Healthy Volunteers

First in human study with a prodrug of galantamine: Improved benefit-risk ratio?

IntroductionGln-1062 (Memogain) is a pharmacologically inactive prodrug of galantamine. Owing to its lipophilic nature, it preferentially enters the brain, where it is cleaved into active galantamine. Gln-1062 is expected to have fewer peripheral side effects than other cholinesterase inhibitors, with improved effectiveness. MethodsThis was a double-blind, comparator and placebo-controlled, sequential cohort, single ascending dose study in 58 healthy subjects with Gln-1062 in doses of 5.5, 11, 22, 33, and 44 mg, compared with oral galantamine 16 mg and donepezil 10 mg. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed. ResultsGln-1062 doses up to 33 mg were well tolerated and induced a dose-dependent increase in the plasma concentrations of Gln-1062 and galantamine. Gln-1062 had a dose-dependent positive effect on verbal memory and attention, mainly in the first hours after drug administration. DiscussionGln-1062 was better tolerated than galantamine in doses with the same molarity and led to improved effects in cognitive tests. This is most likely caused by the more favorable distribution ratio between peripheral and central cholinesterase inhibition. These results give reason for further exploration of this compound.

Pharmacokinetics, Safety, and Tolerability of Amygdalin and Paeoniflorin After Single and Multiple Intravenous Infusions of Huoxue-Tongluo Lyophilized Powder for Injection in Healthy Chinese Volunteers

PurposeHuoxue-Tongluo lyophilized powder for injection (HTLPI), a traditional Chinese medicine preparation, is a compound of Persicae semen and Paeoniae Radix Rubra that is used mainly for treating blood-stasis obstruction syndrome in the acute stage of cerebral ischemic stroke. Amygdalin (AD) and paeoniflorin (PF) are 2 typical bioactive components in HTLPI and were selected as indicators for this pharmacokinetic study of HTLPI. The objective of this study was to investigate the safety profile, tolerability, and pharmacokinetic properties of AD and PF after single and multiple intravenous infusions of HTLPI in healthy Chinese volunteers. MethodsTwenty-one healthy Chinese subjects were recruited for this open-label, single ascending-dose (3, 6, and 9 g) and multiple-dose (6 g, once daily) study. Safety profile was assessed by adverse events and physical examination throughout the study. Serial plasma and urine samples were analyzed by HPLC-MS/MS. Pharmacokinetic parameters of AD and PF were calculated using noncompartmental analysis. FindingsIn the single-dose phase of the study, the mean maximum plasma concentration and the mean area under the plasma concentration−time curve of AD and PF increased proportionally with each dose escalation. In the multiple-dose phase, the steady state was achieved by day 4 after multiple-dose administration of 6 g HTLPI. Mean pharmacokinetic parameters achieved on day 1 were similar to those on day 7. No significant accumulation was observed after repeat doses of 6 g HTLPI. Approximately 79.6% of the administered AD and 48.4% of the administered PF were excreted unchanged in urine within 24 hours. No serious adverse events were observed during the entire study. ImplicationsThe pharmacokinetic properties of AD and PF were linear after a single intravenous infusion of HTLPI in the dose range of 3−9 g. No systemic accumulation was observed with repeat doses of HTLPI. Sex had no significant effect on the pharmacokinetic properties of AD and PF. Intravenous infusion of HTLPI was well tolerated in healthy Chinese subjects.

A single infusion of MDCO-216 (ApoA-1 Milano/POPC) increases ABCA1-mediated cholesterol efflux and pre-beta 1 HDL in healthy volunteers and patients with stable coronary artery disease.

AimsApolipoprotein A-1 (ApoA-1), based on epidemiology, is inversely associated with cardiovascular (CV) events. Human carriers of the ApoA-1 Milano variant have a reduced incidence of CV disease. Regression of atherosclerotic plaque burden was previously observed on intravascular ultrasound (IVUS) with ETC-216, a predecessor of MDCO-216. MDCO-216, a complex of dimeric ApoA-1 Milano and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, is being developed to reduce atherosclerotic plaque burden and CV events. We investigated the efficacy and safety of a single infusion of MDCO-216 in healthy volunteers and in patients with coronary artery disease (CAD).Methods and resultsTwenty-four healthy volunteers and 24 patients with documented CAD received a 2-h infusion of MDCO-216 in a randomized, placebo controlled, single ascending dose study. Five cohorts of healthy volunteers and four cohorts of CAD patients received ApoA-1 Milano doses ranging from 5 to 40 mg/kg. Subjects were followed for 30 days. Dose-dependent increases in ApoA-1, phospholipid, and pre-beta 1 HDL and decreases in ApoE were observed. Prominent and sustained increases in triglyceride, and decreases in HDL-C, endogenous ApoA-1 and ApoA-II occurred at doses >20 mg/kg and profound increases in ABCA1-mediated cholesterol efflux were observed. Other lipid and lipoprotein parameters were generally unchanged. MDCO-216 was well tolerated.ConclusionsMDCO-216-modulated lipid parameters profoundly increased ABCA1-mediated cholesterol efflux and was well tolerated. These single-dose data support further development of this agent for reducing atherosclerotic disease and subsequent CV events.

A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-CC5) Targeting Complement C5 for Treatment of PNH and Complement-Mediated Diseases: Interim Phase 1 Study Results

Introduction: Uncontrolled complement activation plays a pivotal role in a variety of disorders such as PNH and aHUS. ALN-CC5 is a subcutaneous (SC) investigational RNAi therapeutic targeting complement C5 (C5). In preclinical studies, ALN-CC5 has demonstrated decreased terminal complement activity. Based on the literature, preventing the generation of the terminal complex protects against intravascular hemolysis and complement-mediated tissue damage. The purpose of this study is to evaluate the safety and tolerability of ALN-CC5 in normal healthy volunteers.Material and methods: A multi-centered, placebo controlled, double blind phase 1 clinical study in healthy volunteers is ongoing. Several cohorts of healthy volunteers in Part A, a single ascending dose study and Part B, a weekly multiple ascending dose study have been completed. Primary endpoints are safety and tolerability. Secondary endpoints are pharmacokinetics, reduction of circulating C5, reduction in hemolytic, CAP and CCP activity.Results: In Part A, 20 healthy volunteers were randomized (1:3) to placebo or single SC dose of 50, 200, 400, 600 or 900mg of ALN-CC5 and followed for at least 70 days. In Part B, 12 healthy volunteers were randomized (1:3) to placebo or 5 weekly doses of 100, 200 or 400mg of ALN-CC5. No SAEs or study discontinuations occurred and overall ALN-CC5 was considered safe and generally well tolerated. A dose dependent and 94% mean maximum C5 knockdown was achieved following weekly administration. Updated safety and tolerability data as well as C5 knockdown, and changes in CAP, CCP and hemolytic activity from the study will be presented.Conclusion: Collectively, these initial results suggest that the use of a novel RNAi therapeutic targeting C5 is a promising approach for inhibiting complement in PNH, aHUS and other complement-mediated diseases. The subcutaneous route of administration and infrequent dosing make this a potentially encouraging therapy. DisclosuresHill:Alnylam: Consultancy. Off Label Use: ALN-CC5 is an investigational RNAi therapeutic targeting complement C5.. Borodovsky:Alnylam Pharmaceuticals: Employment, Equity Ownership. Kawahata:Alnylam Pharmaceuticals: Employment, Equity Ownership. Mclean:Alnylam Pharmaceuticals: Employment, Equity Ownership. Powell:Alnylam Pharmaceuticals: Employment, Equity Ownership. Chaturvedi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Warner:Alnylam Pharmaceuticals: Employment, Equity Ownership. Garg:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership.

First in Human Single-Ascending Dose Study: Safety, Biomarker, Pharmacokinetics and Exposure-Response Relationships of ALXN1210, a Humanized Monoclonal Antibody to C5, with Marked Half-Life Extension and Potential for Significantly Longer Dosing Intervals

▪Introduction: ALXN1210 is a humanized monoclonal antibody (mAb), with a sequence closely related to eculizumab (Soliris®). ALXN1210 binds specifically to human complement protein C5 and was engineered to eliminate the formation of C5a and the terminal complement complex with extended duration of complete complement inhibition. The mechanism of action of ALXN1210 provides strong clinical rationale for potential therapeutic use in patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, and other complement-mediated diseases. Clinical experience with eculizumab supports the reduction of free C5 to undetectable levels for complete inhibition of hemolysis.Methods: In this Phase 1, randomized, blinded, placebo-controlled, single-ascending dose study, healthy subjects received a single intravenous (IV) dose of 200 mg (cohort 1) or 400 mg (cohort 2) ALXN1210 or placebo (PBO), and were then followed for 150 days. Subjects were vaccinated with a tetravalent conjugate N. meningitidis vaccine and received prophylactic penicillin V. The primary objective was to evaluate the safety and tolerability of a single dose of ALXN1210. Secondary objectives were to characterize the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of ALXN1210. PD effects of ALXN1210 were assessed as the change in serum free C5 and ex vivo (cell-based) hemolytic activity.Results: Fourteen subjects enrolled in the study: 4 received 200 mg ALXN1210, 6 received 400 mg ALXN1210, and 4 received PBO. Serum ALXN1210 concentrations were measureable for the entire 150-day follow-up period. Mean Cmax and AUC∞ increased in a dose-proportional manner, with a mean terminal half-life of approximately 32 days and low (<20%) intersubject variability in PK parameters.Levels of free C5 were reduced by >99% from baseline in all subjects who received ALXN1210. Additionally, all subjects who received a single dose of 400 mg ALXN1210 reached or exceeded the ALXN1210 threshold level of 100 µg/ml and had >99% elimination of free C5. For subjects with ALXN1210 levels >100 µg/ml, average elimination of C5 was >99%. No reductions in free C5 concentrations were observed in subjects who received PBO. Mean chicken red blood cell (cRBC) hemolytic activity was completely inhibited after a single dose of 200 or 400 mg ALXN1210. The duration of suppression of mean cRBC hemolysis was dose dependent. No anti-drug antibody (ADA) response was observed during the 150-day follow-up period.Seven subjects (70%) receiving ALXN1210 reported 21 treatment-emergent adverse events (TEAEs); 3 in cohort 1 (200 mg) reported 6 TEAEs, and 4 in cohort 2 (400 mg) reported 15 TEAEs. The most frequently reported event was headache in subjects receiving ALXN1210 (3 subjects [50%], 3 events) or PBO (3 subjects [75%]; 7 events). Most (17/21; 81%) TEAEs were reported as mild, and all resolved during the trial. No drug-related serious AEs or treatment discontinuations due to TEAEs were reported.Conclusions:•Single IV doses of 200 mg or 400 mg ALXN1210 were well tolerated in healthy subjects.•Serum ALXN1210 concentration data exhibited a terminal half-life of 32 days-longer than eculizumab (9 days).•Mean ALXN1210 Cmax and AUC∞ increased in a dose-proportional manner.•100% of subjects who received ALXN1210 had samples with >99% elimination of free C5.•In subjects who received a single IV 400-mg dose of ALXN1210: •100% reached or exceeded the ALXN1210 threshold level of 100 µg/mL;•100% obtained >99% elimination of free C5;•Mean elimination of free C5 was >99%.•For ALXN1210 levels >100 µg/ml, average elimination of free C5 was >99%.•Mean cRBC hemolytic activity was completely inhibited after a single dose of 200 or 400 mg ALXN1210, and duration of suppression of mean cRBC hemolysis was dose dependent.•No ADA response was observed after a single dose of ALXN1210 during the 150-day follow-up period.•Data modeling supports that >99% elimination of free C5 will be achieved with doses of ALXN1210 administered at 4-week or longer dosing intervals.A multiple ascending dose study is ongoing, and 2 studies examining the safety, tolerability, efficacy, PK, and PD of ALXN1210 administered at ≥4-week dosing intervals will be initiated in PNH patients before the end of 2015. DisclosuresSahelijo:Alexion Pharmaceuticals: Employment, Equity Ownership. Mujeebuddin:Alexion Pharmaceuticals: Employment, Equity Ownership. Mitchell:Alexion Pharmaceuticals: Consultancy. Larouche:Inventiv Health: Employment, Other: Inventiv Health Conducted the Study; Alexion Pharmaceuticals: Other: Principal Investigator Of Trial Related to Abstract, Research Funding. Yu:Alexion Pharmaceuticals: Employment, Equity Ownership. Zhang:Alexion Pharmaceuticals: Employment, Equity Ownership. Patel:Alexion Pharmaceuticals: Employment, Equity Ownership. Lasaro:Alexion Pharmaceuticals: Employment. Bouchard:Alexion Pharmaceuticals: Employment. Andrien:Alexion Pharmaceuticals: Employment. Wang:Alexion Pharmaceuticals: Employment. Tamburini:Alexion Pharmaceuticals: Employment, Equity Ownership. Macdonald:Alexion Pharmaceuticals: Employment, Equity Ownership. Sheridan:Alexion Pharmaceuticals: Employment, Equity Ownership. Soni:Alexion Pharmaceuticals: Employment, Equity Ownership.

DRIVE PK: A Phase 2 Trial of AG-348 in Patients with Pyruvate Kinase Deficiency

▪ INTRODUCTIONPyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficient function of the PK enzyme. This condition is currently managed with supportive care, including transfusions, folate supplementation, splenectomy, and reducing iron overload, but there are no treatments specifically targeting the underlying metabolic defect. AG-348 is a novel, orally available, small molecule activator of wild-type and mutant red blood cell PK. METHODSResults of single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy adult volunteers (Yang H et al. Blood 2014;124[21]:4007; Yang H et al. Haematologica 2015;100[s1]:Abs S138) indicated good safety and tolerability and predictable pharmacokinetics at doses that demonstrated significant pharmacodynamic responses of increased whole blood adenosine triphosphate (ATP) and decreased 2,3-diphosphoglycerate (2,3-DPG) levels. In pre-clinical studies AG-348 inhibited the enzyme aromatase, and sex hormone profiles in the MAD study showed signs of aromatase inhibition. RESULTSDRIVE PK is a multicenter, international, randomized, open-label, two-arm dose ranging trial of AG-348 in adults with PK deficiency. DRIVE PK is currently open for enrollment. Eligible patients are randomized to either low dose (50 mg BID) or high dose (300 mg BID) arms and receive treatment for 6 months, with the option of extended treatment. Patients are stratified by genotype to allow for genotype-phenotype correlations. A third dose may be added based on the observations made in the two original arms. The primary objective is to evaluate the safety and tolerability of AG-348. Secondary objectives include evaluation of pharmacokinetics and pharmacodynamics, as measured by AG-348, ATP and 2,3-DPG levels. A range of biochemical markers of clinical benefit will be assessed, including hemoglobin levels, reticulocyte count, bilirubin, erythropoietin, ferritin, transferrin saturation, and haptoglobin. PK activity, glycolytic flux assay and PK protein levels in blood will be analyzed as exploratory endpoints. The trial population consists of adult patients with PK deficiency with hemoglobin levels at screening of ≤12.0 g/dL (men) or ≤11.0 g/dL (women), who have received no more than three units of red blood cells in the 12 months preceding the first dose of AG-348, and no transfusion within 4 months. Full inclusion/exclusion criteria can be found on www.clinicaltrials.gov, NCT02476916. CONCLUSIONDRIVE PK, an ongoing phase 2 trial of the PK activator, AG-348, is the first interventional trial to target the underlying metabolic defect in patients with PK deficiency. This flexible trial with two dose arms, and potential for a third dose arm, is designed to evaluate safety and tolerability, pharmacokinetic and pharmacodynamic responses, as well as hematological markers of red blood cell metabolism. DisclosuresBarbier:Agios: Employment, Equity Ownership. Silver:Agios: Consultancy. Merica:Agios Pharmaceuticals: Employment, Equity Ownership. Cohen:Agios: Consultancy. Kung:Agios: Employment, Equity Ownership. Yang:Agios Pharmaceuticals: Employment, Equity Ownership. Grace:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Agresta:Agios: Employment, Equity Ownership.

A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-AT3) Targeting Antithrombin for Treatment of Hemophilia: Interim Weekly and Monthly Dosing Results in Patients with Hemophilia A or B

Background: Hemophilia A and B are bleeding disorders characterized by a profound defect in thrombin generation (TG). Furthermore, in the presence of normal levels of endogenous anticoagulants a deficiency in factor VIII and IX results in major hemostatic imbalance and a bleeding phenotype. ALN-AT3 is a subcutaneously administered investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin (AT) that aims to restore the hemostatic balance by increasing TG.Methods: We are conducting a phase 1 multi-center study (NCT02035605) in healthy volunteers and patients with moderate to severe hemophilia A or B. Part A of this study has been completed and assessed a single ascending dose study in healthy volunteers. Parts B and C are multiple ascending dose studies in patients with hemophilia who are receiving weekly or monthly dosing, respectively. Primary endpoints are safety and tolerability. Secondary endpoints include PK, AT knockdown; change in thrombin generation and whole blood clot formation as measured by Calibrated Automated Thrombin generation and ROTEM thromboelastometry. Exploratory endpoints include evaluations of bleed pattern and control.Results: Part A enrolled 4 healthy volunteers, randomized (3:1) to 30 mcg/kg ALN-AT3 or placebo; no serious adverse events (SAE) or injection site reactions were observed. A total of 12 patients with severe hemophilia (10 hemohilia A; 2 hemophilia B) were enrolled in Part B and received 3 weekly subcutaneous doses of ALN-AT3 at 15 (n=3), 45 (n=6), and 75 (n=3) mcg/kg. Similar to part A, weekly administration of ALT-AT3 was generally safe and well tolerated in patients with hemophilia; no SAEs, discontinuations, clinical thromboembolic events or clinically significant D-dimer increases were reported. In the 75 mcg/kg dosing cohort, the mean maximum AT knockdown was 59% (p<0.05, relative to baseline), with nadir levels achieved between days 28 and 42. Maximum plasma AT knockdown of 86% was achieved, resulting in thrombin generation increases that correlated with AT knockdown and a bleed-free period of 114 days in the patient achieving the highest level of AT knockdown. The association between AT KD and TG was assessed in a post hoc exploratory analysis in which AT KD was categorized into tertiles. Part C aims to enroll several cohorts (n=3 per cohort) and will assess a monthly dosing schedule (x3 doses) of ALN-AT3. Patients in cohort 1 and 2 were dosed at 225 and 450 mcg/kg, respectively. Up to 4 additional cohorts may be enrolled within Part C. Updated safety, PK, AT knockdown, TG results as well as bleed patterns from Parts B and C will be presented.Conclusions: Emerging clinical data suggest that targeting AT could be a promising approach for restoring hemostatic balance in hemophilia. The potential for low volume subcutaneous administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make ALN-AT3 a potentially encouraging investigational therapy. DisclosuresPasi:Octapharma: Research Funding; Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria. Off Label Use: ALN-AT3 is an investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin.. Mant:Quintiles: Employment, Equity Ownership. Creagh:Bayer Healthcare UK: Honoraria. Austin:SOBI: Other: member of advisory board and received educational support; Pfizer: Other: member of advisory board and received educational support; Novo Nordisk: Other: member of advisory board and received educational support; CSL Behring: Other: member of advisory board and received educational support; Bio Products Laboratory: Other: member of advisory board and received educational support; Bayer: Other: member of advisory board and received educational support; Baxter: Other: member of advisory board and received educational support. Brand:Alnylam: Honoraria. Chowdary:Bayer: Consultancy; Biogen Idec: Consultancy; Baxter: Consultancy; CSL Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; SOBI: Consultancy. Ragni:Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Bristol Myers Squibb: Research Funding; Biogen: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dimension: Research Funding; Bayer: Research Funding; SPARK: Research Funding; Genentech Roche: Research Funding; Pfizer: Research Funding; Vascular Medicine Institute: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; CSL Behring: Research Funding. Chen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Rangarajan:Octapharma: Other: Investigator.

Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age

PurposeThe objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. MethodsThe first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. FindingsDelafloxacin Cmax and AUC0–∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0–∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0–∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in the creatinine clearance in the elderly men and women. Delafloxacin was well tolerated at the tested doses, with gastrointestinal adverse effects observed more commonly at doses ≥1200 mg. ImplicationsDelafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (≥1200 mg).

Safety, pharmacokinetics, and pharmacodynamics of PD 0348292, an oral, direct factor Xa inhibitor, after single and multiple dosings in healthy subjects

The objective of this study was to evaluate PD 0348292 safety, pharmacokinetics, and pharmacodynamics in healthy subjects. Three phase 1 studies were conducted. Studies 1001 and 1021 were single ascending-dose studies in healthy subjects randomized to oral PD 0348292 (2.5-150 and 0.1-2.5 mg, respectively) or placebo. Study 1003 was a multiple ascending-dose study in which 3 cohorts of young subjects received multiple doses of PD 0348292 (5-30 mg) every 12 hours or placebo, and 1 cohort of elderly subjects received a single dose (5 mg) of PD 0348292 or placebo. Drug plasma concentrations were measured. The effects of PD 0348292 on thrombin generation and typical coagulation measures such as prothrombin time, and international normalized ratio were evaluated. Single doses of PD 0348292 were well tolerated. Minor bleeding-related adverse events were observed following multiple doses of PD 0348292. PD 0348292 exposure increased less than proportionally at doses > 20 mg. Median peak concentrations occurred 3 to 4 hours following administration, and the mean terminal t1/2 value was approximately 10 hours. PD 0348292 demonstrated robust and concentration-dependent inhibition of thrombin generation, and modest and dose-related increases in typical coagulation measures. The safety, pharmacokinetics, and pharmacodynamics of PD 0348292 were acceptable for future clinical development.

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity.

BackgroundE-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects.MethodsThirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day).ResultsIn this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis.ConclusionThe sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal.Trial RegistrationEU Clinical Trials Register EudraCT 2010 020343 13

Mitochondria as targets of drug toxicity: Lessons from the R118 phase I experience.

Low Wang et al. report the results of the phase I program for R118 in this issue.(2) R118 was designed as an activator of adenosine monophosphate activated protein kinase (AMPK) to treat claudication. The single ascending dose study in healthy subjects was characterized by an unacceptable number of serious adverse events and substantial risk to the participants. The probable mitochondrial mechanism underlying these adverse events suggests important lessons for future drug development.