Single Ascending Dose Study Research Articles

Tafolecimab, a novel potential long-acting PCSK9 monoclonal antibody: efficacy and safety in healthy and hypercholesterolemia subjects

Abstract Background LDL cholesterol (LDL-C) is a well-established risk factor for cardiovascular disease. PCSK9 binds LDL receptors, targeting them for degradation. The dosing intervals for currently available PCSK9 monoclonal antibodies are once every 2 or 4 weeks. Tafolecimab, a novel recombinant human PCSK9 monoclonal antibody, was found to have higher affinity with PCSK9 and show longer LDL-C reduction compared to evolocumab in preclinical studies. Purposes The objectives for the SAD and MAD studies were to investigate the safety and efficacy of tafolecimab and explore the optimal dosing schedule. Methods The phase 1 study was a randomized, placebo-controlled, double-blind, single-ascending dose study (SAD) in Chinese healthy subjects, who were randomized 3:1 to tafolecimab and placebo (n=58). SAD subjects received tafolecimab subcutaneously at 25/75/150/300/450/600mg, or intravenously at 75/450mg, monitored up to day 84. The phase 2 study was a randomized, double-blind, placebo-controlled, repeated-dosing, multiple ascending dose (MAD) study in patients with hypercholesterolemia, who were randomized 4:1 to tafolecimab and placebo (n=60). MAD subjects received tafolecimab subcutaneously at 75/140mg every 2 weeks, 300/420mg every 4weeks, 450/600mg every 6 weeks up to day 84 or 98 with 3 months follow-up. Results In the SAD, the maximum mean reduction in LDL-C ranged from 52.2% to 72.1% and was achieved as early as 5 days (figure 1a). The duration of LDL-C reduction was tafolecimab dose dependent. In the MAD, the mean LDL-C concentrations were reduced by tafolecimab for each dose at 12 weeks relative to baseline (ranging from 54.30% to 72.26%; p<0.001). Particularly, a 56.52% (−72.50%, −40.54%) reduction of LDL-C was observed in the cohort of 600mg Q6W. The effect sustained till week 14 (8 weeks after the last dose) where there was still a 43.46% (−60.96%, −25.96%) reduction from baseline (figure 1b). The mean reduction of Lp(a) at week 12 ranged from 24.04% to 50.59% relative to baseline. Tafolecimab reduced the other lipids when comparing with placebo. The pharmacokinetics/pharmadynamics (LDL-C) profiles of tafolecimab were well characterised and support the potential dosing interval of 6–8 weeks subcutaneously. Both healthy and hypercholesterolemia subjects are generally tolerable to tafolecimab. Reported treatment-emergent adverse events (TEAEs) were: tafolecimab 23 (52.3%) vs. placebo 8 (57.1%); tafolecimab 34 (70.8%) vs. placebo 9 (75.0%) in the SAD and MAD respectively. There were no serious TEAEs or events leading to death or treatment discontinuation in both SAD and MAD. Conclusions Tafolecimab was well tolerated in both healthy and hypercholesterolemia in Chinese subjects, and improved lipid profile including LDL-C, Lp(a) and other lipids. The sustained effects on LDL-C suggests the potential of tafolecimab as a long-lasting PCSK9 inhibitor with dosing interval of 6–8 weeks or beyond. Figure 1. LDL-C: Percent change from baseline Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Innovent Biologics (Suzhou), China

Treprostinil iontophoresis in systemic sclerosis-related digital skin ulcers: A single ascending dose safety study

Digital skin ulcers are a severe complication of systemic sclerosis(SSc). The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a two-stage, randomized, placebo-controlled single ascending dose study in healthy volunteers and patients with SSc-related digital ulcer (SSc-DU). We further explored the effect of the procedure on skin blood flux. The objectives were to assess the safety of an iontophoresis of treprostinil hydrogel administered on healthy volunteers finger pad, leg and foot and asses the safety of ascending doses in patients with SSc-DU. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 different locations (i.e. 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1 mg/mL hydrogel of treprostinil. We then randomly treated SSc-DUs in a 3/1 ratio treprostinil or placebo respectively. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated (according to the CTCAE), while skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC0-4 h at 88460 ± 6436 versus 12730 ± 3397%BL.min respectively, P < 0.001) and on the sole of the foot (AUC0-3 h at 20124 ± 6119 versus 3142 ± 3036% BL.min respectively, P = 0.018) with a trend on the finger (AUC0-3 h was 10773 ± 4888). Among five patients with SSc-UD, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil was safe in SSc patients with digital ulcers. Treprostinil at 1 mg/mL will be used in the next study, i.e. repeated iontophoresis in SSc-related ulcer.

Single Ascending Dose Study to Assess Pharmacokinetic Linearity, Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human Subjects.

This study assessed the linearity of pharmacokinetics (PK) of trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on therapy for stable angina pectoris) and measured its renal elimination, safety, and tolerability in healthy subjects. This was a randomized, open-label, single-ascending dose study in healthy subjects. Subjects were administered with a single dose of 35, 70, or 105 mg TMZ-modified release tablets (six subjects each). Pharmacokinetic evaluations and safety analysis were performed before the first dose and till 48 h post-first dose. Following administration of 35, 70, and 105 mg TMZ-modified release; the Cmax (mean±SD) was 79.32 (±23.08), 153.17 (±23.08), and 199.67 (±23.08) ng/mL, the Tmax was 5.42 (±0.49), 4.51 (±1.27), and 4.57 (±0.96) h, t1/2 was 7.75 (±1.62), 6.40 (±1.23), and 6.50 (±1.18) h, AUC(0-inf) was 1116.89 (±378.35), 1838.39 (±284.50), and 2504.84 (±348.35) ng.h/mL, CLR was 13.70 (±2.24), 14.80 (±5.91), and 19.58 (±6.24) L·h-1 and CL/F was 33.69 (±8.51), 38.85 (±6.15), and 42.74 (±7.10) L·h-1, respectively. Slope estimates for AUC(0-inf), AUC(0-t), and Cmax were less than 1. Corresponding 95% CI of the slope for the AUC parameters excluded 1, indicating that the deviation from dose-proportionality was statistically significant. Corresponding 95% CI of the slope for Cmax included 1, indicating that the less than dose-proportional increase in Cmax was not statistically significant. No significant adverse events were observed. Substantial deviation from a dose-proportional increase in AUC(0-inf) and AUC(0-t) suggested a non-linear PK for TMZ-modified release. Single dose of TMZ-modified release was well tolerated and safe.

First-in-Human study of JNJ-55920839 in healthy volunteers and patients with systemic lupus erythematosus: a randomised placebo-controlled phase 1 trial.

Activation of the type I interferon (IFN) pathway is associated with systemic lupus erythematosus (SLE). We assessed the safety and tolerability of JNJ-55920839, a human monoclonal antibody that selectively neutralises most human IFNα subtypes and IFNω, in healthy participants and those with SLE. This was a two-part, first-in-human, phase 1, randomised, double-blind, placebo-controlled, multicentre study of single-ascending intravenous doses of 0·3-15 mg/kg or a single subcutaneous dose of 1 mg/kg JNJ-55920839 administered to healthy participants (part A) and multiple intravenous doses of 10 mg/kg JNJ-55920839 administered to participants with SLE (part B). Healthy men and women (women had to be postmenopausal or surgically sterile) aged 18-55 years; bodyweight of 50-90 kg; and body-mass index (BMI) of 18-30 kg/m2 were eligible for inclusion in part A. Men and women with SLE were recruited to part B, fertile female participants were required to have a negative pregnancy test result before and during the study and be using two highly effective methods of birth control. The inclusion criteria for participants with SLE in part B matched part A, except for bodyweight (40-100 kg). In both parts, participants were randomly assigned (3:1) to receive JNJ-55920839 or placebo; a computer-generated randomisation schedule was used in part A, and randomisation was stratified by racial and ethnic subpopulation and elevated levels of serological disease activity in part B. The primary outcome was evaluation of safety and tolerability of the study regimen assessed using clinical and laboratory tests compared with placebo. This study is registered with ClinicalTrials.gov, NCT02609789. Between Dec 11, 2015, and Sept 20, 2018, 48 healthy participants from a single site and 28 participants with mild-to-moderate SLE from 19 participating centres in seven countries were enrolled in the study. 12 healthy volunteers in part A and eight participants with SLE in part B received placebo. The most common treatment-emergent adverse events in both part A and B were in the system organ class of infections and infestations with a higher percentage of participants administered JNJ-55920839 with infections (ten [28%] of 36 in part A and nine [50%] of 18 in part B) than those exposed to placebo (two [17%] of 12 in part A and one [13%] of eight in part B). Particpants in part B were permitted to continue on defined ongoing standard of care medications. In two participants with SLE, locally disseminated herpes zoster of the skin was reported. No other clinically significant safety or tolerability issues were identified beyond the infections observed in participants treated with JNJ-55920839. JNJ-55920839 was well tolerated and safe. Additional studies are warranted to determine optimal dosing of patients and further explore safety. Janssen.

FRI115 - A randomized, double-blinded, placebo-controlled single ascending dose study to assess safety, tolerability, immunogenicity, and pharmacokinetics of a novel long-acting GLP-1/GIP/glucagon triple agonist (hm15211) in healthy obese subjects

FRI115 - A randomized, double-blinded, placebo-controlled single ascending dose study to assess safety, tolerability, immunogenicity, and pharmacokinetics of a novel long-acting GLP-1/GIP/glucagon triple agonist (hm15211) in healthy obese subjects

Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies.

BackgroundCognitive impairment is a core feature of schizophrenia. While first- and second-generation antipsychotic drugs treat psychotic exacerbations, no treatment is approved for the cognitive dysfunction. We have identified ASP4345, a positive allosteric modulator of the dopamine type 1 (D1) receptor that selectively binds to, and enhances the activity of, D1 receptors. ASP4345 has the potential to be an effective and well-tolerated treatment option for cognitive impairment associated with schizophrenia.ObjectiveThe objective of this study was to determine the pharmacokinetics of ASP4345 in two phase I single ascending-dose and multiple ascending-dose studies.MethodsBoth phase I studies were randomized, double blind, and placebo controlled. The single dose-ascending study assessed pharmacokinetics of single oral doses of 3–900 mg of ASP4345 or placebo in the fasted state in healthy adult volunteers. This study also assessed cerebrospinal fluid pharmacokinetics, as well as the effects of food on pharmacokinetic parameters. The multiple ascending-dose study (NCT02720263) assessed the pharmacokinetics of multiple oral doses of 3–150 mg of ASP4345 in patients with schizophrenia or schizoaffective disorder receiving stable antipsychotic drug treatment. The pharmacokinetic data from both studies were summarized using descriptive statistics.ResultsThe plasma concentration–time profile in both studies showed a rapid increase in concentrations of ASP4345. The median time to maximum concentration range was 1.00–2.26 h in the single ascending-dose study in the fasted state and 1.25–3.02 h in the multiple ascending-dose study at steady state. There were less than dose-proportional increases in maximum concentration and area under the curve in the single ascending-dose study, where doses had a range from 3 to 900 mg, and in the multiple ascending-dose study in patients with stabilized schizophrenia or schizoaffective disorder, where doses had a range from 3 to 150 mg. The mean terminal elimination half-life was dose independent and had a range from 9.12 to 14.3 h in the single ascending-dose study and from 11.1 to 26.8 h in the multiple ascending-dose study. Additionally, in the single ascending-dose study, absorption of 300 mg of ASP4345 was slightly delayed when administered in the fed state compared with the fasted state; median time to maximum concentration was 1.5 h under the fasting state and 4.0 h under fed states. All other pharmacokinetic parameters were comparable for both conditions. ASP4345 appeared in the cerebrospinal fluid with some delay; time to maximum concentration range was from 2.48 to 7.98 h in cerebrospinal fluid compared with 0.75 to 1.03 h in plasma (median cerebrospinal fluid/plasma = 0.188). The ratio of cerebrospinal fluid to total plasma for area under the curve from 0 to 24 h (0.157–0.573%) and maximum concentration (0.0899–0.311%) and the ratio of cerebrospinal fluid to unbound plasma for maximum concentration (25.0–86.4%) confirm the distribution of ASP4345 into the brain.ConclusionsThe pharmacokinetics of ASP4345 suggest that single daily dosing is appropriate for ASP4345. Furthermore, the concentration of ASP4345 in cerebrospinal fluid compared to free drug concentrations in plasma provides evidence of penetration of ASP4345 into the brain.

Safety and pharmacokinetic profiles of MGS0274 besylate (TS-134), a novel metabotropic glutamate 2/3 receptor agonist prodrug, in healthy subjects.

AimsThe safety and pharmacokinetics of single and multiple doses of a novel mGlu2/3 receptor agonist prodrug, MGS0274 besylate (TS‐134), were investigated in healthy subjects.MethodsPhase 1 single‐ascending dose (5–20 mg) and multiple‐ascending dose titration (5–80 mg) studies were conducted in healthy male and female subjects. Both studies were randomized, double‐blinded and placebo‐controlled. In one cohort of single‐ascending dose study (10 mg), concentrations of MGS0008, the active compound, in the cerebrospinal fluid (CSF) were measured for up to 24 hours postdose.ResultsFollowing single and multiple oral administrations, MGS0274 was rapidly absorbed and extensively converted into MGS0008, which reached a maximum concentration (Cmax) in plasma within 4 hours postdose and declined with a terminal half‐life (t1/2) of around 10 hours. Plasma exposure to MGS0274 was minimal, accounting for approximately 3% of the area under the concentration–time curve (AUC) of MGS0008. Plasma Cmax and AUC of MGS0008 at steady state increased dose proportionally (5–80 mg). MGS0008 penetrated into CSF, with a CSF‐to‐plasma Cmax ratio of 3.66%, and was eliminated with a t1/2 of approximately 16 hours. The most frequent treatment‐emergent adverse events observed following single and multiple oral administration included headache, nausea, somnolence, dizziness and vomiting.ConclusionTS‐134 is orally bioavailable in humans and converts rapidly and extensively to MGS0008, which exhibits good CSF penetration. Orally administered TS‐134 was safe and generally well‐tolerated; hence, TS‐134 is a promising candidate for further clinical development for the treatment of disorders in which glutamatergic abnormalities are involved, such as schizophrenia.

107-LB: Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MK-1092 in Healthy Subjects (HS)

Background: MK-1092, a first-in-class insulin receptor partial agonist, is being developed as a novel basal insulin for patients with T1DM and T2DM. The primary objective of this first-in-human study was to assess safety and tolerability of single subcutaneous (SC) doses of MK-1092 in HS. Secondary objectives were to estimate PK profiles, to determine the maximal glucose infusion rate (GIRmax) required to maintain target glucose levels during euglycemic clamp conditions and to explore the glycemic effect of insulin lispro when added to a single dose of MK-1092 in HS. Methods: In part 1 of this single-site study, 5 cohorts of HS (n=8/cohort) were blinded and randomized (3:1) to receive MK-1092 (4, 8, 16, 32 or 64 nmol/kg) or glargine (3 nmol/kg [0.5 units/kg]). Subjects received single SC doses of MK-1092 or glargine and placebo matched to the alternative active treatment under euglycemic clamp conditions. Part 2 of the study was started once a safe and tolerated MK-1092 dose that achieved GIRmax ~1-2 mg/kg/min was identified in Part 1. In the open-label part 2 of the study, 4 HS received lispro (1.2 nmol/kg [0.2 units/kg], IV) approximately 12 hr after a single SC dose of MK-1092 (8 nmol/kg) to confirm high dose lispro could reduce hyperglycemia (defined as GIRmax &amp;gt; 4mg/kg/min) after MK-1092 dosing. Results: All doses tested were safe and well tolerated. There were no SAEs and no discontinuations due to AEs. AEs were mild or moderate and resolved spontaneously. The geometric mean of apparent terminal t1/2 ranged from 5.4 to 9.3 hr, Tmax ranged from 12 to 18 hr, AUC0-∞ ranged from 10.6 to 161 nM*hr and Cmax ranged from 0.38 to 6.82 nM at 4 to 64 nmol/kg MK-1092. Mean GIRmax for glargine was 2.72 mg/kg/min and 0.92, 1.69, 3.10, 3.32 and 4.39 mg/kg/min for 4, 8, 16, 32 and 64 nmol/l MK-1092, respectively. Adding lispro to 8.0 nmol/kg MK-1092 resulted in a mean GIRmax of 11.34 mg/kg/min. Conclusion: Single doses of MK-1092 are well-tolerated and lower glucose in healthy subjects. Disclosure L. Morrow: Employee; Spouse/Partner; Lilly Diabetes. Employee; Self; ProSciento. M. Grimm: None. C. Beysen: Employee; Self; ProSciento. G. Walford: Employee; Self; Merck &amp; Co., Inc. K. Duncan: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. P.K. Mitra: Employee; Self; Merck Sharp &amp; Dohme Corp. Stock/Shareholder; Self; Bristol-Myers Squibb. P. Vaddady: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. M. Hompesch: Board Member; Self; ProSciento. Employee; Self; ProSciento. Stock/Shareholder; Self; ProSciento.

948-P: A Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of HM15136, a Novel Long-Acting Glucagon Analogue, in Healthy Subjects

HM15136 is a novel long-acting glucagon analogue with an extended half-life. In vivo efficacy studies of HM15136 in animal models showed its therapeutic potential in congenital hyperinsulinism, hypoglycaemia post-bariatric surgery, and obesity. We performed a randomized, double-blind, placebo-controlled first-in-human trial to assess the safety, pharmacokinetics, and pharmacodynamics of a single subcutaneous dose of HM15136 in healthy adults. Fifty-six subjects of a mean age, BMI, and HbA1c of 31.1 years, 23.1 kg/m2, and HbA1c 5.2%, respectively, randomly received HM15136 or its matching placebo in a ratio of 6:2 in 7 cohorts (10, 20, 30, 50, 80, 100, and 120 µg/kg). All adverse events were mild in severity and transient. Neither serious adverse event nor discontinuation due to adverse event occurred during the study. The most frequent Treatment Emergent Adverse Event was nausea (7.2%, only in the 100 and 120 µg/kg groups). Injection site erythema, which was barely noticeable and spontaneously subsided without sequelae, was reported in 2 out of 42 subjects who received HM15136. HM15136 was slowly, but steadily absorbed with the peak serum concentration reaching 34.2-65.2 hours after dose. The terminal half-life ranged from 69.8 to 85.6 hours, which was significantly greater than that of glucagon (&amp;lt; 1 hour). HM15136, particularly at doses &amp;gt;50 µg/kg, increased mean serum glucose from baseline by up to 27.7 mg/dL, which was maintained until 17 days after dose. In conclusion, a single subcutaneous dose of HM15136 at 10-120 µg/kg was safe and well-tolerated. The long half-life of HM15136, coupled with increase in serum glucose for ∼2 weeks, may warrant a weekly dosing regimen. Disclosure K. Huh: None. W. Shin: None. E. Baek: None. S. Seo: None. W. Lee: None. S. Baek: Employee; Self; Hanmi Pharmaceutical. H. Lee: None.

106-LB: Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MK-1092 in Subjects with T1DM and T2DM

Background: MK-1092, a first-in-class insulin receptor partial agonist, is being developed as a novel basal insulin to treat diabetes. Primary objectives were to assess safety and tolerability of single subcutaneous (SC) doses of MK-1092 in T1DM and T2DM and to determine safe single SC doses of MK-1092 in T1DM with a maximum glucose infusion rate (GIRmax) between 1.5 and 4.5 mg/kg/min. Secondary objectives were to estimate PK profiles in T1DM and T2DM and to determine the GIRmax in T2DM. Methods: All subjects received blinded treatments of MK-1092 or glargine and placebo matched to the alternative active treatment under euglycemic clamp conditions. T1DM: 2 cohorts (n=8/cohort) were each randomized (3:1) to receive MK-1092 (8 nmol/kg in cohort 1 or 32 nmol/kg in cohort 2) or glargine (3 nmol/kg [0.5 units/kg]). T2DM: 1 cohort (n=9) was randomized to receive either MK-1092 (n=6) or glargine (n=3). Each subject underwent 3 dosing periods. MK-1092 was dosed at 32, 16 and 64 nmol/kg in periods 1, 2, and 3, respectively and glargine was dosed at 3 nmol/kg in all periods. Results: All doses tested were safe and well tolerated. There were no SAEs or discontinuations due to AEs. AEs were mild or moderate and resolved spontaneously. No anti-MK-1092 or anti-insulin antibodies were observed. In T1DM, the geometric mean of apparent terminal t1/2 was 8.54 and 6.70 hr; Tmax was 15.00 and 15.04 hr; AUC0-∞ was 21.5 and 74.9 nM*hr and Cmax was 0.79 and 3.43 nM for 8 and 32 nmol/kg MK-1092, respectively. PK parameters for 32 nmol/kg MK-1092 were comparable for T1DM and T2DM except for a ~40-50% lower AUC0-∞ and Cmax in T2DM. In T1DM, the mean GIRmax was 1.33 and 2.74 mg/kg/min for 8 and 32 nmol/kg MK-1092, respectively and 2.32 mg/kg/min for glargine. In T2DM, the mean GIRmax was 1.90, 1.40 and 2.83 mg/kg/min for 32, 16 and 64 nmol/kg MK-1092, respectively and ~ 1.2 mg/kg/min for glargine. Conclusion: Single doses of MK-1092 are well-tolerated and lower glucose in patients with diabetes. Disclosure L. Morrow: Employee; Spouse/Partner; Lilly Diabetes. Employee; Self; ProSciento. M. Grimm: None. C. Beysen: Employee; Self; ProSciento. G. Walford: Employee; Self; Merck &amp; Co., Inc. K. Duncan: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. P.K. Mitra: Employee; Self; Merck Sharp &amp; Dohme Corp. Stock/Shareholder; Self; Bristol-Myers Squibb. P. Vaddady: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. M. Hompesch: Board Member; Self; ProSciento. Employee; Self; ProSciento. Stock/Shareholder; Self; ProSciento.

A Phase I Study on the Pharmacokinetics and Pharmacodynamics of DJT1116PG, a Novel Selective Inhibitor of Sodium-glucose Cotransporter Type 2, in Healthy Individuals at Steady State

PurposeDJT1116PG, which selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter type 2, was developed as an insulin-independent treatment for type 2 diabetes mellitus. This Phase I trial evaluated the pharmacokinetic and pharmacodynamic properties of DJT1116PG at steady state in healthy Chinese individuals. MethodsThis was a multiple ascending dose study of DJT1116PG (20, 50, and 100 mg once daily for 7 days) that included 36 healthy individuals. FindingsThere were no serious adverse events or deaths in these studies, and no adverse event led to study discontinuation. Oral DJT1116PG was rapidly absorbed with a Tmax of 0.75–1.5 h and a t½ of 12–16.2 h. Systemic exposure (Cmax and AUC) of DJT1116PG and its inactive metabolites (T1444, T1454, and T1830) increased in a dose-dependent manner. Urinary glucose excretion (UGE) plateaued at 50 mg of DJT1116PG in a previous single ascending dose study and on day 1 of this study. UGE plateaued at 20 mg of DJT1116PG on day 7 of this study. Serum glucose parameters were similar in individuals who received DJT1116PG or placebo. ImplicationsDJT1116PG was well tolerated in healthy Chinese individuals. At steady state, UGE plateaued at 20 mg of DJT1116PG in these individuals. These findings will inform the selection of doses for further early-stage clinical trials of DJT1116PG. Chinese Drug Trial Identifier: CTR20160986.

The safety and pharmacokinetics of a novel, selective S1P1R modulator in healthy participants

ABSTRACTBackground: Safety, pharmacokinetics and pharmacodynamics of BMS-986166, a novel sphingosine-1-phosphate receptor 1 modulator, were assessed.Research design and methods: Two double-blind, placebo-controlled, randomized Phase l studies were conducted in healthy participants. In the single ascending dose study (N = 70), BMS-986166 was administered as a single dose, upwardly titrated daily doses or a single dose in participants who were fed, fasted or administered famotidine. In the multiple ascending dose study (N = 32), BMS-986166 was administered daily for 28 days. Safety, pharmacokinetics and pharmacodynamics (absolute lymphocyte count [ALC]) were assessed.Results: BMS-986166 was generally well tolerated; treatment-related adverse events were mild. Dose-related, clinically insignificant reductions in time-matched heart rate were recorded versus placebo. Pharmacokinetics were linear and stationary with approximately dose-related increases in blood exposure of BMS-986166. Decreases in ALC percent change from baseline with multiple doses of BMS-986166 versus placebo were dose-related. Between Day 0 and 35, median nadir lymphocyte reductions were 53.7%, 75.9% and 81.9% with 0.25-, 0.75- and 1.5-mg BMS-986166 doses. ALC recovery began 14, 14–21 and 7 days after last dose of 0.25, 0.75 and 1.5 mg.Conclusions: BMS-986166 was generally well tolerated in this population and warrants further investigation.Trial registration: ClinicalTrials.gov: NCT02790125, NCT03038711.

Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers.

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty-two healthy subjects (single ascending dose (n = 32) and multiple ascending dose (n = 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 µg (single dose), but not 200 µg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0–1.5 h post-dose and mean terminal elimination half-life values from 20.5–26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady-state plasma exposure measures were observed where evaluable, with mean steady-state peak-to-trough ratios ranging from 3.34–4.49 (QD dosing) and 1.95–2.36 (BID dosing). Mean effective half-life values ranged from 17.5–18.4 h, reflecting ∼1.7-fold (QD dosing) and ∼2.6-fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediate-release ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady-state peak-to-trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended-release formulation to facilitate QD dosing.

FUNCTIONAL ACTIVITY OF THE MUSCARINIC POSITIVE ALLOSTERIC MODULATOR VU319 DURING A PHASE 1 SINGLE ASCENDING DOSE STUDY

Introduction The development of neurotransmitter based cognitive enhancers for Alzheimer's disease have focused recently on allosteric modulation, as a way of reducing potential drug-limiting toxicities that have been the hallmark of earlier orthosteric compounds. VU319 is an investigational positive allosteric modulator of the M1 muscarinic acetylcholine receptor that has recently finished initial testing in healthy volunteers. Cognitive tasks and event-related potentials (ERPs) have been used during the randomized, double-blind, placebo controlled Single Ascending Dose (SAD) study of VU319. This presentation includes both data from the initial SAD study, and the Food Effect substudy. The main pharmacodynamic objectives of the SAD were to identify early markers of functional engagement. Following the ascending dose cohorts, a Food Effect substudy was conducted to assess whether there was any change in the cognitive performance if VU319 was dosed with food compared to in a fasted state. Methods VU319 was given orally to 52 healthy volunteers aged 18-55?years. The SAD study tested 40 participants in five dose escalating cohorts of eight participants, in which six received VU319 and two received placebo. The Food Effect substudy consisted of 12 participants, in which ten received oral VU319 and two received placebo. The five doses for the SAD study were 60, 120, 240, 400 and 600mg. Participants in the Food Effect substudy received VU319 at a single dose of 120mg. For the 5 cohorts of the SAD study, all participants were dosed in a fasted stated. In contrast, all 12 participants in the Food Effect substudy completed were dosed twice; once fasted, and once following breakfast. Cognitive and electrophysiological tasks were examined pre-dosing and at 5?hours post-dose. The tasks were selected for their sensitivity to cholinergic tone. Cognitive tasks tested spatial and sustained attention, episodic and working memory, perceptual vigilance and psychomotor speed. Recorded ERP examined auditory and visual discrimination using oddball tasks, and an incidental memory task in which participants passively observed novel and repeated complex images. Results The analysis showed a trend for improvements in cognitive and ERP performance on the higher doses of VU319 compared to placebo. Participants on the highest dose of VU319 responded significantly faster to targets on the continuous performance test compared to participants on placebo (p = 0.03, effect size d = 1.2). Additionally, on the incidental memory task, participants who received the higher two doses of VU319 exhibited larger P300 amplitudes compared to placebo, when present with repeated compared to novel images (d > 0.8). Examination of the relationship between plasma levels of VU319 and cognitive performance showed that the response time on the continuous performance task decreased in relation to increasing concentration of VU319 in the bloodstream. Conclusions We conclude that these results demonstrate potential enhancement of the cholinergic system functioning in healthy adults following a single dose of VU319. These results provide an indication of the potential measures that are sensitive to cognitive activity by VU319 and therefore provide a potential framework to examine the cognitive impact of multiple doses of VU319 in AD patients. This research was funded by: This work was supported by the following grants: VKC Hobbs Discovery Grant 4-04-218-9745, Alzheimer's Association PCTR-16-383171; NICHD U54 HD083211, NCATS UL1 TR000445, 2RO1MH082867, R01MH073676, R01MH86601, MH087965, MH093366.

Phase 1 study to evaluate safety, tolerability and pharmacokinetics of a novel intra-tympanic administered thiosulfate to prevent cisplatin-induced hearing loss in cancer patients

SummaryCisplatin is a widely used chemotherapy for the treatment of certain solid tumors. Ototoxicity and subsequent permanent hearing loss remain a serious dose-limiting side effect associated with cisplatin treatment. To date, no therapies have been approved to prevent or treat cisplatin-induced hearing loss (CIHL). Sodium thiosulfate effectively inactivates cisplatin through covalent binding and may provide protection against cisplatin-induced ototoxicity. DB-020 is being developed as a novel formulation of sodium thiosulfate pentahydrate in 1% sodium hyaluronate for intratympanic injection (IT), enabling the delivery of high concentrations of thiosulfate into the cochlea prior to cisplatin administration. In the DB-020-002 phase 1a single-ascending dose study, healthy volunteers were enrolled into 5 cohorts to receive different doses of DB-020 via IT injection. Cohorts 1–4 received unilateral injections while Cohort 5 received bilateral injections. Plasma thiosulfate pharmacokinetics was measured, and safety and audiometric data were collected throughout the study. This study has demonstrated that intratympanic administration of DB-020 results in nominal systemic increases in thiosulfate levels, hence it should not compromise cisplatin anti-tumor efficacy. Furthermore, DB-020 was safe and well tolerated with most adverse events reported as transient, of mild-to-moderate severity and related to the IT administration procedure. These results support the design and execution of the ongoing proof-of-concept study, DB-020-002, to assess otoprotection using DB-020 in cancer patients receiving cisplatin without negatively impacting cisplatin anti-tumor efficacy.

Single Ascending Dose of ASP3772 Study in Japanese Healthy Male and Female Adults, and Single Ascending Dose Study of ASP3772 in Comparison With PPSV23 in Japanese Elderly Male and Female Subjects

Single Ascending Dose of ASP3772 Study in Japanese Healthy Male and Female Adults, and Single Ascending Dose Study of ASP3772 in Comparison With PPSV23 in Japanese Elderly Male and Female Subjects

Single and Multiple Ascending Dose Study of CORT113176 in Healthy Participants

Single and Multiple Ascending Dose Study of CORT113176 in Healthy Participants

P066 GB004, A NOVEL GUT-TARGETED PROLYL HYDROXYLASE INHIBITOR FOR INFLAMMATORY BOWEL DISEASE: FIRST-IN-HUMAN, MUTLIPLE-DOSE STUDY IN HEALTHY SUBJECTS WITH GUT BIOPSIES

Abstract Background GB004 is a small molecule prolyl hydroxylase inhibitor (PHDi) that stabilizes hypoxia inducible factors (HIF1-α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF1-α stabilization. Consistent with this, orally administered GB004 in a healthy non-human primate model engaged HIF-related genes in the gut, and, in animal models of colitis, demonstrated a significant reduction in disease activity, improvements in histologic measures, and greater exposure in GI tissue relative to plasma. GB004 is in clinical development for treatment of inflammatory bowel disease (IBD) and was shown to be safe in a single ascending dose study. The study described here evaluates the safety, tolerability, and pharmacokinetics (PK) of multiple daily doses of GB004 in plasma and colon biopsies. Methods This was a randomized, double-blind, placebo-controlled, multiple dose, Phase 1a study conducted in healthy subjects at a single site in Canada. Three dose levels of GB004 formulated as a solution or placebo solution were administered orally once a day for 8 days; safety and PK were evaluated. Plasma levels of HIF target genes EPO and VEGF were determined by immunoassays from samples collected at pre-dose, 4, 8, and 12 hours post dose on Day 1 and Day 7. Colon biopsies were obtained one day prior to first dose and at Day 8. Results 42 subjects (20 male and 22 female) were dosed. No serious adverse events or deaths were recorded. The most commonly observed adverse event in GB004-treated subjects was dizziness (31%;10/22); all events were mild and did not result in study drug discontinuation. There were no identified risks of GB004. Following oral dosing, GB004 was rapidly absorbed and eliminated from the systemic circulation, with a median time to maximum concentration of 0.5 hour for all doses. Both Cmax and AUC of GB004 increased in a dose-dependent manner on Day 1 and 7. Concentrations of GB004 measured in colon biopsies were greater than concentrations in the plasma at the time of biopsy. Changes in plasma EPO or VEGF levels were similar for GB004 and placebo with no dose-related effects observed. Conclusions This study demonstrated that multiple daily doses of GB004 solution were safe and tolerable. The PK profile was consistent with its intended preferential exposure in the gut. In support of the gut-targeted exposure, HIF target genes EPO and VEGF were not modulated in plasma. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, PK, and pharmacodynamics both systemically and within colonic tissue (NCT03860896). A tablet formulation is also being developed.

P066 GB004, A NOVEL GUT-TARGETED PROLYL HYDROXYLASE INHIBITOR FOR INFLAMMATORY BOWEL DISEASE: FIRST-IN-HUMAN, MUTLIPLE-DOSE STUDY IN HEALTHY SUBJECTS WITH GUT BIOPSIES

GB004 is a small molecule prolyl hydroxylase inhibitor (PHDi) that stabilizes hypoxia inducible factors (HIF1-α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF1-α stabilization. Consistent with this, orally administered GB004 in a healthy non-human primate model engaged HIF-related genes in the gut, and, in animal models of colitis, demonstrated a significant reduction in disease activity, improvements in histologic measures, and greater exposure in GI tissue relative to plasma. GB004 is in clinical development for treatment of inflammatory bowel disease (IBD) and was shown to be safe in a single ascending dose study. The study described here evaluates the safety, tolerability, and pharmacokinetics (PK) of multiple daily doses of GB004 in plasma and colon biopsies.

P540 GB004, a novel prolyl hydroxylase inhibitor for inflammatory bowel disease, leads to gut-targeted HIF-1α pathway engagement in a multiple-dose study in healthy subjects

Abstract Background GB004 is a small-molecule prolyl hydroxylase inhibitor that stabilises hypoxia-inducible factors (HIF-1α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF-1α stabilisation. GB004 is in clinical development for the treatment of inflammatory bowel disease and was shown to be safe in a single ascending dose study. The study described here evaluates the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple daily doses of GB004 in plasma and colon biopsies. Methods This was a randomised, double-blind, placebo-controlled, multiple-dose, Phase 1a study conducted in healthy subjects at a single site in Canada. Three dose levels of GB004 or placebo formulated as a solution were administered orally once a day for 8 days; safety and PK were evaluated. Colon biopsies were obtained one day prior to the first dose and on Day 8. Colonic tissue concentrations of GB004 and HIF pathway target genes were determined. Results Forty-two subjects (20 male and 22 female) were dosed. No serious adverse events or deaths were recorded. The most commonly observed adverse event in GB004-treated subjects was dizziness (31%,10/32); all events were mild and did not result in study drug discontinuation. There were no identified risks of GB004. Following oral dosing, GB004 was rapidly absorbed and eliminated from the systemic circulation, with a median time to maximum concentration of 0.5 h for all dose levels. Concentrations of GB004 measured in colon biopsies were greater than in plasma at the time of the biopsy. Dose-related HIF pathway target gene engagement and PD were confirmed. Conclusion This study demonstrated that multiple daily doses of GB004 solution were safe and tolerable. The PK profile was consistent with its intended preferential exposure in the gut. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, tolerability, PK and PD both systemically and within colonic tissue (NCT03860896). A tablet formulation is also being developed.