Multiple-dose Study Research Articles

A Potential Long-Acting LDL-Cholesterol-Lowering PCSK9 MonoclonalAntibody: Randomized, Placebo-Controlled Phase 1 Studies.

The aim of the studies was to evaluate the safety, tolerability, and efficacy of tafolecimab, a novel proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody, in Chinese healthy volunteers and patients with hypercholesterolemia. Fifty-eight healthy volunteers (phase 1a) were randomized to receive a single dose of 25, 75, 150, 300, 450, or 600mg tafolecimab subcutaneously, 75 or 450mg intravenously, or placebo. Sixty patients with hypercholesterolemia (phase 1b) were randomized to receive 75 or 140mg tafolecimab every 2weeks, 300 or 420mg every 4weeks, or 450 or 600mg every 6weeks subcutaneously or placebo for 12weeks. Tafolecimab was well tolerated. Adverse events in both studies were either mild or moderate. In the phase 1a study, a single dose of tafolecimab reduced low-density lipoprotein-cholesterol (LDL-C) levels up to 72% in healthy volunteers. In the phase 1b study, tafolecimab reduced LDL-C levels up to 71.6% and by more than 50% consistently to week 12 for all tafolecimab dose regimens. Tafolecimab is a safe PCSK9 monoclonal antibody with significant and potential long-acting LDL-C-lowering effect. (Single Ascending Dose Study of PCSK-9 Inhibitor [IBI306] in Healthy Subjects; NCT03366688) (Multiple Ascending Dose Study of PCSK-9 Inhibitor [IBI306] in Chinese Patients With Hypercholesterolemia; NCT03815812).

Bispecific Vγ9Vδ2-T and Type 1 NKT Cell Engager Lava-051 As First-in-Class Clinical Candidate to Target CD1d Expressing CLL, MM and AML

Bispecific Vγ9Vδ2-T and Type 1 NKT Cell Engager Lava-051 As First-in-Class Clinical Candidate to Target CD1d Expressing CLL, MM and AML

Phase 1 Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AG-946 in Healthy Volunteers

Background: Glycolysis is the primary source of ATP in red blood cells (RBCs), which is critical for maintaining RBC health. Pyruvate kinase red cell isoform (PKR) catalyzes the final step of glycolysis to generate ATP. Enhancing ATP production via PKR activation is under investigation as a potential therapeutic approach in hemolytic anemias. Increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG) in sickle cell disease (SCD) decreases hemoglobin oxygen affinity and results in increased RBC sickling. PKR activation has been shown to reduce 2,3-DPG. In previous clinical studies in pyruvate kinase deficiency, thalassemia and SCD, treatment with mitapivat, a PKR activator, led to improvements in hemoglobin and markers of hemolysis.AG-946 is an investigational, next-generation, oral small molecule activator of wild-type and mutant PKR isoforms, with high potency. Modelling from preclinical studies suggest that AG-946 is likely to have a pharmacokinetic (PK) profile that allows for once daily (QD) dosing and long duration of pharmacodynamic (PD) effects in humans. Here we report preliminary blinded results from an ongoing study assessing the safety, tolerability, PK and PD of AG-946 in healthy volunteers (NCT04536792).Methods: In this phase 1, randomized, double-blind, placebo (P)-controlled study, single ascending oral doses (SAD) or multiple ascending oral doses (MAD) of AG-946 were administered under fasting conditions to healthy men and women (18-55 years of age) in sequential cohorts. In SAD (4 cohorts of 8 subjects each) and in MAD (2 cohorts of 8 subjects each) subjects were planned to be randomized to receive either AG-946 (n=6) or P (n=2). The dose levels studied so far are 1, 3, 10, and 30 mg in SAD and 1 mg QD and 2 mg QD for 14 days in MAD. Safety assessments included vital signs, physical exams, electrocardiograms, clinical laboratory parameters and adverse events (AEs). Serial blood samples were drawn for PK and PD (2,3-DPG; ATP) assessments at regular intervals throughout the study period.Results: As of June 02, 2021, 39 (median age 33 years; n = 33 male) subjects in SAD and 17 (median age 36 years; all male) subjects in MAD received AG-946 or P. There were 6 (SAD, n = 5; MAD, n = 1) early discontinuations; all were unrelated to study treatment. In SAD, 4/39 (10.3%) subjects experienced ≥ 1 treatment-emergent AE (TEAE); all TEAEs were assessed as mild (Grade [Gr] 1). In MAD 4/17 (23.5%) subjects experienced ≥ 1 TEAE; the majority of the TEAEs were mild (Gr 1), with 1 subject experiencing a serious AE (Gr 2) of exercise-induced rhabdomyolysis 14 days after last dose, considered unrelated to study treatment. All other AEs in SAD and MAD were also considered unrelated to study treatment.In both SAD and MAD, AG-946 exhibited rapid absorption with median T max (time to maximum concentration) ranging from 0.5 to 1 hour. Following SAD, dose-normalized AG-946 exposures (AUC and C max [area under the curve and maximum concentration observed]) increased with increasing AG-946 doses, suggesting a greater than dose proportional increase in exposure over the tested dose range. Following MAD, AG-946 exposures were higher on Day 14 compared with Day 1, with mean accumulation ratios based on AUC of 3.6 at 1 mg QD and 3.3 at 2 mg QD, and mean accumulation ratios based on C max of 1.95 at 1 mg QD and 1.6 at 2 mg QD.In both SAD and MAD, an increase in AG-946 dose was associated with a decrease in 2,3-DPG concentrations (Figure 1), and an increase in ATP concentrations (Figure 2). The PD changes were sustained up to 168 hours after a single dose and > 7 days after the last day of multiple QD dosing, consistent with the slow off-rate from PKR.As expected, no clinically significant changes in Hb have been observed in the SAD or MAD cohorts, to date.Conclusions: AG-946, a highly potent PKR activator, was well tolerated in healthy volunteers following single dose administrations up to 30 mg and multiple 14-day dosing with 1 mg QD and 2 mg QD. The PK profile of AG-946 supports QD dosing, and is accompanied by sustained dose-dependent increases in ATP and decreases in 2,3-DPG, consistent with activation of the glycolytic pathway. Enrollment into additional SAD and MAD cohorts is ongoing and will be followed by an open-label phase in subjects with SCD. [Display omitted] DisclosuresIyer: Novartis: Current equity holder in publicly-traded company; Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Ronseaux: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Gamache: Agios Pharmaceuticals: Current Employment. Callaghan: Agios Pharmaceuticals: Current Employment.

Tolerability and Single Agent Anti-Neoplastic Activity of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory AML or MDS

Tolerability and Single Agent Anti-Neoplastic Activity of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory AML or MDS

Activation of Pyruvate Kinase-R with Etavopivat (FT-4202) Is Well Tolerated, Improves Anemia, and Decreases Intravascular Hemolysis in Patients with Sickle Cell Disease Treated for up to 12 Weeks

Activation of Pyruvate Kinase-R with Etavopivat (FT-4202) Is Well Tolerated, Improves Anemia, and Decreases Intravascular Hemolysis in Patients with Sickle Cell Disease Treated for up to 12 Weeks

Pharmacokinetics of the Melanocortin Type 1 Receptor Agonist PL8177 After Subcutaneous Administration.

Background and ObjectivePL8177 is a selective melanocortin 1 receptor agonist in development for the treatment of various immunologic and inflammatory conditions. Here we describe the pharmacokinetics of PL8177 after subcutaneous (sc) delivery in animals and humans.MethodsMice, rats, and dogs were administered sc PL8177 at single doses of 1.0 and 3.0 mg/kg (mice); 1.0, 5.0, and 25.0 mg/kg/day (rats); or 1.5, 8.0, and 40.0 mg/day (dogs). Blood was collected over 24 h (mice) or 28 days (rats and dogs). Safety and pharmacokinetics of single and multiple sc doses were also examined in human volunteers. Two dose levels were tested in two dosing cohorts of 1.0 and 3.0 mg/day for 7 days. Blood samples were collected through Day 1 and on Days 2 to 6 at peak and trough times based on analysis of the first two single-dose cohorts.ResultsIn mice, 3 mg/kg PL8177 resulted in an area under the plasma concentration–time curve from 0 to infinity (AUC∞) of 1727 ng·h/mL, a maximum plasma concentration (Cmax) of 2440 ng/mL, an elimination half-life (t½) of 0.5 h, and a time to maximum concentration (tmax) of 0.25 h. Results for the 1-mg/kg dose were generally proportional. In rats, mean tmax values were independent of dose and ranged from 0.25 to 1.0 h for single and multiple dosing. Cmax values ranged from 516 to 695 ng/mL (1-mg/kg dose) and from 666 to 1180 ng/mL (25-mg/kg dose). In dogs, mean tmax values ranged from 0.4 to 1.3 h for single and multiple dosing. Values for tmax decreased with increasing dose and mean plasma Cmax increased less than dose proportionally (96–129 ng·h/mL [1.5 mg], 275–615 ng·h/mL [8.0 mg], and 633–1280 ng·h/mL [40.0 mg]). In humans, PL8177 was observed in the plasma within 15 min after a single dose and persisted for up to 48 h at higher doses. The tmax was 30–45 min (single dose) and 15–45 min (multiple doses). In multiple-dose studies, maximum steady-state plasma concentration (Cmax,ss) and AUC∞ increased with dose. Geometric mean Cmax,ss values were 20.1 ng/mL (1.0 mg) and 57.2 ng/mL (3.0 mg). AUC∞ values were 54.3 ng·h/mL (1.0 mg) and 199 ng·h/mL (3.0 mg). Unchanged PL8177 excreted in the urine was ≤ 1%, and accumulation was minimal.ConclusionPL8177 administration resulted in a consistent pharmacokinetic profile. The measured exposure levels resulted in pharmacologically active PL8177 concentrations at the targeted MC1R. Rapid absorption was seen in healthy volunteers, and multiple-dose administration over 7 days resulted in pharmacokinetic characteristics similar to those observed after single-dose administration. Results support the continued development of PL8177 to treat immunologic and inflammatory conditions.

Requirements for Additional Strength Biowaivers for Modified Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities.

This article describes an overview of waivers of in vivo bioequivalence studies for additional strengths in the context of the registration of modified release generic products and is a follow-up to the recent publication for the immediate release solid oral dosage forms. The current paper is based on a survey among the participating members of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Program (IPRP) regarding this topic. Most jurisdictions consider the extrapolation of bioequivalence results obtained with one (most sensitive) strength of a product series as less straightforward for modified release products than for immediate release products. There is consensus that modified release products should demonstrate bioequivalence not only in the fasted state but also in the fed state, but differences exist regarding the necessity of additional multiple dose studies. Fundamental differences between jurisdictions are revealed regarding requirements on the quantitative composition of different strengths and the differentiation of single and multiple unit dosage forms. Differences in terms of in vitro dissolution requirements are obvious, though these are mostly related to possible additional comparative investigations rather than regarding the need for product-specific methods. As with the requirements for immediate release products, harmonization of the various regulations for modified release products is highly desirable to conduct the appropriate studies from a scientific point of view, thus ensuring therapeutic equivalence.

Development of ICT01, a first-in-class, anti-BTN3A antibody for activating Vγ9Vδ2 T cell-mediated antitumor immune response.

Gamma delta T (γδ T) cells are among the most potent cytotoxic lymphocytes. Activating anti–butyrophilin 3A (BTN3A) antibodies prime diverse tumor cell types to be killed by Vγ9Vδ2 T cells, the predominant γδ T cell subset in peripheral circulation, by mechanisms independent of tumor antigen–major histocompatibility complex (MHC) complexes. In this report, we describe the development of a humanized monoclonal antibody, ICT01, with subnanomolar affinity for the three isoforms of BTN3A. We demonstrate that ICT01-activated Vγ9Vδ2 T cells kill multiple tumor cell lines and primary tumor cells, but not normal healthy cells, in an efficient process requiring approximately 20% target occupancy. We show that ICT01 activity is dependent on BTN3A and BTN2A but independent of the phosphoantigen (pAg)–binding B30.2 domain. ICT01 delays the growth of hematologic and solid tumor xenografts and prolongs survival of NOD/SCID/IL2rγnull (NSG) mice adoptively transferred with human Vγ9Vδ2 T cells. In single- and multiple-dose safety studies in cynomolgus macaques that received up to 100 mg/kg once weekly, ICT01 was well tolerated. With respect to pharmacodynamic endpoints, ICT01 selectively activated Vγ9Vδ2 T cells without affecting other BTN3A-expressing lymphocytes such as αβ T or B cells. A first-in-human, phase 1/2a, open-label, clinical study of ICT01 was thus initiated in patients with advanced-stage solid tumors (EVICTION: NCT04243499; EudraCT: 2019-003847-31). Preliminary results show that ICT01 was well tolerated and pharmacodynamically active in the first patients. Digital pathology analysis of tumor biopsies of a patient with melanoma suggests that ICT01 may promote immune cell infiltration within the tumor microenvironment.

Safety, tolerability, and pharmacokinetics (PK) of treprostinil palmitil inhalation powder (TPIP): a phase 1, randomised, double-blind, single- and multiple-dose study

Abstract Background/Introduction Use of treprostinil in the treatment of pulmonary arterial hypertension (PAH) is limited by a short half-life and dose-limiting adverse events. TPIP, a dry powder formulation of the treprostinil prodrug treprostinil palmitil, is under investigation for PAH. In preclinical models, TPIP provided sustained treprostinil release in the lung and demonstrated sustained reduction of pulmonary arterial pressures. Purpose To examine the safety, tolerability, and PK of single- and multiple-dose administration of once-daily (QD) TPIP in healthy volunteers. Methods In this phase 1 study, healthy adults (aged 18–45 years) were randomised to receive single or multiple QD inhalation doses of TPIP. Single-dose participants received TPIP 112.5, 225, 450, or 675 μg (n=6 per dose) or placebo (n=2). Multiple-dose participants received TPIP 225 μg QD for 7 days (n=6), 112.5 μg QD for 4 days followed by 225 μg QD for 3 days (n=6), or placebo for 7 days (n=4). Results Of 42 randomly assigned participants who received ≥1 dose, 41 (97.6%) completed the study. Of the single-dose TPIP–treated participants, 70.8% (n=17/24) experienced a treatment-emergent adverse event (TEAE) vs 0% (0/2) of placebo-treated participants; the most common TEAEs (≥15%) among TPIP-treated participants were cough (45.8%), dizziness (29.2%), throat irritation (20.8%), nausea (16.7%), and hypotension (16.7%). Of the multiple-dose TPIP–treated participants, 83.3% (n=10/12) experienced a TEAE vs 50.0% of placebo-treated participants (2/4); the most common TEAEs were cough (58.3% TPIP vs 50.0% placebo), headache (50.0% vs 0%), nausea (33.3% vs 0%), and dizziness (25.0% vs 0%). Overall, 69.0% of participants (29/42) experienced mild TEAEs and 16.7% (7/42) experienced moderate TEAEs; no severe or serious TEAEs occurred. TEAEs were more frequent with increasing TPIP doses. Participants titrated from TPIP 112.5 μg QD to 225 μg QD experienced fewer TEAEs than those who received 225 μg QD at treatment initiation; all TEAEs were mild. After single-dose TPIP treatment, treprostinil exposure was dose proportional, with mean (CV%) Cmax = 78.4–717 pg/mL (38.6-72.9%) and AUC(0–∞) = 1.09–5.48 h·ng/mL (11.5–30.0%). At steady-state (225 μg), the mean (CV%) of Cmax, Cmin, and AUC(0–t) were 193–228 pg/mL (32.9–46.4%), 17.6–22.8 ng/mL (43.7%-64.4%) and 1.68–1.82 ng·h/mL (28.7–36.6%), respectively. No steady-state accumulation was observed. Elimination t1/2 was 8.7–11.6 h after a single dose and 6.8–8.8 h at steady state. Plasma concentrations of treprostinil palmitil were below the limit of quantification (100 pg/mL) at all time points measured. Conclusions In this phase 1 study, single and multiple TPIP dosing was generally well tolerated in healthy volunteers, with a PK profile that supports QD dosing. TEAEs were dose related; most were mild, none were severe or serious, and a titration schedule improved tolerability. These results support further examination of TPIP in patients with PAH. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Insmed Incorporated

Pharmacokinetics and pharmacodynamics of itepekimab in healthy adults and patients with asthma: Phase I first-in-human and first-in-patient trials.

Itepekimab is a monoclonal antibody that targets interleukin (IL‐33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single‐ascending and multiple‐ascending doses of itepekimab in two randomized, double‐blind, placebo‐controlled phase I studies. Healthy adults (N = 40) were randomized to the single‐dose study and patients with moderate asthma (N = 23) to the multiple‐dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single‐dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple‐dose study. Itepekimab exhibited linear PKs across studies and dose‐proportional increases in mean maximum concentration in serum and area under the concentration–time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59–73% and a long terminal half‐life (30.0–31.6 days). IL‐33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL‐33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well‐tolerated in both studies with no detection of treatment‐emergent anti‐drug antibody responses.

Pharmacokinetic Properties of S-oxiracetam After Single and Multiple Intravenous Infusions in Healthy Volunteers.

As a chiral drug, oxiracetam (ORT) can exist in two different isomeric forms: S-oxiracetam (S-ORT) and R-oxiracetam (R-ORT). S-ORT has emerged as a promising nootropic drug with the potential to treat brain injury and the resulting loss of neural function, memory and mental impairment as assessed by studies in various animal models. However, limited data are available on the pharmacokinetics of S-ORT in humans, so the present study was designed to evaluate the safety and pharmacokinetic profile of S-ORT in healthy volunteers. In part 1, subjects were intravenously administered single ascending dose (2.0, 4.0 and 8.0 g) S-ORT. In part 2, subjects were treated at a single intravenous infusion dose of 3.0 g S-ORT or 6.0 g racemic ORT using a two-sequence, two-period crossover design. In part 3, subjects were intravenously injected with 4.0 g S-ORT once a day for 7 days. Blood and urine samples were collected to evaluate the pharmacokinetic parameters and urine excretion rate. The safety profile of the drug was also evaluated throughout the study. Fifty-two subjects (30 in part 1, 12 in part 2, 10 in part 3) completed the study; only one subject displayed a mild adverse event, which possibly was treatment related, and no serious adverse event occurred. In part 1 for a single dose of 2.0, 4.0 and 8.0 g, the maximum concentration (Cmax) values were 111.28±18.99, 230.76±29.16 and 352.67±42.94 μg/ml, respectively; the values of area under the plasma concentration-time curve (AUC) from time zero to the time of last quantifiable concentration (AUC0-t) were 267.09±59.66, 524.50 ±72.87 and 822.68±95.21 μg·h/ml, respectively; the AUC from 0 h to infinity (AUC0-∞) values were 274.72±61.65, 536.06±78.13 and 832.07±96.91 μg·h/ml, respectively. The urine excretion rate of the unchanged drug was approximately 60%. After consecutive administration of S-ORT for 7 days, the accumulation index was 1.05±0.08. The plasma drug concentration-time curves for both S-ORT and R-oxiracetam (R-ORT) were almost identical. S-ORT was well tolerated, and no serious adverse events occurred in 2.0, 4.0 and 8.0 g in single- and 4.0 g in multiple-dose studies. S-ORT showed dose linearity with increasing doses and no drug accumulation after 7 days of continuous administration was observed.

Pharmacokinetic Characterization and Bioavailability Barrier for the Key Active Components of Botanical Drug Antitumor B (ATB) in Mice for Chemoprevention of Oral Cancer.

This study aims to characterize the pharmacokinetic (PK) profiles and identify important bioavailability barriers and pharmacological pathways of the key active components (KACs) of Antitumor B (ATB), a chemopreventive agent. KACs (matrine, dictamine, fraxinellone, and maackiain) of ATB were confirmed using the antiproliferative assay and COX-2 inhibition activities in oral cancer cells. The observed in vitro activities of KACs were consistent with their cell signaling pathways predicted using the in silico network pharmacology approach. The pharmacokinetics of KACs were determined after i.v., i.p., and p.o. delivery using ATB extract and a mixture of four KACs in mice. Despite good solubilities and permeabilities, poor oral bioavailabilities were estimated for all KACs, mostly because of first-pass metabolism in the liver (for all KACs) and intestines (for matrine and fraxinellone). Multiple-dose PK studies showed 23.2-fold and 8.5-fold accumulation of dictamine and maackiain in the blood, respectively. Moreover, saliva levels of dictamine and matrine were found significantly higher than their blood levels. In conclusion, the systemic bioavailabilities of ATB-KACs were low, but significant levels of dictamine and matrine were found in saliva upon repeated oral administration. Significant salivary concentrations of matrine justified its possible use as a drug-monitoring tool to track patient compliance during chemoprevention trials.

Pharmacokinetics, Safety, and Tolerability of the α2C‐Adrenoreceptor Antagonist BAY 1193397 in Healthy Male Subjects

The α2C -adrenoreceptor antagonist BAY 1193397 is in development for the oral treatment of diabetic foot ulcers. Safety, tolerability, and pharmacokinetics of BAY 1193397 were investigated in 3 randomized, single-center phase 1 studies in healthy male subjects: a first-in-human study (single oral doses of 0.5-50mg), a relative bioavailability and food effect study (single doses of 1 and 10mg), and a multiple-dose escalation study (using 2 and 5mg twice daily and 10 and 20mg once daily for 9 consecutive days). BAY 1193397 was rapidly absorbed in the fasted state, peak concentrations were reached between 0.6 and 2 hours. The mean terminal half-life was in the range of 17 to 20 hours. Area under the plasma concentration-time curve and maximum concentration appeared to be dose proportional, with a negligible food effect. There were no high-accumulation effects of BAY 1193397 after repeated dosing. BAY 1193397 was safe and well tolerated. At supratherapeutic plasma concentrations, there were slight transient increases in norepinephrine levels, heart rate, and blood pressure that were more pronounced after a single dose compared to steady state and appeared to be maximum concentration dependent. The results of the presented studies support the conduct of subsequent clinical trials with BAY 1193397 in patients with diabetes and compromised microcirculation.

First-in-Human, Double-Blind, Randomized, Placebo-Controlled Trial of TQ-F3083, a New Dipeptidyl Peptidase-4 Inhibitor, in Healthy Chinese Adults.

Background: As a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, TQ-F3083 represents a promising new drug for type 2 diabetes mellitus (T2DM). This phase I, first-in-human study evaluated the tolerability, pharmacokinetics, and pharmacodynamics of TQ-F3083 in healthy Chinese adults. Methods: Sixty healthy participants total were enrolled in the single-ascending dose, multiple-dose, and food-effect studies. Safety endpoints included adverse events (AEs), vital signs, 12-lead electrocardiogram, abdominal ultrasound, chest X-ray, physical examination, and clinical laboratory tests. Blood, urine, and feces samples were collected for pharmacokinetic analyses. Pharmacodynamic parameters were evaluated based on DPP-4 activity and the active glucagon-like peptide-1 concentration. Results: In total, 22 treatment-related AEs, mostly grade 1 or 2, were reported in 14 individuals. No deaths, serious AEs, or grade ≥4 AEs occurred, and no dose-dependent AEs were demonstrated. For pharmacokinetic characteristics, dose linearity was analyzed using power model. The slopes (90% CIs) were 1.08 (1.02–1.13) and 1.05 (0.99–1.11) for AUC0-t and AUC0-∞, suggesting liner pharmacokinetic characteristic after oral dose TQ-F3083 from 2 to 160 mg. The accumulation factor was 1.39 after multiple dose for 7 days. Decreased plasma exposure (84.87% decrease in Cmax, 49.23% in AUC0-t, and 47.77% in AUC0-∞) was observed with administration after a high-fat and high-calorie standardized breakfast. The 0–72 h TQ-F3083 excretion recovery percentages were 7.84% in urine and 5.76% in feces. Over 80% DPP-4 inhibition for 24 h was observed in the 20–160 mg cohorts, and the model-estimated 50% effective concentration was 1.10 ng/ml. The concentration of active glucagon-like peptide-1 increased after TQ-F3083 administration, but no obvious dose dependency was observed. Conclusion: TQ-F3083 was well tolerated in healthy Chinese adults, and the pharmacokinetic and pharmacodynamic characteristics support further evaluation of TQ-F3083 in a trial in T2DM patients.

A randomized dose-escalation study on the safety, tolerability, immunogenicity, pharmacokinetics and pharmacodynamics of a novel recombinant human albumin in healthy subjects

ObjectiveRecombinant human albumin (rHA) is an alternative to human serum albumin (HSA) for treating ascites in cirrhosis patients. This study was to evaluate the safety, tolerability, immunogenicity, and pharmacokinetics/pharmacodynamics (PK/PD) of rHA in healthy subjects to guide the design for further clinical trials. MethodsHealthy subjects aged 18–55 years were enrolled in this double-blinded, first-in-human, placebo-controlled single ascending dose (SAD) (1.25, 5, 10, 20, or 30g) and positive-controlled multiple-dose study (3-day treatment of 10g/day for three cycles every three weeks). The safety was assessed by adverse events (AEs). Antibodies (IgE and IgD) and cytokines were analyzed for immunogenicity. Serum albumin levels and changes in plasma colloid osmotic pressure (PCOP) and hematocrit (HCT) were measured for PK/PD analysis. ResultsrHA was well tolerated as all AEs were assessed as mild or moderate. No severe allergy or difference in the incidence of AEs was observed among the different cohorts in the SAD study or in the different cycles in the multiple-dose study. The incidence of AEs was similar for the rHA and HSA cohort. Antibodies or cytokines showed no changes after drug administration. As expected, serum albumin levels and PCOP increases, and HCT ratio decreases were dose-related with significant differences (p < 0.01). No differences were observed between rHA and HSA. ConclusionrHA is safe and well-tolerated in healthy Chinese subjects. rHA and HSA exhibited similar safety, tolerability, and PK/PD profiles. The results support further evaluation of rHA treatment in cirrhotic patients with ascites. The clinical trial registration numbers are CTR20191221 (http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml).

Abstract 1855: Potent anti-tumor activity against patient CLL, MM and AML by LAVA-051, a bispecific Vγ9Vδ2-T and type 1 NKT cell engager targeting CD1d

Abstract Bispecific antibodies that target tumors by engaging innate-like semi-invariant T cell subsets with inherent anti-tumor activity, such as Vγ9Vδ2-T cells and type 1 natural killer T (NKT) cells, may combine high therapeutic efficacy with limited off-tumor toxicity. Type 1 NKT cells respond to self and foreign (glyco)lipid antigens presented in the context of the MHC class I like molecule CD1d which is expressed on various (hematological) malignancies. Vγ9Vδ2-T cells respond to intracellular accumulation of phosphoantigens in cancer cells by sensing conformational alterations in the butyrophilin (BTN)2A1-3A1 complex. By linking a CD1d-specific single domain antibody (VHH) to a Vδ2-TCR specific VHH, we created a bispecific VHH, termed LAVA-051. Besides targeting Vγ9Vδ2-T cells to CD1d-expressing tumor cells, LAVA-051 has the unique ability to also trigger strong activation of type 1 NKT cells in a CD1d-restricted fashion, resulting in potent killing of CD1d-expressing tumor cells by engagement of Vγ9Vδ2-T cells and/or type 1 NKT cells (EC50 1 pM for Vγ9Vδ2-T cells and 216 pM for type 1 NKT cells; &amp;gt;85% target cell lysis in overnight assays at low effector:target ratios of 1:2). LAVA-051 triggered strong activation, pro-inflammatory cytokine production, and proliferation of type 1 NKT and Vγ9Vδ2-T cells and exerted substantial antitumor activity against human primary acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) cells that express CD1d. Moreover, improved survival was observed in in vivo AML and MM mouse models. Due to lack of cross-reactivity of LAVA-051 with non-human primate (NHP) CD1d and Vγ9Vδ2-T cells, a cross-reactive surrogate bispecific engager was generated to assess safety, pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Multiple dose studies in NHP (7 daily doses up to 1 mg/kg i.v.) showed clear signs of Vγ9Vδ2-T cell engagement but no clinical, laboratory, or histopathological toxicity. Reflecting the low molecular size of this bispecific engager, PK studies revealed a short plasma half-life which was however compensated for by the prolonged (up to 5 days) binding of the bispecific engager to peripheral blood Vγ9Vδ2-T cells allowing intermittent dosing. Although VHHs have low inherent immunogenicity LAVA-051 was humanized and engineered to avoid binding to pre-existing anti-VHH antibodies that have been reported in ±15% of human individuals and that may limit therapeutic activity. Based on the here reported strong activity against CD1d-expresssing tumors in in vitro, ex vivo and in vivo models and the favorable safety profile of the surrogate engager in NHP, LAVA-051 has been selected for a first-in-human clinical phase 1-2 study in patients with CD1d-expressing, therapy refractory, CLL, MM, or AML. Initiation of this clinical program is scheduled for Q1 2021. Citation Format: Roeland Lameris, Jurjen M. Ruben, Iris de Weerdt, Rob C. Roovers, Arnon P. Kater, Thilo A. Riedl, Victoria Iglesias, Ton Adang, Tanja D. de Gruijl, Paul W.H.I Parren, Hans J. van der Vliet. Potent anti-tumor activity against patient CLL, MM and AML by LAVA-051, a bispecific Vγ9Vδ2-T and type 1 NKT cell engager targeting CD1d [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1855.

Abstract CT119: Development and preliminary clinical activity of QL1706 (PSB205), a combination of anti-PD1 and anti-CTLA-4 antibodies manufactured together as a single product

Abstract Purpose: QL1706 (PSB205) is a novel biological entity consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1) that are expressed together in a fixed ratio from the same production cell line and manufactured as one product. In this Phase I, multiple-dose study (NCT04296994), the tolerability, safety, pharmacokinetics, and preliminary clinical activity of QL1706 in patients with advanced malignant tumors were evaluated. Experimental Design: Dose-escalation was based on an accelerated 3 + 3 design for doses of QL1706 from 0.3 to 10 mg/kg that was administered intravenously every 3 weeks (q3w). The expansion stage was carried out in selected dose cohorts. The primary objective of this study was to define the safety and tolerability of QL1706, and the recommended Phase 2 dose (RP2D) of QL1706 in patients that have advanced malignant tumors. Result: The trial is ongoing. By December 2020, 47 patients with solid tumors were enrolled, 16 patients in dose-escalation and 31 patients in expansion cohorts, respectively. Nineteen (40.4%) patients had previous immunotherapy, and the median lines of previous systemic therapy were 2 (0-5). QL1706 demonstrated a well-tolerated safety profile in the doses from 0.3 to 5 mg/kg. Two patients at 10 mg/kg experienced a dose-limiting toxicity, respectively. Due to the unique design, the clearance rate of anti-CTLA-4 antibody was faster than that of anti-PD-1 component of QL1706 in all dosage groups, and the elimination half-lives (t1/2) of anti-CTLA-4 antibody and anti-PD-1 component following single-dose administration were 4~5 days and 6~9 days, respectively. As a result, a much-reduced level of exposure was achieved for the anti-CTLA-4 antibody compared to the anti-PD-1 antibody. This unique feature may have contributed to the good overall safety profile of the product. Treatment related adverse events (TRAEs) occurred in 66.0% (31/47) of patients. Five (10.6%) patients in the 5 mg/kg and 10 mg/kg groups experienced grade 3 or higher TRAEs. The most common (≥10%) TRAEs were pruritus [23.4% (11/47)], rash [21.3% (10/47)], AST increased [14.9% (7/47)], fatigue [12.8% (6/47)], hyperthyroidism [10.6% (5/47)], and hypothyroidism [10.6% (5/47)]. Partial responses were observed in 10 out of 35 (28.6%) evaluated patients and the overall DCR was 48.6% (17/35) in the mixed population. The regime of 5 mg/kg q3w was recommended as the RP2D based on the overall assessment of tolerability, pharmacokinetics, and clinical activity. Significance: QL1706, a dual immune checkpoint pathways (PD-1 and CTLA-4) blockade product evaluated in this phase I dose-escalation and expansion study, showed an acceptable safety profile and early evidence of clinical activity in advanced solid malignancies. Citation Format: Li Zhang, Hongyun Zhao, Yuxiang Ma, Yan Huang, Yang Zhang, Xiaoli Wei, Yanhua Yang, Wei Yang, Furong Liu, Zhuan Lin, Jianing Li, Wenfeng Fang, Qianwen Liu, Benyan Zou, Kunlun Liao, Liuqun Liu. Development and preliminary clinical activity of QL1706 (PSB205), a combination of anti-PD1 and anti-CTLA-4 antibodies manufactured together as a single product [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT119.

Hypoglycemic and anti-lipidemic Evaluation of Fruit Extract and Solvent Fractions of Ziziphus oenoplia in Streptozotocin-Induced Diabetic Rats

Stem Bark, Root and fruit of Ziziphus oenoplia (Rhamnaceae) has been used in traditional health systems to treat diabetes and many more disorders in southern Asia as India, Sri Lanka and Burma. However hypoglycemic and hypo-lipidemic potential of fruit of this valuable plant is not scientifically validated till date. The aim of present study is to evaluate hypoglycemic and hypo-lipidemic effect of ethanol extracts and solvent fractions of Ziziphus oenoplia fruit. The ethanol extracts and solvent fractions in different dose concentration 100, 200, 400 mg/kg of Ziziphus oenoplia fruit were evaluated for hypo-glycemic effect in single dose and multiple dose study for 21 days as well as for hypo-lipidemic potential in streptozotocin induced diabetic rats. The outcome of present study indicates, crude extract and solvent fractions significantly reduce blood glucose level on normoglycemic and diabetic rats.The acute oral toxicity study of Z. oenoplia fruit extract did not show mortality in the animals at the limit dose of 2g/kg. In STZ induced diabetic rat, maximum BGL lowering effect produced by EEZO400 followed by CF400 after 21 days of treatment. Total cholesterol, triglycerides and low-density lipoprotein was also significantly decreased. The observed result may be due to active principles present in extract and fractions. The result showed the potential effects of Z.oenoplia fruit extract and fractions as hypoglycemic and anti hyper-lipidemic in dose dependant manner compare to glibenclemide as standard drug. The claimed traditional use as anti-diabetic has scientific back ground.&#x0D;

Abstract CT021: INVAC-1, an optimized telomerase DNA vaccine in patients with advanced solid tumors: Final results of first-in-human phase I study

Abstract Background INVAC-1 is an optimized DNA plasmid encoding an inactive form of human Telomerase Reverse Transcriptase (hTERT), a universal tumor antigen expressed in most of human tumors with little or no expression in normal somatic cells. Primary pharmacodynamics, safety and toxicology studies showed that INVAC-1 was enzymatically inactive, immunogenically safe and well tolerated. In murine models, we demonstrated that INVAC-1 was able to induce hTERT specific cellular immune responses with CD4+ Th1 effector and memory CD8+ T-cells as well as slow tumor growth and increase survival rate by 50% in tumor-bearing mice. Methods We conducted a First-In-Human (FIH) study, 2-centre, Phase I, open label, 3+3 escalation design and multiple dose study examining the safety and tolerability of INVAC-1 administered at three dose levels (100, 400 and 800 µg) in 26 patients with relapsed or solid refractory tumors. INVAC-1 was administered either by intradermal (ID) injection followed by electroporation (EP) (n=20) or by Tropis® Needle Free Injection System (n=6). Results INVAC-1 vaccination was safe and well tolerated when administered ID (either with EP or by Tropis®) at the three tested doses. Only one treatment-related grade 3 SAE was reported. 58% of patients experienced disease stabilization up to 9.9 months. One-year survival was reached for 65% of patients. INVAC-1 elicited both hTERT specific Th1-dominant CD4 and cytotoxic CD8 T cell responses with no vaccine-induced peripheral immunosuppression. Anti-hTERT immune responses were enhanced by adding anti-PD-1 immune checkpoint inhibitor ex vivo. In addition, INVAC-1 vaccination was able to promote epitope spreading. Finally, correlation analysis between clinical and immunological data showed that patients with OS &amp;gt;1 year presented a significantly higher hTERT immune response after INVAC-1 vaccination compared to patients with OS &amp;lt;1 year. Moreover, estimated median OS in INVAC-1 immune responders was 17.4 months vs. 7 months for non-responders. Conclusion INVAC-1 vaccination was safe, well tolerated and immunogenic when administered ID at the three tested doses. Disease stabilization was observed for the majority of patients during the treatment period and beyond. Clinical trial identification #NCT02301754 Citation Format: Julie Garibal, Jacques Medioni, Luis Teixeira, Olivier Adotevi, Marie-Agnès Dragon-Durey, Caroline Laheurte, Claire Germain, Marie Escande, Maria Wehbe, Valérie Doppler, Thierry Huet, Pierre Langlade Demoyen. INVAC-1, an optimized telomerase DNA vaccine in patients with advanced solid tumors: Final results of first-in-human phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT021.

Phase 1 Study of the Anti-HtrA1 Antibody-binding Fragment FHTR2163 in Geographic Atrophy Secondary to Age-related Macular Degeneration

FHTR2163 is a novel antigen-binding fragment (Fab) directed against high-temperature requirement protein A1 (HtrA1). HTRA1 inhibition may preserve retinal integrity and slow disease progression in geographic atrophy (GA) secondary to age-related macular degeneration (AMD). This study examined the safety, pharmacokinetics, immunogenicity, and changes in the HTRA1-specific substrate Dickkop-related protein 3 (DKK3) in patients with GA who received FHTR2163. Phase I, open-label, single ascending dose escalation and multiple-dose expansion study. Adults aged ≥ 50 years with GA secondary to AMD with best corrected visual acuity ranging between Snellen 20/125 and 20/400 were enrolled. In the first stage, a single intravitreal injection of FHTR2163 was given in 5 dose-escalation cohorts ranging from 1 to 20 mg (n=3 patients/cohort; n=15 total patients). The second stage evaluated the maximum tested dose of 20mg administered every 4 weeks for 3 doses (n=13 patients). No dose limiting toxicities or ocular serious AEs were reported. The most frequently reported AEs in the study eye were conjunctival hemorrhage (n=7), conjunctival hyperemia (n=4), and eye pain (n=2). No non-ocular or ocular AEs were assessed as drug related. There were no clinically significant changes in ocular exams. A sustained pharmacodynamic effect of anti-HtrA1 was observed in the aqueous humor, as measured by levels of cleaved DKK3. FHTR2163, a novel Fab directed against HtrA1, was well tolerated with no DLTs or significant ocular AEs. The molecule when injected intravitreally for 3 doses showed a sustained pharmacodynamic effect at the maximum tested dose of 20 mg.