Multiple-dose Escalation Study Research Articles

Pharmacokinetics, pharmacodynamics, and safety of asundexian in healthy Chinese and Japanese volunteers, and comparison with Caucasian data.

There is an unmet clinical need for effective anticoagulant therapies for the management of thromboembolic diseases that are not associated with a relevant risk of bleeding. Asundexian (BAY 2433334) is an oral, direct, small-molecule inhibitor of activated factor XI (FXIa). Phase I data from healthy Caucasian male participants indicated predictable pharmacokinetic (PK) and pharmacodynamic (PD) profiles and no clinically relevant bleeding-related adverse events (AEs). Reported here are data from two phase I, randomized, placebo-controlled, single- and multiple-dose escalation studies of asundexian conducted in 60 healthy men: 24 Japanese and 36 Chinese. Baseline characteristics were comparable between the treatment groups. All treatment-emergent AEs were mild, with no serious AEs or AEs of special interest reported. Systemic exposure to asundexian increased dose proportionally after single or multiple dosing, with relatively low accumulation following multiple once-daily dosing in both Chinese and Japanese volunteers. Asundexian induced dose-dependent prolongation of activated partial thromboplastin time and inhibition of FXIa activity, with no effects on prothrombin time or FXI concentration in Japanese participants. There were no clinically relevant interethnic differences in PK profile across the Japanese, Chinese, and Caucasian (data from the previous phase I study) participants and no clinically relevant difference in PD response between Japanese and Caucasian participants.

A Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose escalation study to evaluate the safety and pharmacokinetics/pharmacodynamics of PF-06835375, a C-X-C chemokine receptor type 5 directed antibody, in patients with systemic lupus erythematosus or rheumatoid arthritis

BackgroundThe objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF‑06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).MethodsThis first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18–70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03–6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3–10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant.ResultsIn total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t1/2 ranged from 3.4–121.4 h (SAD cohorts) and 162.0–234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3–99.3%/62.4–98.7% [SAD] and 91.1–99.6%/89.5–98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375.ConclusionsThese data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases.Trial registrationClinicalTrials.gov identifier: NCT03334851.

Abstract LB388: Super potent and efficacious ALK/ROS1/TRK inhibitor that overcomes multiple drug-resistant mutations

Abstract Abnormal activation of ALK, ROS1 and TRK is implicated in tumorigenesis, progression, invasion, and metastasis of malignancies through various mechanisms. The first generation TRK inhibitors including larotrectinib and entrectinib have limited applications due to acquired resistance in clinical settings. Multiple on-target mutations occur at the solvent-front, gatekeeper, and xDFG motif inside the ATP binding pocket of the TRK kinase domain. While some candidates under current clinical development aim to address the solvent-front mutation, they are ineffective against the xDFG mutations (e.g.NTRK1.G667X). There is strong unmet medical needs for next generation TRK inhibitors that can address resistance mutations. We employ the synergistic advantages of domain expertise and modern technology to accelerate early stage drug discovery. On our deep learning (DL) centric AI platform, extensive scientific computing supports large scale virtual screening, generative design, drug property prediction and multi-objective lead optimization. Only the optimized candidate compounds are passed along for synthesis and testing to save time and cost. In Ba/F3-TPM3 cellular assays, LB-2159 showed superior potencies that are hundreds to thousands of fold higher than larotrectinib and/or entrectinib, with IC50 values of 0.02 nM for NTRK1.WT, 0.3 nM for NTRK1.G595R and 0.88 nM for NTRK1.G667C. Similar cellular potencies were demonstrated for ALK and ROS1. In xenograft models LB-2159 at 10 mg/kg bid resulted in complete tumor regression in Ba/F3-TPM3-NTRK1-WT tumors, 96% TGI in Ba/F3-TPM3-NTRK1-G595R tumors, 84% TGI and 100% survival in mice bearing Ba/F3-TPM3-NTRK1-G667C tumors. The pharmacokinetic profiles of LB-2159 are overall favorable, demonstrating extended stability and half life. In vitro safety screens yielded clean profiles without any DDI signal or hERG liability. Preclinical safety evaluations exhibited good tolerance in rats. In multiple dose escalation studies LB-2159 was well tolerated at 50 mg/kg/day and beyond. Empowered by our proprietary AI platform, we have discovered the novel ALK/ROS1/TRK inhibitors that overcome clinically known resistance mutations. Our drug candidate exhibited good tolerance in animals in preclinical safety evaluations. In xenograft models that are resistant to current treatments the compound demonstrates strong tumor suppression efficacy. LB-2159 is advancing through IND enabling studies, and its preclinical profiles support the potential for best-in-class treatment for NTRK fusion-positive solid tumors. Citation Format: Li Xing, Jingbing Wang, Wei Zhu. Super potent and efficacious ALK/ROS1/TRK inhibitor that overcomes multiple drug-resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB388.

Safety, tolerability, pharmacokinetics and neutrophil elastase inhibitory effects of Sivelestat: A randomized, double-blind, placebo-controlled single- and multiple-dose escalation study in Chinese healthy subjects

Background and objective: Neutrophil elastase has been identified as a potential therapeutic target for acute lung injury or acute respiratory distress syndrome, and Sivelestat is a selective, reversible and competitive neutrophil elastase inhibitor. This study was designed to investigate the safety, tolerability, pharmacokinetics and neutrophil elastase inhibitory effects of Sivelestat in healthy Chinese subjects. Methods: A randomized, double-blind, placebo-controlled single- and multiple-dose escalation clinical trial was carried out. Briefly, healthy volunteers in twelve cohorts with 8 per cohort received 1.0–20.2 mg/kg/h Sivelestat or placebo in an intravenous infusion manner for two hours, and healthy volunteers in four cohorts received two hours intravenous infusion of 2.0–5.0 mg/kg/h Sivelestat or placebo with an interval of twelve hours for seven times. The safety and tolerability were evaluated and serial blood samples were collected for pharmacokinetics and neutrophil elastase inhibitory effects analysis at the specified time-point. Results: A total of 128 subjects were enrolled and all participants completed the study except one. Sivelestat exhibited satisfactory safety and tolerability up to 20.2 mg/kg/h in single-dose cohorts and 5.0 mg/kg/h in multiple-dose cohorts. Even so, more attention should be paid to the safety risks when using high doses. The Cmax and AUC of Sivelestat increased in a dose dependent manner, and Tmax was similar for different dose cohorts. In multiple-dose cohorts, the plasma concentrations reached steady state 48 h after first administration and the accumulation of Cmax and AUC was not obvious. Furthermore, the Cmin_ss of 5.0 mg/kg/h dose cohort could meet the needs of clinical treatment. For some reason, the pharmacodynamics data revealed that the inhibitory effect of Sivelestat on neutrophil elastase content in healthy subjects was inconclusive. Conclusion: Sivelestat was safe and well tolerated with appropriate pharmacokinetic parameters, which provided support for more diverse dosing regimen in clinical application. Clinical trial registration: www.chinadrugtrials.org.cn identifier is CTR20210072.

Tolerability and Efficacy of a 10:25 Preparation of Δ9-Tetrahydrocannabinol and Cannabidiol for Treatment of Chronic Back or Neck Pain: A Multiple-Dose Escalation Study

Introduction: The aim was to demonstrate the safety and tolerability of cannabidiol (CBD) with Δ9-THC in patients with moderate to severe chronic back or neck pain unresponsive to over-the-counter non-opioid analgesics. Methods: This was a non-randomized, single-arm, open-label study. Participants received escalating doses of an oromucosal-administered combination containing 10 mg/mL of Δ9-THC, 25 mg/mL of CBD. On day 1, patients received once-daily 0.5 mL Cybis® 10:25 (5 mg Δ9-THC plus 12.5 mg CBD daily), escalated at days 8, 15, and 22 to 0.5 mL twice-daily (bd) (10 mg Δ9-THC plus 25 mg CBD daily), 1.0 mL bd (20 mg Δ9-THC plus 50 mg CBD daily), and 1.5 mL bd (30 mg Δ9-THC plus 75 mg CBD daily), respectively. The primary outcome was safety and tolerability, with secondary objectives including pharmacokinetic and efficacy outcomes. Results: 28 patients were enrolled in the study. Their median age was 63.3 years, and half were female. The median history of neck/back pain was 10 years. The pharmacokinetics following single doses of 0.5 mL were variable; however, there were dose-dependent increases in trough levels of CBD and Δ9-THC. Cybis® 10:25 was well tolerated, with the majority of adverse events of mild severity. The most common adverse events were nausea, vomiting, fatigue, dizziness, headache, paresthesia, and anxiety. There were dose-dependent improvements in numerical pain rating scores (p < 0.001), with clinically significant reductions in pain at 1.0 mL bd and 1.5 mL bd doses (28.8% and 34.1% reductions, respectively, p < 0.001). Depressive symptoms and stress had dose-dependent reductions (p = 0.0182, p < 0.01, respectively). Conclusion: In patients with chronic neck/back pain, CBD and Δ9-THC are well tolerated and doses of 1.0 mL bd and 1.5 mL bd showed clinically significant reductions in pain compared to baseline pain scores.

88-LB: Safety, PK, PD, and Efficacy of Weekly Dosing Supaglutide in Patients with T2D

Supaglutide (Supa) is a weekly dosing GLP-1 analog. We conducted a randomized, double-blind, placebo-controlled, multiple dose-escalation study to investigate the safety, PK/PD and efficacy of Supa in patients with T2D. 40 subjects were randomized in a 4:1 ratio to receive Supa (sc., 1, 2, 3 and 4mg) or placebo. We performed intensive PK blood sampling for two weeks after the first dose, followed by weekly repeated dosing for 4 consecutive weeks. The 4mg group received an adaptive dose of 1mg to reduce gastrointestinal reactions. The PK results revealed that the T1/2 of Supa was ∼207 h with median Tmax of 60∼84 h. The PD results showed that after 7 weeks of therapy, Supa significantly reduced fasting blood glucose, and HbA1c decreased by 1.3%. Supa increased fasting insulin/C-peptide while decreasing body weight. OGTT results showed significantly reduced glucose excursion, and the glucose-stimulated insulin secretion assay demonstrated significantly increased insulin secretion, suggesting improved glucose tolerance and enhanced β-cell function. AEs identified during the study were mainly mild to moderate gastrointestinal symptoms. None of the subjects developed anti-drug antibodies. Safety assessments including AEs, vital signs, ECGs and laboratory parameters, revealed that Supa was safe and well-tolerated. These data suggest Supa is a novel alternative therapy for T2D and metabolic disorders. Disclosure Y. Zhou: None. X. Jiang: None. Y. Lou: None. A. Ma: None. J. Li: None. Y. Zhao: None. G. J. Prud'homme: None. Q. Wang: None.

Pharmacokinetics and Tolerability of Intraperitoneal Chloroprocaine After Fetal Extraction in Women Undergoing Cesarean Delivery.

Intraperitoneal chloroprocaine has been used during cesarean delivery to supplement suboptimal neuraxial anesthesia for decades. The short in vitro half-life of chloroprocaine (11-21 seconds) has been cited to support the safety of this approach. However, there are no data regarding the rate of absorption, representing patient drug exposure, through this route of administration. Accordingly, we designed a study to determine the in vivo half-life of intraperitoneal chloroprocaine and assess clinical tolerability. We designed a single-center, prospective, cohort, multiple-dose escalation study of women 18 to 50 years of age undergoing cesarean delivery with spinal anesthesia. Chloroprocaine (40 mL) was administered after delivery of the newborn and before uterine closure. The first cohort (n = 5) received 1%, the second cohort (n = 5) received 2%, and the third cohort (n = 5) received 3% chloroprocaine solution. Maternal blood samples were obtained before administration and 1, 5, 10, 20, and 30 minutes after dosing. The primary objective was to define the pharmacokinetic profile of intraperitoneal chloroprocaine, including in vivo half-life. The secondary objective was to evaluate tolerability through determination of peak plasma concentration and prospective assessment for local anesthetic systemic toxicity. The peak plasma concentration occurred 5 minutes after intraperitoneal administration in all 3 cohorts: 64.8 ng/mL (6.5 µg/kg), 28.7 ng/mL (2.9 µg/kg), and 799.2 ng/mL (79.9 µg/kg) for 1%, 2%, and 3% chloroprocaine, respectively. The in vivo half-life of chloroprocaine after intraperitoneal administration was estimated to be 5.3 minutes (95% confidence interval, 4.0-6.6). We did not detect clinical signs of local anesthetic systemic toxicity in any of the 3 cohorts. The in vivo half-life of intraperitoneal chloroprocaine (5.3 minutes) is more than an order of magnitude greater than the in vitro half-life (11-21 seconds). However, maximum plasma concentrations of chloroprocaine (C max range, 0.05-79.9 µg/kg) were not associated with local anesthetic systemic toxicity and remain well below our predefined safe level of exposure (970 µg/kg) and levels associated with clinical symptoms (2.6-2.9 mg/kg). Therefore, our study suggests that intraperitoneal chloroprocaine, in a dosage ≤1200 mg, administered after fetal extraction, is well tolerated during cesarean delivery.

A phase I, randomized, double‐blind, placebo‐controlled, single‐ and multiple dose escalation study evaluating the safety, pharmacokinetics and pharmacodynamics of VX‐128, a highly selective Nav1.8 inhibitor, in healthy adults

Selective inhibition of certain voltage‐gated sodium channels (Navs), such as Nav1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX‐128 is a highly potent and selective Nav1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX‐128 in healthy subjects in a single‐ and multiple‐ascending dose (MAD) first‐in‐human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX‐128 up to 300 mg were well‐tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX‐128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily [q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX‐128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor‐ and pressure pain, which was dose‐dependent for the latter. VX‐128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half‐life of ~80 h at 10 mg q.d., and approximately two‐fold accumulation ratio after 10 and 30 mg q.d. Although VX‐128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Nav1.8 inhibitors as pain treatments.

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.

Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma.

PurposeTAK-639 is a topical, nine-amino acid, synthetic, C-type natriuretic peptide analog in Phase 1 development for the treatment of ocular hypertension (OHT) and primary open-angle glaucoma (POAG). TAK-639 is postulated to lower intraocular pressure (IOP) through a novel mechanism of action (MOA) that increases trabecular meshwork outflow. We investigated the safety and tolerability of TAK-639 in subjects with OHT or POAG.MethodsThis was a phase 1, multicenter, randomized, double-masked, placebo-controlled, single- and multiple-dose escalation study. Subjects (aged 18–90 years) with OHT or POAG were randomized 5:2 to TAK-639 or placebo. Three dose levels were planned (0.1%, 0.3%, 0.6% TAK-639), each with four dosing regimens (QD, BID, TID, QID). Safety measures included treatment-emergent adverse events (TEAEs) and ophthalmologic examinations. Pharmacokinetics and pharmacodynamics (reduction of IOP) were also evaluated.ResultsIn total, 63 subjects were randomized and received 0.1%, 0.3% and 0.6% TAK-639, as single dose, QD, or BID, and 0.1% and 0.3% TID. The study was terminated before 0.6% TID or QID dosing cohorts were studied; instead, 0.6% BID was repeated in a new cohort. TEAEs were instillation related and of mild-to-moderate intensity. There were no TEAEs leading to premature discontinuation, and no serious TEAEs. The most common treatment-related TEAEs were instillation site pain and transient corneal staining with fluorescein. There were no clinically significant concerns across dose groups for all other safety measures, including drop comfort, best corrected visual acuity, slit-lamp biomicroscopy, and corneal epithelial integrity. Little or no systemic exposure was observed. There was a marginal reduction in IOP in one cohort at the highest dose (0.6%) and regimen (BID) tested, suggesting biological plausibility of targeting the trabecular meshwork through this mechanism.ConclusionTAK-639 was generally well tolerated up to 0.6% BID. Further non-clinical studies will improve understanding of the MOA and the penetration of TAK-639 to the anterior chamber.

A phase I multiple-dose escalation study to assess the safety, tolerability, and pharmacokinetics of VEGF-receptor inhibitor telatinib (EOC315) in Chinese patients with advanced solid tumors.

3061 Background: Telatinib (EOC315) is a highly selective inhibitor of VEGFR/PDGFR (VEGFR 1-3, PDGFR-β, and c-Kit tyrosine kinases). This phase I study was to assess the safety, tolerability, and pharmacokinetics (PK) of Telatinib in Chinese patients with advanced solid tumors. Methods: Telatinib was administered to Chinese patients with advanced refractory solid tumors as a single agent in 3+3 dose escalation design, starting from 600mg and escalated to 900mg and 1200mg, given orally twice daily. The PK profile, safety, and tolerability were evaluated per protocol. Efficacy was evaluated with RECIST 1.1 criteria every 6 weeks. Results: A total of 15 subjects (6 colorectal cancer, 4 lung cancer, 1 head and neck cancer, 1 melanoma, 1 thymic carcinoma, 1 esophageal carcinoma,1 peritoneal carcinoma) were enrolled per protocol between July 2017 and August 2018, and 13 subjects received at least second line therapies before enrollment. Telatinib was well tolerated in the three dose arms. No dose limiting toxicities (DLTs) occurred during the dose escalation phase. CTC grade 3 AEs observed include hypertension (46.7%, 7/15), fatigue (6.7%, 1/15), transaminase elevation (6.7%, 1/15), hand-foot syndrome (6.7%, 1/15), oral mucositis (6.7%, 1/15), neutropenia (6.7%, 1/15), urobilinogen elevation (6.7%, 1/15), left ventricular systolic dysfunction/decreased ejection fraction (6.7%, 1/15). No CTC grade 4 AE were observed. There were 2 drug related SAEs (hospitalization due to high blood pressure. The PK profile of Telatinib (EOC315) at 600, 900, 1200 mg in Chinese patient cohorts is summarized in Table. For 12 evaluable patients, DCR was 58.3%. For all patients, mPFS was 15 weeks (3.3-34.3w). Conclusions: This study demonstrated the safety and tolerability of Telatinib (EOC315) in a multiple dose escalation design at 600, 900, and 1200 mg PO bid in Chinese patients with advanced refractory solid tumor. Telatinib AUC increased dose-proportionally from 600 mg to 900 mg bid, where 900 mg Telatinib bid is the maximum feasible and recommended dose for future studies in Chinese patients with advanced tumors. Clinical trial information: NCT03175497. [Table: see text]

Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab.

Replacement therapy with missing factor (F) VIII or IX in haemophilia patients for bleed management and preventative treatment or prophylaxis is standard of care. Restoration of thrombin generation through novel mechanisms has become the focus of innovation to overcome limitations imposed by protein replacement therapy. Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type serine protease inhibitor that regulates tissue factor (TF)-induced coagulation through a FXa-dependent feedback inhibition of the TF.FVIIa complex in plasma and on endothelial surfaces. Concizumab is a monoclonal, humanised antibody, specific for the second Kunitz domain of TFPI that binds and inhibits FXa, abolishing the inhibitory effect of TFPI. Concizumab restored thrombin generation in FVIII and FIX deficient plasmas and decreased blood loss in a rabbit haemophilia model. Phase 1 single and multiple dose escalation studies in haemophilia patients demonstrated a dose dependent decrease in TFPI levels and a pro-coagulant effect with increasing d-dimers and prothrombin fragment 1 + 2. A dose dependent increase in peak thrombin and endogenous thrombin potential was observed with values in the normal range when plasma TFPI levels were nearly undetectable. A few haemophilia patients in the highest dose cohorts with complete inhibition of plasma TFPI showed a decreased fibrinogen concentration with normal levels of anti-thrombin and platelets and no evidence of thrombosis. Pharmacokinetic parameters were influenced by binding to the target (TFPI), demonstrating target mediated drug disposition. A trend towards decreasing bleeding tendency was observed and this preventative effect is being studied in Phase 2 studies with additional data gathered to improve our understanding of the therapeutic window and potential for thrombosis.

Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis

ObjectiveTo evaluate safety, pharmacokinetics and pharmacodynamics of anti-interferon (IFN)-γ monoclonal antibody AMG 811 in subjects with SLE without or with lupus nephritis (LN).MethodsIn this phase Ib, randomised, multiple-dose escalation study...

A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients.

Correction to: Molecular Psychiatry advance online publication, 8 December 2015; doi:10.1038/mp.2015.178 Following publication of this paper, the authors noticed that Figures 5a and b contained the same image. In addition, there was a typo in Table 3 at #703. The correct figure and table appear here.

Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects

Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels - apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily- with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ~3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3-1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration-time profile. Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.

A randomized, double-blind, multiple-dose escalation study of a Chinese herbal medicine preparation (Dang Gui Buxue Tang) for moderate to severe menopausal symptoms and quality of life in postmenopausal women

This study is a phase II clinical trial that aims to investigate the dose-response relationship of a Chinese herbal medicine preparation, Dang Gui Buxue Tang (DBT), with short-term menopausal symptoms and quality of life in local postmenopausal women. A randomized, double-blind, multiple-dose escalation trial was performed in 60 postmenopausal women experiencing severe hot flashes and night sweats. The participants were randomized to receive DBT preparations at 1.5, 3.0, or 6.0 g/day for 12 weeks. The primary outcomes were vasomotor symptoms, Greene Climacteric Scale (GCS) score, and Menopause-Specific Quality of Life (MENQOL) score. Secondary outcomes included serum hormones and lipids. There were between-group differences in psychological/psychosocial (P = 0.015, GCS; P = 0.013, MENQOL) and somatic/physical (P = 0.019, GCS; P = 0.037, MENQOL) domains, and improvement was significantly greatest (P < 0.05) in the 6.0 g/day dose group. The frequency and severity of hot flashes and night sweats were significantly reduced in the 3.0 g/day (14.5%-21.2%, P < 0.05, hot flashes; 28.6%-39.6%, P < 0.05, night sweats) and 6.0 g/day (34.9%-37.4.0%, P < 0.01, hot flashes; 10.1%-12.8%, P < 0.01, night sweats) dose groups. The female hormones follicle-stimulating hormone, luteinizing hormone, and 17β-estradiol, as well as the lipids total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, were not significantly different within groups and between groups. DBT preparations at 6.0 g/day significantly improve physical and psychological scores and significantly reduce vasomotor symptoms from baseline. The treatment was well tolerated, with no serious adverse events noted during the 12-week intervention period. The changes do not affect hormones and lipid profiles.

Phase Ib Study of Recombinant Circularly Permuted TRAIL (CPT) in Relapsed or Refractory multiple Myeloma Patients

AbstractAbstract 1857 Background:Circularly permuted TRAIL (CPT) is a recombinant mutant of human Apo2L/TRAIL developed by Beijing Sunbio Biotech Co. Ltd. as a targeted therapy for multiple myeloma and other hematologic malignancies. CPT is a dual pro-apoptotic receptor agonist that directly activates both pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). CPT selectively induces apoptosis in a variety of cancer cells, while sparing most normal cells in the preclinical models. Objective:The safety, pharmacokinetics and preliminary efficacy of CPT in relapsed or refractory multiple myeloma patients (Ral/Ref MM) has been evaluated. Methods:This is a phase Ib, multiple-center, open-label, single/multiple dose-escalation study,18 patients were enrolled in the single dose-escalation study, and 29 patients were recruited in multiple dose-escalation study (including some patients from single dose-escalation study of CPT). Five escalation dosage levels include 5.0, 6.5, 8.0, 10.0 and 15.0 mg/kg/day. Patients received single dose of CPT, or once daily for 5 consecutive days (multiple dose) of each 21-days cycle. Patients receiving multiple doses were treated up to 4 cycles. The clinical response was evaluated at the end of each cycle by an independent review committee according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT). Results:In single dose-escalation study, no dose limiting toxicity (DLT) and maximum tolerated dose (MTD) was observed. The most common treatment-related adverse events (≥10%) were elevated AST, fever, elevated LDH, leucopenia and shivers. In multiple dose-escalation study, the most common treatment-related adverse events(≥10%) were fever, leucopenia, elevated AST, fatigue and vomit. No significant difference of related adverse event was observed among the different dose groups. Two patients (33.3%) experienced laboratorial or clinical tumor lysis syndrome in 15.0 mg/kg multiple dose. The efficacy was evaluated in 27 patients, 1 patient achieved complete response (CR), 4 partial response (PR), 4 minor response (MR) and 12 no change (NC). No response better than MR was observed in 5.0mg/kg and 6.5mg/kg group. In 8.0mg/kg, 10.0mg/kg and 15.0mg/kg groups, the overall response rate (CR+PR %) was 33.33%, 16.67% and 33.33%, respectively. The disease control rate for five dose groups was 50.00%, 66.67%, 83.33%, 83.33% and 100% respectively, indicating that the optimal dose for CPT may be between 8.0 and 15.0mg/kg. PK results are linear at dose range from 5 mg/kg to 15 mg/kg with CL of 32.47±9.33 ml/h/kg, Vd of 51.89±9.20 ml/kg and t1/2 of 1.16±0.22h. No drug accumulation was observed in repeated administration. No anti-drug antibodies were detected after 1 to 4 cycle’s treatment. Conclusion:CPT was well tolerated up to 15mg/kg with promising efficacy in patients with Ral/Ref MM. The MTD has not been reached. A randomized phase 2 trial in patients with Ral/Ref MM is ongoing. Disclosures:Yang:Beijing Sunbio Biotech Co., Ltd.: Employment. Zhu:Beijing Sunbio Biotech Co., Ltd.: Employment.

A Double-Blind, Placebo-Controlled, and Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Ono-7746 in Healthy Subjects

Abstract 4828 Background:ONO-7746 is a potent orally administered thrombopoietin receptor (c-Mpl) agonist and can elevate platelet counts after a single dose in healthy subjects. Therefore, it could be potentially used for the treatment of thrombocytopenia associated with a variety of etiologies. Objectives:This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ONO-7746 after multiple dose administration in healthy subjects. Methods:A total of 60 subjects were randomly assigned to 5 groups of 12 subjects each to receive active ONO-7746 (9 subjects) or placebo (3 subjects) once daily for 14 days at doses of 1, 2, 4, 6, and 10 mg per day. Dose selection was adjusted based on data from earlier cohorts according to the dose-escalation procedures, i.e. Dose escalation was only permitted if adequate safety and tolerability were demonstrated and the results did not meet the stopping rule criteria at the previous dose level as described in the single-dose study. Subjects returned on Day 42 for follow-up assessments. ONO-7746 was administered once daily under fasted conditions at the dose of 1 mg to 10 mg for 14 days. Subjects were admitted to the clinical study site on Day –1 and remained at the site until discharge on Day 32. Intensive safety, tolerability, PK, and PD assessments were made throughout the study. Safety assessments included 12-lead ECGs, vital signs, serum chemistry, hematology, urinalysis and adverse event (AE) reporting. Plasma samples for ONO-7746 concentration-time analysis were collected at several time points. PD parameters included platelet count, platelet activation, and aggregation. Results:Maximum platelet count and change from Baseline values increased with ascending ONO-7746 dose level. The mean platelet counts in the ONO-7746 cohorts increased from Baseline beginning on Days 3 or 4, peaked between Days 12 and 17, decreased from Days 22 to 32, and returned to baseline levels by Day 42. The largest mean percent change from Baseline in average platelet count (145.9%) was observed in the 10-mg cohort, compared with 17.4% in the placebo cohort. Platelet function as measured by the exploratory platelet aggregation and activation tests was not affected by administration of ONO-7746. In general, endogenous TPO values and CD34+ cell counts seemed not to be affected by the administration of ONO-7746. The PK profiles of ONO-7746 showed that Cmax and AUC24h increased with dose and T1/2 after the last dose was similar to that after a single dose. The plasma trough concentration of ONO-7746 reached steady state by Day 10. The PK of ONO-7746 was not affected by multiple-dose administration. Six subjects in the 10-mg cohort had an adverse event of special interest (AESI) of increased platelet count > 500 × 109/L. No treatment- or dose-related trends were observed in AEs, clinical laboratory results, influence on other blood cell counts, physical examination findings, vital sign measurements, 12-lead ECG and telemetry results, or slit lamp examination results. There were no deaths, serious AEs, severe AEs, or AEs that led to study discontinuation. Conclusion:ONO-7746 is safe and well-tolerated at all tested dose levels. The PK, PD, and safety profile demonstrated in this study supports further clinical studies in thrombocytopenic patients.Observed Platelet Count by Study Day [Display omitted] Disclosures:Hunt:ONO Pharma USA: Research Funding. Lu:ONO Pharma USA: Employment. Kawasaki:Ono Pharmaceutical Co., Ltd.: Employment. Hall:ONO Pharma USA: Employment. Komaba:Ono Pharmaceutical Co., Ltd.: Employment. Takeuchi:Ono Pharmaceutical Co., Ltd.: Employment. Imamura:ONO Pharma USA: Employment. Kuter:ONO Pharma USA: Consultancy.

YM150, An Oral Direct Inhibitor of Factor Xa, Demonstrated a Predictable and Dose-Proportional Pharmacokinetic/Pharmacodynamic Profile After Single and Multiple Dosing: Results From Three Studies

AbstractAbstract 3323 Background:YM150 is a potent oral direct factor Xa (FXa) inhibitor that is rapidly and extensively metabolized into YM-222714 after oral administration. YM-222714 predominantly determines the antithrombotic effect of YM150. Three studies were undertaken to assess the pharmacokinetic/pharmacodynamic (PK/PD) profiles of YM150 and YM-222714 in healthy male subjects (aged 18–55 yrs) after single and multiple doses over a wide dose range. Methods:Study 1a was a sequential-group, double-blind (DB), randomized, placebo-controlled, single-dose escalation study (3, 10, 20 and 30 mg; n=6 per dose group, except for 30 mg, where n=5). Study 1b was an open-label, randomized, 2-period crossover study to explore the effect of food on PK (n=10). Study 2 was a sequential-group, DB, randomized, placebo-controlled, multiple-dose escalation study (3, 10, 20 and 30 mg twice daily; n=6 per dose group); subjects received a single dose of YM150 (Day 1) followed by a washout period (48 h) and, thereafter, repeated dosing (Days 3–10). Study 3 was a sequential-group, DB, randomized, placebo-controlled, multiple-dose escalation study (60, 120, 180, 240, 360, 480 and 720 mg once daily; n=12 per dose group, except for 720 mg, where n=6); subjects received a single dose of YM150 (Day 1) followed by a washout period (48 h) and, thereafter, repeated dosing (Days 3–9). In all studies, blood samples were collected for PK/PD analysis up to 48, 72 or 96 hrs post-dose for 3–120, 180–480 and 720 mg dosages, respectively. All doses were tested separately in each study. Data are presented as arithmetic means. Results:YM-222714 maximum concentration (Cmax) and area under the curve (AUC)inf generally increased proportionally with dose in all studies. After single dosing across the studies (3–720 mg), YM-222714 Cmax and AUCinf ranged from 103–13,550 ng/mL and 404–14,0793 ng·h/mL, respectively; at steady state (SS), similar ranges were observed (Cmax: 116–18,680 ng/mL; AUCtau: 630–16,6009 ng·h/mL). The time to maximum concentration (tmax) of YM-222714 was 0.75–1.08 h after single dosing and at SS in Studies 1 and 2; in Study 3, tmax slightly increased with dose (range for 60–720 mg; single dose, 0.92–2.10 h; SS, 1.00–2.20 h). YM-222714 elimination half-life (t1/2) was 14.3–20.0 h after single dosing and 14.3–20.5 h at SS. YM150 plasma concentrations were generally below the lower limit of quantification in Studies 1 and 2. In Study 3, YM150 Cmax and AUCinf increased proportionally with dose after single dosing (4.5–65.4 ng/mL and 197–590 ng·h/mL), with a t1/2 range of 12.5–17.9 h; consistent with this, YM150 Cmax and AUCtau also increased proportionally with dose at SS (6.8–90.0 ng/mL and 43.7–723 ng·h/mL), with a t1/2 of 16.2–22.3 h. Administration of YM150 10 mg in fed vs fasted state led to an increase in YM-222714 tmax (1.7 vs 0.8 h) and decrease in Cmax (253 vs 310 ng/mL); other parameters were similar in both states. Small amounts of YM150 (<0.65%) were excreted unchanged in urine after single dosing and at SS; 20–40% and 25–39% of dose was excreted as YM-222714 after single dosing and at SS, respectively. Across the studies, renal clearance (CLR) ranged from 1.60–2.91 L/h after single dosing; a similar range was observed at SS (1.37–2.57 L/h). Across studies (YM150 3–720 mg) maximum prothrombin time (PTmax; INR) increased with dose and was similar under single dosing (1.42–14.1) and at SS (1.48–14.3), as was maximum activated partial thromboplastin time (aPTTmax; single dose, 37.0–81.6 s; SS, 38.0–92.4 s). A dose-dependent decrease in FXa activity was observed that was similar after single dosing and at SS (60–720 mg; 58.0–28.1% and 50.7–22.3%, respectively). Treatment with YM150 was generally safe and well tolerated across all studies. Conclusions:YM150 is rapidly and extensively converted to YM-222714 after oral administration. YM-222714 demonstrated a predictable, dose-proportional PK profile that was similar under single dosing and SS conditions, including a linear increase in Cmax and AUC, consistent t1/2 and no dose effect on CLR; no relevant food effect was observed, with administration of YM150 in fasted or fed state, having minimal effects on YM-222714 PK. Additionally, YM150 exhibited dose-dependent antithrombotic activity, as shown by increasing PT and aPTT and decreasing FXa activity with dose. Disclosures:Groenendaal – van de Meent:Astellas Pharma Global Development Europe: Employment. Heeringa:Astellas Pharma Global Development Europe: Employment. Kadokura:Astellas Pharma Inc.: Employment. Verheggen:Astellas Pharma Global Development Europe: Employment. Heinzerling:Astellas Pharma Global Development Europe: Employment.

Two-stage model-based clinical trial design to optimize phase I development of novel anticancer agents

Summary Background The phase I program of anticancer agents usually consists of multiple dose escalation studies to select a safe dose for various administration schedules. We hypothesized that pharmacokinetic and pharmacodynamic (PK–PD) modeling of an initial phase I study (stage 1) can be used for selection of an optimal starting dose for subsequent studies (stage 2) and that a post-hoc PK–PD analysis enhances the selection of a recommended dose for phase II evaluation. The aim of this analysis was to demonstrate that this two-stage model-based design, which does not interfere in the conduct of trials, is safe, efficient and effective. Methods PK and PD data of dose escalation studies were simulated for nine compounds and for five administration regimens (stage 1) for drugs with neutropenia as dose-limiting toxicity. PK–PD models were developed for each simulated study and were used to determine a starting dose for additional phase I studies (stage 2). The model-based design was compared to a conventional study design regarding safety (number of dose-limiting toxicities (DLTs)), efficiency (number of patients treated with a dose below the recommended dose) and effectiveness (precision of dose selection). Retrospective data of the investigational anticancer drug indisulam were used to show the applicability of the model-based design. Results The model-based design was as safe as the conventional design (median number of DLTs = 3) and resulted in a reduction of the number of patients who were treated with a dose below the recommended dose (−27%, power 89%). A post-hoc model-based determination of the recommended dose for future phase II studies was more precise than the conventional selection of the recommended dose (root mean squared error 8.3% versus 30%). Conclusions A two-stage model-based phase I design is safe for anticancer agents with dose-limiting myelosuppression and may enhance the efficiency of dose escalation studies by reducing the number of patients treated with a dose below the recommended dose and by increasing the precision of dose selection for phase II evaluation.