This first-in-human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003-10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration-time curves ranging from 0.7 to 251.6 lg/mL and 6.5 to 55409.6 h·lg/mL following doses 0.1 mg/kg-10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose-dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested. Key words: ASKP1240, anti-CD40, pharmacodynamics, pharmacokinetics, randomizedAbbreviations: AEs, adverse events; AUC inf , area under the concentration-time curve from time zero extrapolated to the infinite time; C max , maximal antibody serum concentration; INR, international normalized ratio; LLOQ, lower limit of quantification; MABEL, minimal anticipated biological effect level; MedDRA, Medical Dictionary for Regulatory Activities; MFI, mean fluorescent intensity; PD, pharmacodynamic; PDAS, pharmacodynamic analysis set; PK, pharmacokinetic; PKAS, pharmacokinetic analysis set; SAF, safety analysis set; SD, standard deviation; t 1/2 , terminal half-life; t max , time to C max ; ULN, upper limit of normal.

ObjectiveTo evaluate the analgesic efficacy and safety of ASP8477 in patients with peripheral neuropathic pain (PNP).DesignEnriched enrollment randomized withdrawal.SettingCenters in Poland (four), Czech Republic (six), and the United Kingdom (two).SubjectsPatients aged 18 years or older with PNP resulting from painful diabetic peripheral neuropathy or postherpetic neuralgia.MethodsA four-week screening period followed by a single-blind period (six-day dose titration and three-week maintenance period with ASP8477 [20/30 mg BID]). Treatment responders (defined as a ≥30% decrease in the mean average daily pain intensity during the last three days of the single-blind period) were stratified by disease and randomized to receive placebo or continue ASP8477 during a three-week, double-blind, randomized withdrawal period. The primary end point was change in mean 24-hour average numeric pain rating scale (NPRS) from baseline to end of double-blind period.ResultsAmong 132 patients who enrolled, 116 entered the single-blind period and 63 (ASP8477, N = 31; placebo, N = 32) completed the double-blind period. There was no difference in mean 24-hour average NPRS score (P = 0.644) or in time-to-treatment failure (P = 0.485) between ASP8477 and placebo. During the single-blind period, 57.8% of patients were treatment responders. ASP8477 was well tolerated. During the single-blind period, 22% of patients experienced at least one treatment-related adverse event (TEAE); during the double-blind period, 8% in the ASP8477 arm and 18% in the placebo arm experienced at least one TEAE.ConclusionsASP8477 was well tolerated in patients with PNP; however, ASP8477 did not demonstrate a significant treatment difference compared with placebo.

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Background: There is an unmet need for therapeutics with greater efficacy and tolerability for the treatment of opioid use disorder (OUD). ASP8062 is a novel compound with positive allosteric modulator activity on the γ-aminobutyric acid type B receptor under development for use with standard-of-care treatment for patients with OUD. Aims: To investigate the safety, tolerability, interaction potential, and pharmacokinetics (PK) of ASP8062 in combination with buprenorphine/naloxone (B/N; Suboxone®). Methods: In this phase 1, randomized, double-masked, placebo-controlled study, patients with OUD began B/N (titrated to 16/4 mg/day) treatment upon enrollment (induction, Days 1–4; maintenance, Days 5–18; downward titration, Days 19–26; and discharge, Day 27). On Day 12, patients received a single dose of ASP8062 60 mg or placebo with B/N and underwent safety and PK assessments. Primary endpoints included frequency and severity of treatment-emergent adverse events (TEAEs), clinical laboratory tests, respiratory depression, and suicidal ideation. Secondary endpoints investigated the impact of ASP8062 on B/N PK. Results: Eighteen patients were randomized and completed the study (ASP8062, n = 12; placebo, n = 6). With this sample size typical for phase 1 drug–drug interaction studies, ASP8062 was well tolerated; most TEAEs were mild in severity, and none led to treatment withdrawal. ASP8062 did not enhance substance use-related TEAEs, respiratory depression, or suicidal ideation and did not have a clinically significant impact on the PK of B/N. Conclusions: In this phase 1 study, ASP8062 was safe, well tolerated, and did not enhance respiratory suppression induced by buprenorphine. Trial registration: Clinicaltrials.gov identifier: NCT04447287.

Conclusion:While policies focused on uDCD may increase overall DD rates, increases in DD from policies that focus on cDCD come at the expense of DBD. We conclude that cDCD negatively impacts the number of donations from brain dead donors and may lead to an overall reduction in the number of transplants performed due to reduced organ retrieval rates. 2546A Phase 1b, Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Single-Dose, Pharmacokinetic, Pharmacodynamic, Safety and Tolerability Study of ASKP1240 in de novo Kidney Transplantation

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