BACKGROUND: De novo pathogenic variants in GNAO1-the gene encoding the major neuronal G protein Gαo-cause pediatric encephalopathies and other neurological deficiencies largely refractory to available therapies. Zn2+ emerged to restore guanosine triphosphate hydrolysis and cellular interactions of pathogenic Gαo; dietary zinc salt supplementation improves lifespan and motoric function in a Drosophila disease model.
METHODS: Using biochemical, animal, and first-in-human studies, we provide support for the patient stratification and application of zinc acetate in GNAO1-associated disorders.
RESULTS: We show that 16 different pathogenic missense variants cluster in three distinct groups in their responsiveness to Zn2+, and we provide the safety study in a mouse disease model. We further describe treatment of a 3-year-old patient with the common pathogenic GNAO1 variant c607G>A, p.Gly203Arg with oral 50 mg zinc (in the form of zinc acetate) daily, as applied in Wilson\'s disease. During 11 months of treatment, the patient shows cessation of daily dyskinetic crises, improved Burke-Fahn Marsden Dystonia Rating Scale movement score, reduction in epileptic seizures, and an excellent safety profile.
CONCLUSIONS: Our findings warrant a large-scale clinical trial and might set the new standard of care for GNAO1-related disorders.
BACKGROUND: This work was funded by the Russian Science Foundation (grant #21-15-00138) and GNAO1 España.

UNASSIGNED: ModulHeart (Puzzle Medical Devices Inc) is a modular device providing hemodynamic support through 3 endovascular pumps inserted in series and assembled in parallel into a self-expandable anchor implanted in the descending aorta. The current study evaluates the feasibility and safety of cardiorenal support with ModulHeart among patients undergoing high-risk percutaneous coronary intervention (PCI).
UNASSIGNED: This study was a prospective, single-center, first-in-human study. The primary end point was procedural success, defined as successful delivery, function, and removal of the ModulHeart device. Secondary end points included pump hemodynamics, cardiac hemodynamics, and urine output.
UNASSIGNED: On June 28 and 29, 2022, 4 patients were enrolled and underwent high-risk PCI with ModulHeart implanted via transfemoral approach. All 4 patients achieved procedural success. The mean delivery time was 8 minutes, the mean support time was 49 minutes, and the mean pump removal time was 7 minutes. The mean pressure gradient across the pump was 5 ± 2 mm Hg. Under ModulHeart support, cardiac index increased by 25%, central venous pressure decreased by 37%, and left ventricular end-diastolic pressure decreased by 78%. Urine output increased by ∼9-fold after 15 minutes of support. No device malfunction or procedural or device-related adverse events occurred. There was no evidence of pump thrombosis. All 4 patients were alive at 30 days.
UNASSIGNED: This first-in-human study demonstrated the feasibility and safety of cardiorenal support with ModulHeart among patients undergoing high-risk PCI. ModulHeart demonstrated significant improvement in cardiac output, left ventricular end-diastolic pressure, and urine output. Future studies are planned to assess outcomes associated with ModulHeart support in patients with heart failure.

UNASSIGNED: Canocapavir (ZM-H1505R) is a small-molecule hepatitis B virus capsid assembly modulator with a novel pyrazole structure. This is the first-in-human study to investigate its safety, tolerability, and pharmacokinetics (PK) following oral administration in healthy subjects.
UNASSIGNED: This was a randomized, double-blind, placebo-controlled study including single ascending dose (SAD) study with an additional crossover food-effect arm, and multiple ascending dose study. In SAD, 40 subjects, 8 in each cohort, were randomized in a 3:1 ratio to receive a single dose of 25, 75, 150, 300, and 450 mg of Canocapavir or placebo in fasted state. For food-effect study, subjects in the 150 mg cohort of SAD received a second dose (150 mg) of Canocapavir in the fed state after a 7-day washout period. In multiple ascending dose, 24 subjects, 8 in each cohort, were randomized in a 3:1 ratio to receive 75, 150, and 300 mg of Canocapavir or placebo once daily for 14 days. The safety and tolerability were assessed using vital signs, physical evaluation, electrocardiogram, laboratory investigations, and adverse events (AEs). Plasma PK parameters measured included area under the curves, Cmax, Cmin, Tmax, and T1/2.
UNASSIGNED: Oral administration of single doses (25-450 mg) and multiple doses (75-300 mg) of Canocapavir was well tolerated. The most common AE seen was increased alanine aminotransferase. No dose dependency was observed in incidence and intensity of AEs. Mean plasma area under the curve and Cmax of Canocapavir increased dose-proportionally. A significant margin was observed between plasma exposure of Canocapavir and its in vitro anti-hepatitis B virus activity. Food had an effect on its absorption.
UNASSIGNED: The safety and PK profile of Canocapavir support its further evaluation in chronic hepatitis B patients. The study was registered on ClinicalTrial.gov with the number NCT04220801.

This first-in-human study assessed safety, tolerability, and pharmacokinetics (PK) of cipargamin (intravenous) in healthy adults. It included part 1, single ascending dose [SAD: 10.5 mg-210 mg; n = 8 (active: 6, placebo: 2)], and part 2, multiple ascending dose [MAD: 60 and 120 mg daily for 5 days; n = 9 (active: 6, placebo: 3)]. Last dose follow-ups were on days 3, 4, and 6 for SAD and 7, 8, and 10 for MAD. Safety and PK review was done at completion of each cohort. We explored the cipargamin use for clinical development in patients with severe malaria. In SAD part, systemic exposure (maximum measured concentration and area under the curve) increased with increasing dose (10.5 mg-210 mg) following single intravenous dose. Cipargamin was eliminated with a mean T1/2 of 21.9-38.9 h. Volume of distribution (92.9 L-154 L) and clearance (2.43 L/h-4.33 L/h) was moderate and low, respectively, across the dose range. In MAD part, the mean accumulation ratio was 1.51 (60 mg) and 2.43 (120 mg) after once-daily cipargamin administration for 5 days. After day 5, the mean T1/2 was 35.5 (60 mg) and 31.9 h (120 mg) with twofold dose increase (60-120 mg) resulting in ~2-fold increased exposure. Cipargamin was well tolerated with commonly reported mild gastrointestinal, neurological, and genitourinary events. Increasing exposure to cipargamin showed higher baseline-corrected QTcF, and model-predicted ΔΔQTcF indicated that an effect on ΔΔQTcF ≥10 ms can be excluded up to 6470 ng/mL. However, these results should be interpreted with caution due to inadequate Fridericia\'s QT correction.
RESULTS: This study is registered with ClinicalTrials.gov as NCT04321252.

SHPL-49 is an innovative glycoside derivative that is synthesized by structural modifications of salidroside，demonstrating therapeutic effects on animal models of ischemia in pre-clinical experiments. A phase I, single-center, randomized, double-blind, placebo-controlled, single and multiple dose administration study of SHPL-49 was conducted in healthy Chinese volunteers. In single-ascending-dose (SAD) study, 32 subjects randomized 6:2 to receive SHPL-49 (30 mg, 75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion. In multiple-ascending-dose (MAD) study, subjects were randomized 6:2 to receive SHPL-49 (75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion every 8 h for 7 days. Safety evaluations were conducted throughout the studies. Plasma and urine concentrations of SHPL-49 were detected and its metabolites were identified. Pharmacokinetic parameters were calculated using noncompartmental methods. SHPL-49 was generally safe and well-tolerated at single ascending doses (30-300 mg) and multiple ascending doses (75-300 mg). All adverse events were mild and resolved without any intervention. No serious adverse events were reported. In the SAD study, SHPL-49 exhibited dose-proportional plasma pharmacokinetics, with peak plasma concentration (Cmax) ranging from 673.83 to 6275.00 ng/mL, area under the plasma concentration-time curve (AUC0-t) ranging from 338.57 to 3732.67 h·ng/mL, and elimination half-life (t1/2) ranging from 0.49 to 0.67 h. In the MAD, the exposure was also dose-proportional and there was no significant accumulation following multiple dosing. Four metabolites were identified in urine and plasma. SHPL-49 shows a favorable pharmacokinetic, safety, and tolerability profile in healthy Chinese volunteers following a single- and multiple-ascending- dose administration in this study. For future therapeutic investigations, it is recommended to administer SHPL-49 intravenously at 8-hour intervals with a dosage range of 150-300 mg.

UNASSIGNED: Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects.
UNASSIGNED: Part A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100 mg cohort. Part B consisted of three treatment groups who received 100 mg, 200 mg, or 400 mg of mefunidone or placebo twice daily (BID, bis in die) on days 1-6 and once in the morning on day 7.
UNASSIGNED: Single oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50 mg-600 mg and the multiple-dose range of 100 mg BID to 400 mg BID by day 7. High-fat fed conditions led to a delay in Tmax by approximately 1 h and a slight reduction of approximately 20% in Cmax compared to that in fasting conditions, but it did not significantly affect systemic exposure.
UNASSIGNED: Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone.
UNASSIGNED: clinicaltrials.gov, identifier CXHL1900206.

BACKGROUND: The aim of the present study was to develop a novel 64Cu-labeled cyclic peptide ([64Cu]Cu-FAP-NOX) that targets fibroblast activation protein (FAP) and may offer advantages in terms of image contrast, imaging time window, and low uptake in normal tissues.
METHODS: The novel cyclic peptide featuring with a N-oxalyl modified tail was constructed and conjugated to NOTA for 64Cu labeling. Biochemical and cellular assays were performed with A549.hFAP cells. The performance of [64Cu]Cu-FAP-NOX was compared to that of two established tracers ([64Cu]Cu-FAPI-04 and [68Ga]Ga-FAP-2286) and three different NOTA-conjugates in HEK-293T.hFAP xenograft mice using micro-PET imaging. Ex vivo biodistribution studies were performed to confirm the FAP specificity and to validate the PET data. Furthermore, a first-in-human study of this novel tracer was conducted on one patient with lung cancer.
RESULTS: Compared to [64Cu]Cu-FAPI-04, [64Cu]Cu-FAP-NOX demonstrated faster and higher rates of cellular uptake and internalization in A549.hFAP cells, but lower rates of cellular efflux. All six radiotracers were rapidly taken up by the tumor within the first 4 h post-injection. However, [64Cu]Cu-FAP-NOX had more intense tumor accumulation and slower washout from the target. The ratios of the tumor to normal tissue (including kidneys and muscles) increased significantly over time, with [64Cu]Cu-FAP-NOX reaching the highest ratio among all tracers. In the patient, [64Cu]Cu-FAP-NOX PET showed a comparable result to FDG PET in the primary malignant lesion while exhibiting higher uptake in pleural metastases, consistent with elevated FAP expression as confirmed by immunohistochemistry.
CONCLUSIONS: [64Cu]Cu-FAP-NOX is a promising FAP-targeted tracer with a highly flexible imaging time window, as evidenced by preclinical evaluation encompassing biodistribution and micro-PET studies, along with a successful patient application. Furthermore, [64Cu]Cu-FAP-NOX showed enhanced image contrast and favorable pharmacokinetic properties for FAP PET imaging, warranting translation into large cohort studies.

Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted.

OBJECTIVE: In patients with three-vessel disease and/or left main disease, selecting revascularization strategy based on coronary computed tomography angiography (CCTA) has a high level of virtual agreement with treatment decisions based on invasive coronary angiography (ICA).
METHODS: In this study, coronary artery bypass grafting (CABG) procedures were planned based on CCTA without knowledge of ICA. The CABG strategy was recommended by a central core laboratory assessing the anatomy and functionality of the coronary circulation. The primary feasibility endpoint was the percentage of operations performed without access to the ICA. The primary safety endpoint was graft patency on 30-day follow-up CCTA. Secondary endpoints included topographical adequacy of grafting, major adverse cardiac and cerebrovascular (MACCE), and major bleeding events at 30 days. The study was considered positive if the lower boundary of confidence intervals (CI) for feasibility was ≥75% (NCT04142021).
RESULTS: The study enrolled 114 patients with a mean (standard deviation) anatomical SYNTAX score and Society of Thoracic Surgery score of 43.6 (15.3) and 0.81 (0.63), respectively. Unblinding ICA was required in one case yielding a feasibility of 99.1% (95% CI 95.2%-100%). The concordance and agreement in revascularization planning between the ICA- and CCTA-Heart Teams was 82.9% with a moderate kappa of 0.58 (95% CI 0.50-0.66) and between the CCTA-Heart Team and actual treatment was 83.7% with a substantial kappa of 0.61 (95% CI 0.53-0.68). The 30-day follow-up CCTA in 102 patients (91.9%) showed an anastomosis patency rate of 92.6%, whilst MACCE was 7.2% and major bleeding 2.7%.
CONCLUSIONS: CABG guided by CCTA is feasible and has an acceptable safety profile in a selected population of complex coronary artery disease.

First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the \"3 + 3\" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0.056) and the number of dose levels in trials (P < 0.001). In addition, the proportion of products with a high ratio in antibody drugs is higher than that in small molecules (P < 0.001). The MTD or MD exceeded the label dose by three or more doses in 22.03% of the products. In conclusion, optimizing the starting dose selection method, refining the way of determining doses, and finding alternative indicators to replace toxicity as the endpoints will increase the effectiveness and broaden the beneficiary scope.