Study In Healthy Volunteers Research Articles

A Phase 1b Trial of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Myelofibrosis and Anemia

Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic elevations in hepcidin contribute to the onset and severity of anemia. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. Preclinical studies have shown that DISC-0974 suppresses hepcidin and increases serum iron. A healthy volunteer study has demonstrated dose-dependent reductions in serum hepcidin, increases in serum iron with doses up to 56 mg administered subcutaneously, and increasing trends in reticulocyte count, reticulocyte hemoglobin, mean corpuscular hemoglobin, total hemoglobin (Hgb), and red blood cell count. In this Phase 1b/2a, open-label, multiple-ascending dose study (NCT05320198), we are assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DISC-0974 in patients with MF and anemia. Eligible participants include patients over 18 years of age with intermediate-2 or higher-risk MF and anemia. MF is required to be confirmed using the World Health Organization 2016 criteria. Anemia is defined per protocol as Hgb < 10 g/dL or transfusion dependence, as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). A stable dose of hydroxyurea and/or Janus kinase (JAK) inhibitor is allowed on trial. Major exclusion criteria include: liver iron concentration ≥ 7 mg/g dry weight; splenectomy; nutritional, genetic, infectious, or autoimmune causes of anemia. Dose escalation is based on a Bayesian optimal interval design with accelerated titration. Safety Review Committee assessments gate escalation decisions. Dosing occurs monthly for a total of 6 doses. Primary endpoints include safety and tolerability assessments of adverse events (AEs), clinical laboratory assessments, vital signs, physical examinations, and electrocardiograms. Secondary endpoints include anemia response as defined by the IWG-MRT, transfusion response as defined by a decrease of 50% in transfusion requirement over any 8-week period, standard PK parameters and PD metrics including serum hepcidin-25, iron, transferrin saturation, ferritin, and hematology biomarkers. All data are summarized using descriptive statistics. Initial data show a dose-related increase in pharmacokinetic parameters. DISC-0974 treatment led to dose-dependent reductions in serum hepcidin-25 and increases in serum iron levels. There have been no serious AEs or AEs leading to study withdrawal. Most AEs were mild, transient, and unrelated to DISC-0974. As of August 1, 2023, enrollment and dose escalation are ongoing. Safety, PK, and PD data from at least the first two cohorts will be presented.

Therapeutic Targeting of FLT3 Gate Keeper Mutation with E2082-0047 in Traditional and a Novel Immunocompetent Murine Adoptive Transfer Model of AML

Signaling mutations such as Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3-ITD) occur in approximately 30% of AML patients which provide AML cells with a constitutively active aberrant growth advantage, resulting in inferior overall survival. Multiple phase 3 studies with different FLT3 inhibitors validated FLT3-ITD as an important therapeutic target in AML. However, resistance to FLT3-ITD inhibitors occurs via mutations in the tyrosine kinase domain (FLT3-TKD), including the gatekeeper mutation F691L for which all approved FLT3 inhibitors are ineffective. Other mechanisms of secondary FLT3 inhibitor resistance include induction of IRAK4 activity and acquisition of RAS/PTPN11/MAPK activating mutations. New FLT3 inhibitors targeting both intrinsic (FLT3 acquired mutations) and extrinsic mechanisms of FLT3 resistance (e.g. IRAK4 induction) are urgently needed. We demonstrated previously the selectivity and potency of a novel FLT3 inhibitor, E2082-0047, against FLT3-ITD and TKD mutations in vitro using a Ba/F3 cell line harboring different TKD mutations. Guided by KinomeScan data, we demonstrated simultaneous IRAK4 inhibition and verified superior in vivo efficacy compared to gilteritinib using the FLT3-ITD MOLM-13 cell line derived xenograft (CDX) murine model (Elgamal OA et al., ASH 2022). Recognizing the exceptional safety profile of E2082-0047 in pre-clinical IND enabling toxicology studies, we moved forward to test the potency of E2082-0047 versus gilteritinib in cells harboring the FLT3-ITD-F691L gatekeeper mutation using two in vivo models, MOLM-14-F691L CDX model and a novel immunocompetent murine adoptive transfer model that does not require conditioning or irradiation. This model is generated by the crossing of the CD45.2 specific Npm1 cA cre inducible model (Vassiliou et al., 2011) with the Flt3 ITD (Lee et al., 2007) model which was previously reported to harbor a F692L mutation, analogous to the human F691L mutation (Dovey et al., 2016) thus, generating the Npm1 cA;Flt3 ITD-F692L AML murine model. In the MOLM-14-F691L CDX model study, we found a consistent reduction in human CD45 cells in bone marrow and increased survival benefit in mice receiving E2082-0047 compared to gilteritinib. Further, mice in the gilteritinib group with progressing disease (> 50% human CD45+ cells in bone marrow) were switched to E2082-0047 with consequent > 5-fold reduction in bone marrow tumor burden within 8 days. These data suggest that E2082-0047 will be effective in gilteritinib resistant disease. Strikingly, in the AML adoptive transfer model, E2082-0047 resulted in a compelling long-term survival benefit. In our first study (donor #1), vehicle and gilteritinib cohorts had 29- and 32-days median survival, respectively with evident circulating CD45.2 AML. In the E2082-0047 cohort, mice remained on study with an average of <2% circulating CD45.2 cells therefore, we stopped treatment and euthanized three mice for tissue collection, leaving eight mice for disease relapse monitoring for an additional two weeks where we lost 3/8 mice due to early removal criteria (ERC) and 5/8 were euthanized at end of study day 100, with an average of <10% circulating CD45.2 cells. This initial study showed the capacity for E2082-0047 to induce long-term survival in a model with a clinically relevant TKD gatekeeper mutation. We repeated our study with a more aggressive donor (donor #2) where vehicle and gilteritinib arms had a median survival of 22 days. While mice receiving E2082-0047 remain on study (week 8 of an ongoing study), with an average of <5% peripheral blood CD45.2 level (Figure 1). Collectively, our previous and follow-up studies herein demonstrate the superiority of E2082-0047 over gilteritinib against FLT3-ITD and with TKD mutations including the gatekeeper F691L variant. We demonstrate significantly improved survival after E2082-0047 treatment in an immune deficient in vivo model of FLT3-ITD/TKD-F691L MOLM-14 AML and a durable long-term survival in a large subset of mice using two donors in an immune competent adoptive transfer model of NPM1+FLT3-ITD/TKD-F692L AML. Given the curative potential of E2082-0047 in the immune competent model, ongoing efforts are focused on investigating the host immune response to AML. Given the safety and efficacy studies performed with E2082-0047 to date, a healthy volunteer study to best estimate dose for trials in AML is ongoing.

Phase 1/2 Study of the Activin Receptor-like Kinase-2 Inhibitor Zilurgisertib (INCB000928, LIMBER-104) As Monotherapy or with Ruxolitinib in Patients with Anemia Due to Myelofibrosis

Introduction:Elevated levels of the iron regulator hepcidin can cause functional iron deficiency anemia. Hepcidin dysregulation is central to anemia of chronic inflammation observed in several malignancies including myelofibrosis (MF). Activin receptor-like kinase-2 (ALK2 [ie, ACVR1]) contributes to MF-associated anemia via hepcidin upregulation. We evaluated the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of zilurgisertib-a potent and selective oral ALK2 inhibitor-in patients (pts) with anemia due to MF. Methods:This ongoing open-label, multicenter, phase 1/2 dose-escalation/expansion INCB 00928-104 study (NCT04455841) is evaluating zilurgisertib alone (treatment group A [TGA]) or with ruxolitinib (RUX; treatment group B [TGB]). Eligible pts are ≥18 years old with primary/secondary MF of intermediate (Int)-1 (TGB only) or Int-2/high-risk (TGA and TGB) per the Dynamic International Prognostic Scoring System (DIPSS) and with anemia, including pts who are transfusion dependent (≥4 units of red blood cell transfusions during the 28 days or 8 weeks before Cycle [C] 1 Day [D] 1 for hemoglobin [Hb] <8.5 g/dL in the absence of bleeding or treatment-induced anemia) or are nontransfusion dependent with symptomatic anemia (Hb <10 g/dL during screening on 3 separate occasions ≥7 days apart and not meeting criteria for transfusion dependence). The zilurgisertib starting dose in TGA was 50 mg once daily (qd), with dose increases of ≤2-fold performed until a grade ≥2 toxicity with reasonable probability of being related to the treatment group was observed; subsequent dose increases were limited to ≤50% until the maximum tolerated dose (MTD) was reached or the recommended doses(s) for expansion were identified. In TGB, pts were on a stable regimen of RUX for ≥12 weeks before initiating zilurgisertib at 100 mg qd. The primary endpoints are safety and tolerability, including determination of dose-limiting toxicities (DLTs) and MTD. Secondary endpoints include efficacy (per anemia response parameters), PK, and PD (hepcidin measurement). Results:A total of36 pts were enrolled at the time of analysis (data cutoff, February 15, 2023), with 20 in TGA and 16 in TGB. Median (range) age was 73 (53-84) years for TGA and 75.5 (54-85) years for TGB; 65% of TGA pts had received prior RUX therapy. Overall, 89% had Int-2 risk DIPSS, and the remainder had high-risk DIPSS (1 in TGA, 3 in TGB). In total, 55% of pts in TGA and 25% in TGB were transfusion dependent at time of enrollment. Median (range) baseline Hb was 7.7 (7-10) g/dL in TGA and 8.0 (5-9) g/dL in TGB. Baseline median (range) hepcidin was high in both cohorts (TGA, 171 [18-535] ng/mL; TGB, 126 [7-421] ng/mL; normal range, 0-50 ng/mL). At the time of analysis, dose escalation was ongoing in both treatment groups. No DLTs occurred in either treatment group, and the MTD had not been reached. Treatment-emergent adverse events (TEAEs) were mainly low grade without apparent dose dependence. Grade ≥3 TEAEs occurred in 11 pts, with thrombocytopenia the most common (n=4). The PK profile for zilurgisertib at steady state was consistent with that observed with previous healthy volunteer studies, with observed time of maximum concentration at 2-4 hours after administration and predicted half-life of approximately 24 hours. Maximum reduction in hepcidin following zilurgisertib dosing in C1D1 was observed at 6-8 hours postdose; the highest doses tested in both TGA and TGB demonstrated more effective maintenance of hepcidin suppression over time compared with lower doses. Among non-transfusion-dependent pts, anemia improvement (Hb increase of ≥1.5 g/dL vs baseline) was observed in both treatment groups (Figure). Among transfusion-dependent pts, anemia response of transfusion independence had not been observed at data cutoff. All pts with anemia improvement have maintained Hb increase in the absence of transfusion and remain on study. Conclusions:Treatment with zilurgisertib monotherapy or in combination with RUX in this pt population was generally well tolerated, with predominantly grade 1/2 TEAEs. Reduced hepcidin levels were observed at all dose levels with both monotherapy and in combination with RUX, with greater control of hepcidin over time observed at higher zilurgisertib doses. Preliminary improvements in anemia were observed in non-transfusion-dependent pts during dose escalation, suggesting potential for therapeutic activity.

Characterization and Pharmacokinetic Assessment of a New Berberine Formulation with Enhanced Absorption In Vitro and in Human Volunteers.

Berberine is a plant-origin quaternary isoquinoline alkaloid with a vast array of biological activities, including antioxidant and blood-glucose- and blood-lipid-lowering effects. However, its therapeutic potential is largely limited by its poor oral bioavailability. The aim of this study was to investigate the in vitro solubility and Caco-2 cell permeability followed by pharmacokinetic profiling in healthy volunteers of a new food-grade berberine delivery system (i.e., Berberine LipoMicel®). X-ray diffractometry (XRD), in vitro solubility, and Caco-2 cell permeability indicated higher bioavailability of LipoMicel Berberine (LMB) compared to the standard formulation. Increased aqueous solubility (up to 1.4-fold), as well as improved Caco-2 cell permeability of LMB (7.18 × 10-5 ± 7.89 × 10-6 cm/s), were observed when compared to standard/unformulated berberine (4.93 × 10-6 ± 4.28 × 10-7 cm/s). Demonstrating better uptake, LMB achieved significant increases in AUC0-24 and Cmax compared to the standard formulation (AUC: 78.2 ± 14.4 ng h/mL vs. 13.4 ± 1.97 ng h/mL, respectively; p < 0.05; Cmax: 15.8 ± 2.6 ng/mL vs. 1.67 ± 0.41 ng/mL) in a pilot study of healthy volunteers (n = 10). No adverse reactions were reported during the study period. In conclusion, LMB presents a highly bioavailable formula with superior absorption (up to six-fold) compared to standard berberine formulation and may, therefore, have the potential to improve the therapeutic efficacy of berberine. The study has been registered on ClinicalTrials.gov with Identifier NCT05370261.

Having breakfast has no clinically relevant effect on bioelectrical impedance measurements in healthy adults

BackgroundBioelectrical impedance analysis (BIA) is commonly used to evaluate body composition as part of nutritional assessment. Current guidelines recommend performing BIA measurements in a fasting state of at least 2 h in a clinical setting and 8 h in a research setting. However, since asking patients with malnutrition or sarcopenia to fast is not desirable and literature to support the strategy in the guidelines is lacking, this study aimed to assess the impact of breakfast on BIA measurements.MethodsWe performed an explorative, prospective study in healthy volunteers aged between 18 and 70 years, with a normal fluid balance and a body mass index between 18.5 and 30 kg/m2. BIA measurements were performed according to the standard operating procedure in the fasting state, and 1, 2, 3, and 4 h after ingesting a standardized breakfast meal of about 400 kcal with a 150 mL drink, using the hand-to-food single-frequency BIA (Bodystat500 ®). The Kyle formula was used to calculate the primary outcome, i.e. fat-free mass (FFM, kg). A linear mixed model was used to compare baseline values with other time points. A difference of 1 kg in FFM was considered clinically relevant.ResultsThirty-nine (85% female) volunteers were included, with a median age of 28 years (IQR 24–38). In 90% of the participants, having breakfast had no clinically relevant impact on the estimated FFM. For the group, the most pronounced mean difference, a statistically but not clinically significant higher value of 0.2 kg (0.4%), was observed after 3 h of fasting compared to baseline. No statistically significant differences were found at the other time points.ConclusionEating affects single-frequency BIA measurements, but differences in FFM remain below clinical relevance for most participants when using a standardized breakfast. Thus, the current study suggests performing a BIA measurement in a fasting state is not required.

Effects of Breathing Patterns on Amide Proton Transfer MRI in the Kidney: A Preliminary Comparative Study in Healthy Volunteers and Patients With Tumors.

The amide proton transfer-weighted (APTw) imaging for kidney diseases is important. However, the breathing patterns on APTw imaging remains unexplored. This study aimed to investigate the effects of intermittent breath-hold (IBH) and free breathing (FB) on renal 3D-APTw imaging. Healthy volunteers were enrolled prospectively, and renal clear cell carcinoma (RCCC) patients were included retrospectively. 58 healthy volunteers and 10 RCCC patients. 3-T, turbo spin echo, and fast field echo. 3D-APTw imaging was scanned using the IBH and FB methods in volunteers and using the IBH method in RCCC patients. The image quality was evaluated by three observers according to the 5-point Likert scale. Optimal images rated at three points or higher were used to measure the APT values. The measurement repeatability was assessed using the intraclass correlation coefficient (ICC) and the Bland-Altman plot. The APT values were analyzed using McNemar's test, one-way analysis of variance, and t test. 50 healthy volunteers and 8 RCCC patients were enrolled. Renal 3D-APTw imaging using the IBH method revealed a higher success rate (88% vs 78%). The ICCs were excellent in the IBH group (ICCs > 0.74) and were good in the FB group (ICCs < 0.74). No significant differences in the APT values among various zones using the IBH (P = 0.263) or FB method (P = 0.506). The mean APT value using the IBH method (2.091% ± 0.388%) was slightly lower than the FB method (2.176% ± 0.292%), but no significant difference (P = 0.233). The APT value of RCCC (4.832% ± 1.361%) was considerably higher than normal renal using the IBH method. The study demonstrated that the IBH method substantially increased the image quality of renal 3D-APTw imaging. Furthermore, APT values may vary between normal and tumor tissues. 2 TECHNICAL EFFICACY: Stage 2.

Incorporation of healthy volunteers data on receptor occupancy into a phase II proof-of-concept trial using a Bayesian dynamic borrowing design.

Receptor occupancy in targeted tissues measures the proportion of receptors occupied by a drug at equilibrium and is sometimes used as a surrogate of drug efficacy to inform dose selection in clinical trials. We propose to incorporate data on receptor occupancy from a phase I study in healthy volunteers into a phase II proof-of-concept study in patients, with the objective of using all the available evidence to make informed decisions. A minimal physiologically based pharmacokinetic modeling is used to model receptor occupancy in healthy volunteers and to predict it in the patients of a phase II proof-of-concept study, taking into account the variability of the population parameters and the specific differences arising from the pathological condition compared to healthy volunteers. Then, given an estimated relationship between receptor occupancy and the clinical endpoint, an informative prior distribution is derived for the clinical endpoint in both the treatment and control arms of the phase II study. These distributions are incorporated into a Bayesian dynamic borrowing design to supplement concurrent phase II trial data. A simulation study in immuno-inflammation demonstrates that the proposed design increases the power of the study while maintaining a type I error at acceptable levels for realistic values of the clinicalendpoint.

Clinical Pharmacology of Vinpocetine: Properties Revisited and Introduction of a Population Pharmacokinetic Model for Its Metabolite, Apovincaminic Acid (AVA).

This paper examines the use of vinpocetine in the context of clinical pharmacology. The main and active metabolite of vinpocetine is apovincaminic acid (AVA). Due to the scarce information in the literature on AVA pharmacokinetics, we propose a population pharmacokinetic (PopPK) model for AVA based on a study in healthy volunteers with three different formulations of vinpocetine. The suggested PopPK model (and simulations) could be helpful in ensuring the more effective and safer use of the vinpocetine in the future given the increasing range of suggested indications for its use.

Determination of Optimal Eosinophil Thresholds for Diagnosis of Eosinophilic Gastritis and Duodenitis: A Pooled Analysis of 4 Prospective Studies.

Consensus is lacking regarding the number of eosinophils (eos) required for the diagnosis of eosinophilic gastritis (EoG) and eosinophilic duodenitis (EoD). In addition, thresholds that require multiple high-power fields (HPFs) may not be practical for clinical use, resulting in delayed or missed diagnoses. This pooled analysis of 4 prospective studies assessed thresholds for multiple and single HPFs used to diagnose EoG and EoD. Studies included the phase 2 ENIGMA1, the phase 3 ENIGMA2, an EoG/EoD prevalence study and a healthy volunteer study. Eos were quantified in the epithelium and lamina propria for controls and symptomatic participants. Symptomatic participants were further divided by histologic diagnosis of EoG/EoD. Peak eos counts were assessed, and the area under the receiver operating characteristic curve was analyzed to identify eos cutoffs for detection of EoG/EoD using the Youden index and sensitivity and specificity equality approaches. Based on the highest specificity analysis in 740 patients, the optimal eos threshold was determined to be 20 eos/HPF in 5 gastric HPFs for EoG (71% sensitivity and 94% specificity) and 33 eos/HPF in 3 duodenal HPFs for EoD (49% sensitivity and 100% specificity). For single-field analysis, the optimal eos thresholds were 33 eos/HPF (EoG) and 37 eos/HPF (EoD), both corresponding to 93% sensitivity and 93% specificity. Highly specific single gastric and duodenal HPF thresholds may have more clinical applicability than thresholds requiring multiple HPFs and could better facilitate development of practical histopathologic guidelines to aid pathologists and clinicians in the detection and diagnosis of EoG and/or EoD.

Exploring the Significance of Immune Checkpoints and EBV Reactivation in Antibody Deficiencies with Near-Normal Immunoglobulin Levels or Hyperimmunoglobulinemia.

This study delves into the intricate landscape of primary immunodeficiencies, with a particular focus on antibody deficiencies characterized by near-normal immunoglobulin levels or hyperimmunoglobulinemia. Contrary to the conventional focus on genetic dysregulation, these studies investigate the key roles of immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, on selected subpopulations of T and B lymphocytes and their serum concentrations of soluble forms in patients recruited for the studies in healthy volunteers. In addition, the studies also show the role of Epstein-Barr virus (EBV) reactivation and interactions with tested pathways of immune checkpoints involved in the immunopathogenesis of this disease. By examining the context of antibody deficiencies, this study sheds light on the nuanced interplay of factors beyond genetics, particularly the immune dysregulations that occur in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical presentation of patients and may contribute to the development of cancer in the future, especially related to hematological malignancies.

Generation of Aerosols by Noninvasive Respiratory Support Modalities

Infection control guidelines have historically classified high-flow nasal oxygen and noninvasive ventilation as aerosol-generating procedures that require specialized infection prevention and control measures. To evaluate the current evidence that high-flow nasal oxygen and noninvasive ventilation are associated with pathogen-laden aerosols and aerosol generation. A systematic search of EMBASE and PubMed/MEDLINE up to March 15, 2023, and CINAHL and ClinicalTrials.gov up to August 1, 2023, was performed. Observational and (quasi-)experimental studies of patients or healthy volunteers supported with high-flow nasal oxygen or noninvasive ventilation were selected. Three reviewers were involved in independent study screening, assessment of risk of bias, and data extraction. Data from observational studies were pooled using a random-effects model at both sample and patient levels. Sensitivity analyses were performed to assess the influence of model choice. The main outcomes were the detection of pathogens in air samples and the quantity of aerosol particles. Twenty-four studies were included, of which 12 involved measurements in patients and 15 in healthy volunteers. Five observational studies on SARS-CoV-2 detection in a total of 212 air samples during high-flow nasal oxygen in 152 patients with COVID-19 were pooled for meta-analysis. There was no association between high-flow nasal oxygen and pathogen-laden aerosols (odds ratios for positive samples, 0.73 [95% CI, 0.15-3.55] at the sample level and 0.80 [95% CI, 0.14-4.59] at the patient level). Two studies assessed SARS-CoV-2 detection during noninvasive ventilation (84 air samples from 72 patients). There was no association between noninvasive ventilation and pathogen-laden aerosols (odds ratios for positive samples, 0.38 [95% CI, 0.03-4.63] at the sample level and 0.43 [95% CI, 0.01-27.12] at the patient level). None of the studies in healthy volunteers reported clinically relevant increases in aerosol particle production by high-flow nasal oxygen or noninvasive ventilation. This systematic review and meta-analysis found no association between high-flow nasal oxygen or noninvasive ventilation and increased airborne pathogen detection or aerosol generation. These findings argue against classifying high-flow nasal oxygen or noninvasive ventilation as aerosol-generating procedures or differentiating infection prevention and control practices for patients receiving these modalities.

An open-label pilot trial assessing tolerability and feasibility of LSD microdosing in patients with major depressive disorder (LSDDEP1)

BackgroundGlobally, an estimated 260 million people suffer from depression [1], and there is a clear need for the development of new, alternative antidepressant therapies. In light of problems with the tolerability and efficacy of available treatments [2], a global trend is emerging for patients to self-treat depression with microdoses of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin [3]. Beyond anecdotal reports from those who self-medicate in this way, few clinical trials have evaluated this practice. In our recently published phase 1 study in healthy volunteers [4], we determined that LSD microdosing was relatively safe and well tolerated in that cohort. Furthermore, the data demonstrated that conducting such microdosing trials is broadly feasible, with excellent adherence and compliance to the regimen observed. In this open-label pilot trial of patients with major depressive disorder (LSDDEP1), we will test the tolerability and feasibility of an 8-week regimen of LSD microdosing in this patient group prior to a larger subsequent randomised controlled trial (LSDDEP2).MethodsTwenty patients meeting the DSM-5 criteria for major depressive disorder will receive an 8-week LSD microdosing treatment regimen. The treatment protocol will use a sublingual formulation of LSD (MB-22001) delivered twice per week under a titration schedule using a dose of 5–15 µg. Tolerability will be assessed by quantifying the percentage of participants who withdraw from the trial due to adverse events attributable to the treatment regimen, while feasibility will be assessed by quantifying the percentage of attended clinic visits once enrolled. To determine whether there is any antidepressant response to the LSD microdosing regimen, MADRS scores will be assessed at baseline and 2, 4, 6, and 8 weeks after the commencement of the regimen.DiscussionThe results of LSDDEP1 will provide valuable information regarding the tolerability and feasibility of a proposed LSD microdosing regimen in patients with MDD. Such information is critically important to optimise trial design prior to commencing a subsequent and more resource-intensive randomised controlled trial.Trial registrationANZCTR, ACTRN12623000486628. Registered on 12 May 2023.

Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval

ObjectiveTo assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate–corrected QT interval (QTc). MethodsThree clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. ResultsAcross all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. ConclusionAt all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

FRI057 Drug Concentrations And Dosing Considerations For Mibavademab, A Novel Leptin Receptor Agonist, In Individuals With Generalized Lipodystrophy

Abstract Disclosure: J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Y. Wang: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B.A. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O.E. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E.A. Oral: Advisory Board Member; Self; Regeneron Pharmaceuticals. Consulting Fee; Self; Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Amryt Pharamceuticals, Ionis Pharmaceuticals Inc., Gemphire Theraputics. Research Investigator; Self; Regeneron Pharmaceuticals, Novo Nordisk, Rhythm pharmaceuticals, Fractyl Laboratories, GI Dynamics. Other; Self; Has IP rights to Metreleptin manufactured by Amryt Pharmaceuticals and receives royalty payments. R.J. Brown: Research Investigator; Self; Regeneron Pharmaceuticals. J. Davis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by deficiency of adipose tissue and, consequently, low levels of the adipose-derived hormone leptin. Leptin deficiency in GLD causes metabolic abnormalities and complications that are often refractory to treatment with usual glucose/lipid-lowering agents. Mibavademab is a first-in-class human leptin receptor (LEPR) agonist monoclonal antibody that activates LEPR. We investigated baseline serum leptin in patients with GLD, pharmacokinetics (PK) of mibavademab, and soluble LEPR (sLEPR) levels from a phase 2 study. Methods: In this phase 2 trial (NCT04159415), patients with GLD (≥12 yrs old) underwent a single-blind placebo run-in, followed by 1:1 randomization to one of two fixed sequence arms: Treatment A (placebo for 8 weeks, then mibavademab low dose for 8 weeks, then mibavademab high dose for 20 weeks) or Treatment B (mibavademab low dose for 8 weeks, then mibavademab high dose for 28 weeks). A loading dose of intravenous mibavademab was administered before low-dose treatment. Mibavademab and sLEPR concentrations in serum were serially measured during mibavademab treatment using validated bioanalytical methods. Results: Sixteen patients were enrolled with median body weight (BW) of 51 kg, corresponding to the approximate BW cut point for mibavademab. Baseline serum leptin was below the lower limit of quantitation (0.078 mg/L) in 5 patients with a median concentration of 0.345 mg/L (n=15). Baseline sLEPR concentrations with Treatments A and B were 30.6 and 33.9 μg/L, respectively. At Week 8, mean (SD) mibavademab trough concentrations (Ctrough) with Treatments A and B were 0 (0) and 1.61 (1.71) mg/L, respectively. Low-dose PK were less than predicted from a first in human study in healthy volunteers with higher leptin levels, reflecting higher target mediated clearance in patients with GLD. At Week 16, Ctrough for Treatments A and B increased to 2.31 and 43.0 mg/L, respectively, but were still below predicted. At Week 36, Ctrough for Treatments A and B were 60 (35.3) and 67.7 (44.2) mg/L, respectively. Clinically meaningful metabolic benefit (i.e reflected by reductions in fasting triglycerides and glycated hemoglobin) was observed at Week 36 with both Treatments A and B. Conclusions: Mibavademab concentrations by Week 36 were associated with clinically meaningful improvement in metabolic parameters. Presentation: Friday, June 16, 2023

SAT626 The Use Of Salivary Cortisol Measurement By Mass Spectrometry To Identify Low Serum Cortisol Values In Healthy Volunteers Receiving CRN04894, A Melanocortin 2 Receptor (MC2R) Antagonist

Abstract Disclosure: A. Ayala: Employee; Self; Crinetics Pharmaceuticals Inc. C. LaCerte: Employee; Self; Crinetics Pharmaceuticals Inc. R. Luo: Employee; Self; Crinetics Pharmaceuticals Inc. C. Davidson: Employee; Self; Crinetics Pharmaceuticals Inc. J. Wang: Employee; Self; Crinetics Pharmaceuticals Inc. P. Trainer: Employee; Self; Crinetics Pharmaceuticals Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals Inc. Clinical trials of cortisol-lowering drug candidates would benefit from user-friendly methods to measure cortisol in an outpatient setting. CRN04894 is a potent, orally bioavailable, MC2R antagonist in development for the treatment of ACTH-dependent Cushing’s syndrome and congenital adrenal hyperplasia. We have previously reported results from a randomized, double-blinded, placebo-controlled (6 active:3 placebo/cohort), multiple (10-day) ascending dose (40 to 80 mg/day) study in healthy volunteers. Declines in basal and ACTH-stimulated serum cortisol levels and a median reduction of 75% in 24-hr urinary-free cortisol (UFC) were seen in the 80 mg cohort. Asymptomatic glucocorticoid deficiency (defined as 08:00 serum cortisol of &amp;lt;5 µg/dL) was the most commonly observed adverse event. Here we report the comparison of salivary cortisol measurements with serum cortisol day curves and 24-hr UFC observed in this study. We evaluated cortisol and ACTH data from the three cohorts dosed once daily (QD) at 22:00 with either 40, 60, or 80 mg. Cortisol (salivary &amp; serum) and ACTH day curves (results reported as the mean of 4 or 5 available samples collected at 22:00, 08:00, 12:00, 16:00 &amp; 20:00) studies were undertaken on days -1, 1, 4, and 9. Mean serum cortisol was moderately correlated with 24-hr UFC:creatinine ratio (ug/g) (r = 0.495) and strongly correlated (r = 0.734) with mean salivary cortisol. There was across all three doses of CRN04894 a consistent magnitude ranking change in measured cortisol analytes: serum (free plus bound) &amp;lt; saliva &amp;lt; urine, with substantial changes being seen within 24 hours of initiation of CRN04894 and no loss of cortisol suppression over 9 days despite median ACTH changes of &amp;gt;1000% from baseline (60 &amp; 80 mg doses). Time-matched individual saliva and serum cortisol values were used (without timepoint or visit restrictions) to explore the relationship between low serum cortisol and salivary levels. A saliva cutoff for cortisol deficiency was optimized for diagnostic accuracy (92.2%) using a serum cortisol value of &amp;lt;5 µg/dL as the reference. Four subjects had 08:00 serum cortisol &amp;lt;5 µg/dL and saliva cortisol data. All four cases were correctly identified as cortisol-deficient using a simultaneous saliva cortisol cutoff of &amp;lt;0.0491 µg/dL. In conclusion, CRN04894 effectively lowered cortisol measured in serum, saliva, and urine in healthy volunteers. Salivary cortisol measured by tandem mass spectrometry correlated well with serum cortisol day curves and may be useful in the diagnosis of biochemical cortisol deficiency in outpatient studies. Future studies will explore the use of salivary glucocorticoid measurement in patients with Cushing’s disease receiving CRN04894. Presentation: Saturday, June 17, 2023

SAT235 An Orally Administered Robotic Pill (RP) Reliably And Safely Delivers the Human Parathyroid Hormone Analog hPTH(1-34) (Teriparatide) With High Bioavailability in Healthy Human Volunteers: A Phase 1 Study

Abstract Disclosure: J.T. Myers: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Dasari: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Battiwala: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. N. Patel: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Toledo Vo: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Yamaguchi: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. K. Horlen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. L.C. Fung: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. B. Syed: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. S. Nguyen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. J. Van Dam: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M. Imran: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M. Hashim: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A.K. Dhalla: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. Background/Purpose: Teriparatide, an effective osteoanabolic agent, requires a chronic regimen of daily subcutaneous (SC) injections, representing a burden for patients which may interfere with compliance and quality of life. We have developed a novel oral robotic pill (RP) to deliver biotherapeutic agents with bioavailability rivaling or surpassing that of parenteral injections. Here we present data from a Phase 1 study in healthy women volunteers designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of 20- and 80 µg of hPTH (1-34) administered orally via RP (RT-102) at single doses. Methods: The study was approved by the Alfred Health HREC in Australia. Participants received a single dose of either RT-102 at 20 µg (RT-102/20 µg group; N=15) or 80 µg (RT-102/80 µg group; N=14) or a single 20 µg dose of the commercially available teriparatide (Forteo®) via SC injection (SC group; N=10). Fluoroscopic images were taken to track the transit/deployment of RT-102 and confirm excretion of remnants. Drug concentration in serum samples serially collected over 6 hours were measured by a validated ELISA assay. Results: All 29 participants in the RT-102 arms were able to swallow RT-102 and none experienced any adverse events (AEs) upon device deployment. Both doses of RT-102 were safe and well-tolerated with no serious adverse events (SAEs) reported. In the SC group, a total of six drug-related AEs were reported in four participants. There were no AEs reported in the RT-102/20 µg group. Mild and transient AEs attributed to the drug were observed in one participant in the RT-102/80 µg group. No AEs related to the RP were reported. Imaging confirmed excretion of all RP device remnants within an average of 2.7 ± 1.4 days. Based on serum analyses, drug was successfully delivered by RT-102 in 12 of 15 participants in the 20 µg group and in all 14 participants in the 80 µg group. PK analyses indicated that RT-102 delivered drug with more sustained peak concentrations than the SC group. The Cmax of RT-102 was 98 ± 10 pg/mL for the 20 µg dose and 971 ± 223 pg/mL for the 80µg dose compared to 128 ± 20 pg/mL for the 20 µg SC injection group. The Tmax for RT-102 delivery was 68 and 60 min for the 20 µg and 80 µg doses, respectively, compared to 13 min for the SC injection. Based on AUC calculations of the PK curves, the relative bioavailability of RT-102 dose groups was 3- to 4-fold higher compared to the SC injection group. Conclusions: This study provides the first clinical evidence of safe and successful delivery of hPTH (1-34) via an orally administered RP with high reliability and bioavailability. These data suggest that RT-102 can potentially offer an easier and more convenient treatment option to osteoporosis patients, and given the high bioavailability, RT-102 may be effective at doses lower than the currently approved 20 µg SC dose of teriparatide. Presentation: Saturday, June 17, 2023

Hematinic Potential of Olive Leaf Extract: Evidence from an In Vivo Study in Mice and a Pilot Study in Healthy Human Volunteers.

Natural resources have recently received considerable attention as complementary or alternative hematinic agents. In this regard, olive leaf extract, which is rich in bioactive phenolic compounds, has been reported to induce erythroid differentiation in human hematopoietic stem cells. Therefore, in the present study, we aimed to explore the potential hematinic properties of aqueous olive leaf extract (WOL) in vivo. After 24 days of administering WOL to healthy mice orally, red blood cell (RBC), hematocrit, reticulocyte, and reticulocyte hemoglobin content (CHr) showed a significant increase. Additionally, WOL promoted plasma iron levels and the expression of splenic ferroportin (Fpn), an iron transporter. Additionally, a single-arm pilot study involving a limited number of healthy volunteers was conducted to assess WOL's feasibility, compliance, and potential benefits. Following an 8-week intervention with WOL, RBC count and hemoglobin level were significantly increased. Notably, there were no significant changes in the safety measures related to liver and kidney functions. Furthermore, we identified oleuropein and oleuroside as the active components in WOL to induce erythroid differentiation in the K562 cell line. Altogether, our study presents evidence of the hematinic potential of WOL in the in vivo studies, opening up exciting possibilities for future applications in preventing or treating anemia.

Effect of Neurodynamic Mobilization on Precision Grip among Healthy Individuals

Over the last three decades, insights into the role of the median nerve in precision grip control have been documented in the study of healthy volunteers using Microneurography Technique 1 or a nerve anesthesia block at the wrist or hand . Accurate grip requires proper adjustment of the grip force (GF) perpendicular to the grip surface of the object and the tangential load (LF). Prevents objects from slipping and prevents premature muscle fatigue. Neurodynamic techniques (NDT) are a type of manual therapy in which forces are supposed to be directed to neural regions via the positioning and movement of several joints . The Changes in the mechanics or physiology of the nervous system can cause other system dysfunctions or dysfunctions in the musculoskeletal tissues that receive its innervations, according to the theory of neural mobilization. The objective of the study is to determine the effects of neuromobilisation on key pinch, three jaw chuck and tip to tip pinch among the healthy individual.

Quantitative Flow Measurements of Pelvic Venous Vasculature Using 4D Flow MRI

To evaluate 4D Flow magnetic resonance imaging (MRI) sequences for quantitative flow measurements of the pelvic venous vasculature. A prospective study of healthy volunteers was performed. After informed consent all subjects underwent 4D flow sequences at a 3 T MRI scanner with different isotropic resolution and different velocity encoding (Venc) settings: (sequence #1) voxel size (VS) 1.63 mm3, Venc 50cm/s; (sequence #2) VS 1.63 mm3, Venc 100cm/s and (sequence #3) VS 2.03 mm3, Venc 50cm/s. Perfusion parameters were calculated for all venous vessel segments starting at the level of the inferior vena cava and extending caudally to the level of the common femoral vein. For reference, arterial flow was calculated using 1.63 mm3 isotropic resolution with a Venc of 100cm/s. Ten healthy subjects (median age 28 years, interquartile range [IQR]: 26.25-28 years) were enrolled in this study. Median scanning time was 12:12 minutes (IQR 10:22-13:32 minutes) for sequence #1, 11:02 minutes (IQR 9:57-11:19 minutes) for sequence #2 and 6:10 minutes (IQR 5:44-6:47 minutes) for sequence #3. Flow measurements were derived from all sequences. The venous pelvic vasculature showed similar perfusion parameters compared to its arterial counterpart, for example the right common iliac arterial segment showed a perfusion of 8.32ml/s (IQR: 6.94-10.68ml/s) versus 7.29ml/s (IQR: 4.70-8.90ml/s) in the corresponding venous segment (P=0.218). The venous flow measurements obtained from the three investigated sequences did not reveal significant differences. 4D Flow MRI is suitable for quantitative flow measurement of the venous pelvic vasculature. To reduce the scanning time without compromising quantitative results, the resolution can be decreased while increasing the Venc. This technique may be utilized in the future for the diagnosis and treatment response assessment of iliac vein compression syndromes.

Treadmill running intensity and post-exercise increase in plasma cardiac troponin I and T-A pilot study in healthy volunteers.

Plasma concentrations of cardiac troponins increase in healthy individuals after strenuous training, but the response to lower exercise intensities has not been characterized. To determine whether exercise at moderate intensity significantly increases plasma cardiac troponins measured with different assays in healthy recreational athletes. Twenty-four self-reported healthy volunteers were instructed to complete three 60-min bouts of treadmill running at variable intensities: High-intensity training (HIT) including a maximal exercise test and an anaerobic threshold test followed by training at 80%-95% of maximum heart rate (HRmax ), Moderate-intensity training (MIT) at 60%-75% of HRmax , and Low-intensity training (LIT) at 45%-55% of HRmax . Blood samples were collected before and at 2, 4, and 6 h after HIT and 4 h after MIT and LIT. Troponin I and T were measured in plasma samples with assays from Abbot, Siemens, and Roche. Plasma troponins measured with all assays were significantly increased compared to baseline after HIT but not after LIT. After HIT, the fraction of all participants with one or more values above the assay-specific 99th percentiles ranged from 13% to 61%. The biomarker criteria for acute myocardial injury were met after HIT for troponin T in 75% of female participants having no clinical evidence of coronary artery disease. High-intensity, but not moderate- or low-intensity, training for 60 min induced a potentially clinically significant increase in plasma cardiac troponins in healthy volunteers. Results exceeding the population 99th percentiles were most frequent with the troponin T assay.