Abstract Background Auxora, a calcium release-activated channel (CRAC) inhibitor, was demonstrated to improve recovery and decrease mortality in patients with severe COVID-19 pneumonia initially in an open-label trial and then in CARDEA, a phase 2, randomized, double-blind, placebo-controlled trial. In the open-label trial, treatment with Auxora was noted to be associated with a decrease in D-Dimer levels. To confirm these findings, blood samples were collected in CARDEA and tested for D-dimer levels. In a subset of patients, additional biomarkers were assessed to elucidate a potential mechanism of action of Auxora in decreasing D-dimer levels. Methods In patients enrolled in CARDEA, blood samples were collected prior to randomization and again at 72 hours after the start of the first infusion of Auxora for testing of D-dimer levels. In patients who consented for additional biomarker testing, blood samples were collected prior to randomization and again at 96 hours for testing of Angiopoietin-1, Angiopoietin-2, renin, and sCD25 levels. Results The baseline mean D-dimer level in the Auxora group was 2.61 mg/L and in the placebo group 2.05 mg/L. Patients treated with Auxora had a significant decrease in D-dimer levels within the first 72 hours compared to those treated with placebo. The difference was -0.92 (95% CI: -1.82, -0.02; P<0.0460). The decrease in D-dimer levels correlated with an increase in imputed PaO2/FiO2 (P/F) at 72 hours (r: -0.193; P<0.05) which in turn correlated with improved clinical outcomes at 168 hours (r: 0.218, P<0.01). Additional biomarker testing demonstrated that treatment with Auxora reduced levels of Angiopoietin-2 and sCD25 and increased Angiopoietin-1 levels at 96 hours. Conclusion In patients with severe COVID-19 pneumonia, Auxora reduced D-dimer levels which correlated with improved oxygenation and clinical outcomes. In addition, Auxora appears to have decreased endothelial activation through a reduction in systemic inflammation and likely had a direct effect on endothelium stabilization. This trial is registered at ClinicalTrials.gov number, NCT04345614.

Abstract Background Auxora, a calcium release-activated channel (CRAC) inhibitor, was demonstrated to improve recovery and decrease mortality in patients with severe COVID-19 pneumonia initially in an open-label trial and then in CARDEA, a phase 2, randomized, double-blind, placebo-controlled trial. In the open-label trial, treatment with Auxora was noted to be associated with a decrease in D-Dimer levels. To confirm these findings, blood samples were collected in CARDEA and tested for D-dimer levels. In a subset of patients, additional biomarkers were assessed to elucidate a potential mechanism of action of Auxora in decreasing D-dimer levels. Methods In patients enrolled in CARDEA, blood samples were collected prior to randomization and again at 72 hours after the start of the first infusion of Auxora for testing of D-dimer levels. In patients who consented for additional biomarker testing, blood samples were collected prior to randomization and again at 96 hours for testing of Angiopoietin-1, Angiopoietin-2, renin, and sCD25 levels. Results The baseline mean D-dimer level in the Auxora group was 2.61 mg/L and in the placebo group 2.05 mg/L. Patients treated with Auxora had a significant decrease in D-dimer levels within the first 72 hours compared to those treated with placebo. The difference was − 0.92 (95% CI: -1.82, -0.02; P < 0.0460). The decrease in D-dimer levels correlated with an increase in imputed PaO2/FiO2 (P/F) at 72 hours (r: -0.193; P < 0.05) which in turn correlated with improved clinical outcomes at 168 hours (r: 0.218, P < 0.01). Additional biomarker testing demonstrated that treatment with Auxora reduced levels of Angiopoietin-2 and sCD25 and increased Angiopoietin-1 levels at 96 hours. Conclusion In patients with severe COVID-19 pneumonia, Auxora reduced D-dimer levels which correlated with improved oxygenation and clinical outcomes. In addition, Auxora appears to have decreased endothelial activation through a reduction in systemic inflammation and likely had a direct effect on endothelium stabilization. This trial is registered at ClinicalTrials.gov number, NCT04345614.

<h3>Objective:</h3> To estimate time-to-progression milestones in IV edaravone–treated vs non–IV edaravone-treated patients with ALS in a real-world setting. <h3>Background:</h3> Intravenous (IV) edaravone was US Food and Drug Administration-approved in May 2017 based on a slowing of functional decline in patients with amyotrophic lateral sclerosis (ALS). Information on real-world outcomes in patients with ALS treated with IV edaravone is limited. <h3>Design/Methods:</h3> This retrospective observational analysis included patients with ALS who were continuously enrolled in Optum’s de-identified Clinformatics® Data Mart database between August 8, 2017, and September 30, 2021. Propensity score matching (1:1) identified IV edaravone–treated patients (cases) and non–IV edaravone-treated patients (controls) matched for covariates: age, race, geographic region, gender, pre-index disease duration (period between the first claim for ALS diagnosis and the first claim for IV edaravone [cases] or August 2017 [controls]), insurance, cardiovascular disease history, riluzole prescription, gastrostomy tube placement, artificial nutrition, noninvasive ventilation, and all-cause hospitalization. Milestones were defined according to the Healthcare Common Procedure Coding System and included the use of canes/walkers/wheelchairs (M1); artificial nutrition (M2); noninvasive ventilation (M3); invasive ventilation/speech-generating devices (M4); and hospice (M5). Difference between cases and controls in cause-specific restricted mean time lost (RMTL) was estimated to examine IV edaravone benefit. <h3>Results:</h3> Cases (n=360) were matched to controls (n=360); mean age in years (SD) was 62.9 (10.2) and 62.8 (10.2) in cases and controls, respectively. In the post-index period, differences in RMTL (95% CI) in months indicate longer milestone-free time in cases than controls: 2.50 (0.93–4.07), 4.30 (2.88–5.72), 2.92 (1.56–4.28), 4.12 (3.00–5.23), and 2.33 (1.31–3.34) for M1, M2, M3, M4, and M5, respectively. <h3>Conclusions:</h3> This analysis describes the time to milestones in patients with ALS treated with IV edaravone in a real-world setting. This information may be useful to payers and clinicians in evaluating use of IV edaravone. <b>Disclosure:</b> Malgorzata Ciepielewska has received personal compensation for serving as an employee of Mitsubishi Tanable Pharma America . Jeffrey Zhang has received personal compensation for serving as an employee of Princeton Pharmatech. Jeffrey Zhang has received stock or an ownership interest from CalciMedica. Ying Liu has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for MPTA. Dr. Hagan has received personal compensation for serving as an employee of Mitsubishi Tanabe Pharma America.

<h3>Objective:</h3> To determine correlations among changes in inflammatory markers, improvements in neuropsychological health, changes in brain metabolism and functional connectivity, and changes in patients’ daily abilities after NE3107 treatment. <h3>Background:</h3> Lowering chronic neuroinflammation may slow Alzheimer’s disease (AD) progression. An exploratory, 3-month, phase 2 trial of NE3107, an oral, anti-inflammatory molecule, enrolled 23 patients, 17 with mild cognitive impairment (MCI) to mild dementia [Mini-Mental State Examination (MMSE) scores ≥20] and 6 patients with moderate dementia (MMSE scores &lt;20). In patients with MMSE ≥20, NE3107 treatment was associated with significant improvements in cognitive performance, including the AD assessment Scale-Cognitive Subscale 12 (ADAS-Cog12), trending improvements in biomarker levels, including tumor necrosis factor-α (TNF-α), significant improvements in the Global Rating of Change (GRC), and enhanced neurophysiological health. We assessed correlations between the anti-inflammatory effects and meaningful clinical outcomes. <h3>Design/Methods:</h3> Eligible patients had a Clinical Dementia Rating score of 0.5 (MCI) or 1 (mild dementia). Clinicians, patients, and caregivers completed a GRC at study completion. Correlations between changes from baseline in cognitive function (ADAS-Cog12) and the key inflammatory biomarker (TNF-α) or patient global impression (GRC) were determined. Hypothesis-based examination of metabolic and functional brain imaging was initiated. <h3>Results:</h3> Patients had a mean age of 71.6 (SD=9.63) years and 15 (65%) were females. In patients with MMSE ≥20, reductions in TNF-α significantly correlated with improvements in ADAS-Cog12 scores (r=0.7; p=0.0077). Improvements in cognition, based on changes in ADAS-Cog12, significantly correlated with clinician-observed improvements in GRC outcomes (r=−0.52; p&lt;0.05). Neuroimaging data suggest correlations with other study outcomes. <h3>Conclusions:</h3> Correlations among improved cognitive function, reduced inflammation, and changes in the clinician-observed GRC (overall impression of patient’s abilities) were consistent with the hypothesized activities of NE3107. Preliminary examination of metabolic and functional brain imaging supports hypothesis-based directional changes in accordance with the expected mechanism of action. <b>Disclosure:</b> Dr. Palumbo has received personal compensation for serving as an employee of BioVie. An immediate family member of Dr. Palumbo has received personal compensation for serving as an employee of Merck Research Laboratories. Dr. Palumbo has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for BioVie. Dr. Palumbo has stock in BioVie. An immediate family member of Dr. Palumbo has stock in Merck Research Laboratories. Dr. Palumbo has received intellectual property interests from a discovery or technology relating to health care. Dr. Palumbo has received intellectual property interests from a discovery or technology relating to health care. Dr. Palumbo has received intellectual property interests from a discovery or technology relating to health care. Jeffrey Zhang has received personal compensation for serving as an employee of Princeton Pharmatech. Jeffrey Zhang has received stock or an ownership interest from CalciMedica. Ms. Mahdavi has nothing to disclose. Ms. Venkatraman has nothing to disclose. Mr. Becerra has nothing to disclose. Mr. Haroon has nothing to disclose. Ms. Jordan has nothing to disclose. Ms. Rindner has nothing to disclose. Mr. Surya has nothing to disclose. Dr. KUHN has nothing to disclose. Dr. POURAT has nothing to disclose. Dr. Jordan has stock in Synaptec Network.

Ganirelix, a drug used in in vitro fertilization (IVF), prevents ovulation in women who are not ready to have children by inhibiting a gene that produces gonadotropin. Peptides are macromolecules that are able to preserve a predetermined shape while carrying out the structural and regulatory roles for which they were originally intended. Peptide structures can be altered in the production and storage processes. Therapeutic peptides' biological activity can be drastically altered by even small modifications in their primary and secondary structures. The molecules' secondary structures can be monitored by subjecting them to different processing or storage conditions. In our investigation, we used circular dichroism (CD) spectroscopy with two different software programs for secondary structure evaluation to look at how environmental factors like temperature and humidity affected the secondary structure of Ganirelix in an injectable formulation. The CD results revealed that the alpha-helical (regular and distorted), beta-sheet, beta-strands (regular and distorted), beta-turn, and random coil structures of temperature and humidity stressed generic drug products are comparable to reference-listed drug.

SummaryBackgroundWe aimed to evaluate overall survival in US patients with amyotrophic lateral sclerosis (ALS) treated with intravenous (IV) edaravone compared with those not treated with IV edaravone in a real-world setting.MethodsThis exploratory retrospective comparative effectiveness observational analysis included patients with ALS who were enrolled in an administrative claims database from 8 August 2017 to 31 March 2020. Propensity score matching identified IV edaravone-treated patients (cases) and non-edaravone-treated patients (controls) matched for covariates: age, race, geographic region, sex, pre-index disease duration, insurance, history of cardiovascular disease, riluzole prescription, gastrostomy tube placement, artificial nutrition, noninvasive ventilation, and all-cause hospitalisation. For cases, the index date was the date of the first claim for IV edaravone. For controls, it was the date IV edaravone was available (8 August 2017). The effect of IV edaravone on all-cause mortality was estimated with shared frailty Cox regression analysis.Findings318 cases were matched to 318 controls. In both groups, 208 patients (65.4%) had a history of riluzole prescription. As of 31 March 2021, there were 155 deaths (48.7%) among the cases and 196 among the controls (61.6%). Median overall survival time was 29.5 months with edaravone and 23.5 months without, respectively, and the risk of death was 27% lower in cases than in controls (HR, 0.73; 95% CI, 0.59–0.91; p=0.005).InterpretationIn this real-world analysis, IV edaravone treatment in a large predominantly riluzole-treated US cohort was associated with prolonged overall survival compared with not using IV edaravone. Data from adequately powered RCTs are needed to support this finding.FundingFunded by Mitsubishi Tanabe Pharma America.

Longitudinal changes in the blood proteome during gestation relate to fetal development and maternal homeostasis. Charting the maternal blood proteome in normal pregnancies is critical for establishing a baseline reference when assessing complications and disease. Using mass spectrometry-based shotgun proteomics, we surveyed the maternal plasma proteome across uncomplicated pregnancies. Results indicate a significant rise in proteins that govern placentation and are vital to the development and health of the fetus. Importantly, we uncovered proteome signatures that strongly correlated with gestational age. Fold increases and correlations between the plasma concentrations of ADAM12 (ρ = 0.973), PSG1 (ρ = 0.936), and/or CSH1/2 (ρ = 0.928) with gestational age were validated with ELISA. Proteomic and validation analyses demonstrate that the maternal plasma concentration of ADAM12, either independently or in combination with either PSG1 or CSH1/2, correlates with gestational age within ±8 days throughout pregnancy. These findings suggest that the gestational age in healthy pregnancies may be determined by referencing the concentration of select plasma proteins.