Dose Of Drug Research Articles

91. Clinical Efficacy Endpoints from the Phase 3 CANOPY Study Evaluating Pemivibart

Abstract Background Pemivibart (PEM) is a half-life extended recombinant human monoclonal IgG1 antibody that targets the SARS-CoV-2 spike protein receptor binding domain. PEM has been granted emergency use authorization (EUA) for the pre-exposure prophylaxis of COVID-19 in certain adults and adolescents with moderate-to-severe immune compromise. Methods CANOPY (NCT06039449) is a Phase 3 study investigating the prevention of COVID-19 in immunocompromised participants (ppts) (Cohort A; single arm, open label) and in ppts at risk of exposure to SARS-CoV-2 (Cohort B; randomized 2:1 PEM 4500 mg or placebo). Ppts received an initial dose of study drug administered via intravenous (IV) infusion on Day 1 followed by a second dose of study drug approximately 3 months later. The safety, tolerability, pharmacokinetics (PK), immunogenicity, and clinical efficacy of PEM is being evaluated. Here we describe an exploratory endpoint of reverse transcription polymerase chain reaction (RT-PCR)-confirmed symptomatic COVID-19 that developed within 90 days following the first administration of either PEM or placebo among ppts without SARS-CoV-2 infection at baseline. Nasopharyngeal and saliva samples were collected for central SARS-CoV-2 testing by RT-PCR and subsequent whole genome sequencing (WGS). Results RT-PCR-confirmed COVID-19 cases were observed in 3 of 298 ppts (1%) with significant immune compromise who received a full initial dose of PEM in Cohort A and 9 of 484 (1.9%) ppts who received either PEM or placebo in Cohort B. In Cohort B, RT-PCR confirmed COVID-19 cases were observed in 1 (0.3%) PEM-treated ppt compared to 8 (5.0%) placebo-treated ppts (Absolute Risk Reduction: -4.73% (95% CI: -8.2, -1.3), nominal p = 0.0070). Characteristics of these cases are described in Table 1. All but one COVID-19 case were self-reported as mild or moderate in severity. SARS-CoV-2 variants including JN.1, EG.5.1, and other related lineages were identified. Conclusion This exploratory analysis of COVID-19 events demonstrated a clinically meaningful reduction in COVID-19 with PEM treatment versus placebo. Disclosures Myra Popejoy, Pharm.D., Invivyd, Inc.: employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Anna Holmes, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Chloe Katz, PMP, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Anne-Marie Phelan, MA, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kazima Tosh, Ph.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Yong Li, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Deepali Gupta, BSc, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Pamela Hawn, Pharm.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kristin Narayan, Ph.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kathryn Mahoney, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Mark Wingertzahn, Ph.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company)

Numerical investigation on the differential injection angle effects of intrathecal anesthetic drug delivery

In lumbar anesthesia surgery, the accurate determination of key parameters such as injection angle and dosage is facilitated by the real-time observation of intrathecal drug distribution. In this study, a non-invasive and visual computational fluid dynamics method was used to simulate drug injections in the “cloverleaf” lumbar thoracic segment with a multiphase mixture model, clarifying the intrathecal unsteady flow behaviors and the drug transport mechanisms. The transport properties of three clinically significant injection angles — [Formula: see text], [Formula: see text] and [Formula: see text]— were compared, determining the fastest and slowest block onset angles based on drug concentration levels in the thoracic vertebral plane. The calculation results are aligned with clinical practice trends, and it is found that significantly different drug amounts are required for different injection angles, with higher doses necessitated for ultrasound-assisted anesthesia. During anesthesia, a trend of increasing and then decreasing local anesthetic concentrations in each vertebral plane was observed, with the presence of a minimum effective dose of local anesthetic at the target block site. Injecting at the “concave” part of the cloverleaf ([Formula: see text] and [Formula: see text]) results in greater drug pulsation, faster diffusion and more efficient mixing than injecting at the positive “convex” part of the cloverleaf cross-section ([Formula: see text]). At the L2 vertebral plane, the flow rate and mixing ratios during injection for angles of [Formula: see text], [Formula: see text] and [Formula: see text] were approximately 1:4:2. Compared with orthostatic [Formula: see text] injections, [Formula: see text] and [Formula: see text] oblique injections resulted in higher drug concentrations in the T12-10 vertebral plane during the pre-transport period, with [Formula: see text] injections being the fastest. However, over a longer period of time, [Formula: see text] injections resulted in the lowest drug concentrations in the target block plane (T10), necessitating a higher dose. A faster anesthetic response was produced by [Formula: see text] injections at the same dose. Valuable insights for the application of appropriate drug dosages in clinical anesthesia practice are offered by the calculations.

Assessing acute effects of methylphenidate and modafinil on inhibitory capacity, time estimation, attentional lapses, and compulsive-like behavior in rats.

Medications known as 'cognitive enhancers' are increasingly being consumed off-label by healthy people, raising concerns about their safety. The aim of our study was to profile behavioral performance upon oral administration of methylphenidate (2.5 mg/kg) and modafinil (64 mg/kg) - two popular cognitive enhancers - and upon their discontinuation. We modeled cognitively demanding challenges in neurotypical individuals using a behavioral task where Wistar-Lewis rats had to withhold responses for a specified time to obtain food rewards. This task allowed us to extract several measures of behavioral performance associated with clinically meaningful indices, such as compulsive-like responding, incapacity to wait (impulsivity), time estimation (precision and accuracy), and attentional lapses. Our study design involved examining these behavioral indices in subjects administered either methylphenidate, modafinil, or vehicle. We found that subjects administered modafinil obtained fewer rewards and were less efficient in reward pursuing than the vehicle group; this result was likely due to a drug-induced inability to wait. Upon modafinil discontinuation, subjects earned more rewards but did not entirely catch up with the vehicle group. As for methylphenidate, neither favorable nor unfavorable effects were found in our main analyses. However, an exploratory analysis of changes in behavioral performance within sessions suggested that methylphenidate fostered favorable, yet short-lived, effects. We discuss our results in terms of the risks and cost-benefits of doses above or below the effective dose of cognitive enhancement drugs.

P-2029. Results from a Phase 1 First in Human Study of Pemivibart: An Extended Half-Life Monoclonal Antibody (mAb)

Abstract Background Pemivibart (PEM) is a half-life extended recombinant human monoclonal IgG1 antibody that targets the SARS-CoV-2 spike protein receptor binding domain. PEM has been granted emergency use authorization (EUA) for the pre-exposure prophylaxis of COVID-19 in certain adults and adolescents with moderate-to-severe immune compromise.Table 1.Preliminary Pharmacokinetic Parameter Estimates of Pemivibart [Mean ± SD] Methods This is an ongoing Phase 1, first in human, randomized, blinded, placebo (PBO) controlled, single ascending dose study conducted in healthy participants (ppts) aged 18-65 years to evaluate PEM administered by slow IV push. Ppts were randomized 8:2 in one of 3 cohorts (n=8 PEM, n=2 placebo): PEM 1500 mg, 2500 mg, and 4500 mg. The primary objective was to assess the safety and tolerability of PEM. Secondary endpoints included serum pharmacokinetic (PK) parameters (estimated using non-compartmental analysis methodology) and immunogenicity. The trial will continue through 12 months; here we summarize the data through the 6-month timepoint.Figure 1:Mean ± Standard Deviation Serum Pemivibart Dose-Normalized Concentration-Time Profile Results Thirty ppts were randomized (24 PEM, 6 PBO); 28 ppts received the full dose as planned; two ppts received approximately 93% of the full dose of study drug due to an administration error. In the PEM arm, the median age was 32.5 years, 13.3% of ppts were 55 years or older, most ppts were white (83.3%) and not Hispanic or Latinx (93.3%). Mean body mass index was 25.78 kg/m2 across all ppts and similar between cohorts and study arms. There were no deaths, serious adverse events (SAEs), or AEs leading to permanent study drug discontinuation. Infusion-related adverse events occurred in 4 ppts (2 each in Cohort 2 and 3, respectively); these events were self-limited and resolved within 5 minutes without treatment. No unexpected safety signals were observed. PEM demonstrated linear PK with apparent dose-proportional exposure and extended serum half-life (mean 46, 44, and 50 days in Cohort 1, 2, and 3, respectively [Table 1]). No substantial anti-drug antibodies (ADAs) have been observed. Conclusion In this Phase 1 study of PEM administered by slow IV push at doses up to 4500 mg, no AEs leading to study drug discontinuation, or SAEs were reported to date in healthy adults. PEM demonstrated linear and dose-proportional PK. Complete trial data to be presented. Disclosures Anna Holmes, PhD, Invivyd, Inc.: employee|Invivyd, Inc.: Stocks/Bonds (Private Company) Yong Li, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Deepali Gupta, BSc, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Ed Campanaro, MS, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Lida Mehr, B.S., Invivyd, Inc.: Advisor/Consultant Anuja Raut, M.S., Invivyd, Inc.: Advisor/Consultant Amanda Copans, Pharm.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kristin Narayan, Ph.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kathryn Mahoney, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company)

P-2035. Pharmacokinetics (PK) and Serum Virus Neutralizing Antibody (sVNA) Titers Following the 2nd dose of Pemivibart in the Phase 3 CANOPY Trial

Abstract Background Pemivibart (PEM) is a half-life extended recombinant human monoclonal IgG1 antibody that targets the SARS-CoV-2 spike protein receptor binding domain. PEM has been granted emergency use authorization (EUA) for the pre-exposure prophylaxis of COVID-19 in certain adults and adolescents with moderate-to-severe immune compromise, with dosing recommended every 3 months. Methods CANOPY (NCT06039449) is a Phase 3 study investigating PEM 4500 mg for the prevention of COVID-19 that enrolled adult (≥18 years) participants (ppts) with immune compromise (Cohort A, single arm, open label) and those at risk of exposure to SARS-CoV-2 (Cohort B, randomized 2:1 to PEM or placebo). Ppts received an initial dose of study drug administered via intravenous (IV) infusion on Day 1 followed by a second dose approximately 3 months later (i.e., month 3). Serum samples were collected for PK analysis at the month 3 visit prior to and after receipt of the second PEM dose and at month 6 and month 12. Here we describe calculated sVNA titers for ppts in Cohort A following a second dose of PEM and further estimates from a population PK (PPK) model constructed with available data from a Phase 1 first-in-human study and the Phase 3 CANOPY study. Results At the completion of the second (i.e., month 3) dose of PEM, the calculated sVNA geometric mean titer (GMT) to the SARS-CoV-2 Omicron JN.1 variant in Cohort A ppts was 17% higher than the corresponding value following the initial PEM dose. This is consistent with the estimated accumulation ratio based on the PPK model. Based on this model, the median calculated GMT is predicted to remain above the predefined protection titer threshold of 3514 for at least 90 days following dosing at month 3 (Figure 1). The steady-state AUC over the entire 3-month dosing interval is estimated to be approximately 30% higher than the AUC observed following the initial dose. Conclusion A second dose of PEM 4500 mg IV given at month 3 boosted calculated sVNA titers and is anticipated to provide continued protection above predefined protection titer thresholds in immune compromised participants through 90 days post-dose for JN.1. The overall risk-benefit of PEM supports use in certain adults and adolescents with moderate-to-severe immune compromise for the prevention of COVID-19 per the EUA. Disclosures Anna Holmes, PhD, Invivyd, Inc.: employee|Invivyd, Inc.: Stocks/Bonds (Private Company) Yong Li, PhD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Deepali Gupta, BSc, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Chloe Katz, PMP, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Mike Gavazzi, B.S., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Pamela Hawn, Pharm.D., Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Kathryn Mahoney, PharmD, Invivyd, Inc.: Employee|Invivyd, Inc.: Stocks/Bonds (Public Company) Myra Popejoy, Pharm.D., Invivyd, Inc.: employee|Invivyd, Inc.: Stocks/Bonds (Public Company)

P-1090. Rifaquizinone for the Treatment of Acute Bacterial Skin and Skin Structure Infections: A Multicenter, Double-Blind, Randomized, Active-Controlled, Phase 2 Trial

Abstract Background Rifaquizinone (RFQ, TNP-2092) is under development for the treatment of serious or life-threatening bacterial infections including those caused by gram-positive pathogens that have developed resistance to commonly used antibiotics. This study compared the safety, tolerability and efficacy of RFQ and vancomycin in patients with acute bacterial skin and skin structure infections (ABSSSIs). Methods A multi-center, randomized, double blind, positive controlled phase 2 clinical trial (NCT03964493) was conducted in adults with ABSSSIs in the USA. Eligible patients were randomized 2:1 to receive RFQ (300 mg) or vancomycin (1 g) IV q12h for 3 to 14 days. Patients who met the switching criteria may switch to commercially available oral antibiotics judged by the investigators. The total duration of the treatment was 7 to 14 days. The primary endpoint was safety and tolerability. The key secondary endpoint was the clinical response at early assessment (EA) visit. Results A total of 117 patients received at least 1 dose of study drugs. The incidences of adverse events (AEs) in RFQ and vancomycin groups were 46.2% (36/78) and 48.7% (19/39), respectively. The most of AEs were mild in severity. No drug-related serious AE was reported. The clinical response rate of RFQ at EA visit was higher than vancomycin in the ITT, modified ITT and Micro-ITT populations (Table 1). In patients infected with MRSA and fluoroquinolone-resistance (RF-Q) S. aureus, the clinical response rate of RFQ and vancomycin group were 78.1% (25/51) vs 57.9% (11/29), and 75.9% (22/51) vs 55.6% (10/29), respectively. Pharmacokinetic-pharmacodynamic (PK-PD) analysis indicated that more than 95% of patients achieved the systemic exposures required (AUC0-24h > 50 µg·h/mL) for the treatment of medical device associated biofilm infections. Conclusion RFQ was safe and well tolerated in patients with ABSSSIs. The early clinical response rates of RFQ in ITT, mITT and micro-ITT populations were all higher than that of vancomycin. More importantly, RFQ demonstrated higher early clinical response rates than vancomycin in patients infected with MRSA and FQ-R S. aureus. The PK-PD analysis indicated that sufficient drug exposures were achieved for medical device associated biofilm infections. Disclosures Huan Wang, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee Guozhu Geng, MD, TenNor Therapeutics (Suzhou) Ltd: Employee Changlin Ai, Master of Medicine, TenNor Therapeutics (Suzhou) Ltd: Employee Zhenkun Ma, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee Jing Chen, Master of Science, TenNor Therapeutics (Suzhou) Ltd: Employee

P-1928. Virologic and Clinical Outcomes Among Participants Hospitalized in a Phase 3 Trial Comparing Molnupiravir with Placebo for Treating Mild-to-Moderate COVID-19

Abstract Background The correlation between virologic and clinical outcomes in COVID-19 remains unclear. The objective of this analysis was to assess SARS-CoV-2 viral load (VL) and laboratory biomarkers in participants who did and did not progress to hospitalization in the phase 3 component of the MOVe-OUT trial.Table 1.Baseline demographics and characteristics of participants who did and did not progress to hospitalization*One participant in the placebo group with an unknown hospitalization status was not included in this analysis. Methods In MOVe-OUT, unvaccinated adults with mild-to-moderate COVID-19 at risk for disease progression were randomized 1:1 to molnupiravir (MOV) 800-mg or placebo (PBO) every 12 hours for 5 days. The primary efficacy endpoint was all-cause hospitalization or death through day 29. In this analysis, the following were evaluated in the modified intent-to-treat (MITT; randomized, received ≥1 dose of study drug, and not hospitalized prior to 1st dose) population (1408 participants) at baseline and at postbaseline time points: VL (quantitative PCR), high-sensitivity C-reactive protein (CRP), and absolute lymphocyte count (ALC).Figure 1.Mean change in SARS-CoV-2 viral load in hospitalized and non-hospitalized participants (A) and SARS-CoV-2 viral load over time in hospitalized participants (B)Hospitalization ± 48 hours excluding baseline.One participant in the placebo group with an unknown hospitalization status was not included in this analysis. Results 115 (8.2%) participants progressed to hospitalization (HP). HP were more likely vs those who remained non-hospitalized (NHP) to be male; ≥65 years; with active cancer, diabetes mellitus, moderate COVID-19, and negative nucleocapsid and neutralizing antibody status at baseline (Table 1). Mean time from symptom onset to hospitalization, and randomization to hospitalization, was 8.9 and 5.3 days. In HP, mean VL at baseline was 7.51 vs 6.83 log10 copies/mL among NHP. Among HP, VL declined in 37/38 (97.4%) MOV and 50/63 (79.4%) PBO-treated participants, respectively, between baseline and the day of hospitalization. Mean decline in VL from baseline to day 5 was 1.90 (SD 1.53) in HP vs 2.12 (SD 1.62) log10 copies/mL in NHP, with greater declines observed in MOV vs PBO-treated participants at all time points (Figure 1). Mean CRP was higher at baseline in HP vs NHP (49.93 vs 16.77 mg/L), and postbaseline values increased in HP and decreased in NHP. Alternatively, mean ALC was lower at baseline in HP vs NHP (1.07 vs 1.54 109/L), and postbaseline values continued to decrease at day 3 and 5 in HP while values increased in NHP (Table 2).Table 2.Mean change in C-reactive protein and absolute lymphocyte count in hospitalized and non-hospitalized participantsHospitalization ± 48 hours excluding baseline. Conclusion HP had a higher VL at baseline, with a smaller decline over time than NHP. A higher VL at baseline in conjunction with an increasing CRP and decreasing ALC may help identify patients with mild-to-moderate COVID-19 at higher risk for hospitalization. Disclosures Matthew G. Johnson, MD, Merck & Co., Inc.: I have an interest in a patent application for the company.|Merck & Co., Inc.: Employee of Merck & Co., Inc.|Merck & Co., Inc.: Stocks/Bonds (Public Company) David W. Hilbert, PhD, Merck & Co., Inc.: Employee of Merck & Co., Inc.|Merck & Co., Inc.: Stocks/Bonds (Public Company) Erin Jensen, MS, Merck & Co., Inc.: Employee of Merck & Co., Inc.|Merck & Co., Inc.: Stocks/Bonds (Public Company) Dorothy McCoy, PharmD, Merck & Co., Inc.: Employee of Merck & Co., Inc.|Merck & Co., Inc.: Stocks/Bonds (Public Company) Brian Maas, PharmD, Merck & Co., Inc.: Employee of Merck & Co., Inc.|Merck & Co., Inc.: Stocks/Bonds (Public Company) Ying Zhang, PhD, Merck & Co., Inc.: Employee of Merck & Co., Inc.|Merck & Co., Inc.: Stocks/Bonds (Public Company) Michelle L. Brown, BS, Merck & Co., Inc.: Employee of Merck & Co., Inc.|Merck & Co., Inc.: Stocks/Bonds (Public Company) Dana L. Byrne, MD, Merck & Co., Inc.: Employee of Merck & Co., Inc.|Merck & Co., Inc.: Stocks/Bonds (Public Company) Carisa S. De Anda, PharmD, Merck & Co., Inc.: MOV patent|Merck & Co., Inc.: Employee of Merck & Co., Inc.|Merck & Co., Inc.: Stocks/Bonds (Public Company)

P-1752. Antimicrobial Stewardship Initiative on Prescribing at Discharge from a Community Medical Center

Abstract Background Inappropriate antimicrobial prescribing and overuse propagates multi-drug resistant organisms and increases risk of adverse drug events. Antimicrobial stewardship programs (ASP) focus a majority of interventions on hospital inpatients, but efforts at discharge remain limited. A recent gap analysis at our institution found that 53% of antimicrobial regimens prescribed at discharge were inappropriate in drug choice, dosing, and/or duration. Therefore, a multifaceted ASP initiative focusing on discharge antimicrobial regimens was implemented at our institution. The study objective was to assess program impact on prescription appropriateness. Overall Appropriateness of Antimicrobial Prescriptions Methods Components of the stewardship initiative included development of an institution-specific prescribing guideline, clinician education, and pharmacist prospective audit and feedback at discharge. This IRB-approved study evaluated oral antimicrobial regimens prescribed to adults patients upon discharge from a community medical center. Patients were randomized irrespective of encounter type or discharge destination. Pregnant and post-partum patients were excluded. The validated National Antimicrobial Prescribing Survey (NAPS) tool was used to categorize antimicrobial appropriateness as appropriate (optimal or adequate), inappropriate (suboptimal or inadequate), or not assessable. Hospital-specific treatment guidelines, literature references, and patient-specific factors were used to determine appropriateness. The primary outcome was the proportion of appropriate discharge antimicrobial regimens before versus after initiative implementation. Proportion of Each NAPS Category Results One hundred antimicrobial regimens were analyzed in each cohort. The proportion of appropriate antimicrobial regimens increased by 15% after program implementation (47% vs. 62%, p = 0.03). Exploratory outcome analyses indicated an increase in optimal regimens (26% vs. 44%) and a decrease in suboptimal (33% vs. 26%) and inadequate (20% vs 12%) therapy as categorized by the NAPS tool. Conclusion ASP initiative implementation increased the proportion of appropriate discharge antimicrobial regimens. Study results highlight the positive impact of a multidisciplinary approach in improving discharge antimicrobial prescribing. Disclosures All Authors: No reported disclosures

Kidney function estimation equations: a narrative review.

Glomerular filtration rate (GFR) as a marker of kidney function is important in health and disease management because decreased kidney function is associated with all-cause and cardiovascular mortality, progression of kidney disease, predisposition to acute kidney injury (AKI), and for drug dosage modification. While measured glomerular filtration rate (mGFR) is acknowledged as the most accurate method for evaluating kidney function, it is at present not feasible to be applied in the clinical arena. Estimated glomerular filtration rate (eGFR) is preferred due to its convenience, cost-effectiveness, and seamless integration into standard clinical practice for kidney function evaluation. The presence of multiple equations for eGFR with applications to differing populations makes their use challenging for clinicians. We reviewed available estimated glomerular filtration rate (GFR) equations and their application in different clinical settings both in normal and chronic kidney disease (CKD) patients. These formulae incorporate serum creatinine and/or serum cystatin C levels and correlate them with measured kidney function. Among the many available equations, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is the most recommended due to its robustness and accuracy across diverse patient populations. Strengths and limitations of different eGFR equations are discussed emphasizing the importance of selecting the appropriate equation based on specific patient demographics and clinical scenarios. There is need for regional validation studies to ensure the global applicability of these equations, considering the variations in population characteristics.

Linear and Non-Linear Optimal Control Methods to Determine the Best Chemotherapy Schedule for Most Effectively Inhibiting Tumor Growth

Background/Objectives: Cancer is a dynamic and complex disease that remains largely untreated despite major advances in oncology and treatment. In this context, we aimed here to investigate optimal control techniques in the management of tumor growth inhibition, with a particular focus on cancer chemotherapy treatment strategies. Methods: Using both linear autoregressive with exogenous inputs (ARX) and advanced non-linear tumor growth inhibition (TGI) modeling approaches, we investigated various single-agent treatment protocols, including continuous, periodic, and intermittent chemotherapy schedules. By integrating advanced mathematical modeling with optimal control theory and methods, namely the Linear Quadratic Regulator (LQR) and the “pseudo-linear” state-space equivalent representation and suboptimal control of a non-linear dynamic system known as the State-Dependent Riccati Equation (SDRE) approach, this work explores and evaluates successfully, more effective chemotherapy treatment strategies at the computer simulation level, using real preclinical data which increases the expectation to be applied in the clinical practice of oncology. Results: The integration of these methods provides insights into how different drug administration schedules may affect tumor response at the preclinical level. This work uses mathematical modeling to evaluate the efficacy of various periodic and intermittent chemotherapy treatment strategies, with a focus on optimizing drug doses while minimizing the potential side effects of chemotherapy due to the administration of less effective chemotherapeutic doses. Conclusions: The treatment scenarios tested in this study could effectively stop tumor growth or even lead to tumor regression to a negligible or near-zero size. This approach highlights the importance of computational tools for more effective treatment strategies in chemotherapy and offers a promising direction for future research and more efficient clinical applications in oncology as part of a more individualized approach.

Ligustrazine hydrochloride Prevents Ferroptosis by Activating the NRF2 Signaling Pathway in a High-Altitude Cerebral Edema Rat Model

High-altitude cerebral edema (HACE) is a disorder caused by low pressure and hypoxia at high altitudes. Nevertheless, as of now, there is still a scarcity of safe and effective prevention and treatment methods. The active component of Ligusticum Chuanxiong, namely Ligustrazine hydrochloride (LH), has shown potential in the prevention and treatment of HACE due to its anti-inflammatory, antioxidant, and neuroprotective effects in nervous system disorders. Consequently, the potential protective effect of LH on HACE and its mechanism still need to be further explored. Prior to modeling, 90 male Sprague-Dawley rats were pretreated with different doses of drugs, including LH (100 mg/kg and 50 mg/kg), dexamethasone (4 mg/kg), and ML385 (30 mg/kg). Subsequently, the pretreated rats were placed in a low-pressure anoxic chamber simulating a plateau environment to establish the rat HACE model. The effects and mechanisms of LH on HACE rats were further elucidated through determination of brain water content, HE staining, ELISA, immunofluorescence, molecular docking, molecular dynamics simulation, western blot, and other techniques. The results showed, first of all, that LH pretreatment can effectively reduce brain water content; down-regulate the expression of AQP4, HIF-1α, and VEGF proteins; and alleviate damage to brain tissue and nerve cells. Secondly, compared with the HACE group, LH pretreatment can significantly reduce MDA levels and increase GSH and SOD levels. Additionally, LH decreased the levels of inflammatory factors IL-1β, IL-6, and TNF-α; reduced total iron content in brain tissue; increased the expression of ferroptosis-related proteins such as SLC7A11, GPX4, and FTH1; and alleviated ferroptosis occurrence. Molecular docking and molecular dynamics simulations show that LH has a strong binding affinity for NRF2 signaling. Western blot analysis further confirmed that LH promotes the translocation of NRF2 from the cytoplasm to the nucleus and activates the NRF2 signaling pathway to exert an antioxidant effect. The NRF2 inhibitor ML385 can reverse the anti-oxidative stress effect of LH and its protective effect on HACE rat brain tissue. In summary, LH may have a protective effect on HACE rats by activating the NRF2 signaling pathway, inhibiting ferroptosis, and resisting oxidative stress.

Chemotherapy in synergy with innate immune agonists enhances T cell priming for checkpoint inhibitor treatment in pancreatic cancer

BackgroundThe combination of conventional chemotherapy and immune checkpoint inhibitors (ICIs) has been unsuccessful for pancreatic ductal adenocarcinoma (PDAC). Administration of maximum tolerated dose of chemotherapy drugs may have immunosuppressive effects.MethodsWe thus tested, by using the preclinical model of PDACs including the genetically engineered mouse KPC spontaneous pancreatic tumor model and the pancreatic KPC tumor orthotopic implant model, the combinations of synthetic innate immune agonists including STING and NLRP3 agonist, respectively, and ICIs with or without chemotherapy.ResultsWe found that innate agonists potentiate the role of chemotherapy in inducing effector T cells and subsequently to prime the tumor microenvironment (TME) better for ICI treatments. Triple combination of chemotherapy, innate agonists, and ICIs is superior to single modalities or double modalities in antitumor efficacies. Adding chemotherapy to innate agonists enhances the infiltration of overall CD8+ T cells and the memory cytotoxic subtype. NLRP3 agonist has a less effect than STING agonist on driving the T cell exhaustion. Adding chemotherapy to innate agonists enhances the infiltration of dendritic cells (DCs) in the tumors and CD86+ mature DCs in tumor draining lymph nodes. RNA sequencing analysis of the pancreatic tumors demonstrates the role of the combination of STING/NLRP3 agonist and chemotherapy, but not either treatment modality alone, in upregulating the T cell activation signaling. The NLRP3 agonist-mediated T cell activation is likely through regulating the nitrogen metabolism pathways.ConclusionThis study supports the clinical testing of both STING and NLRP3 agonists, respectively, in combination with chemotherapy to sensitize PDAC patients for ICI treatments.

Abstract B027: Investigating NRF2-mediated radioresistance in HPV-negative head and neck squamous cell carcinoma preclinical models

Abstract Background: Head and neck squamous cell carcinomas (HNSCC) that are not driven by human papillomavirus (HPV) are associated with a higher likelihood of treatment resistance and recurrence compared to HPV-positive HNSCC. There are currently no genomic-guided treatments for HPV-negative HNSCC, meaning that patients do not benefit from precision medicine approaches. Thus, it is critical to understand the mechanisms underlying HNSCC progression to identify molecular targets and better stratify therapeutic options for patients. NFE2L2 encodes for nuclear erythroid 2-related factor 2 (NRF2), a transcription factor that plays a crucial role in responding to oxidative stress by regulating the expression of genes associated with cellular defense mechanisms. Mutations in NFE2L2 and its negative regulator, KEAP1, make up approximately 25% of HPV-negative HNSCCs. Additionally, constitutive activation of NRF2 confers a growth advantage and causes resistance to chemotherapy and radiotherapy. We will elucidate the role of NRF2, identifying novel radiosensitizers to better guide therapeutic strategies for HPV-negative HNSCC patients. Methods: Using clonogenic and long-term viability assays measuring radiation response, we identified radioresistant and radiosensitive cells in a panel of 19 HPV-negative SCC cell lines. An area-under-the-curve (AUC) metric was used to measure cellular response to multiple doses of ionizing radiation. Reactive oxygen species (ROS) and DNA double strand breaks (DSBs) were quantified using DCFDA and γH2AX assays, respectively. Radiosensitization was measured using the ∆AUC of varying drug doses of NRF2 inhibitor, ML385. NFE2L2 and KEAP1 were knocked down using RNA interference in radioresistant and radiosensitive cells, respectively. Results: We identified 13 radiosensitive and 6 radioresistant cell lines out of the 19 HPV-negative SCC cell lines. There was a strong correlation between AUCs of the clonogenic and long-term viability assays (Pearson r=0.74, p=3.0×10–4). Six cell lines were consistently radioresistant (AUC>3.5) in both assays. None of the cell lines contained mutations in the NRF2 pathway, and only 1/6 were radiosensitized by ML385 (∆AUC=2); this effect was not correlated with ROS or DSBs, yet was abrogated by NFE2L2 knockdown. KEAP1 knockdown cell lines were generated for ongoing functional characterization and for genetic screens to identify radiosensitizers in HPV-negative HNSCC. Conclusions: We aim to identify the role of NRF2 in the treatment response of HPV-negative HNSCC. Although NRF2 is an important pathway in driving a radioresistant phenotype, the majority of radioresistant cell lines were not sensitized by NRF2 inhibition. Therefore, elucidating the molecular underpinnings of NRF2-mediated therapeutic resistance will be critical to identifying novel radiosensitizers with activity in HPV-negative HNSCC. Citation Format: Aakshi Puri, Meghan Lambie, Scott V. Bratman. Investigating NRF2-mediated radioresistance in HPV-negative head and neck squamous cell carcinoma preclinical models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B027.

Efficacy and safety of SHEN26, a novel oral small molecular RdRp inhibitor for COVID-19 treatment: a multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial

BackgroundSHEN26 (ATV014) is an oral RNA-dependent RNA polymerase (RdRp) inhibitor with potential anti-SARS-CoV-2 activity. Safety, tolerability, and pharmacokinetic characteristics were verified in a Phase I study. This phase II study aimed to verify the efficacy and safety of SHEN26 in COVID-19 patients.MethodsThis was a multicenter randomized double-blind placebo-controlled study. Mild-to-moderate adult patients with COVID-19 were recruited and randomly assigned to the high-dose (400 mg), low-dose (200 mg), or placebo groups (1:1:1). The primary outcome measure was “changes in RNA levels on Day seven (D7)”. The second outcome measures were “changes of RNA levels on D3, D5, D10, D28,” “Time of clearance of virus.”ResultsA total of 91 patients were recruited in this study between December 08, 2022, and January 27, 2023. Twelve patients dropped out due to a lack of examination results. Finally, the data of 79 patients (24 in the placebo group, 31 in the 200 mg group, and 24 in the 400 mg group) were analyzed. No significant differences in the baseline data were observed between the groups. The changes of viral load were significantly higher on D3 (P = 0.0119), and D5 (P = 0.0120) in 400 mg group (vs. placebo group), and the difference value achieved 1.06 log10 copies/mL on D3 and 1.21 log10 copies/mL on D5. No significant difference was found in the viral clearance time between SHEN26 administrating groups and placebo groups. Administration of SHEN26 did not enhance drug-related ADEs and did not induce ADEs, and ADE inducing drug withdrawal, dose reduction, or death. Moreover, SHEN26 did not worsen the renal function.ConclusionsOur findings indicate a better efficacy of a high dose (400 mg) for COVID-19 treatment. These preliminary data on the efficacy and safety provide useful information and a working basis for further verification and development of SHEN26 as a novel oral small-molecule antiviral drug for treating COVID-19.

Healthcare resource utilization and costs in immunodeficient patients receiving subcutaneous Ig: Real-world evidence from France.

Subcutaneous immunoglobulin (SCIg) replacement therapy is indicated for patients with hypogammaglobulinemia caused by primary (PID) and secondary immunodeficiencies (SID). To compare healthcare resource utilization (HCRU) and related direct medical costs of patients in France treated with weekly conventional SCIg (cSCIg) vs monthly hyaluronidase-facilitated SCIg (fSCIg). This retrospective study of Ig-naïve patients with PID or SID newly receiving a SCIg between 2016 and 2018, extracted from the French National Healthcare reimbursement database (SNDS), analyzed the SCIg-related HCRU and reimbursed costs generated from in-hospital (hospitalizations and SCIg doses) or at-home (nurse visits [NV] and pump provider visits [PPV], drug doses) SCIg administration. Overall, 2,012 patients (PID:534; SID:1,478) were analyzed. The follow-up duration varied between 7.5 and 8.7 months according to sub-groups. Compared with fSCIg-treated patients, monthly mean rates of NV and PPV were respectively 2.5 and 3.1 times higher in PID, and 1.6 and 3.1 times higher in SID cSCIg-treated patients. Monthly mean rates for SCIg administration-related hospitalizations were lower overall, while their costs were 1.6 and 1.8 times higher for cSCIg than fSCIg subgroups, in PIDs and SIDs respectively; these results are due to more frequent hospitalizations with fSCIg being mainly shorter, without stayover. Total HCRU costs from the French NHI's perspective were estimated to be lower with fSCIg vs cSCIg, in PIDs and SIDs. This study provides real-world evidence of SCIg administration in a large French population. Patients with PID or SID treated with fSCIg had fewer at-home HCRU and lower overall costs for in-hospital or at-home SCIg administration compared with cSCIg-treated patients.

3D Bioprinted Multidrug Resistance (MDR)-Dependent Tumor Spheroids.

Multidrug resistance (MDR) refers to the ability of cancer cells to resist various anticancer drugs and release them from the cells. This phenomenon is widely recognized as a significant barrier that must be overcome in chemotherapy. MDR varies depending on the number and expression level of the ATP-binding cassette transporter (ABC transporter), which is expressed differently in various cancer cells. Therefore, the dose of anticancer drugs should be adjusted according to the extent of MDR. The demand for drug screening that considers the differences in MDR is increasing in the process of drug discovery. In this study, three types of tumor spheroids were fabricated from HeLa (MRP1-/BCRP-), HepG2 (MRP1+/BCRP-), and A549 cells (MRP1+/BCRP+) using three-dimensional (3D) bioprinting. The fabricated tumor spheroids maintained their own MDR phenotypes. The EC50 values of doxorubicin (DOX) against the three tumor spheroids were more than 2-fold higher than those against the 2D cells. In addition, the EC50 value of DOX against tumor spheroids was proportional to the number of ABC transporters. The EC50 value of DOX against A549 tumor spheroids had the largest value of 9.5 μM among the three spheroids. In addition, the EC50 values of DOX against HepG2 and A549 tumor spheroids were remarkably reduced when they were treated with ABC transporter inhibitors, such as MK-571 against MRP1 and/or NOV against BCRP. These results demonstrate the successful construction of a 3D bioprinting-based screening platform to quantitatively evaluate the anticancer efficacy of chemodrugs, considering the MDR of cancer cells.

Considerations and expectations for the administration of dispersible arpraziquantel to young children: a landscape analysis.

Schistosomiasis is a serious public health problem in many African countries and beyond. Preventive chemotherapy with praziquantel is a successful public health intervention that is recommended for all communities at risk, commonly reached through large-scale mass drug administration campaigns. However, preschool-age children are currently not routinely targeted for treatment due to operational challenges related to dosing and administration with the standard drug formulation. In response to the need for a suitable, child-friendly treatment, the multistakeholder Pediatric Praziquantel Consortium has developed a novel dispersible tablet with improved taste and smaller size. To prepare the introduction and inform future uptake of the novel paediatric formulation in endemic countries, we conducted a landscape analysis to explore perspectives, opinions and experiences of key stakeholders on operational and practical issues in relation to drug dosing and administration. Our findings confirm that child-friendly drug formulations mitigate several operational constraints related to the dosing and administration in young children. The introduction of this novel child health intervention into routine platforms and programs requires solid training and careful communication by engaging with communities, caregivers, healthcare workers and decision-makers to ensure acceptance and future uptake of treatment.

Experentia Et Progressus: An Experiential Needs Assessment of Military Health care Providers in Treating Pediatric Combat Trauma.

Children are among the most vulnerable populations affected by armed conflicts, yet there is limited data on the preparedness of military medical personnel to care for pediatric combat trauma casualties in austere or large-scale combat operations. This study aimed to assess the confidence, training needs, and resource requirements of military medical providers who have managed pediatric patients during deployment. This IRB-exempt, cross-sectional mixed-methods study used a survey created via a modified Delphi method with input from subject matter experts. The survey was distributed to active duty and reservist physicians, nurses, medics, and corpsmen who had previously deployed to combat environments. Respondents answered Likert-style questions anonymously on the SurveyMonkey platform. Data were analyzed using Welch's t-test, with statistical significance defined as P < .05. Qualitative data were coded into discrete themes and summarized. A total of 84 respondents participated in the survey. Only 27% reported feeling confident or very confident in resuscitating pediatric casualties. Health care providers with prior exposure to pediatric patients reported significantly higher confidence in pediatric trauma resuscitation (P = .02). Key factors contributing to low confidence included difficulty with pediatric medication dosing, anatomical and physiological differences, lack of experience, and insufficient pediatric-specific equipment during deployment. Nearly all respondents with prior pediatric combat trauma experience expressed a desire for additional pediatric-specific predeployment training, with nearly half (47%) advocating for more robust military-civilian trauma center partnerships. Furthermore, 59% of respondents felt they lacked adequate emotional support following negative pediatric events and recommended stronger post-traumatic event debriefing and support mechanisms. Many recently deployed military medical providers reported low confidence in resuscitating pediatric patients in the combat environment, because of drug dosing, anatomic and physiologic differences, and inexperience. Regardless of specialty, almost all providers requested additional pediatric training to improve baseline preparedness. These results can guide future predeployment training and inform policy to reduce unnecessary pediatric mortality on the battlefield.

Effect of rapamycin-eluting stents on in-stent restenosis and early inflammatory response in coronary artery narrowing animal models

Objectiveit was to evaluate the efficacy and safety of rapamycin-eluting stents at different doses in the treatment of coronary artery narrowing in miniature pigs.Methodsa total of 20 miniature pigs were randomly assigned into four groups: S1 group (low-dose rapamycin-coated stent, 55 µg/mm2), S2 group (medium-dose rapamycin-coated stent, 120 µg/mm2), S3 group (high-dose rapamycin-coated stent, 415 µg/mm2), and D0 group (bare metal stent). The stent size was 3.0 mm × 18 mm, with an over-expansion ratio of 1.1. Each group consisted of five pigs. Stent implantation was followed by euthanasia and tissue collection after 1 month. Vascular measurements, inflammatory response scores, cardiovascular injury scores, endothelialization scores, liver and kidney function indices, and myocardial injury markers were compared among the groups.Resultsthe neointimal thickness in the S2 and S3 groups was significantly lower than that in the S1 and D0 groups (S1 group: 24.08 ± 3.95, S2 group: 1.86 ± 0.28, S3 group: 2.72 ± 0.74, D0 group: 22.85 ± 3.15, P < 0.05). The residual lumen area in the S2 and S3 groups was significantly larger than that in the S1 and D0 groups (S1 group: 2.73 ± 0.51, S2 group: 4.25 ± 0.78, S3 group: 3.91 ± 0.73, D0 group: 2.91 ± 0.44, P < 0.05). The neointimal area in the S2 and S3 groups was significantly smaller than that in the S1 and D0 groups (S1 group: 3.44 ± 0.84, S2 group: 1.78 ± 0.25, S3 group: 2.07 ± 0.41, D0 group: 3.43 ± 0.72, P < 0.05). The degree of lumen narrowing in the S2 and S3 groups was significantly lower than that in the S1 and D0 groups (S1 group: 44.25 ± 3.66%, S2 group: 14.19 ± 2.01%, S3 group: 15.29 ± 2.45%, D0 group: 21.79 ± 3.51%, P < 0.05). The inflammation scores of coronary artery walls in the S2 and S3 groups of miniature pigs were markedly lower than those in the S1 and D0 groups (P < 0.05). The cardiovascular injury scores (P = 0.072) and endothelialization scores (P = 0.085) differed slightly among the four groups (P > 0.05). Post-operative liver function indicators (alanine transaminase, aspartate transaminase), kidney function indicators (blood urea nitrogen, serum creatinine), and myocardial injury markers (creatine kinase, creatine kinase-MB) also showed neglectable differences among the four groups (P > 0.05).Conclusionmedium and high doses of rapamycin-eluting stents effectively inhibit neointimal hyperplasia and local vascular inflammatory response in miniature pigs without causing damage to liver and kidney functions or myocardial cells. These stents demonstrate high efficacy and safety. Rapamycin-coated coronary stents, as an effective treatment for coronary artery stenosis, may achieve further improvement in therapeutic efficacy through optimization of drug dosage and stent design.

P0220 Anti-TNFα, anti-integrin α4β7 and anti-IL23p19 biologic treatment dose optimization in a dextran sodium sulphate (DSS)-induced colitis mouse model

Abstract Background Current immunotherapy for inflammatory bowel disease (IBD) treatment is based on anti-TNFα, anti-integrin α4β7, anti-IL12/IL23 and anti-IL23 antibodies that have demonstrated to be safe and effective. In vivo models are crucial for research with biologics, but the literature on doses of above-mentioned drugs in in vivo IBD models is scarce, highly variable and covers wide ranges. Thus, we aim to find the optimal dose for biologic treatment in a DSS-induced colitis model. Methods C57BL/6 mice were randomized into a control group and treatment groups receiving 3% DSS combined with varying doses of neutralizing antibodies against TNFα, integrin α4β7, and IL-23p19. Treated mice received 3% DSS ad libitum for 5 days and clean water for another 3 additional days (5 + 3 model). Neutralizing antibodies were injected intraperitoneally on days 2 and 5 of the experiment. Doses used for optimization were set for each dose at 100, 250 and 500 μg/mouse for anti-integrin α4β7 and anti-IL23p19 antibodies, and at 10, 25 and 50 μg/mouse for anti-TNFα antibody for covering ranges found in bibliography. Weight loss, fecal consistency and fecal occult blood parameters were measured every day of experiment to elaborate a disease activity index (DAI). Mice were sacrificed at day 8 and the colon was obtained for histological evaluation by H/E staining, and for extraction of lamina propria mononuclear cells (LPMCs). Longitude was also measured. Blood was obtained by intracardiac punction and peripheral blood mononuclear cells (PBMCs) were obtained. Distal and proximal colon sections were fixed in 4% paraformaldehyde and embedded in paraffin. 4 μm sections were hydrated and H/E stained for histological score assessment. Extracted LPMCs and PBMCs were stained for flow cytometry evaluation of inflammation markers. Results Proximal and distal colon of mice treated with two doses of 10 μg/mouse of anti-TNFα, 250 μg/mouse of anti-integrin α4β7 and 100 μg/mouse of anti-IL23p19 showed the greatest tissue conservation and repair (Figure 1). In addition, these groups had less weight loss throughout the experiment as well as a reduced DAI (Figure 2). LPMCs and PBMCs inflammatory markers were also decreased in these groups in comparison with the others. Slight differences were found in 250 and 500 μg/mouse anti-integrin α4β7 treated mice. Conclusion The optimal treatment doses of neutralizing anti-TNFα, anti-integrin α4β7 and anti-IL23p19 antibodies are set at two doses of 10, 250 and 100 μg/mouse respectively for this 5 + 3 model of DSS-induced colitis. By establishing precise dosimetry baselines, our work provides a robust framework for combinatorial therapies, which could unlock novel approaches for IBD treatment.