2C5-surface modified nanocarriers targeting neutrophil extracellular traps

Background: Neutrophil extracellular traps (NETs) are composed of processed chromatin bound to granular and selected cytoplasmic proteins and released by neutrophils. NETs consist of smooth filaments composed of stacked nucleosomes. Fully hydrated NETs have a cloud-like appearance and occupy a space 10-15-fold larger than the volume of the cells they originate from. DNases are the enzymes that cleave extracellular DNA including NETs. Together with their protective role in microbial infections, NETs are involved in multiple pathological processes and represent key events in a variety of pathologies including cancer, autoimmunity, and cardiovascular disease. Sites of NETs concentration are dangerous for the host if the process of NETs formation becomes chronic or the mechanism of NETs removal does not work. NETosis has been linked to the development of periodontitis, cystic fibrosis, type 2 diabetes, COVID-19 or rheumatoid arthritis as well as cancer progression. Purpose(s): Thus, the destruction of NETs is of primary significance in many pathologies. In our approach, we are focusing on mimicking one of the natural mechanisms of destroying excessive NETs by delivering deoxyribonuclease I to the specific site of pathological NETs accumulation by modifying the nanoparticles using an anti-nucleosome monoclonal antibody (2C5). The antibody is specific to nucleosomes and can recognize histones in NETs. DNase I is U.S. Food and Drug Administration (FDA)-approved active component and is commonly used in therapeutic methods of modern medicine for cystic fibrosis to clear extracellular DNA fibers in the lungs and systemic lupus erythematosus. Recent findings have also shown the effectiveness of DNase I in the digestion of NETs. However, the low serum stability and fast deactivation by environmental stimuli have been considered as the limiting factors for clinical applications of DNase I, which can be overcome by its targeted specific delivery in pharmaceutical nanocarriers. Method(s): In this study, we generate NETs in vitro using human neutrophils and HL-60 cells differentiated into granulocyte-like cells. We used interleukin-8, lipopolysaccharide from E.Coli (LPS), phorbol myristate acetate (PMA), and calcium ionophore A23187 (CI) to generate the NETs. We confirmed the specificity of 2C5 toward NETs by ELISA, which showed that it binds to NETs with the specificity like that for purified nucleohistone substrate. We further utilized that feature to create two delivery systems (liposomes and micelles) for DNAse I enzyme to destroy NETs, which was confirmed by staining NETs with SYTOX Green dye and followed by flow cytometric measurements and microscopic images. Conclusion(s): Our results suggest that 2C5 could be used to identify and visualize NETs and serve as a ligand for NET-targeted diagnostics and therapies. Also, we proved that our carrier can successfully deliver DNase to NETs to provide their degradation.

Updated Real-World Safety of the Pfizer-BioNTech COVID-19 Vaccine in Pregnancy: Data from the Organization of Teratology Information Specialists (OTIS) Pregnancy Registry

Purpose: Preliminary data indicate that pregnant women infected with COVID-19 are at increased risk of pregnancy complications (US Centers for Disease Control and Prevention, October 2022). Information on the real-world safety of COVID-19 vaccination in pregnancy is essential. We sought to describe preliminary results for pregnancy status among pregnancy registry participants enrolled in an ongoing safety study of the Pfizer-BioNTech COVID-19 vaccine to date. Method(s): This study uses data from the Organization of Teratology Information Specialists (OTIS) Pregnancy Registry as part of the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) which enrolls pregnant women residing in the US or Canada. Data are captured through maternal interviews and the ion of medical records. The study population for this descriptive analysis includes Registry participants who met eligibility criteria on or after December 11, 2020, the date the US Food and Drug Administration granted emergency-use authorization for the Pfizer-BioNTech vaccine. The target sample size is 1,100 pregnant women who received any dose of the Pfizer-BioNTech vaccine from 30 days prior to the last menstrual period through the end of pregnancy, and 900 comparison women who received no COVID-19 vaccine in pregnancy. Result(s): Among pregnant women participating in the Registry between 11 December 2020 and 22 July 2022, 1,100/1,100 participants (100.0% of the target sample) were enrolled as part of the Pfizer-BioNTech COVID-19 vaccine exposure cohort, and 635/900 participants (70.6% of the target sample) were enrolled in the comparator cohort. As of 22 July 2022, 858 (78.0%) in the vaccine exposure cohort and 313 (34.8%) in the comparator cohort had completed pregnancies. Descriptive data indicated numerically similar percentages of pregnancies ending in at least one liveborn infant, spontaneous abortions, stillbirths, and elective terminations across the exposed cohort stratified by trimester of the earliest dose of the Pfizer-BioNTech COVID-19 vaccine received in pregnancy, and overall in the unexposed comparator cohort. Conclusion(s): Preliminary data have not identified any new safety concerns thus far for pregnant women who receive the Pfizer-BioNTech COVID-19 vaccine during pregnancy. Funding(s): This study was conducted as a collaboration between the University of California San Diego and Pfizer. Pfizer is the study sponsor.

The Future of COVID-19: What Is Next in the Drug Pipeline

Objectives: Development of new and repurposed medicines in response to the COVID-19 pandemic has occurred at an unprecedented rate, resulting in a dynamic pipeline marked by significant challenges and successes. This analysis provides an overview of the vaccines and therapies undergoing clinical evaluation or with recent approval for the treatment and prevention of COVID-19 in global markets. Method(s): For this analysis, COVID-19 pipeline medicines are defined in three categories: vaccines, new treatments and repurposed medicines. GlobalData is the primary data source for this study, in addition to online databases from Health Canada, the US FDA, and the EMA. International markets examined include the US and geographic Europe (excluding Russia and Turkey). Result(s): As of November 2022, the global pipeline contained over 600 therapies and vaccines undergoing Phase I, II, III clinical trials or pre-registration for the prevention and treatment of COVID-19. Preventive and repurposed medicines include antivirals, immunoglobulins, monoclonal antibodies, cellular therapies, and convalescent plasma. In Canada, twelve medicines, including six vaccines, have been approved for COVID-19. The number of global approvals is greater, with approximately 9 vaccines on the market in OECD countries. In addition to pre-exposure preventative therapies, manufacturers are also developing COVID-19 drugs to be used as prophylactic therapy. The analysis identifies new oral antiviral treatments and preventative therapies in the pipeline and under review in various jurisdictions globally. Conclusion(s): This research provides a clearer picture of the characteristics and evolution of the market for new and emerging COVID-19 medicines, which will help policy-makers and other stakeholders understand and anticipate the unique pressures of the COVID-19 pandemic.Copyright © 2023

Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases: Third of Three Sets of Expanded Proceedings from the 2020 ISCTM Autumn Conference on Pediatric Drug Development

This article expands on a session, titled "Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases," that was presented as part of a two-day meeting on Pediatric Drug Development at the International Society for Central Nervous System (CNS) Clinical Trials and Methodology (ISCTM) Autumn Conference in Boston, Massachusetts, in October 2020. Speakers from various areas of pediatric drug development addressed a variety of implications of including children in drug development programs, including implications for rare/orphan diseases. The speakers have written summaries of their talks. The session's lead Chair was Dr. Joan Busner, who wrote introductory and closing comments. Dr. Simon Day, regulatory consultant, outlined some of the past mistakes that have plagued trials that did not consult with patient groups in the early design phase. Dr. Atul Mahableshwarkar provided an industry perspective of a recent trial that benefited from the inclusion of patient input. Drs. Lucas Kempf and Maria Sheean provided regulatory input from the perspectives of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA), respectively. Dr. Judith Dunn outlined a novel approach for assessing and rank ordering patient and clinician clinical meaningfulness and the disconnect that may occur. Dr. Busner provided closing comments, tied together the presented issues, and provided a synopsis of the lively discussion that followed the session. In addition to the speakers above, the discussion included two representatives from patient advocacy groups, as well as an additional speaker who described the challenges of conducting a pediatric trial in the US and European Union (EU), given the often competing regulatory requirements. This article should serve as an expert-informed reference to those interested and involved in CNS drug development programs that are aimed at children and rare diseases and seek to ensure a patient-centric approach.Copyright © 2023, Matrix Medical Communications. All rights reserved.

Protecting Mothers and Babies Through Research: A Time for Change

Pregnant patients deserve access to curated information that informs them on the safe use of medicines to treat or prevent disease. Limited or absent drug information can lead to unsafe use of medicines or even refusal or reluctance to prescribe or receive treatment. Decisions not to treat or inadequately treat comorbid conditions during pregnancy can pose significant health risks to mothers impacted by these decisions and their babies. Experiences gained during the SARS-CoV-2 pandemic that found a higher risk of hospitalization and death in pregnant populations have accentuated the need for targeted efficacy and safety data to optimally treat or prevent disease during pregnancy. In the United States, Congress has previously recognized that the lack of information within drug labels to convey certainty in prescribing medications during pregnancy is an urgent public health issue. Similarly, regulatory agencies such as the Food and Drug Administration acknowledge the role that data evaluating drug disposition, pharmacology, and disease biology play in reducing regulatory uncertainty and informing decisionmaking for the good of public health. Historically, in the absence of labeled drug information, networks such as MotherToBaby, have become the trusted expert source providing evidence-based information on the benefit or risk of medications and other exposures during pregnancy. To facilitate the more timely generation of data to inform the use of medicines in pregnancy, multistakeholder initiatives such as the Task Force on Research in Pregnant Women and Lactating Women (PRGLAC) have been established to identify gaps and provide findings to Congress for action. These initiatives have identified a set of opportunities to address the many challenges contributing to the disproportionate exclusion of pregnant populations in clinical trials. As a complimentary mechanism, broader reforms could be considered to foster a research culture that is purposeful and inclusive of pregnant patients. Together, these approaches can reduce uncertainty in prescribing in pregnancy and better address the needs of mothers and their babies.

Medication Update

The article offers medical briefs. Topics include the authorization of a new drug called Gohibic for critically ill patients with COVID-19;the approval of an over-the-counter naloxone nasal spray for opioid overdose treatment;and the Food and Drug Administration approval of a long-acting antifungal called Rezzayo for the treatment of candidemia and invasive candidiasis for hypertension medications.

New science, drug regulation, and emergent public health issues: The work of FDA's division of applied regulatory science.

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.

A new score to predict severe respiratory failure and guide anakinra treatment in COVID-19 pneumonia: analysis of the randomized SAVE-MORE trial

Introduction: Anakinra treatment is approved for the treatment of COVID-19 pneumonia in hospitalized adults in need of oxygen and at risk for progression into severe respiratory failure (SRF) defined as circulating concentrations of the biomarker suPAR (soluble urokinase plasminogen activator receptor) >= 6 ng/mL by the EMA and has been authorized for emergency use by FDA under an EUA [1]. This is based on the results of the randomized SAVE-MORE trial where suPAR >= 6 ng/ mL was used to select patients at risk for SRF [2]. The suPAR test is not commercially available in the USA and an alternative method of patient selection was needed. Method(s): In collaboration with the US FDA, an alternative method to select patients most likely to have suPAR >= 6 ng/mL based on commonly measured patient characteristics was developed. Patients with at least 3 of the following criteria are considered likely to have suPAR >= 6 ng/ ml: age >= 75 years, severe pneumonia by WHO criteria, current/previous smoking status, Sequential Organ Failure Assessment score >= 3, neutrophil-to-lymphocyte ratio >= 7, hemoglobin <= 10.5 g/dl, history of ischemic stroke, blood urea >= 50 mg/dl and/or history of renal disease. Result(s): The positive predictive value of this new score was 95.4% in SAVE-MORE population. However, a lower sensitivity meant a small proportion of patients with suPAR >= 6 ng/ml will not be identified by the new score. The adjusted hazard ratio for survival at 60 days for patients meeting this score and who receive anakinra is 0.45 (Fig. 1). Conclusion(s): The developed score predicts accurately patients with suPAR levels >= 6 ng/mL and may be used as an alternative to guide anakinra treatment in patients with COVID-19 pneumonia. Based on these subgroup results, patients in SAVE-MORE who met the new score appeared to show beneficial efficacy results with treatment of anakinra consistent with the overall studied population.

Invited Commentary: Undiagnosed and Undertreated-the Suffocating Consequences of the Use of Racially Biased Medical Devices During the COVID-19 Pandemic.

While medical technology is typically considered neutral, many devices rely upon racially biased algorithms that prioritize care for White patients over Black patients, who may require more urgent medical attention. In their accompanying article, Sudat et al. (Am J Epidemiol. 2023;XXX(XX):XXX-XXX) document striking inaccuracies in pulse oximeter readings among Black patients, with significant clinical implications. Their findings suggest that this resulted in racial differences in delivery of evidence-based care during the coronavirus disease 2019 (COVID-19) pandemic, affecting admissions and treatment protocols. Despite the medical community's growing awareness of the pulse oximeter's significant design flaw, the device is still in use. In this article, I contextualize Sudat et al.'s study results within the larger history of racial bias in medical devices by highlighting the consequences of the continued underrepresentation of diverse populations in clinical trials. I probe the implications of racially biased assessments within clinical practice and research and illustrate the disproportionate impact on patients of color by examining 2 medical tools, the pulse oximeter and pulmonary function tests. Both cases result in the undertreatment and underdiagnosis of Black patients. I also demonstrate how the social underpinnings of racial bias in medical technology contribute to poor health outcomes and reproduce health disparities, and propose several recommendations for the field to rectify the harms of racial bias in medical technology.

Study on the risk signal mining related to lopinavir/ritonavir based on the US FDA Adverse Event Reporting System.

Objective: To explore the clinical safety of lopinavir/ritonavir (LPV/r) by mining the risk signals of adverse events (AEs) related to LPV/r for the safe application of the drug in the treatment of novel coronavirus pneumonia (COVID-19). Method(s): The risk signals related to LPV/r in AE reports of US FDA Adverse Event Reporting System (FAERS) from the first quarter of 2010 to the third quarter of 2019 were mined by reporting odds ratio (ROR). An AE with reports more than 3 and 95% confidence interval (CI) lower limit of ROR greater than 1 was defined as a positive signal. AEs were counted and classified using the preferred system organ class (SOC) and preferred term (PT) of Medical Dictionary for Regulatory Activities (MedDRA). The PTs of top 50 adverse event reports and signal strength were selected and analyzed. Result(s): From the first quarter of 2010 to the third quarter of 2019, a total of 13 335 AE reports with LPV/r as the primary suspicious drug were reported in the FAERS database. Four hundred and fifty-five AE risk signals with reports more than 3 and the 95%CI lower limit of ROR greater than 1 were detected, involving 7 718 AE reports. The top 2 system organs involved in AE reports were "injury, poisoning and procedural complications" [13.6% (1 051/7 718)] and "pregnancy, puerperium and perinatal conditions" [11.7% (899/7 718)]. However, 998 (95.0%) of 1051 AE reports involved in "injury, poisoning and procedural complications" were related to drug exposure during pregnancy. The system organ with the highest signals was "congenital, familial and genetic disorders" [16.3% (74/455)]. In addition, 144 AEs caused by drug interactions were detected, which ranked the 7th in the AE reports. Conclusion(s): The risk signals of fetal, neonatal and infant abnormalities related to LPV/r during pregnancy were detected, suggesting that attention should be paid to the risk of using LPV/r in pregnant women and infants. The interaction between LPV/r and other drugs was also worthy of attention.Copyright © 2020 by the Chinese Medical Association.

A case of anaphylaxis to the BNT162b2 mRNA COVID-19 vaccine in a patient with confirmed polyethylene glycol allergy

Case report The Food and Drug Administration (FDA) provided emergency use authorization (EUA) for the Pfizer/BioNTech (BNT162b2) COVID-19 vaccine in December 2020. Implementation of COVID-19 mass vaccination efforts were implemented soon after. However, following the FDAs EUA, COVID-19 vaccine allergic reactions were reported. These findings led to concerns about vaccine hesitancy and the possible avoidance of future doses. The Texas Children's Hospital COVID-19 Vaccine Hypersensitivity Clinic was established in December 2020 to help address these concerns and to evaluate both pediatric and adult patients with immediate allergic reactions to the COVID-19 vaccines, as well as evaluating patients with polyethylene glycol (PEG) or polysorbate (PS) allergy. We present the case of an 18yo female who experienced anaphylaxis following her second Pfizer mRNA COVID-19 vaccine. The patient developed symptoms of generalized hives, chest tightness and dyspnea 17 minutes after receiving the Pfizer mRNA COVID-19 vaccine. She was treated in the emergency department with IM prednisone and PO diphenhydramine. Of note, in 2018, she had a similar response to her HPV9 vaccine (containing PS 80). Tryptase wasn't obtained at the time of her COVID-19 or HPV9 vaccine reactions, but she did have a baseline that was normal around 4ng/mL. Skin testing was performed to the following: PEG 3350, PS 20 and PS 80. Skin testing (skin prick and intradermal) were negative for PS20 and PS80. PEG 3350 skin prick was negative but methylprednisone acetate (PEG 3350) was positive at the 4mg/mL intradermal testing strength. She underwent a Miralax (PEG 3350) oral challenge. Within 20 minutes of ingesting 0.17grams PEG 3350 she developed an itchy macular rash on neck and upper chest, nausea and a globus throat sensation. She was treated with PO cetirizine and symptoms improved. Tryptase level was obtained 30 min after the start of her reaction and was 4ng/mL. Given the patient's reaction, she was advised to avoid PEG containing products and will return to undergo a graded-step challenge to the Janssen (J&J) COVID-19 vaccine. The prevalence of COVID-19 mRNA vaccine anaphylaxis and PEG allergies is rare. However, allergy referral is warranted in cases of immediate reactions to the COVID-19 vaccine or history of PEG or polysorbate allergies.

Gender disparities in isotretinoin prescribing patterns for pediatric patients before and during the COVID-19 pandemic

Background: Isotretinoin is an effective therapy for severe, recalcitrant, and nodular acne. Due to its teratogenic effects, isotretinoin requires strict adherence to the iPLEDGE risk management program and mandatory lab work. During the COVID-19 pandemic, the U.S. Food and Drug Administration lifted laboratory requirements, accepted remote pregnancy tests, and permitted telemedicine visits. This study examines the impact of reduced in-person evaluation and testing on physician likelihood of prescribing isotretinoin. Method(s): A retrospective review on demographics, acne history, and treatment was conducted on 142 patients <=18 years old who met inclusion criteria. Dates were divided into 1/1/2019-3/16/2020 (pre-MGH COVID shutdown and required in-person lab testing) and 5/25/2020-8/8/2021 (post-MGH COVID shutdown and paused lab testing requirements). Multivariate linear regression with backward elimination and Wilcoxon rank-sum tests were conducted. Result(s): The median number of dermatology visits to isotretinoin initiation was 3 visits pre-COVID and remained 3 visits during COVID (p=0.85). Backward elimination demonstrated gender (p<.0001) and the interaction between gender and acne severity (p=0.042) as significantly associated with increased number of visits before isotretinoin initiation, with female patients requiring more visits than males before starting isotretinoin at every acne severity level. Race, pre- or during COVID, and insurance type were removed as nonsignificant. Discussion(s): Removal of lab mandates during the COVID-19 pandemic did not result in fewer visits to initiation of isotretinoin. Female patients continue to face delays in receiving isotretinoin even with the acceptance of remote pregnancy tests and increased utilization of virtual visits, highlighting the persistent gender disparities in prescribing practices for pediatric patients with acne.Copyright © 2023

Trends and incidence of reported events associated with staplers: An analysis of the food and drug administration's manufacturer and user facility device experience database

Introduction & Objectives: To summarize medical device reports (MDRs) between 2012 and 2022 relating to staplers within the Manufacturer and User Facility Device Experience (MAUDE) database maintained by The Food and Drug Administration (FDA). Material(s) and Method(s): The MAUDE database was analyzed for all MDRs relating to each FDA-approved stapler for the last ten years. Event descriptions were reviewed and characterized into specific event types. Outcome measures include specific staplers and reported events as detailed by the MDRs. All data is de-identified and in compliance with the Health Insurance Portability and Accountability Act (HIPAA). No further data was available in the database. Pooled Relative risk was used to compare data. Result(s): Overall, 712 reports were retrieved in 10 years, between 2013 and 2015 a higher number of events were reported. In all, 413/712 (58%) were reported as malfunction of the device while 292/712 (41%) as injury. The most frequently reported adverse events (AEs) were Misfire (111/712: 15.6%), Failure to form staple (92/712: 12.9%), Mechanical jam (76/712: 10.7%) and Failure to fire (72/712: 10.1%). In terms of manufacturer: 401/712 (56%) were Covidien, 172/712 (24%) were Teleflex Medical and 139/712 (19.5%) were Ethicon Instruments. When comparing on disproportional analysis the different manufacturers, in terms of Misfire, Covidien presented the better profile when compared to Teleflex Medical and Ethicon (PRR= 0.32-0.65;p<0.05);in terms of failure to form staple Teleflex Medical presented the better profile when compared to Covidien and Ethicon (PRR 0.27-0.49;p<0.05);in terms of mechanical jam Covidien and Ethicon presented the best profile compared to Teleflex Medical (PRR 0.10-0.15;p<0.05). Lastly, in terms of failure to fire Teleflex presented the best profile (0% of events). Table 1: Trends and principal patient problems reported by the MAUDE database. Conclusion(s): Standing to MAUDE database the most frequent complications related to stapler are misfire, failure to form staple, mechanical jam and failure to fire. As well, the reported adverse events vary among the different manufacturers. [Figure presented]Copyright © 2023.