Notable Safety Research Articles

Characterization of the nicotine uptake and safety of Nordic spirit tobacco-free oral nicotine pouches: A randomized cross-over study.

Given the nascency of tobacco-free oral nicotine pouches (NPs) and the heterogeneity of commercially available NP brands, there is a need for scientific evaluation of different NP formulations. Nordic Spirit, novel NPs are distinguished by their unique composition. To characterize blood nicotine delivery, pharmacokinetics (PK), subjective and physiological effects and to monitor safety of three Nordic Spirit NPs (6mg, 9mg and 11.2mg/pouch) compared with LD tobacco snus (11.2mg/pouch) and Nicorette® gum (4mg/unit) following single 30min use. This was a randomized, open-label, ten-sequence, single-use, cross-over clinical study with 30 healthy adult Swedish snus users. Peak nicotine concentrations (Cmax) ranged from 10.92 to 17.32ng/mL for the three Nordic Spirit NPs, with a trend toward dose proportionality, and 8.18ng/mL and 9.23ng/mL for the LD snus and Nicorette® gum comparators, respectively. Peak concentration for Nordic Spirit NPs was reached (Tmax) after 30 to 38min, and after 45min for LD snus and Nicorette® gum. No notable safety concerns were observed after single use for any of the study products. Delivery of nicotine from the three Nordic Spirit NPs appeared to be nicotine content-dependent, based on Cmax and AUC. The amount of nicotine extracted showed positive correlation with the reported Cmax and AUC. For Nordic Spirit NPs, Tmax was immediately after end of use. The characteristics of Nordic Spirit NPs were found to be favourable for profiling NP nicotine delivery and safety in human use, and for further product development. ISRCTN registry study no. ISRCTN75583947.

Post-marketing safety concern of PI3K inhibitors in the cancer therapies: an 8-year disproportionality analysis from the FDA Adverse Event Reporting System

ABSTRACT Background The Phosphoinositide 3-kinases (PI3Ks) family plays a crucial role in tumorigenesis. Alpelisib (inhibiting PI3Kα), copanlisib (inhibiting PI3Kα andPI3Kδ), duvelisib (inhibiting PI3Kδ and PI3Kγ), and idelalisib (inhibiting PI3Kδ) were developed to target the PI3K pathway. However, the toxicity limits their application to some extent. It’s necessary to investigate the adverse effects (AEs) of these inhibitors. Research design and methods We conducted a comparative analysis of the safety signals of AEs in PI3K inhibitors using disproportionality analysis in the FDA Adverse Event Reporting System database(FAERS). Results Our study identified significant safety signals for metabolic disorders with all PI3K inhibitors. Notable safety signals for gastrointestinal disorders were observed with most PI3K inhibitors, with the exception of copanlisib. Common AEs shared among all PI3K inhibitors included colitis and dehydration. Alpelisib displayed unique AEs associated with metabolic disorders, whereas copanlisib exhibited idiosyncratic AEs linked to cardiac and vascular disorders. Stevens-Johnson syndrome emerged as a common severe adverse event (SAE) among alpelisib, copanlisib, and idelalisib, while febrile neutropenia was prevalent among copanlisib, duvelisib, and idelalisib. Intestinal perforation was solely associated with alpelisib. Conclusions The safety profiles of the five PI3K inhibitors vary concerning adverse events. These findings could guide drug selection and inform future prospective research.

Photoredox phase engineering of transition metal dichalcogenides

Crystallographic phase engineering plays an important part in the precise control of the physical and electronic properties of materials. In two-dimensional transition metal dichalcogenides (2D TMDs), phase engineering using chemical lithiation with the organometallization agent n-butyllithium (n-BuLi), to convert the semiconducting 2H (trigonal) to the metallic 1T (octahedral) phase, has been widely explored for applications in areas such as transistors, catalysis and batteries1–15. Although this chemical phase engineering can be performed at ambient temperatures and pressures, the underlying mechanisms are poorly understood, and the use of n-BuLi raises notable safety concerns. Here we optically visualize the archetypical phase transition from the 2H to the 1T phase in mono- and bilayer 2D TMDs and discover that this reaction can be accelerated by up to six orders of magnitude using low-power illumination at 455 nm. We identify that the above-gap illumination improves the rate-limiting charge-transfer kinetics through a photoredox process. We use this method to achieve rapid and high-quality phase engineering of TMDs and demonstrate that this methodology can be harnessed to inscribe arbitrary phase patterns with diffraction-limited edge resolution into few-layer TMDs. Finally, we replace pyrophoric n-BuLi with safer polycyclic aromatic organolithiation agents and show that their performance exceeds that of n-BuLi as a phase transition agent. Our work opens opportunities for exploring the in situ characterization of electrochemical processes and paves the way for sustainably scaling up materials and devices by photoredox phase engineering.

A multi-targeting immunotherapy ameliorates multiple facets of Alzheimer’s disease in 3xTg mice

Alzheimer’s disease (AD) is an intricate disorder involving amyloid deposits, neurofibrillary tangles, and chronic neuroinflammation. Though current Aβ-directed immunotherapies effectively eliminate amyloid plaques, their limited clinical benefits and notable safety concerns arise from overlooking two other neglected neurodegenerative features. Compelling evidence highlights synergistic cooperation between Aβ and tau, underscoring the imperative need to develop combinational therapies to target the diverse pathologies of AD. In this study, we present a dual AD vaccine combining Aβ and pTau vaccines, eliciting robust and enduring antibody responses against pathological Aβ and pTau in 3xTg transgenic mice. It significantly eradicated Aβ plaques and pTau tangles, suppressed neuroinflammatory factors, and markedly enhancing cognitive abilities in 3xTg mice. Mechanistically, peripheral antibodies penetrated the brain, recognizing and inhibiting Aβ and pTau aggregation, thereby reducing their cytotoxicity. In summary, this innovative multi-targeting immunotherapy remarkably ameliorates diverse AD pathologies, demonstrating maximum benefits in slowing the clinical progression of AD.

Prussian Blue Analogues Derived Bimetallic CoNi@NC as Efficient Oxygen Reduction Reaction Catalyst for Mg‐Air Batteries

The magnesium‐air (Mg‐air) batteries are regarded as a highly promising system for electrochemical energy conversion and storage, owing to exceptional energy density, notable safety and eco‐friendliness. The development of high‐performance and durable non‐noble metal catalysts for the cathodic oxygen reduction reaction (ORR) is crucial for advancing the practical use of Mg‐air batteries. The synergistic interaction between different metals in bimetallic catalysts is an effective strategy for enhancing the activity and stability of the catalysts. Herein, various prussian blue analogues (PBA) were selected as precursors to synthesis the bimetallic CoNi@NC, monometallic Co@NC and Ni@NC catalysts due to tunable chemical compositions. Compared with Co@NC and Ni@NC, the bimetallic CoNi@NC pyrolyzed at 600°C (CoNi@NC‐600) exhibits outstanding ORR performances and stability in alkaline (0.1 M KOH) and neutral (3.5 wt% NaCl) electrolytes. Following 5000 CV cycles, the half‐wave potentials for CoNi@NC‐600 show only minor negative shifts of 8 and 7 mV, respectively. Meanwhile, the CoNi@NC‐600 possesses the similar ORR reaction mechanism and activity with Pt/C. The primary Mg‐air battery assembled with CoNi@NC‐600 displays better discharge performances than that of Co@NC and Ni@NC. This study lays the foundation for future investigations into the advancement of non‐precious bimetallic catalysts for ORR in Mg‐air batteries.

Failure Mechanisms and Strategies Toward Flexible Zinc‐Air Batteries

AbstractFlexible zinc‐air batteries (FZABs) have emerged as a promising alternative to lithium‐ion batteries in flexible electronic devices due to the advantages of excellent mechanical properties, high energy density, and notable safety. However, the unclear causes of performance degradation and failure mechanisms of FZABs significantly impede their commercialization. Therefore, extensive research is needed to fully reveal the factors and mechanisms responsible for the performance decline of FZABs. In this review, the failure mechanisms of FZABs' key components, including the Zn anode, solid electrolyte, catalyst air cathode, and electrolyte/electrode interface are analyzed and discussed. To promote further research and development of FZABs, a series of challenges and corresponding strategies are summarized and analyzed. Finally, the future development of FZABs is envisioned. This paper aims to comprehensively elucidate the failure mechanisms of FZABs, guide the development of high‐performance FZABs, and thus promote their commercialization.

Comparison of seven CD19 CAR designs in engineering NK cells for enhancing anti-tumour activity.

Chimeric antigen receptor-natural killer (CAR-NK) cell therapy is emerging as a promising cancer treatment, with notable safety and source diversity benefits over CAR-T cells. This study focused on optimizing CAR constructs for NK cells to maximize their therapeutic potential. We designed seven CD19 CAR constructs and expressed them in NK cells using a retroviral system, assessing their tumour-killing efficacy and persistence. Results showed all constructs enhanced tumour-killing and prolonged survival in tumour-bearing mice. In particular, CAR1 (CD8 TMD-CD3ζ SD)-NK cells showed superior efficacy in treating tumour-bearing animals and exhibited enhanced persistence when combined with OX40 co-stimulatory domain. Of note, CAR1-NK cells were most effective at lower effector-to-target ratios, while CAR4 (CD8 TMD-OX40 CD- FcεRIγ SD) compromised NK cell expansion ability. Superior survival rates were noted in mice treated with CAR1-, CAR2 (CD8 TMD- FcεRIγ SD)-, CAR3 (CD8 TMD-OX40 CD- CD3ζ SD)- and CAR4-NK cells over those treated with CAR5 (CD28 TMD- FcεRIγ SD)-, CAR6 (CD8 TMD-4-1BB CD-CD3ζ 1-ITAM SD)- and CAR7 (CD8 TMD-OX40 CD-CD3ζ 1-ITAM SD)-NK cells, with CAR5-NK cells showing the weakest anti-tumour activity. Increased expression of exhaustion markers, especially in CAR7-NK cells, suggests that combining CAR-NK cells with immune checkpoint inhibitors might improve anti-tumour outcomes. These findings provide crucial insights for developing CAR-NK cell products for clinical applications.

P.141 Endoscopic transorbital approach to the skull base: a single centre experience

Background: Minimally invasive endoscopic techniques via the transorbital approach (ETOA) have emerged as a promising alternative for addressing skull base tumours. This study aims to showcase our institution’s extensive experience with ETOA, detailing the surgical technique employed and presenting comprehensive patient outcomes. Methods: A retrospective analysis was conducted on data from patients who underwent ETOA within the past five years. Results: Over the study period, 24 ETOA procedures were performed on 21 patients, with an average age of 48.92, 13 of whom were women. The superior orbital corridor was utilized in 95.83% of cases, and in 79.17%, ETOA was complemented by a transnasal approach. Spheno-orbital meningioma accounted for the most common surgical indication (33.33%, n=8), all resulting in vision improvement, followed by lateral frontal sinus mucocele (25%, n=6). The median length of stay was one day, and ETOA achieved the procedure goal in 19 patients. Transient V1 numbness was the primary complication (29.17%, n=7), and 20.83% (n=5) necessitated another surgery. Notably, no mortality was associated with this procedure. Conclusions: Our institution’s experience underscores the notable safety and efficacy potential of ETOA, with 19 out of 21 patients exhibiting positive outcomes, obviating the need for revision surgery in most cases.

Targeting cellular cathepsins inhibits hepatitis E virus entry.

HEV is estimated to be responsible for 70,000 deaths annually, yet therapy options remain limited. In the pursuit of effective antiviral therapies, targeting viral entry holds promise and has proven effective for other viruses. However, the precise mechanisms and host factors required during HEV entry remain unclear. Cellular proteases have emerged as host factors required for viral surface protein activation and productive cell entry by many viruses. Hence, we investigated the functional requirement and therapeutic potential of cellular protease during HEV infection. Using our established HEV cell culture model and subgenomic HEV replicons, we found that blocking lysosomal cathepsins (CTS) with small molecule inhibitors impedes HEV infection without affecting replication. Most importantly, the pan-cathepsin inhibitor K11777 suppressed HEV infections with an EC 50 of ~0.02nM. Inhibition by K11777, devoid of notable toxicity in hepatoma cells, was also observed in HepaRG and primary human hepatocytes. Furthermore, through time-of-addition and RNAscope experiments, we confirmed that HEV entry is blocked by inhibition of cathepsins. Cathepsin L (CTSL) knockout cells were less permissive to HEV, suggesting that CTSL is critical for HEV infection. Finally, we observed cleavage of the glycosylated ORF2 protein and virus particles by recombinant CTSL. In summary, our study highlights the pivotal role of lysosomal cathepsins, especially CTSL, in the HEV entry process. The profound anti-HEV efficacy of the pan-cathepsin inhibitor K11777, especially with its notable safety profile in primary cells, further underscores its potential as a therapeutic candidate.

Efficacy and Safety of PSCK9 Inhibitors on Patients with Acute Coronary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

PCSK9 MaB (Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor) may reduce the occurrence of major adverse cardiovascular events (MACEs) in patients diagnosed with acute coronary syndrome (ACS). In this meta-analysis, we conducted a thorough compilation of evidence from established clinical studies to evaluate PCSK9 MaB's capacity to control blood lipid levels and prevent MACEs in ACS patients. We conducted searches on Pubmed, Embase, the Cochrane Library, and Web of Science to identify relevant articles. Data from ACS patients were extracted using a standardized format for aggregating data. We calculated the risk ratio (RR) for MACE and assessed changes in blood lipid parameters. All statistical analyses were performed using RevMan. 11 articles representing 5 trials were included in our systematic review and meta-analysis. When compared to a placebo, PCSK9 MaB significantly reduced the risk of MACEs ( = 0%, p = 0.63, RR [95% CI] = 0.88 [0.81, 0.97], p 0.01) and the recurrence rate of ACS ( = 45%, p = 0.18, RR [95% CI] = 0.89 [0.83, 0.95], p 0.01). Additionally, PCSK9 MaB notably reduced low-density lipoprotein cholesterol (LDL-C) levels (SMD [95% CI] = -2.12 [-2.32, -1.92], p 0.01) and Apolipoprotein B (ApoB) levels (SMD [95% CI] = -1.83 [-2.48, -1.18], p 0.01). Importantly, there were no significant differences in adverse reactions between the PCSK9 MaB group and the control group. PCSK9 MaB, whether used as a standalone treatment or in combination with other therapies, can effectively inhibit PCSK9. It substantially lowers key blood lipid parameters, including low-density lipoprotein (LDL), ApoB, and triglycerides, all without giving rise to notable safety concerns.

α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose-dependently and reached its maximum approximately 4 hours after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated its somatic efficacy was comparable to that of laronidase.

Defense Against Adversarial Ai

The increasing prevalence of deep learning technology has paved the way for a new era of AI-powered capabilities, promising revolutionary advancements across various societal domains such as healthcare and autonomous vehicles. Despite offering potent solutions to complex problems, the formidable power of these AI systems is accompanied by a susceptibility that malicious actors could exploit. Adversarial attacks, particularly targeting deep learning models, involve the crafting of altered inputs, often imperceptible changes to images, to deceive or undermine the functionality of the AI system. Within the domain of autonomous driving systems, adversarial attacks pose a severe risk. Envision a situation where a precisely manipulated adversarial attack targets a red traffic light sign, causing the AI system to misclassify it as an entirely unrelated object, perhaps identifying it as a bird. The potential consequences of such misclassifications underscore the serious impact that adversarial attacks can exert on the safety and dependability of autonomous vehicles. The potential repercussions of such misclassification are severe, with the risk of causing traffic accidents and posing a notable safety threat. Ensuring the resilience and security of AI technologies against adversarial threats is of utmost importance as AI continues to play a pivotal role in critical applications such as healthcare, finance, and autonomous systems. It necessitates a holistic strategy that melds advanced research, meticulous testing, and the deployment of robust security measures. This comprehensive approach is essential for fostering trust and mitigating potential harm in an ever- growing, AI-driven world.

An Integrated Autonomous Dynamic Navigation Approach toward a Composite Air-Ground Risk Construction Scenario.

Unmanned transportation in construction scenarios presents a significant challenge due to the presence of complex dynamic on-ground obstacles and potential airborne falling objects. Consequently, the typical methodology for composite air-ground risk avoidance in construction scenarios holds enormous importance. In this paper, an integrated potential-field-based risk assessment approach is proposed to evaluate the threat severity of the environmental obstacles. Meanwhile, the self-adaptive dynamic window approach is suggested to manage the real-time motion planning solution for air-ground risks. By designing the multi-objective velocity sample window, we constrain the vehicle's speed planning instructions within reasonable limits. Combined with a hierarchical decision-making mechanism, this approach achieves effective obstacle avoidance with multiple drive modes. Simulation results demonstrate that, in comparison with the traditional dynamic window approach, the proposed method offers enhanced stability and efficiency in risk avoidance, underlining its notable safety and effectiveness.

Pterostilbene suppresses gastric cancer proliferation and metastasis by inhibiting oncogenic JAK2/STAT3 signaling: In vitro and in vivo therapeutic intervention

BackgroundGastric cancer (GC) represents a significant health burden with dire prognostic implications upon metastasis and recurrence. Pterostilbene (PTE) has been proven to have a strong ability to inhibit proliferation and metastasis in other cancers, while whether PTE exhibits anti-GC activity and its potential mechanism remain unclear. PurposeTo explore the efficacy and potential mechanism of PTE in treating GC. MethodsWe employed a comprehensive set of assays, including CCK-8, EdU staining, colony formation, flow cytometry, cell migration, and invasion assays, to detect the effect of PTE on the biological function of GC cells in vitro. The xenograft tumor model was established to evaluate the in vivo anti-GC activity of PTE. Network pharmacology was employed to predict PTE's potential targets and pathways within GC. Subsequently, Western blotting, immunofluorescence, and immunohistochemistry were utilized to analyze protein levels related to the cell cycle, EMT, and the JAK2/STAT3 pathway. ResultsOur study demonstrated strong inhibitory effects of PTE on GC cells both in vitro and in vivo. In vitro, PTE significantly induced cell cycle arrest at G0/G1 and S phases and suppressed proliferation, migration, and invasion of GC cells. In vivo, PTE led to a dose-dependent reduction in tumor volume and weight. Importantly, PTE exhibited notable safety, leaving mouse weight, liver function, and kidney function unaffected. The involvement of the JAK2/STAT3 pathway in PTE's anti-GC effect was predicted utilizing network pharmacology. PTE suppressed JAK2 kinase activity by binding to the JH1 kinase structural domain and inhibited the downstream STAT3 signaling pathway. Western blotting confirmed PTE's inhibition of the JAK2/STAT3 pathway and EMT-associated protein levels. The anti-GC effect was partially reversed upon STAT3 activation, validating the pivotal role of the JAK2/STAT3 signaling pathway in PTE's activity. ConclusionOur investigation validates the potent inhibitory effects of PTE on the proliferation and metastasis of GC cells. Importantly, we present novel evidence implicating the JAK2/STAT3 pathway as the key mechanism through which PTE exerts its anti-GC activity. These findings not only establish the basis for considering PTE as a promising lead compound for GC therapeutics but also contribute significantly to our comprehension of the intricate molecular mechanisms underlying its exceptional anti-cancer properties.

Current Understanding on Psilocybin for Major Depressive Disorder: A Review Focusing on Clinical Trials.

Previous studies suggested effectiveness of psilocybin in the field of mental health. FDA designated psilocybin as a "breakthrough therapy" for the treatment of treatment-resistant depression (TRD) in 2018. This paper provided a review of psilocybin's potential role in treatment of depression by focusing on published clinical trials. Studies showed that psilocybin, an agonist on 5-HT2A receptors, manifests antidepressant and anxiolytic effects by increasing glutamate transmission, reducing brain inflammation, decreasing default mode network activity. In terms of clinical trials, eleven studies (six open-label and five double blinded randomized clinical trials [DB-RCTs]) trials exploring psilocybin's impact on depression were found. Among open-label studies, a pilot study on TRD patients demonstrated significant reductions in depressive symptoms after two psilocybin sessions. Psilocybin also improved cognitive bias associated with depression. Extension studies confirmed sustained improvements and high remission rates. Among five DB-RCTs, two showed that psilocybin led to significant reductions in anxiety and depression in cancer patients, and the improvements sustained for over six months. In MDD, psilocybin showed rapid reductions in depression, with higher remission rates compared to escitalopram in a DB-RCT. Another DB-RCT showed that psilocybin induced higher decrease in depression around 6 hours after their administrations than placebo. The last DB-RCT showed that in patients with TRD, a single dose of psilocybin 25 mg, but not psilocybin 10 mg, resulted in superior antidepressant effect than psilocybin 1 mg. Overall, psilocybin showed promise in treating depression and anxiety, with notable safety profiles. Further research should explore optimal dosages and long-term effects.

A drug-drug interaction study with letermovir and acyclovir in healthy participants.

Letermovir inhibits renal tubular organic anion transporter 3 (OAT3) in vitro and is predicted to inhibit OAT3 in vivo. Acyclovir, a substrate for OAT3, is likely to be coadministered with letermovir; therefore, letermovir may increase acyclovir concentrations. A drug-drug interaction study was conducted in healthy participants (N= 16) to assess the effect of letermovir on acyclovir pharmacokinetics. On Day 1, participants received a single oral dose of 400 mg acyclovir; on Days 2-7, participants received oral doses of 480 mg letermovir once daily with a single oral dose of 400 mg acyclovir coadministered on Day 7. Coadministration with letermovir resulted in geometric mean ratios (90% confidence intervals) for acyclovir area under the concentration-time curve from administration to infinity and maximum plasma concentration of 1.02 (0.87-1.20) and 0.82 (0.71-0.93), respectively. No notable safety issues were reported. No clinically significant interaction was observed between letermovir and acyclovir in healthy participants and no dose adjustment is required for coadministration.

Splenic-targeting biomimetic nanovaccine for elevating protective immunity against virus infection

BackgroundThe prevalence of viral infectious diseases has become a serious threat to public safety, economic and social development. Vaccines have been served as the most effective platform to prevent virus transmission via the activation of host immune responses, while the low immunogenicity or safety, the high cost of production, storage, transport limit their effective clinical application. Therefore, there is a need to develop a promising strategy to improve the immunogenicity and safety of vaccines.MethodsWe developed a splenic-targeting biomimetic nanovaccine (NV) that can boost protective humoral and cellular immunity against african swine fever virus (ASFV) infection. The universal PLGA nanoparticles (CMR-PLGA/p54 NPs) coated with mannose and CpG (TLR9 agonist) co-modified red blood cell (RBC) membrane were prepared, which comprised a viral antigen (p54) and can be served as a versatile nanovaccine for elevating protective immunity.ResultsCMR-PLGA/p54 NVs could be effectively uptaken by BMDC and promoted BMDC maturation in vitro. After subcutaneous immunization, antigen could be effectively delivered to the splenic dendritic cells (DCs) due to the splenic homing ability of RBC and DC targeting capacity of mannose, which promoted antigen presentation and DCs maturation, and further elicited higher levels of cytokines secretion and specific IgG titers, CD4+ and CD8+ T cells activation and B maturation. Moreover, NVs demonstrated notable safety during the immunization period.ConclusionsThis study demonstrates the high potential of CMR-PLGA NPs as vaccine delivery carriers to promote humoral and cellular immune responses, and it provides a promising strategy to develop safe and effective vaccines against viral infectious diseases.

Safety Aspects and Rational Use of Lanadelumab Injections in the Treatment of Hereditary Angioedema (HAE): Clinical Insights.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of skin/mucosal swelling, and/or attacks of severe abdominal pain when it affects the gastrointestinal tract. The disease might be unexpectedly fatal when the upper airways are compromised. HAE clinical presentation, disease course and prognosis are associated with significant disease burden and severely impaired quality of life. Lanadelumab is a breakthrough therapy for the prevention of attacks in HAE type 1 and 2 patients. This revolutionary approach to administer a single subcutaneous injection (once every two to four weeks) and achieve complete disease control has dramatically improved patient care resulting in significant change in the life of affected families. Current data support the drug's tolerability in adult and adolescent patients without notable safety concerns in both clinical research and real-world settings. Rational use of prophylactic treatments of HAE searches for a socio-economic balance, taking into account the life-long course of the disease, the public health funds who pay the monetary price, and the patients who might need to receive the therapy for a period longer than investigated during the development program. In this review, we address the current evidence on lanadelumab's tolerability, highlighting aspects of the drug's rationale use in clinical practice. Further studies need to investigate whether this therapy might be appropriate in other forms of angioedema, such as idiopathic primary angioedema and HAE with normal C1 inhibitor. Future efforts must focus to improve modern drugs' accessibility in more countries. Although modern prophylactic options lessen the risk of fatal laryngeal attacks, patients must be equipped with reliable on-demand therapies and be trained how to use them as such a risk cannot be fully diminished with potentially life-threatening attacks occurring even in subjects with successful and stable long-term prophylaxis. Notwithstanding, further studies are needed to identify early responders from non-responders and develop therapies for the latter.

Phase I Study to Assess the Safety and Immunogenicity of an Intradermal COVID-19 DNA Vaccine Administered Using a Pyro-Drive Jet Injector in Healthy Adults

We conducted a nonrandomized, open-label phase I study to assess the safety and immunogenicity of an intradermal coronavirus disease 2019 (COVID-19) DNA vaccine (AG0302-COVID-19) administered using a pyro-drive jet injector at Osaka University Hospital between Yanagida November 2020 and December 2021. Twenty healthy volunteers, male or female, were enrolled in the low-dose (0.2 mg) or high-dose (0.4 mg) groups and administered AG0302-COVID19 twice at a 2-week interval. There were no adverse events that led to discontinuation of the study drug vaccination schedule. A serious adverse event (disc protrusion) was reported in one patient in the high-dose group, but the individual recovered, and the adverse event was not causally related to the study drug. In the analysis of the humoral immune response, the geometric mean titer (GMT) of serum anti-SARS-CoV-2 spike glycoprotein-specific antibody was low in both the low-dose and high-dose groups (246.2 (95% CI 176.2 to 344.1, 348.2 (95% CI 181.3 to 668.9)) at the 8 weeks after first vaccination. Regarding the analysis of the cellular immune, the number of IFN-γ-producing cells responsive to the SARS-CoV-2 spike glycoprotein increased with individual differences after the first dose and was sustained for several months. Overall, no notable safety issues were observed with the intradermal inoculations of AG0302-COVID19. Regarding immunogenicity, a cellular immune response was observed in some subjects after AG0302-COVID19 intradermal inoculation, but no significant antibody production was observed.

A Randomized Clinical Trial of Regdanvimab in High-Risk Patients With Mild-to-Moderate Coronavirus Disease 2019.

BackgroundWe evaluated clinical effectiveness of regdanvimab (CT-P59), a severe acute respiratory syndrome coronavirus 2 neutralizing monoclonal antibody, in reducing disease progression and clinical recovery time in patients with mild-to-moderate coronavirus disease 2019 (COVID-19), primarily Alpha variant.MethodsThis was phase 3 of a phase 2/3 parallel-group, double-blind, randomized clinical trial. Outpatients with mild-to-moderate COVID-19 were randomized to single-dose regdanvimab 40 mg/kg (n = 656) or placebo (n = 659), alongside standard of care. The primary endpoint was COVID-19 disease progression up to day 28 among “high-risk” patients. Key secondary endpoints were disease progression (all randomized patients) and time to recovery (high-risk and all randomized patients).ResultsOf 1315 randomized patients, 880 were high risk; the majority were infected with Alpha variant. The proportion with disease progression was lower (14/446, 3.1% [95% confidence interval {CI}, 1.9%–5.2%] vs 48/434, 11.1% [95% CI, 8.4%–14.4%]; P < .001) and time to recovery was shorter (median, 9.27 days [95% CI, 8.27–11.05 days] vs not reached [95% CI, 12.35–not calculable]; P < .001) with regdanvimab than placebo. Consistent improvements were seen in all randomized and non-high-risk patients who received regdanvimab. Viral load reductions were more rapid with regdanvimab. Infusion-related reactions occurred in 11 patients (4/652 [0.6%] regdanvimab, 7/650 [1.1%] placebo). Treatment-emergent serious adverse events were reported in 5 of (4/652 [0.6%] regdanvimab and 1/650 [0.2%] placebo).ConclusionsRegdanvimab was an effective treatment for patients with mild-to-moderate COVID-19, significantly reducing disease progression and clinical recovery time without notable safety concerns prior to the emergence of the Omicron variant.Clinical Trials RegistrationNCT04602000; 2020-003369-20 (EudraCT).