Injection Site Research Articles

7636 Once-weekly Insulin Icodec versus Once-daily Long-acting Insulins for Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis

Abstract Disclosure: S.G. Ribeiro: None. M.P. Chavez: None. L.C. Hespanhol: None. A.B. Neto: None. M.D. Gauza: None. E. Paqualotto: None. C.A. Balieiro: None. C.C. Padovese: None. J.R. Sa: None. Background: Insulin icodec is a novel, long-acting, once-weekly basal insulin analog. Its comparative efficacy and safety with basal once-daily insulins in type 2 diabetes mellittus is uncertain. Objective: Evaluate potential efficacy, benefits and risks associated with icodec compared to once-daily basal insulin analogs (degludec or glargine). Methods: We systematically searched PubMed, Cochrane, and Embase for randomized controlled trials (RCTs) published until June 2023 comparing icodec versus long-acting insulin analogs (degludec and glargine) in type 2 diabetes mellitus (T2DM) with at least 12 weeks of follow-up. Binary endpoints were assessed with risk ratios (RRs) and continuous endpoints were compared using weighted mean differences (WMDs), with 95% confidence intervals (CIs). The protocol was registered in PROSPERO (CRD42023452468). Results: A total of seven RCTs and 3,286 patients with T2DM were included, of whom 1,509 (60.6%) received icodec treatment. The follow-up period ranged from 16 to 78 weeks. Compared with once-daily basal insulin analogs, icodec led to a greater improvement in HbA1c (WMD -0.15%; 95% CI -0.21, -0.10; p<0.0001; I²=0%) and time in range (TIR) (WMD 2.83%; 95%CI 0.94; 4.71; p=0.003; I2=22%). Body weight was increased with icodec treatment (WMD 0.78 Kg; 95%CI 0.42, 1.15; p<0.01; I2=86%). There was also a higher rate of injection site reactions (RR 1.89; 95%CI 1.12, 3.18; p=0.016; I²=0%) and nasopharyngitis (RR 1.94; 95%CI 1.11, 3.38; p=0.020; I²=0%) in the icodec group, compared with once-daily regimens. There was no significant difference between groups in fasting plasma glucose. Conclusions: In this meta-analysis of RCTs, insulin icodec led to better control of HbA1c and TIR as compared with once-daily insulin regimens, albeit with increased weight gain and a higher rate of injection site reaction in the Icodec group. Presentation: 6/3/2024

7376 Efficacy and Safety of CAM2029 in Patients With Controlled or Inadequately Controlled Acromegaly on Standard-of-Care Treatment: Interim Data for the “New to CAM2029” Patient Subgroup in a Phase 3 Study (ACROINNOVA 2)

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Grant Recipient; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. G. Fidan Yaylali: None. M. Doknic: Speaker; Self; Pfizer, Inc., Novo Nordisk, Merck, Sandoz. E. Isaeva: None. A. Dreval: None. A. Gilis-Januszewska: None. E. Gezer: None. I. Bancos: Advisory Board Member; Self; Diurnal, Spruce, Neurocrine, Adrenas, Sparrow, Corcept, HRA Pharmaceuticals, Recordati, Xeris, AstraZeneca, Novo Nordisk. Grant Recipient; Self; Recordati, HRA Pharmaceuticals. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Background: Acromegaly is a rare, serious disorder characterized by overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). There is a need for new, convenient therapies that provide effective disease control. CAM2029 is a novel subcutaneous octreotide depot designed for convenient once-monthly self-administration (ready-to-use syringe or injection pen). In a 24-week, Phase 3 trial (ACROINNOVA 1), CAM2029 was superior to placebo at attaining IGF-1 response (≤upper limit of normal [ULN] at week 22/24: 72.2% vs 37.5%; P=0.0018) in patients with acromegaly previously controlled under standard of care (SoC; octreotide long-acting repeatable [LAR]/lanreotide Autogel). Here, we report interim data from another Phase 3 trial of CAM2029 (ACROINNOVA 2; NCT04125836), focusing on the “New to CAM2029” subgroup of patients whose acromegaly was either controlled or uncontrolled under SoC. Methods: This 52-week, Phase 3, open-label trial (with a 52-week extension) enrolled patients who had received CAM2029 or placebo in ACROINNOVA 1 (reported separately) and “New to CAM2029” patients who were adequately or inadequately controlled (IGF-1 ≤2x ULN) on a stable dose of octreotide LAR/lanreotide Autogel for ≥3 months (data reported here). In the main part of the trial, new patients received once-monthly CAM2029 20 mg for up to 52 weeks. The primary endpoint was adverse events (AEs). Secondary endpoints included (i) the proportion of patients with IGF-1 ≤1x ULN (weeks 50/52 mean), (ii) the change from baseline in IGF-1, and (iii) the combined IGF-1 and GH response. Baseline values reflected SoC treatment. Data cutoff: May 23, 2023. Results: Eighty-one new patients were enrolled (mean age 51.8 years; 59.3% female). No new or unexpected safety signals were observed. The most common treatment-emergent AEs were injection site erythema (n=22) or swelling (n=13), and headache (n=12). AEs were mostly mild (grade 1/2); there were no serious or Grade 3 treatment-related AEs attributed to CAM2029. IGF-I response increased from 14.8% at baseline SoC (12/81) to 33.3% (20/60 patients with available data) at weeks 50/52. The estimated increase in IGF-1 response (linear probability model) from baseline at week 52 was 21.9% (95% CI: 9.6, 34.1). Biochemical control for both IGF-1 and GH improved over time: 30.0% of patients (18/60) had a combined IGF-1 and GH response at the end of the main part of trial, vs 11.7% (7/60) at baseline. Conclusion: CAM2029 was well tolerated with a safety profile consistent with that of SoC. Biochemical control rates improved from SoC baseline over 52 weeks of CAM2029 treatment in the “New to CAM2029” patients. These findings reinforce the efficacy and safety of CAM2029 in patients with acromegaly, including patients with uncontrolled disease with current SoC treatment (octreotide LAR/lanreotide Autogel). Presentation: 6/1/2024

6461 VRDN-003, A Full Antagonist Antibody To The IGF-1 Receptor For Thyroid Eye Disease (TED): Safety And Pharmacokinetic Results Of Subcutaneous Administration In Healthy Volunteers

Abstract Disclosure: K. Foster: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. B. Dickinson: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. A. Matthew: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. J. Vijayaraghavan: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. C. Michalsky: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. V. Bedian: Employee; Self; Viridian Therapeutics. Stock Owner; Self; Viridian Therapeutics. Introduction: While VRDN-001 is a full antagonist antibody to the IGF-1 receptor (IGF-1R) with phase 2 proof-of-concept data showing clinically meaningful improvements in thyroid eye disease (TED) symptoms after 2 intravenous (IV) infusions, VRDN-003 is a next-generation half-life extended version of VRDN-001. VRDN-003’s half-life extension has the potential to provide sustained pharmacokinetics (PK) and pharmacodynamics (PD) with less frequent administration. We present results from an ongoing study to assess the safety, PK, PD, and bioavailability of VRDN-003 for subcutaneous (SC) administration. Methods: Healthy volunteers (HVs) were randomized to receive a single dose of VRDN-003 or placebo in the following 4 IV or SC dose cohorts: IV 5.0 mg/kg, IV 15.0 mg/kg, SC 300 mg, or SC 600 mg. Preliminary treatment-emergent adverse events (AEs) were assessed through December 12, 2023, and will continue to be assessed through study exit (120 days). Preliminary PK parameters including bioavailability were assessed by noncompartmental analysis, and a 2-compartment Population PK model was employed to simulate exposures following repeat SC dosing. Results: Twenty-eight HVs received either VRDN-003 IV (n=8), VRDN-003 SC (n=12), placebo IV (n=4), or placebo SC (n=4). AEs were reported by 25% (2/8) of participants who received VRDN-003 IV, 25% (3/12) who received VRDN-003 SC, and 13% (1/8) who received placebo. Of the AEs, 3 were deemed treatment related, all occurring in VRDN-003 SC-treated patients and all grade 1/mild as follows: injection site reaction, insomnia, and hepatic enzyme increased. No serious AEs were reported. VRDN-003 half-life was estimated at 40-50 days, 4-5 times longer than VRDN-001; bioavailability is currently estimated to be approximately 60% after SC administration. Simulated dosing regimens show the potential for VRDN-003 to be administered SC Q4W or Q8W and reach exposure levels observed with the VRDN-001 parent molecule in its prior phase 2 study. Conclusions: A single dose of VRDN-003 administered IV or SC to HVs was well tolerated and showed favorable PK for SC administration including a half-life of 40-50 days, 4-5 times longer than its parent molecule, VRDN-001. These results show the potential for VRDN-003 SC dosing regimens with the goal of reducing the treatment burden associated with achieving IGF-1R blockade in TED. Safety and efficacy of VRDN-003 SC will be further assessed in planned clinical studies enrolling patients with TED. Presentation: 6/1/2024

7373 CAM2029, Octreotide Subcutaneous Depot, Provides Sustained Biochemical Control of Acromegaly: Interim Results From a Phase 3 Study (ACROINNOVA 2)

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Recordati, Novartis-AAA, Ipsen. Grant Recipient; Self; Camurus AB, Recordati, Novartis-AAA, Ipsen. Research Investigator; Self; Camurus AB. J. Silverstein: Consulting Fee; Self; Xeris Pharmaceuticals. Research Investigator; Self; Camurus AB. P. Freda: Research Investigator; Self; Camurus AB. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. F. Gatto: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. P. Kadioglu: None. P. Maffei: Research Investigator; Self; Camurus AB. J. Seufert: Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. E. Isaeva: None. A. Dreval: None. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Background: Acromegaly is characterized by excess growth hormone (GH) and insulin-like growth factor 1 (IGF-1) production. A key treatment goal is long-term biochemical control to minimize adverse effects of prolonged excess GH. CAM2029 is a novel, subcutaneous, octreotide depot, designed for convenient monthly self-administration using a pre-filled injection/pen. In a 24-week Phase 3 trial (ACROINNOVA 1, NCT04076462), CAM2029 achieved superior IGF-1 control vs placebo (IGF-1 ≤ upper limit of normal [ULN]: 72.2 vs 37.5%; P=0.0018) in acromegaly patients previously controlled with standard-of-care (SoC; octreotide long-acting repeatable/lanreotide Autogel). On trial completion, patients could roll over to a Phase 3, 52-week, open-label, long-term safety trial (ACROINNOVA 2, NCT04125836). Here, we report data from an interim analysis of roll-over patients in ACROINNOVA 2. Methods: Roll-over patients received monthly CAM2029 20 mg for 28 weeks in ACROINNOVA 2. Primary endpoint: occurrence of adverse events (AEs). Key secondary endpoints: proportion of patients with available assessments who had (i) IGF-1 ≤1x ULN (mean of weeks 50/52 measurements) and (ii) both IGF-1 ≤1x ULN (weeks 50/52 mean) and mean GH <2.5 µg/L (week 52). Data are reported according to prior treatment in ACROINNOVA 1. Safety data from the whole trial period are reported. Results: Fifty-four of the 64 patients completing ACROINNOVA 1 (prior CAM2029 n=36; prior placebo n=18) entered ACROINNOVA 2. At data cut-off (May 23, 2023) 28 and 15 patients in the prior CAM2029 and prior placebo groups, respectively, had completed treatment week 52; 7 and 3 were ongoing; 1 and 0 had discontinued. The medication was well tolerated with a safety profile comparable to SoC treatment; no new safety signals were observed. One treatment-related serious AE (cholelithiasis, moderate severity, resolved) occurred in the prior placebo group. Injection site treatment-emergent AEs (Grade ≤2) occurred in 50% of patients in the prior CAM2029 (18/36) and prior placebo (9/18) groups. Of evaluable patients in the prior CAM2029 and prior placebo groups, 89.3% (25/28) and 100% (15/15) had IGF ≤1x ULN at weeks 50/52; 88.5% (23/26) and 100% (14/14) had both IGF ≤1x ULN (week 50/52) and GH <2.5 µg/L (week 52). Mean IGF-1 levels remained <ULN throughout the 52-week study period for the prior CAM2029 group; in the prior placebo group, mean IGF-1 increased above 1x ULN during placebo treatment, returning to <ULN after switching to CAM2029 for 28 weeks. All patients previously treated with placebo regained IGF-I control upon switching to CAM2029. Conclusions: The safety profile of CAM2029 was consistent with SoC, with no new or unexpected safety signals during extended treatment. CAM2029 provided persistent control of IGF-1 and GH during 52 weeks of treatment. All patients in the prior placebo group regained biochemical control of acromegaly after switching to CAM2029. Presentation: 6/1/2024

Recurrent, multisystem angioedema induced by 5-azacitidine.

5-azacitidine is a hypomethylating agent (HMA) used for treating myelodysplastic syndrome (MDS) and certain myeloproliferative neoplasms (MPNs). Common side effects include myelosuppression, nausea and injection site reactions. Serious allergic reactions are rare with this class of agents. We describe a 71-year-old man with MDS/MPN who developed repeated episodes of angioedema after starting treatment with subcutaneous 5-azacitidine. Angioedema involved multiple body areas including the neck, genitalia, lower back and gastrointestinal system. Causality assessment linked this entity to 5-azacitidine via the Naranjo nomogram questionnaire, by scoring 9. 5-azacitidine was discontinued due to recurrent episodes of angioedema that occurred even after dose reduction. Steroids were helpful in terms of reversing this reaction. Afterwards, no further episodes of angioedema have been documented. The patient's thrombocytosis is currently well-controlled with low dose hydroxyurea. We report herein a unique case of recurrent, multisystem angioedema likely related to 5-azacitidine. The exact mechanism of azacitidine-induced angioedema is not currently known. Symptoms, clinical findings and timing of presentation are not always clear-cut, and it may take more than one cycle of 5-azacitidine before the diagnosis is made. Supportive and symptomatic treatment will be provided based on the severity of the reaction. Future studies may offer more insights into the mechanism underlying this rare and serious, yet intriguing side effect.

Safety of a 4-Dose 20-Valent Pneumococcal Conjugate Vaccine Series in Infants: A Randomized Trial.

The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to expand protection for pneumococcal disease. It contains all 13-valent pneumococcal conjugate vaccine (PCV13) components plus conjugates for 7 additional serotypes. Our primary objective with this study was to evaluate PCV20 tolerability and safety. In this phase 3, multi-country, double-blind study, healthy infants born at ≥34 weeks' gestation were randomly assigned 2:1 to receive PCV20 or PCV13 at 2, 4, 6, and 12 to 15 months of age. Safety assessments included local reactions and systemic events within 7 days after each vaccination, adverse events (AEs) from dose 1 to 1 month after dose 3 and from dose 4 to 1 month after dose 4, and serious AEs and newly diagnosed chronic medical conditions from dose 1 through 6 months after the last dose. Participants received PCV20 (N = 1000) or PCV13 (N = 504); 91.7% received all 4 doses. The frequencies of local reactions and systemic events were generally similar in PCV20 and PCV13 groups, with most reported as mild or moderate. The most common local reaction was injection site pain (PCV20, 24.7% to 40.5%; PCV13, 26.8% to 42.0%); irritability was the most common systemic event (PCV20, 54.8% to 68.2%; PCV13, 54.7% to 68.5%). AE frequencies were similar in both groups. No serious AEs were related to study vaccines. Few newly diagnosed chronic medical conditions were reported (2.8% in both groups). PCV20 was safe across multiple countries, in late preterm infants, and when administered with other vaccines. A 4-dose series of PCV20 had a tolerability and safety profile similar to that of PCV13.

Post-marketing safety of tralokinumab: a real-world pharmacovigilance study based on the FDA adverse event reporting system

ABSTRACT Background Tralokinumab is a fully human IgG4 monoclonal antibody targeting IL-13, used for treating atopic dermatitis. This study analyzed tralokinumab-related adverse drug events by mining the Food and Drug Administration Adverse Event Reporting System (FAERS) database to provide a safety reference for clinical application. Methods Adverse drug event reports from Q1 2022 to Q2 2024 were extracted from the FAERS database. After standardizing the data, various signal detection methods were used for analysis, including ROR, PRR, BCPNN, and MGPS. Results A total of 1,820 reports of adverse events (AEs) with tralokinumab as the primary suspected drug were identified. 70 preferred terms (PTs) met the criteria across four signal detection methods, involving 11 system organ classes (SOCs). These included known adverse reactions like conjunctivitis and injection site reactions, and signals not previously reported in clinical trials, such as eye pruritus, dry eye, eye swelling, pneumonia pneumococcal, and cutaneous T-cell lymphoma. Most AEs occurred within one month of initiating tralokinumab treatment. Conclusions Based on the FAERS database, this study comprehensively and systematically analyzed AE signals in tralokinumab treatment. The results enhance the understanding of tralokinumab’s safety and serve as valuable references for reducing the risk of adverse reactions during clinical use.

Dupilumab-related late adverse events in patients with chronic rhinosinusitis with nasal polyps

Background Anti-IL-4 receptor α antibody (dupilumab) has demonstrated favorable sinonasal outcomes for chronic rhinosinusitis with nasal polyps (CRSwNP), which is mainly caused by type 2 inflammation. Although increased blood eosinophil levels and injection site symptoms are frequently observed as acute adverse events (AEs) of dupilumab, limited knowledge is available regarding the late AEs of dupilumab for CRSwNP. Objectives We investigated the late AEs following the initiation of dupilumab treatment for CRSwNP. Material and methods Fifty-one patients with CRSwNP treated with dupilumab for > 3 months were enrolled, and their clinical data were collected from their medical records. Results Six (11.8%) patients experienced late AEs. One case of eczema with pruritus, one case of psoriasis-like dermatitis, two cases of severe rash, one case of malignant lymphoma, and one case of alopecia areata were observed. Skin disorders were the most common late AEs in this study. It is a Th1-inflammatory disease, and its mechanism is thought to be due to the immune imbalance caused by dupilumab. We could not confirm whether malignant lymphoma in our case was caused by dupilumab use. Conclusions and significance Skin disorders are often late AEs associated with dupilumab; therefore, careful monitoring after dupilumab initiation should be considered.

The Efficacy, Safety, and Persistence of Therapy after Non-Medical Switching from an Originator Adalimumab in Inflammatory Bowel Disease: Real-Life Experience from Two Tertiary Centres.

During the last two decades, an increased number of molecules with multiple mechanisms of action have been approved for the treatment of inflammatory bowel disease (IBD), with a substantial increase in the costs related to therapy, which has become a concern for payers, regulators, and healthcare professionals. Biosimilars are biologic medical products that are highly structurally similar to their reference products; have no clinically meaningful differences in terms of immunogenicity, safety, or effectiveness; and are available at a lower price. Materials and Methods: This was an observational prospective study conducted in two IBD centres in Bucharest and included 53 patients, 27 male (M) and 26 female (F), diagnosed with IBD according to standard clinical, endoscopic, radiological, and histological criteria, who were non-medically switched at the indication of the National Insurance House to a biosimilar of Adalimumab. Aims: The aim was to determine the rates of clinical remission, adverse effects, and treatment persistence at one year. Results: No significant differences were found in terms of the faecal calprotectin (FC) and C-reactive protein (CRP) levels 6 and 12 months after changing from the originator biologic treatment to a biosimilar. Only one patient required a change in their biological treatment following the clinical and biological loss of response. The main adverse effect reported by the patients was pain at the injection site. Of the 53 patients, only 2 reported pain at the injection site, and 1 patient reported experiencing abdominal pain and rectal bleeding immediately after the switch, but no recurrence was observed clinically or endoscopically. Conclusions: This observational study is the first to be carried out in Romania that shows that, after a non-medical switch, biosimilars of Adalimumab are as efficient and safe as the originator Adalimumab in the clinical treatment of patients with IBD.

Molecular mechanisms of Coxiella burnetii formalin-fixed cellular vaccine reactogenicity.

Local and systemic reactogenic responses to Q-VAX have prevented licensing of this vaccine outside of Australia. These reactogenic responses occur in previously sensitized individuals and have not been well defined at the cellular level, in part because many studies have been done in guinea pigs that have limited molecular tools. We previously characterized a mouse model of reactogenicity where local reaction sites showed an influx of CD8+ and IFNγ-expressing IL17a+ CD4+ T cells consistent with a Th1 delayed-type hypersensitivity. In this study, we determined, using depletion and adoptive transfer experiments, that both anti-Coxiella antibodies and CD4+ T cells were essential for localized reactions at the site of vaccination. Furthermore, IFNγ depletion showed significant histological changes at the local reaction sites demonstrating the essential nature of this cytokine to reactogenicity. In addition to the cells and cytokines required for this response, we determined that whole cell vaccine (WCV) material remained at the site of vaccination for at least 26 weeks post-injection. Transmission electron microscopy (TEM) of these sites demonstrated intact rod-shaped bacteria at 2 weeks post-injection and partially degraded bacteria within macrophages at 26 weeks post-injection. Finally, because small cell variants (SCVs) are an environmentally stable form, we determined that local reactions were more severe when the WCV material was prepared with higher levels of SCVs compared to typical WCV or with higher levels of large cell variant (LCV). These studies support the hypothesis that antigen persistence at the site of injection contributes to this reactogenicity and that anti-Coxiella antibodies, CD4+ T cells, and IFNγ each contribute to this process.

Findings of Hypotension in Spinal Anesthesia Patients with Lumbar 3-4 And Lumbar 4-5

Background: Hypotension is a common complication associated with spinal anesthesia, often resulting from sympathetic nerve block. Factors such as the type of drug, patient positioning, injection site, dosage, and age influence the incidence of hypotension. Purpose: This study aimed to evaluate the incidence of hypotension in patients receiving spinal anesthesia at the lumbar 3-4 (L3-L4) and lumbar 4-5 (L4-L5) injection sites. Methods: A quantitative descriptive study with a cross-sectional approach was conducted, involving 190 respondents selected via purposive sampling. Univariate data analysis was performed. Findings: Findings indicated that patients receiving spinal anesthesia at the L3-L4 site experienced an average systolic blood pressure decrease of 24.69% and a diastolic decrease of 16.17%. In contrast, patients with L4-L5 injections showed a lesser reduction, with systolic pressure dropping by 15.51% and diastolic pressure by 12.31%. Additionally, the pulse rate decreased progressively within the first 20 minutes following induction. The average pulse rate at the 20th minute was 75.06 for patients with L3-L4 injections and 75.65 for those with L4-L5 injections. Conclusion: The study highlights that the incidence of hypotension varies based on the spinal injection site, with more significant decreases in blood pressure observed in patients receiving injections at L3-L4 compared to L4-L5. These findings have important implications for anesthesia management in clinical practice.

Two-Phase Fluid Dynamics in Proton Exchange Membrane Fuel Cells: Counter-Flow Liquid Inlets and Gas Outlets at the Electrolyte-Cathode Interface

Understanding the counter-flow of liquid inlet and gas outlet at the interface between the electrolyte and cathode gas diffusion layer (GDL) is crucial for water management in proton exchange membrane fuel cells. Existing studies typically overlook air outlets and assume a fixed liquid inlet direction. This study uses a volume of fluid method to model two-phase interactions in a T-shaped GDL and gas channel (GC) assembly, with GDL geometry derived from nano-computer tomography. Considering potential electrode deformations, such as local cracks and blockages, this research investigates the impact of the size and shape of liquid invasion on the liquid-gas behavior in the cathode GDL and GC using five liquid injection configurations. Simulations also incorporate GDL gas outlets, integrating them with a tailored liquid inlet setup. Results show that the injection site and configuration significantly affect water behavior in the GDL, affecting saturation, stabilization, and breakthrough, followed by drainage in the GCs. Comparisons of simulations with and without air outflow show distinct counter-flow interactions, highlighting variations in water distribution and discrepancies in two-phase transport across the GCs.

Poly(β-amino ester) polymer library with monomer variation for mRNA delivery

Non-viral vectors for mRNA delivery primarily include lipid nanoparticles (LNPs) and polymers. While LNPs are known for their high mRNA delivery efficiency, they can induce excessive immune responses and cause off-target effects, potentially leading to side effects. In this study, we aimed to explore polymer-based mRNA delivery systems as a viable alternative to LNPs, focusing on their mRNA delivery efficiency and potential application in mRNA vaccines. We created a library of poly(β-amino ester) (PBAE) polymers by combining various amine monomers and acrylate monomers. Through screening this polymer library, we identified specific polymer nanoparticles (PNPs) that demonstrated high mRNA expression efficiency, with sustained mRNA expression for up to two weeks. Furthermore, the PNPs showed mRNA expression only at the injection site and did not exhibit liver toxicity. Additionally, when assessing immune activation, the PNPs significantly induced T-cell immune activation and were effective in the plaque reduction neutralization test. These results suggest that polymer-based mRNA delivery systems not only hold potential for use in mRNA vaccines but also show promise for therapeutic applications.

Current vaccination and immunization strategies in dermatology

Vaccinations are an important pillar of public health. They have high benefits for individuals and society as awhole by specifically preventing or mitigating infectious diseases. In many cases, they offer benefits that go beyond protection against the disease in question, e.g., protective cardiovascular effects. Vaccination recommendations in Germany are drawn up by the Standing Committee on Vaccination (STIKO), while the European Medicines Agency (EMA) is responsible for the approval of vaccines in the EU. Vaccinations may be carried out by physicians regardless of their specialty. In dermatology, vaccinations against varicella (chickenpox), herpes zoster, and human papillomavirus are established. The development of vaccines against other dermatologically relevant diseases and cancer vaccines is the subject of intensive research. Particularly in the case of immunosuppression, the physician must also take into consideration which vaccinations are possible and useful or contraindicated. TypeI or typeIV allergies to components of vaccinations are very rare, but reactions at the injection site often occur as adermatological side effect. Urticarial reactions are also possible, as does the worsening of underlying dermatological conditions such as psoriasis vulgaris.

ReCLAIM-2: A Randomized Phase 2 Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation

ObjectiveThis study evaluated the safety and efficacy of elamipretide in dry age-related macular degeneration (AMD) with non-central geographic atrophy (GA). DesignReCLAIM-2 was a prospective, phase 2, randomized, placebo-controlled, double-masked, multicenter trial (NCT03891875). SubjectsPatients aged ≥55 years with at least one eye with dry AMD with GA were enrolled. MethodsAdministration of daily subcutaneous elamipretide 40 mg was investigated in subjects for 48 weeks followed by a 4-week follow-up period. Main Outcome MeasuresThe primary efficacy endpoints were the mean change from baseline in low-luminance best-corrected visual acuity (LL BCVA) and the change in square root converted GA area from baseline as measured by optical coherence tomography (OCT). Additional predefined endpoints included ellipsoid zone (EZ) integrity preservation assessment and categorical changes in LL BCVA. The primary safety endpoint was the incidence and severity of adverse events. ResultsOf the 176 patients randomized, there were 117 and 59 patients in the elamipretide and placebo groups, respectively. Although elamipretide did not meet statistical significance for the primary endpoints (mean change in LL BCVA and mean change in square root converted GA area), elamipretide produced a 43% reduction in the mean progression from baseline in the macular percentage of total EZ attenuation/loss (i.e., complete loss of EZ band; nominal P=0.003) and 47% reduction in the mean progression of macular percentage of partial EZ attenuation/degradation (i.e., EZ-RPE thickness of 20 microns or less; nominal P=0.004) versus placebo at week 48. Elamipretide treatment was also associated with significantly more patients experiencing a ≥10 letter gain in LL-BCVA versus placebo (14.6% vs 2.1%; nominal P=0.0404). Adverse events were reported in 86% of those receiving elamipretide and 71% of the placebo group with the most common events being injection site reactions (e.g., pruritus, injection site pain, bruising, erythema). ConclusionsWhile the primary endpoints were not met in this phase 2 study, elamipretide treatment was associated with a slowing of progressive EZ degradation/loss, a surrogate for photoreceptor damage. These findings have important clinical relevance since EZ attenuation/photoreceptor loss precedes and predicts the progressive pathological changes associated with vision loss and AMD. The EZ attenuation/loss endpoint will serve as the regulatory-approved primary endpoint in the elamipretide Phase 3 clinical development program.

COVID-19 Vaccine mRNA Biodistribution: Maternal and Fetal Exposure Risks.

SARS-CoV-2 infection during pregnancy has severe consequences on maternal and neonatal health. Presently, vaccination stands as a critical preventive measure for mitigating infection-related risks. Although the initial clinical trials for the COVID-19 vaccines excluded pregnant women, subsequent investigations have indicated mRNA vaccinations' effectiveness and short-term safety during pregnancy. However, there is a lack of information regarding the potential biodistribution of the vaccine mRNA during pregnancy and lactation. Recent findings indicate that COVID-19 vaccine mRNA has been detected in breast milk, suggesting that its presence is not confined to the injection site and raises the possibility of similar distribution to the placenta and the fetus. Furthermore, the potential effects and responses of the placenta and fetus to the vaccine mRNA are still unknown. While potential risks might exist with the exposure of the placenta and fetus to the COVID-19 mRNA vaccine, the application of mRNA therapies for maternal and fetal conditions offers a groundbreaking prospect. Future research should leverage the unique opportunity provided by the first-ever application of mRNA vaccines in humans to understand their biodistribution and impact on the placenta and fetus in pregnant women. Such insights could substantially advance the development of safer and more effective future mRNA-based therapies during pregnancy.

Estimation of the adverse effects following immunization after SARS-CoV-2 Vaccine (Covishield and Covaxin) in lactating women: A single centre exploratory study from India

ABSTRACT Context: The global COVID-19 pandemic has universally impacted individuals, with lactating women being uniquely susceptible to severe infection. Vaccination plays a critical role in building population immunity, mitigating severe illness and curtailing the health crisis. However, data on adverse effects and vaccine safety in lactating women remains scarce. Aims: To assess the prevalence and types of adverse effects post-COVID vaccination in lactating women. Methods: This study was conducted at a tertiary care hospital’s COVID-19 vaccination centre in North India, and followed a prospective observational design over a specific timeframe. A total of 200 lactating women were surveyed, with specific inclusion and exclusion criteria applied. Telephonic follow-up was conducted for one month after the first dose for 152 participants and after the second dose for 123 participants. Adverse effects following immunization (AEFIs) were recorded and analyzed. Results: Of the study cohort, 45 (29.60%) reported minor adverse effects following the first vaccine dose, with just four (3.25%) experiencing adverse effects after the second dose. Common AEFIs included fever (18.42%) and body aches (9.21%), along with headache, malaise, injection site pain and diffuse abdominal pain. Conclusions: This study provides valuable insights into the adverse effects of COVID-19 vaccines in lactating women, which can help primary physicians and policy maker to improve vaccination policies and guidelines. The study revealed that lactating mothers experienced only mild AEFIs, aligning with current literature. Further broader, multicentre research is needed to reinforce these findings and to assess the long-term safety and efficacy of COVID-19 vaccines in this population.

Impaired Awareness of Hypoglycemia and its Risk Factors among Diabetic Patients in Jazan, Saudi Arabia: A Cross-Sectional Study.

Impaired awareness of hypoglycemia (IAH) is related to a three- to sixfold increase in the risk of severe hypoglycemia in adults with type 1 diabetes mellitus (T1D). This study aimed to assess the prevalence of IAH and its risk factors and determine the frequency of hypoglycemic symptoms. This study aimed to assess the prevalence of IAH and its risk factors and determine the frequency of hypoglycemic symptoms. A cross-sectional study was conducted among T1D patients attending Jazan Endocrine and Diabetes Center in Jazan province, Saudi Arabia. A total of 151 patients participated, using the interview-based Clarke questionnaire, a validated eight-item questionnaire to evaluate IAH. Scoring four or more answers as reduced awareness categorizes the participant as having IAH. The prevalence of IAH was 25.2% among the T1D patients. IAH was significantly associated with body mass index (BMI; p = 0.034), occupation (p = 0.014), and blood glucose monitoring methods (p = 0.027). Shaking and sweating were the most commonly reported symptoms of hypoglycemia. A BMI of <25 kg/m2 was higher linked to hunger and speech difficulty compared to a BMI of ≥25 kg/m2 (p < 0.05). Changing the insulin injection site was associated with confusion, odd behavior, and speech difficulty (p < 0.05). Monitoring blood glucose four times daily was associated with sweating, odd behavior, and incoordination (p = 0.024) compared to monitoring less than four times daily (p < 0.05). A hemoglobin A1c (HbA1c) reading of ≥7 was linked to odd behavior compared to an HbA1c reading of <7 (p = 0.032). Patients committed to insulin injections were more likely to experience palpitations than non-committed patients (p = 0.038). Each one-unit increase in age, monitoring blood glucose, and income was associated with a decrease in the odds of IAH (OR of Age = 0.89, 95% CI: 0.83-0.95) (OR of income = 0.10, 95% CI: 0.01-0.55). Moreover, individuals with a Body Mass Index (BMI) greater than or equal to 25 (OR = 2.99, 95% CI: 1.13-8.25), employed individuals (OR = 18.2, 95% CI: 3.75-105), and diabetes duration of more than ten years (OR = 3.96, 95% CI: 1.31- 13.2) exhibited an increase in the higher risk of IAH. IAH was prevalent among T1D patients attending Jazan Endocrine and Diabetes Center. The main associated factors included BMI, blood glucose monitoring method, and occupation. Future research should investigate the underlying causes of the observed associations and explore strategies to enhance the awareness of hypoglycemia.

Recaticimab Monotherapy for NonfamilialHypercholesterolemia andMixed Hyperlipemia: ThePhase 3 REMAIN-1 Randomized Trial.

Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have been used to reduce the level of low-density lipoprotein cholesterol (LDL-C), but require either biweekly or monthly dosing frequency. Recaticimab is a new humanized monoclonal antibody selectively targeting PCSK9, with long-acting characteristic. The purpose of this study was to assess the efficacy and safety of recaticimab monotherapy in patientswith nonfamilial hypercholesterolemia and mixed hyperlipemia at low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk, and to explore different dosing strategies to provide patients with flexible administration options. This was a randomized, double-blind, placebo-controlled, phase 3 study conducted at 59 sites in China. Patients with fasting LDL-C≥2.6 to<4.9mmol/L, fasting triglyceride≤5.6mmol/L, and 10-year ASCVD risk score<10% were randomly assigned (2:2:2:1:1:1) to receive subcutaneous injections of recaticimab at 150mg every 4weeks (Q4W), 300mg every 8weeks (Q8W), or 450mg every 12weeks (Q12W), or matching placebo, on background lipid-lowering diet. Primary endpoint was percentage change in LDL-C from baseline to week 12 for 150mg Q4W and 450mg Q12W and to week 16 for 300mg Q8W. A total of 703 patients underwent randomization and received recaticimab (n=157, 156, and 155 for 150mg Q4W, 300mg Q8W, and 450mg Q12W, respectively) or placebo (n=78, 79, and 78, respectively). Compared with placebo, recaticimab further reduced LDL-C by 49.6% (95%CI: 44.2%-54.9%) at 150mg Q4W, 52.8% (95%CI: 48.3%-57.2%) at 300mg Q8W, and 45.0% (95%CI: 41.0%-49.0%) at 450mg Q12W (P< 0.0001 for all comparisons). Safety with recaticimab was comparable to placebo. After 12 or 16weeks of treatment, patients who received recaticimab continued treatment until week 24, whereas those allocated to placebo were switched to recaticimab treatment with the same dosing strategy. Both 24-week recaticimab and 12- or 8-week recaticimab switched from placebo were effective. With 24weeks of recaticimab treatment, the most common treatment-related adverse event was injection site reaction (n = 23 [4.9%]). Recaticimab monotherapy yielded significant LDL-C reductions and showed comparable safety vs placebo in patients with nonfamilial hypercholesterolemia and mixed hyperlipemia at low-to-moderate ASCVD risk, even with an infrequent dosing interval up to Q12W.

N-803, an IL-15 Superagonist Complex as Maintenance Therapy After Allogeneic Donor Stem Cell Transplant for Acute Myeloid Leukemia or Myelodysplastic Syndrome; A Phase 2 Trial

Maintenance therapy may improve natural killer (NK) cell surveillance after allogeneic donor hematopoietic cell transplant (HCT) for myeloid malignancies and represents a potential approach to improve cure rates. Interleukin-15 (IL-15) enhances lymphocyte proliferation and antitumor activity. In a prior Phase 1 study of an IL-15 superagonist (N-803) in patients with AML who relapsed after HCT, we observed in vivo expansion of NK cells and antitumor responses. The primary objective of this Phase 2 trial was to determine if post-transplant N-803 could reduce relapse. We administered N-803 (n = 20) (dosed 6 mcg/kg subcutaneously [SQ] at day 60 after HCT to patients with myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML] who were in complete remission [CR]). N-803 treatment was planned weekly, biweekly or every 4 weeks in 2 sequential cohorts. The most common adverse events after administration were self-limited injection sites skin rashes (n = 20). One week after an N-803 dose, we observed enhanced NK cell proliferation and improved antitumor cytotoxicity without inducing immune exhaustion. Five patients who developed acute graft versus host disease (aGVHD) after N-803 responded promptly to steroids and 4 patients developed chronic GVHD. Patients receiving >4 doses of N-803 had a 3-fold decrease in relapse at two years (P = .06). These findings support the safety, immune activation, and potential efficacy of N-803 to prevent relapse of AML/MDS after HSCT.