Safety Evaluation Research Articles

2025 Clinical Trials Update on Hemophilia, VWD, and Rare Inherited Bleeding Disorders.

Clinical trial programs for inherited bleeding disorders feature an array of innovative prophylaxis options: engineered clotting factor concentrates, FVIIIa mimetics, gene therapies, and biologics to bolster thrombin generation (rebalancing agents). Increasingly, non-hemophilia bleeding disorders and a broader demographic (females, children, and infants) are being incorporated into study populations. Ongoing clinical trials broadly address three themes: (1) indication expansion for licensed therapeutics in previously uninvestigated patient subgroups or clinical scenarios, (2) evaluation of efficacy and safety among other bleeding disorders such as von Willebrand disease, platelet function defects, and rare clotting factor deficiencies, and (3) longitudinal assessment of approved treatments particularly with regard to longer-term efficacy outcomes such as musculoskeletal health and treatment-specific safety outcomes including thrombotic risk and liver health. With these new prophylaxis modalities, providers must have a nuanced understanding of each therapy's mechanism of action, advantages, side effect profile, therapeutic limitations, and impact on hemostasis and laboratory monitoring. Treatment is no longer "one size fits all." Rather, management is tailored to individual needs and preferences. Here, we review active investigational trials and highlight promising approaches in preclinical development, expanding the innovative, complex landscape of inherited bleeding disorders therapeutics.

Phytoconstituent analysis, bioactivity, and safety evaluation of various colors of Chrysanthemum morifolium flower extracts for cosmetic application

This study evaluated the phytochemical composition, bioactivity, and safety of purple, yellow, and white Chrysanthemum × morifolium (Ramat.) Hemsl. (C. morifolium) flower extracts using a hydroglycolic solvent blend of water and propylene glycol (PG) in a 1:1 ratio as a solvent for extraction. Quantitative analysis revealed that the purple and yellow flower extracts possessed significantly higher total phenolic content (TPC) and total flavonoid content (TFC) compared to the white flower extract (p < 0.05). These extracts also exhibited superior antioxidant activity, as measured by DPPH and ABTS assays. High-performance liquid chromatography (HPLC) analysis indicated that the purple extract had the highest concentration of luteolin (0.2403% w/w, p < 0.05), while the yellow extract contained the highest levels of chlorogenic acid (0.4320% w/w, p < 0.05) and caffeic acid (0.0289% w/w, p < 0.05). In vitro anti-glycation assays demonstrated that the purple extract exhibited the highest anti-glycation activity (p < 0.05). However, there was no significant difference in anti-collagenase activity between the purple and yellow extracts (p > 0.05). Safety evaluations confirmed that the extracts did not induce skin irritation or sensitization. These preliminary findings suggest the potential of C. morifolium flower extracts, particularly from yellow and purple varieties, as a promising ingredient in plant-based formulations. Initial results indicate antioxidant, anti-glycation, and anti-collagenase properties without apparent adverse skin reactions in vitro. However, further studies, including human clinical trials, are needed to confirm these biological activities and safety profiles.

Evaluation of Permeability, Safety, and Stability of Nanosized Ketoprofen Co-Spray-Dried with Mannitol for Carrier-Free Pulmonary Systems

Pulmonary drug delivery presents a promising approach for managing respiratory diseases, enabling localized drug deposition and minimizing systemic side effects. Building upon previous research, this study investigates the cytotoxicity, permeability, and stability of a novel carrier-free dry powder inhaler (DPI) formulation comprising nanosized ketoprofen (KTP) and mannitol (MNT). The formulation was prepared using wet media milling to produce KTP-nanosuspensions, followed by spray drying to achieve combined powders suitable for inhalation. Cell viability and permeability were conducted in both alveolar (A549) and bronchial (CFBE) models. Stability was assessed after storage in hydroxypropyl methylcellulose (HPMC) capsules under stress conditions (40 °C, 75% RH), as per ICH guidelines. KTP showed good penetration through both models, with lower permeability through the CFBE barrier. The MNT-containing sample (F1) increased permeability by 1.4-fold in A549. All formulations had no effect on cell barrier integrity or viability after the impedance test, confirming their safety. During stability assessment, the particle size remained consistent, and the partially amorphous state of KTP was retained over time. However, moisture absorption induced surface roughening and partial agglomeration, leading to reduced fine particle fraction (FPF) and emitted fraction (EF). Despite these changes, the mass median aerodynamic diameter (MMAD) remained stable, confirming the formulation’s continued applicability for pulmonary delivery. Future research should focus on optimizing excipient content, alternative capsule materials, and storage conditions to mitigate moisture-related issues. Hence, the findings demonstrate that the developed ketoprofen–mannitol DPI retains its quality and performance characteristics over an extended period, making it a viable option for pulmonary drug delivery.

PretoxTM: a text mining system for extracting treatment-related findings from preclinical toxicology reports

Over the last few decades the pharmaceutical industry has generated a vast corpus of knowledge on the safety and efficacy of drugs. Much of this information is contained in toxicology reports, which summarise the results of animal studies designed to analyse the effects of the tested compound, including unintended pharmacological and toxic effects, known as treatment-related findings. Despite the potential of this knowledge, the fact that most of this relevant information is only available as unstructured text with variable degrees of digitisation has hampered its systematic access, use and exploitation. Text mining technologies have the ability to automatically extract, analyse and aggregate such information, providing valuable new insights into the drug discovery and development process. In the context of the eTRANSAFE project, we present PretoxTM (Preclinical Toxicology Text Mining), the first system specifically designed to detect, extract, organise and visualise treatment-related findings from toxicology reports. The PretoxTM tool comprises three main components: PretoxTM Corpus, PretoxTM Pipeline and PretoxTM Web App. The PretoxTM Corpus is a gold standard corpus of preclinical treatment-related findings annotated by toxicology experts. This corpus was used to develop, train and validate the PretoxTM Pipeline, which extracts treatment-related findings from preclinical study reports. The extracted information is then presented for expert visualisation and validation in the PretoxTM Web App.Scientific ContributionWhile text mining solutions have been widely used in the clinical domain to identify adverse drug reactions from various sources, no similar systems exist for identifying adverse events in animal models during preclinical testing. PretoxTM fills this gap by efficiently extracting treatment-related findings from preclinical toxicology reports. This provides a valuable resource for toxicology research, enhancing the efficiency of safety evaluations, saving time, and leading to more effective decision-making in the drug development process.

Real-world safety evaluation of brivaracetam: insights from the US FDA Adverse Event Reporting System

ABSTRACT Background Brivaracetam (BRV) is a novel drug for the treatment of epilepsy. This study aimed to detect and characterize adverse events (AEs) associated with BRV from the first quarter of 2016 to the second quarter of 2024 using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Research design and methods We utilized disproportionality analysis methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), to assess the associations between reported AEs and BRV usage in the FAERS data. Results A total of 1,781 adverse event reports were analyzed, with Brivaracetam as the primary suspected drug. We identified 13 positive system organ classes (SOCs) and 78 positive preferred term signals (PTs), with a particular focus on nervous system disorders, psychiatric disorders, and injury, poisoning, and procedural complications. Exposures related to injury, poisoning, and procedural complications during pregnancy and lactation showed positive signals, including exposure before pregnancy, during breastfeeding, and during pregnancy. These exposures warrant significant attention. Conclusions Based on the FAERS database, we conducted a comprehensive analysis of AEs associated with BRV. This study aims to provide guidance for the clinical application of BRV in epilepsy treatment, thereby improving its safety.

First clinical experiences with the tetravalent live vaccine against dengue (Qdenga ®) in travellers: a multicentric TravelMedVac study in Germany.

A study was conducted to assess the safety and tolerability of the tetravalent live-attenuated dengue vaccine Qdenga®, which received marketing approval in Germany in 2022. The study evaluated vaccine-related reactions in a predominantly dengue-naïve population, highlighting the importance of post-marketing surveillance as an essential component of safety evaluation for newly licensed vaccines. Following dengue vaccination, participants were recruited for an anonymous online questionnaire through the national 'Trav VacNet' network in Germany. The questionnaire focused on post-vaccination reactions up to 18days after the first and second vaccination, as well as previous travel history and coadministration. The study included 1176 participants, with a median age of 39years (IQR 28-56), 53.2% female (n = 625), 46.5% male (n = 547), and 0.3% non-binary participants (n = 4). After the first dose, 51% of the participants reported systemic reactions such as headache (40% (190/474)), weakness (40% (189/474)) and malaise (32% (154/474)), which were most pronounced between days 7-11 post vaccination. After the second dose, localized signs and symptoms such as pain at the injection site (22% (n = 55/250)) were more common. Fever was more common after the first dose (20% (96/474)) vs. 2% (6/250) after the second. Females reported significantly more reactions than males after both vaccinations (1st dose p = 0.0002; 2nd dose p = 0.0003). A total of 334 (28%) co-administrations were reported whereby AEs were reported in 47% (157/333) of participants, with the highest prevalence observed when combined with the Japanese encephalitis vaccine (56.8%, (42/74)). Differences in age groups were observed, with a decrease in reactions in the elderly (≥65years). Vaccine-related reactions were frequently reported, predominantly after the first dose in dengue-naïve participants. Coadministration was a common strategy without significantly increasing side effects. The study provides important insights into reactogenicity and may help improve vaccination strategies in dengue-naïve populations.

Preliminary results of benmelstobart plus anlotinib combined with SOX in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma with low PD-L1 expression: A single-arm, multicenter phase II clinical trial.

444 Background: First-line chemotherapy for advanced HER2-negative gastric/gastroesophageal (G/GEJ) adenocarcinoma has limited efficacy. PD-1 inhibitors plus chemotherapy show promise but need improvement, especially for patients (pts) with low PD-L1 expression. Anlotinib, a multi-targeted TKI for tumor angiogenesis/proliferation, is approved in China. This study aims to evaluate the efficacy and safety of benmelstobart a PD-L1 blockade) in combination with anlotinib and SOX (S-1 plus oxaliplatin) as a first-line regimen for advanced G/GEJ adenocarcinoma in patients with low PD-L1 expression, Preliminary findings will be reported promptly. Methods: Pts with HER2-negative, unresectable, locally advanced, or metastatic G/GEJ adenocarcinomas and a PD-L1 Combined Positive Score (CPS) &lt; 5, who had not received prior systemic therapy were included. They received benmelstobart (1200mg, iv, d1, q3w) combined with anlotinib (10mg, po, d1~14, q3w), oxaliplatin (130mg/m 2 , d1, iv, q3w) and S-1 (40mg, po, bid, d1~14, q3w) for 6 cycles as initial therapy. Maintenance therapy with benmelstobart (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) followed for non-progressive diseaseuntil PD or unacceptable toxicity occurred. Tumor responses were evaluated by RECIST 1.1 criteria. The target sample size was 37, with ORR as the primary endpoint, and safety, DCR, DoR, PFS, and 1-year OS rate as secondary endpoints. Results: From Jun 2023 to Sep 2024, 28 pts were enrolled and 27 were available for efficacy and safety evaluation. The patients’ characteristics were as follows; median age (range): 59 (38-77) years, Male/Female: 19 (70%)/8 (30%), ECOG PS 0/1: 2 (7%)/25 (93%), Surgical history yes/no: 6 (22%)/21 (78%), CPS: ＜1/ ≥1: 4 (15%)/23 (85%), respectively. In the response assessment, 19 PR (70.4%), 6 SD (22.2%), and 2 NE (7.4%) were observed, yielding an ORR of 70.4% (95% CI: 49.8-86.2) and DCR of 92.6% (95% CI: 75.7-99.1). As of September 17, 2024, 6 of 27 patients discontinued (3 due to PD, 3 voluntary), leaving 21 ongoing. The longest DoT was 15.08 months, and the median PFS was not reached. Common TEAEs ≥10% included thrombocytopenia (37%), anemia (33%), leukopenia (22%), HFS (19%), fatigue (15%), liver function abnormalities (15%), and appetite loss (11%). Grade ≥3 TEAEs were thrombocytopenia (4%) and anemia (4%). Conclusions: Preliminary findings indicate that the combination of benmelstobart and anlotinib with the SOX regimen as a first-line treatment for advanced G/GEJ adenocarcinoma with low PD-L1 expression demonstrates promising therapeutic efficacy and tolerable adverse events. Further validation of these results in a larger, consecutive patient population is warranted. Clinical trial information: ChiCTR2400085396.

Pulmonary inflammatory responses and retention dynamics of cellulose nanofibrils.

Cellulose nanofibrils (CNFs) are advanced biomaterials valued for their strength, lightweight nature, and low thermal expansion, making them suitable for diverse industrial applications. However, their potential inhalation risks necessitate thorough safety evaluations. This study investigates the pulmonary inflammatory effects and retention of CNFs following intratracheal instillation in rats. TEMPO-oxidized CNF (CNF1; 11.5 nm × 1.8 μm), mechanically fibrillated CNF (CNF2; 23.9 nm × 2.4 μm), and shorter-fibrillated CNF (CNF3; 21.6 nm × 1.2 μm) were administered at 2.0 mg/kg body weight. Endotoxin contamination was assessed using lipopolysaccharide (LPS) controls. Pulmonary inflammation was evaluated 28 days post-instillation, and lung retention of chemically stained CNFs was tracked for 90 days. Results indicated: (1) CNFs were taken up by alveolar macrophages, but no significant acute inflammation was observed; (2) CNF characteristics, particularly fiber diameter and length, play a key role in influencing lung inflammation responses and determining inflammation sites; (3) endotoxin levels in the CNF dispersions may have limited effects on inflammatory responses; and (4) CNFs persist in lung tissue for extended periods, indicating slow clearance. While immediate inflammatory responses were minimal, the prolonged retention of CNFs in the lungs could contribute to chronic low-grade inflammation. Given the variability in CNF properties influenced by raw materials and manufacturing processes, it is essential to test each CNF type individually, including toxicological endpoints beyond inflammation, to accurately assess their potential health risks.

Abstract WP364: Translational Relevance and Versatility of the Thromboembolic Stroke Model in Mice: Implications for Pharmacological and Safety Evaluations

Abstract WP364: Translational Relevance and Versatility of the Thromboembolic Stroke Model in Mice: Implications for Pharmacological and Safety Evaluations

Exploring the therapeutic potential of lupeol: A review of its mechanisms, clinical applications, and advances in bioavailability enhancement.

Lupeol, a naturally occurring triterpenoid, has garnered significant attention for its diverse range of biological activities and potential therapeutic applications. This comprehensive review delves into the various aspects of lupeol, including its sources, extraction methods, chemical characteristics, pharmacokinetics, safety evaluation, mechanisms of action, and applications in disease treatment. We highlight the compound's unique carbon skeleton and its role in inflammation regulation, antioxidant activity, and broad-spectrum antimicrobial effects. The review also underscores lupeol's potential in cancer therapy, cardiovascular protection, metabolic disease management, and wound healing. Furthermore, we discuss the challenges and future perspectives of lupeol's clinical application, emphasizing the need for further research to improve its bioavailability and explore its full therapeutic potential. The review concludes by recognizing the significance of lupeol in drug development and healthcare, with expectations for future breakthroughs in medical applications.

Functionalized MXenes nanosheets inspired flame retardant epoxy composites: Mechanisms investigation and safety evaluation

Functionalized MXenes nanosheets inspired flame retardant epoxy composites: Mechanisms investigation and safety evaluation

Intra-articular Injection of a Cross-Linked Hyaluronic Acid Combined with Triamcinolone Hexacetonide Improves Pain at 6 Months in Patients with Mild to Moderate Hip Osteoarthritis: A Prospective Observational Study

ObjectivesJoint-preserving interventions, such as intra-articular viscosupplementation injections, are evolving, requiring efficacy and safety evaluation through an evidence-based approach. The objective of this study was to assess the use of a hyaluronic acid and corticosteroid-based injection (Cingal™; Anika Therapeutics, Bedford, MA, USA) in improving pain and functional outcomes for patients aged 40 to 65 with mild to moderate hip osteoarthritis (OA) six months post-injection. MethodsThis prospective observational study included 100 patients receiving a single ultrasound-guided intra-articular injection of Cingal™. Eligible patients seen in participating orthopaedic, physiatry and sports medicine clinics, were evaluated at baseline, one-month, and six-month follow-up. The primary outcome was patient-reported hip pain (Visual Analogue Scale, VAS) at six months post-injection. Secondary outcomes included hip function (Hip Disability and Osteoarthritis Outcome Score, HOOS), quality of life (Short-Form 12, SF-12), pain medication use, range of motion (ROM), physical activity (activity tracker), and adverse events. Results96 patients received the injection; 91 had complete data for primary outcome analysis. Statistically significant improvements were observed in VAS (p<0.001), HOOS (p<0.001), and SF-12 scores (Physical Component Summary, p=0.005; Mental Component Summary, p=0.022) from baseline to six months post-injection. Pain medication use decreased from 50.0% to 34.0% (p=0.035). No statistically significant change was observed in ROM or activity level. Adverse events were reported in 9.5% of patients: five (5.3%) experienced hip pain for less than seven days, one for greater than seven days but less than one month, and three (3.2%) underwent hip arthroplasty. ConclusionPatients receiving an ultrasound-guided Cingal™ injection for hip OA reported statistically significantly reduced hip pain, improved function and quality of life, and reduced pain medication use at six months. The most common adverse event was transient hip pain. Level of EvidenceProspective observational study, Level III

Safety evaluation and prediction of overtaking behaviors in heterogeneous traffic considering dynamic trust and automated driving styles

Safety evaluation and prediction of overtaking behaviors in heterogeneous traffic considering dynamic trust and automated driving styles

Pharmaceuticals, Pesticides, and PFAS: Quantifying Endocrine Disrupting Compounds in Plastics and Fish Tissues Using Solvent Extraction and LC-MS/MS.

The rise of plastic pollution in marine environments has been heavily documented, with particular focus on the physical impacts the plastics can have on biota. But, plastics also sorb a range of hydrophobic chemical pollutants, acting as vectors for the transportation of these compounds throughout marine environments. Therefore, an analytical method that can target both marine biota and plastic matrices will be key to advance our understanding of the link between chemicals in the environment, plastic pollution, and effects on biota. Here, an efficient method for the detection and quantification of a broad suite of compounds in marine samples was developed. Five extraction methods were trialed for the analysis of 21 pesticides, PFAS, and pharmaceuticals in biota and plastics. This included three ultrasonic extraction methods and two QuEChERS methods. Ultrasonic extraction in acetonitrile with a microcentrifuge step then concentration by Bond Elut Carbon SPE resulted in best recovery across most compounds. Of the 21 compounds trialed, 16 were efficiently quantified. Method limits of quantification and detection were between 0.02 and 4.81ppb (mLODs) and between 0.06 and 14.60ppb (mLOQs). This method is widely applicable to a range of marine environments and supports routine evaluations of environmental safety and monitoring protocols.

A randomised, double-masked, placebo-controlled trial evaluating the efficacy and safety of teprotumumab for active thyroid eye disease in Japanese patients.

Teprotumumab significantly improved proptosis and diplopia in patients with active, moderate-to-severe thyroid eye disease (TED) in previous North American and European studies. This is the first evaluation of efficacy and safety of teprotumumab for active, moderate-to-severe TED in Japanese patients. This randomised, double-masked, placebo-controlled trial was conducted in 16 centres in Japan. Main inclusion criteria were as follows: age 20-80 years; Graves' disease, in a euthyroid or mild hypo/hyperthyroid state; clinical activity score (CAS) ≥3; moderate-to-severe TED; ≥3-mm increase in proptosis before TED onset and/or proptosis ≥18mm at baseline; and TED duration ≤9 months. Patients were randomised (1:1, stratified by smoking status) to either teprotumumab or placebo. Patients received eight intravenous infusions, one every three weeks for 24 weeks. Patients, investigators, site personnel (except formulating pharmacists) were masked. Primary endpoint was proptosis responder rate (percentage of patients with ≥2-mm proptosis reduction from baseline) at week 24 in the intent-to-treat population. Adverse events were assessed in all patients. This trial was registered at Japan Registry for Clinical Trials (jRCT2031210453). Fifty-four patients were randomised (teprotumumab, 27; placebo, 27) between February and November 2022. All patients completed the randomised period, although one teprotumumab patient and two placebo patients missed ≥2 doses. At week 24, the proportion of patients with proptosis response was higher in the teprotumumab group (89%, 24/27) compared with the placebo group (11%, 3/27), 95% confidence interval, 61-95; P<0.0001. Study drug-related adverse events (AEs) occurred in 14 patients (52%) in the teprotumumab group and two patients (7%) in the placebo group; hyperglycaemia-related events were reported in six (22%) and one patient (4%), and hearing impairment in four (15%) and one (4%) patient, respectively. Study drug-related serious AEs and deaths were not reported. Teprotumumab significantly improved proptosis compared with placebo in Japanese patients with active TED. No study drug-related serious AEs were observed. Horizon Therapeutics plc (now Amgen).

Evaluation and analysis of efficacy in bisphosphonate treatment of chronic nonbacterial osteomyelitis.

This study aimed to analyze the influence of drug factors on the efficacy of bisphosphonate for chronic nonbacterial osteomyelitis to provide a reference for clinical treatment and promote clinical rational drug use by evaluation of effectiveness and safety of bisphosphonate treatment of chronic nonbacterial osteomyelitis. Literature on the treatment of chronic nonbacterial osteomyelitis by using bisphosphonate was collected and analyzed from PubMed, Medline, Embase, Cochrane, ISI Web of Knowledge, CNKI, VIP, and Wanfang databases. A total of 489 cases were collected, with an average complete response rate of clinical presentation, laboratory tests and imaging findings of 80.37%, 80.56% and 79.22%, respectively. Except for opadronate, risedronate, ibandronate, pamidronate, alendronate, neidronate and zoledronate showed good efficacy, and the average complete response rates were 100%, 100%, 81.64%, 87.50%, 69.23% and 69.23%, respectively.The study found that in the pamidronate group, the average complete response rate of 0.5-1 mg/kg (maximum single dose≤60 mg) subgroup and the frequency of administration once every 3 months subgroup were better than other subgroups. Bisphosphonate could be used to treat chronic nonbacterial osteomyelitis, which of efficacy were affected by different drug types, dose and frequency of administration. The optimal dose and frequency of administration of pamidronate were 0.5-1 mg/kg (maximum single dose≤60 mg) and once every 3 months, respectively.

Update of phase 1b/2 study of muzastotug (ADG126, an anti-CTLA-4 SAFEbody) in combination with pembrolizumab in advanced/metastatic MSS CRC.

193 Background: ADG126 is an anti-CTLA-4 IgG1 masked antibody with cleavable masking peptides that is preferentially activated in the tumor microenvironment, which in turn binds to a unique epitope to block CTLA-4 function, prime T cells and deplete Tregs. We previously reported that repeated dosing of the IO doublet therapy ADG126 plus pembrolizumab (Pembro) was well-tolerated with promising clinical efficacy in 3L MSS CRC patients (pts) free of liver metastasis (NCT05405595) 1,2 . Here we update clinical safety and efficacy of the study as result of continued dose optimization for the IO doublet therapy. Methods: This is a Phase 1b/2, open-label, multicenter dose escalation (DE) and expansion (EXP) study. Primary endpoints were safety and tolerability. Secondary endpoints were PK, ADA, ORR, DCR, DOR, PFS and OS. Results: A total of 72 pts were dosed with ADG126/Pembro (Table). 27.8% pts had ≥ 3 prior therapies and 6.9% pts had prior IO therapies. There was no Grade 4/5 TRAE, and MTD was not reached. Grade 3 TRAEs were 5.9% (1/17), 16.2% (6/37), 33% (4/12) for 10 mg/kg Q6W, 10 mg/kg Q3W and 20 mg/kg loading dose (LD) &amp; cohorts, respectively. Repeated dosing of ADG126 at 20 mg/kg (Q3W)/Pembro was not well-tolerated. In MSS CRC EXP cohorts, ADG126 of 10 mg/kg Q3W/Pembro treatment resulted in 4 confirmed PRs (n=24 EE), 17% ORR (95% CI: 5-37%), 75% DCR, 4.7-mon mPFS and OS rate of 88% (6 mons) and 75% (9 mons). Subgroup analysis revealed that in pts without liver and peritoneal metastasis (NLPM), ADG126 of 10 mg/kg Q6W/Pembro (10 EE) showed 70% SD and ~ 100% OS (6 and 9 mons); ADG126 of 10 mg/kg Q3W/Pembro (17 EE) showed 24% ORR (4 PR (95% CI: 7-50%)), 88% DCR, 47% CBR, 8.5-mon mPFS and OS rate of 89% (6 mons) and 83% (9 mons). Detailed safety and efficacy results, including those from ADG126 20 mg/kg LD cohort, will be reported. Conclusions: Extensive effort on ADG126 dose optimization, aided by PK-informed dosing strategy, suggested that ADG126 10 mg/kg Q6W and Q3W are appropriate dose/regimen for the IO doublet; this is supported by the well-balanced safety and efficacy (ORR, PFS and OS) profile observed in MSS CRC. ADG126 20 mg/kg Q3W appears to have reached safety ceiling for the IO doublet. The totality of the data further verifies that ADG126 possesses potential best-in-class therapeutic index, and provides basis for continued development of the IO doublet in MSS CRC and for additional exploration of the IO doublet in combination with SOCs/other anti-cancer agents in broader patient populations. Clinical trial information: NCT05405595 . Patient number for safety and efficacy evaluation. Evaluated for ADG126 Dose/Pembro* 10 mg/kg Q6W 10 mg/kg Q3W 20 mg/kg Q3W 20 mg/kg LD &amp; Overall Safety (all pts of DE &amp; EXP) 17 37 6 12 72 Efficacy (MSS CRC NLM, EXP) 10 24 / 5 39 *200mg, Q3W, IV; &amp; 20 mg/kg LD: 20 mg/kg x1 cycle followed by 10 mg/kg Q3W. NLM: liver metastasis-free; DE: Dose Escalation; EXP: Dose Expansion; EE: efficacy evaluable. Data cut date: Aug 30, 2024.

Interim safety and efficacy data of [ 212 Pb]VMT-α-NET in somatostatin receptor 2 (SSTR2) expressing neuroendocrine tumors (NETs).

668 Background: After the approval of 177Lu DOTATATE, a new generation of radiopharmaceutical therapies (RPT) utilizing alpha-emitting radiometals is being developed as front-line therapies for advanced NETs with the hope of higher clinical efficacy. In this Phase I study, [ 212 Pb]VMT-α-NET, a novel targeted alpha radionuclide therapy (TAT) to SSTR2, is being evaluated in SSTR2-expressing NETs tumors in patients with no prior PRRT treatment. Here we present interim safety and the first efficacy results from dose escalation cohorts 1 and 2. Methods: In this first-in-human dose-escalation study, safety, PK, and efficacy of [ 212 Pb]VMT-α-NET were investigated in a population of well-differentiated adult NETs of any grade which progressed after prior standard of care therapy as assessed by RECIST v1.1 (NCT05636618). No patient may have received prior 177 Lu-DOTATATE or PRRT. The dose escalation design includes four cohorts, 3 mCi, 5 mCi, 7.5 mCi and 10 mCi based on a Bayesian modified toxicity probability interval (mTPI-2) design. Subjects in cohorts 1 and 2 underwent dosimetry evaluations using the therapeutic surrogate [ 203 Pb]VMT-a-NET. Therapeutic [ 212 Pb]VMT-a-NET was administered for 4 cycles Q8W in combination with reno-protective amino acids. The DLT assessment period is defined as the first 6 weeks of cycle 1. The primary objectives include the evaluation of safety and tolerability, the PK and RP2D of [ 212 Pb]VMT-a-NET as well as ORR as assessed by RECIST 1.1 criteria. Results: The current data cut occurred on September 19 th , 2024. A total of 9 patients were enrolled (2 in cohort 1 and 7 in cohort 2). Median exposure for cohort 1 was 2.5 mCi (2.5 mCi, 2.5 mCi) and for cohort 2 was 5.1 mCi (4.7 mCi, 5.2 mCi). No DLTs were observed. Two grade 3 AEs occurred in Cohort 2 (diarrhea, syncope). The most frequent related TEAE were alopecia, fatigue, anemia, lymphopenia and nausea (all grade 1 or 2). One subject in Cohort 2 was discontinued due to progressive disease. Landmark PFS at 9 months is 89%. ORR is not yet mature and will be shown at the time of the meeting. Safety Monitoring Committee (SMC) meeting was held on July 17 th , 2024, recommended dose escalation to cohort 3 at 7.5 mCi. No nephrotoxicity was reported in either cohort. Conclusions: [ 212 Pb]VMT-α-NET is safe up to 185 MBq (5 mCi) dose level, and the SMC supported dose escalate to cohort 3 at 277.5 MBq (7.5 mCi) following a mandated FDA review in fall. Cohort 2 remains open for dose level expansion. Early efficacy results demonstrate encouraging progression-free survival. Clinical trial information: NCT05636618 .

Longer-term efficacy and safety evaluation of arimoclomol treatment in patients with Niemann-Pick disease type C – Data from 48 months open label trial

Longer-term efficacy and safety evaluation of arimoclomol treatment in patients with Niemann-Pick disease type C – Data from 48 months open label trial

Preclinical Safety Evaluation of SloIron CFTN-PS 5: a Pea-Derived Ferritin Product.

Ferritins are proteins present in plants and animals that are highly effective in storing iron and maintaining iron homeostasis. Iron deficiency anemia is a widespread nutritional disorder, and plant ferritins (phytoferritin) are potential sources of bioavailable iron with slow-release characteristics that prevent oxidative damage. These characteristics are related to receptor mediated endocytosis, the primary absorption mechanism in humans. However, the available toxicological data are insufficient to determine whether the use of phytoferritin as a nutritional supplement to enhance iron consumption in human populations is safe. Therefore, several GLP-compliant toxicology studies have been conducted with phytoferritin prepared from the seed of Psium sativum (trade name: SloIron CFTN-PS5). SloIron CFTN-PS5 was non-mutagenic and non-clastogenic in vitro and did not induce the formation of micronuclei in vivo. SloIron CFTN-PS5 was well-tolerated in a 90-day subchronic toxicity studies conducted in Sprague-Dawley rats at doses up to 1,950 mg/kg bw/day. These findings suggest that the oral consumption of SloIron CFTN-PS5 is of low toxicological concern, with a 90-day oral subchronic No Observed Adverse Effect Level (NOAEL) of 1,950 mg/kg-day, the highest dose tested.