Food And Drug Administration Research Articles

Dupilumab Demonstrates a Higher Likelihood of Achieving Improvements in Signs, Symptoms, and Quality of Life vs. Tralokinumab at Week 16: Results from a Bucher Indirect Treatment Comparison

Background: Dupilumab and tralokinumab are biologics approved by the US Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe atopic dermatitis (AD), aged ≥6 months and ≥12 years, respectively. Dupilumab and tralokinumab have demonstrated efficacy and safety in clinical trials. However, no direct head-to-head trials have been performed to compare the efficacy of dupilumab vs tralokinumab. The Bucher indirect treatment comparison (ITC) is a robust, placebo-adjusted, and accepted method to evaluate the relative efficacy of drugs in the absence of direct comparisons. The objective of this analysis was to report results from a Bucher ITC comparing the efficacy of dupilumab+topical corticosteroid (TCS) vs tralokinumab+TCS at Week 16. Methods: The placebo-adjusted Bucher ITC included published data from the two similarly designed phase 3 trials, LIBERTY AD CHRONOS (NCT02260986) and ECZTRA 3 (NCT03363854). For both studies, data from the 16-week period were used, employing non-responder imputation, with the following doses: 300mg dupilumab every 2 weeks (q2w)+TCS or placebo+TCS, and 300mg tralokinumab q2w+TCS or placebo+TCS. The evaluated endpoints included the proportions of patients achieving an Investigator’s Global Assessment score 0/1 (IGA 0/1; clear/almost clear), 75% and 90% improvements from baseline in Eczema Area and Severity Index (EASI-75 and EASI-90), ≥4-point improvement from baseline in the Peak Pruritus Numerical Rating Scale score (PP-NRS >4), and ≥4-point improvement from baseline in the Dermatology Life Quality Index (DLQI >4). The Bucher ITC with the frequentist approach was performed using R software (v 4.20; netmeta package) with a fixed-effect model. Results were reported as odds ratio (OR) with 95% confidence interval (CI). Results: A total of 801 patients (LIBERTY AD CHRONOS: placebo+TCS: 315; dupilumab+TCS: 106; ECZTRA 3: placebo+TCS: 127; tralokinumab+TCS: 253) were included in the Bucher ITC. Baseline disease characteristics indicated comparable severity between the two trial populations based on IGA and PP-NRS. However, CHRONOS showed slightly higher baseline EASI scores (median [Q1, Q3] score 30.9 [22.3, 41.6] vs. ECZTRA 3: 24.7 [18.4, 35.9]), while ECZTRA 3 showed slightly higher DLQI scores (median [Q1, Q3] score 18.0 [12.0, 23.0] vs. CHRONOS: 13.5 [8.0, 20.0]). Patients treated with dupilumab+TCS had a significantly higher likelihood of achieving IGA 0/1 (OR=2.49, 95%CI 1.24–5.00), EASI-75 (OR=3.21, 95%CI 1.66–6.19), EASI-90 (OR=2.92, 95%CI 1.41–6.02), PP-NRS ≥4 (OR=3.62, 95%CI 1.87–7.00), and DLQI ≥4 (OR=2.16, 95%CI 1.03–4.54) at Week 16 vs those treated with tralokinumab+TCS. Conclusions: A placebo-adjusted Bucher ITC showed that the likelihood of achieving improvements in signs, symptom, and quality of life is significantly higher for patients treated with dupilumab+TCS vs tralokinumab+TCS at Week 16.

Provider Burden Associated With Apremilast Adverse Events

Introduction: In December 2021, the US Food and Drug Administration (FDA) expanded its initial approval for apremilast to include moderate and severe cases of psoriasis. However, real-world epidemiology data regarding the use of apremilast, the influence of adverse events (AEs), and the burden of AEs on managing physicians, has been lacking. This retrospective, observational, multisite study aimed to describe real-world patient characteristics, AEs (including diarrhea, nausea, and headache), and healthcare provider-level burden associated with the psoriasis treatment apremilast in the US. Methods: Dermatologists abstracted medical record data for adults treated with apremilast on or after January 1, 2018, who had ≥3 months of data available. Dermatologist and patient characteristics, including demographics and clinical characteristics, AEs, and provider burden in managing AEs were summarized using descriptive statistics. Results: Forty-seven dermatologists nationwide responded to a survey and conducted a chart review of 308 patients. Dermatologists practiced in various US geographic regions. The most common practice setting was in a private community with 2 to 5 physicians (34.0%). Most patients were White (74.4%), non-Hispanic (86.0%), and male (55.2%). The mean age at diagnosis was 43.6 years (SD, 16.8 years). AEs occurred in 29.2% of patients, with the most common being diarrhea (16.2%), followed by nausea (13.6%) and headache (4.9%). Diarrhea mostly occurred ≤30 days into treatment (87.2%) and resulted in 1 additional office visit (39.5%) and 3 phone calls per patient to their providers (34.9%). Nausea mostly occurred within 30 days (70.2%) and resulted in 1 additional visit (29.7%) and 1 phone call per patient (35.1%). The burdens of managing both diarrhea and nausea were similar, although diarrhea resulted in more phone calls to the healthcare provider. Conclusion: Diarrhea and nausea were common and resulted in an additional time and resource burden on dermatologists and their staff. Future research on the AE burden on providers and patients related to apremilast is needed.

Methyl-Beta-Cyclodextrin Restores Aberrant Bone Morphogenetic Protein 2-Signaling in Bone Marrow Stromal Cells Obtained from Aged C57BL/6 Mice

During aging, disruptions in various signaling pathways become more common. Some older patients will exhibit irregular bone morphogenetic protein (BMP) signaling, which can lead to osteoporosis (OP)—a debilitating bone disease resulting from an imbalance between osteoblasts and osteoclasts. In 2002, the Food and Drug Administration (FDA) approved recombinant human BMP-2 (rhBMP-2) for use in spinal fusion surgeries as it is required for bone formation. However, complications with rhBMP-2 arose and primary osteoblasts from OP patients often fail to respond to BMP-2. Although patient samples are available for study, previous medical histories can impact results. Consequently, the C57BL/6 mouse line serves as a valuable model for studying OP and aging. We find that BMP receptor type Ia (BMPRIa) is upregulated in the bone marrow stromal cells (BMSCs) of 15-month-old mice, consistent with prior data. Furthermore, conjugating BMP-2 with Quantum Dots (QDot®s) allows effective binding to BMPRIa, creating a fluorescent tag for BMP-2. Furthermore, after treating BMSCs with methyl-β-cyclodextrin (MβCD), a disruptor of cellular endocytosis, BMP signaling is restored in 15-month-old mice, as shown by von Kossa assays. MβCD has the potential to restore BMPRIa function, and the BMP signaling pathway offers a promising avenue for future OP therapies.

Qualitative examination of US and Israeli adults' perceptions of IQOS advertising messages: modified exposure and risk statements, US FDA endorsement, and health warnings.

IQOS, a leading heated tobacco product, is advertised as less harmful than cigarettes and received US Food and Drug Administration (FDA) authorization for 'reduced exposure' advertising claims. Perceptions of advertising messages, including reduced exposure/risk claims, FDA endorsements, and health warning labels (HWLs), are understudied. Qualitative interviews (N=84) from US and Israeli adults (2022) examined perceptions of advertising messages, specifically: 1) scientific claims that switching completely from cigarettes to IQOS reduces 1a) chemical exposure and 1b) tobacco-related disease risk; 2) FDA endorsement of IQOS as a 2a) better choice for adult smokers and 2b) fundamentally different product (heat-not-burn); and 3) promoting IQOS as cigarette alternatives with a HWL pertaining to cigarettes. For half of participants, referencing scientific studies or the FDA enhanced credibility; some believed this implied unbiased, rigorous research. Half were skeptical due to lack of research-related details. Half interpreted message 1 (switching) to mean any substitution could be beneficial; half interpreted it as complete substitution was necessary. Most did not perceive differences between message 1a (reduced exposure) vs. 1b (reduced risk). Some believed message 2a (FDA endorsement, not targeting youth) demonstrated IQOS' social responsibility. Some interpreted message 2b (fundamentally different product) as risk reduction; others perceived no difference. The majority paraphrased messages using the terms 'safer', 'healthier', or 'less harmful'. For message 3 (safer alternative), some did not think the HWL applied to IQOS; some believed it promoted IQOS. Regulators and researchers must monitor harm reduction advertising messaging and take actions to prevent consumer misinterpretations. Philip Morris International's IQOS received US Food and Drug Administration (FDA) authorization for 'reduced exposure' advertising claims, which are often misinterpreted, and has exploited FDA authorization to promote IQOS globally. This qualitative study showed that most participants perceived no difference between reduced risk vs. exposure messages in IQOS ads, half believed that references to scientific studies or FDA enhanced credibility, some believed certain messages demonstrated IQOS' social responsibility, and some perceived warnings in IQOS ads to promote IQOS. Product ads using harm reduction messages must be monitored to inform efforts to prevent potentially harmful misinterpretations and mitigate negative population-level impacts.

A Novel Spectrofluorimetric Method for Vibegron in the Newly FDA Approved Pharmaceutical Formulation and in Human Plasma: Analytical QbD Strategy for Method Development and Optimization.

Vibegron is a novel selective beta-3 adrenergic receptor agonist molecule, recently approved by US Food and Drug Administration (FDA) in tablet pharmaceutical formulation for treating overactive bladder syndrome. Such formulation necessitates the development of a simple, fast and cost-effective methodology capable of assaying the drug in various real samples with high sensitivity. Herein, a facile and robust spectrofluorimetric method was introduced, for the first time, for vibegron quantification based on analytical quality-by-design approach. The method involves drug reaction with dansyl chloride at pH 9.8, as a smart approach to overcome the non-fluorescent nature of vibegron, giving a highly fluorescent yellow derivative measured at 514nm after being excited at 345nm. Plausible reaction scheme between the drug and dansyl chloride was elucidated through studying the differences in their infrared (IR) spectra. Variables affecting fluorescence intensities were carefully screened and rationally optimized via preliminary scouting studies and central composite design for accurate and robust results. Full International Council for Harmonisation (ICH) validation protocol was followed where linearity was achieved in range of 20.0-400.0 ng/mL with minimum detectability of 3.6 ng/mL. The proposed method expressed good capability in assaying the marketed dosage forms with no excipient inference. Finally, the high sensitivity of such method paved the way for extending its application to quantify vibegron in spiked human plasma at concentrations around its real human plasma concentrations for further bioavailability studies.

Quality enhancement of potato chips through acrylamide mitigation and comparison with local potato chips in Bangladesh

Potato chips are popular and frequently consumed ready-to-eat food in the world. Acrylamide is a possible carcinogenic and neurotoxic compound formed in potato chips during heat processing, a public health concern. This study aimed to develop potato chips to mitigate acrylamide formation, followed by Food and Drug Administration (FDA) guidelines with some modifications. A total of 15 local chip samples were collected by a stratified random sampling method and were assessed for nutritional values, sensory attributes, microbial quality, and acrylamide levels. Acrylamide was extracted from potato chips using a novel activated charcoal method, then determined by the High- Performance Liquid Chromatography (HPLC) method and showed that only 40% of local potato chips were above the benchmark level established by the EU 2017/2158 (750 ppb) (parts per billion) and ranged from 461 ppb to 2129 ppb while in the developed chips it was not detected. The microbial results showed that the developed chips are safe according to Bangladesh Standards and Testing Institution (BSTI) standard, while the local chips contain total viable count (TVC) (>104 ) and yeast-mold count in a significant amount (>103 ). Sensory evaluation results showed that the developed potato chip samples had high ratings for all the evaluated attributes. From the nutritional point of view, fat content is lower while protein and fiber content is higher in developed potato chips. Moisture content is significantly higher in local potato chips than in developed potato chips, which is the major concern for microbial quality. As a result of the study's findings, acrylamide formation in potato chips was successfully mitigated by adhering to FDA modification guidelines without compromising quality, despite the fact that many locally produced potato chips are unfit for human consumption.

IDH1/2 Mutations in Cancer: Unifying Insights and Unlocking Therapeutic Potential for Chondrosarcoma.

Chondrosarcomas, a rare form of bone sarcomas with multiple subtypes, pose a pressing clinical challenge for patients with advanced or metastatic disease. The lack of US Food and Drug Administration (FDA)-approved medications underscores the urgent need for further research and development in this area. Patients and their families face challenges as there are no systemic therapeutic options available with substantial effectiveness. A significant number (50-80%) of chondrosarcomas have a mutation in the isocitrate dehydrogenase (IDH) genes. This review focuses on IDH-mediated pathogenesis and recent pharmacological advances with novel IDH inhibitors, explores their potential therapeutic value, and proposes potential future avenues for clinical trials combining IDH inhibitors with other systemic agents for chondrosarcomas.

Exploring peptide dendrimers for intestinal lymphatic targeting: formulation and evaluation of peptide dendrimer conjugated liposomes for enhancing the oral bioavailability of Asenapine maleate.

Asenapine maleate (ASPM) is a second-generation atypical antipsychotic that is approved for treating acute schizophrenia and bipolar disorder in adults by the US FDA. The major downside of ASPM therapy is rapid, extensive first-pass hepatic metabolism following its oral administration with a very low oral bioavailability of < 2%. In this work, we developed ASPM nanoformulations conjugated with ligands such as arginine-glycine-aspartic acid (RGD) and peptide dendrimers (PDs) with the intention of improving the oral bioavailability of the drug by targeting it to the intestinal lymphatic system (ILS). Peptide dendrimers (PDs), both lipidated and nonlipidated, were synthesized by Fmoc solid phase peptide synthesis (SPPS). Reverse phase high performance chromatography (RP-HPLC) was used to purify the synthesized PDs, and the PDs were characterized by differential scanning calorimetry (DSC) electrospray ionization mass spectroscopy (ESI+-MS), Nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy. The thin film hydration method was used to prepare liposomes, and the process variables affecting the liposome parameters were optimized using the Box‒Behnken design (BBD).Liposomes were PEGylated using DSPE-PEG-COOH2000 and further conjugated with ligands (RGD, PD-1 and PD-2) using EDC-NHS chemistry. The formulation was characterized using different spectroscopic techniques. In vitro, cell line studies, such as cytotoxicity, cell uptake, uptake mechanism, and receptor saturation studies, were performed on both Caco2 and Raji-B cells. The pharmacokinetic parameters of the developed liposomal formulation were evaluated using pharmacokinetic studies on Sprague- Dawley (SD) rats. The psychostimulant-induced hyperactivity model was used to evaluate the pharmacodynamic performance of the developed formulations by measuring the reversal of hyperlocomotor activity induced by levodopa-carbidopa.

Alcohol Use Disorder: Current and Emerging Therapies

Alcohol use disorder (AUD) is a medical condition characterized by problematic and unhealthy patterns of alcohol use ranging from frequent to heavy alcohol consumption. It is a well-recognized psychiatric syndrome that includes a broad spectrum of symptoms and behaviors associated with alcohol misuse. People with AUD don’t stop drinking alcohol despite emotional distress, social, occupational, or health problems. Pharmacological management of AUD depends on the patient’s condition to reduce the symptoms and improve the patient’s health. The US FDA approved three medications, namely naltrexone, acamprosate, and disulfiram for the treatment of AUD. Apart from these medications, psychological therapy, cognitive behavioral therapy, and encouraging patient participation in support groups have been showing promising results. The present review briefly discusses the epidemiology, symptoms, stages, diagnosis, screening, and emerging psychosocial therapies and pharmacotherapy of AUD including approved and off-label uses of drugs and newer agents. Keywords: Alcohol use disorder, Acamprosate, Baclofen, Disulfiram, Gabapentin, Naltrexone, Nalmefene

Pharmacokinetics of Antiretroviral Drugs in Older People Living with HIV, Part II: Drugs Licensed Before 2005.

Advances in antiretroviral therapy led to an increase in life expectancy among people living with human immunodeficiency virus (HIV). As aging is characterized by several physiological changes that can influence pharmacokinetics (PK), this systematic review aims to describe the impact of aging on the PK of antiretrovirals (ARV) approved by the Food and Drug Administration (FDA) before 2005. Searches were performed in BVS, EMBASE, and PubMed databases for publications until June 2024. Peer-reviewed published studies were included if they met the following criteria: adults (≥ 18 years) living with HIV; reporting at least one PK parameter or plasma concentration of any ARV approved by the US FDA before 2005 and still used in the clinic: lamivudine (3TC), emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), abacavir (ABC), zidovudine (ZDV), efavirenz (EFV), nevirapine (NVP), atazanavir (ATV), lopinavir (LPV), ritonavir (RTV), tipranavir (TPV), and fosamprenavir (FPV); PK parameters stratified per age group as young (aged 18-49 years) or older (age ≥ 50 years) adults; and manuscripts published in English, Portuguese, or Spanish. All studies were evaluated for risk of bias. The review protocol was registered in the PROSPERO database (registration no. CRD42023463092). Among 106 studies included, only 22 evaluated the PK of participants aged 50 years or older and only 5 studies compared the PK between young and older adults for ATV, RTV, EFV, and 3TC. Our analysis revealed an increase in minimal concentration (Cmin) values for LPV, RTV, and ATV in older adults. While increased values of the area under the curve (AUC) and maximum concentration (Cmax) were observed in older adults using ATV, 3TC, and FTC, no differences in PK were apparent between young and older adults for ABC and EFV, with no estimation possible for ZDV. Exposure to 3TC, TDF, FTC, ATV, LPV, and RTV increases with age, while exposure to ABC and EFV appears to be unaffected. Despite the large quantity of data on PK in young adults, there is still a gap in knowledge about the effects of aging on the PK of these ARVs.

Comparative Safety of Ultrasound Enhancing Agents: A Systematic Review and Bayesian Network Meta-Analysis: Comparative Safety Evaluation of Optison.

Ultrasound enhancing agents (UEAs), including Optison, Definity, and Lumason, enhance the diagnostic performance of echocardiography, particularly in patients with suboptimal acoustic windows. However, there remains a paucity of comparative safety assessments among the Food and Drug Administration (FDA)-approved UEAs. A PRISMA-guided systematic literature review performed in August 2023 searched Medline, Embase, Cochrane Library, and grey literature. Randomized and non-randomized comparative evidence on safety of contrast enhanced procedures were included. A feasibility assessment ensured homogeneity across studies by comparing patient characteristics and outcomes. Bayesian hierarchical network meta-regression was employed to indirectly compare published safety outcomes across different UEAs. In addition, adverse events (AEs) between 2019-2023 for each UEA were retrieved from the FDA Adverse Events Reporting System (FAERS), and comparative safety outcomes were derived using annual UEA administration in the US. Screening of 4146 records rendered 19 studies for inclusion in the indirect comparison analysis after feasibility assessment. Optison demonstrated favorable safety in direct comparisons with Definity and Lumason across the majority of investigated AEs. Network meta-regression results on serious adverse events (SAEs) within 30 minutes revealed odds ratios (ORs) of 0.59 (95% confidence interval: 0.27-1.23) and 0.63 (0.29-1.33) for Optison vs. Lumason and Definity, respectively, indicating a decreased risk of SAEs for Optison vs. Lumason and Definity, further supported by statistically significant ORs within FAERS: 0.01 (0-0.02), P<0.001 and 0.15 (0.05-0.48), P=0.001, for Optison vs. Lumason and Definity, respectively. In conclusion, our results restate the favorable comparative safety profile of Optison, providing new evidence to inform clinical decision-making.

Upcoming multi-visceral robotic surgery systems: a SAGES review.

Robotic surgical procedures continue to increase both in the United States (US) and worldwide. Several novel robotic surgical platforms are under development or undergoing regulatory approval. This review explores robotic platforms that are expected to reach US consumers within the next 2-3years. The SAGES Robotic Platforms Working Group identified robotic surgery platforms in various stages of development and selected multi-visceral systems nearing or completing the US Food and Drug Administration (FDA) approval process. We outline key system components including architecture, unique features, development status, regulatory approval, and expected markets. We identified twenty robotic platforms that met our selection criteria. Ten companies were based in North America, and ten were based in Europe or Asia. Each system is described in detail and key features are summarized in table form for easy comparison. The emergence of novel robotic surgical platforms represents an important evolution in the growth of minimally invasive surgery. Increased competition has the potential to bring value to surgical patients by stimulating innovation and driving down cost. The impact of these platforms remains to be determined, but the continued growth of robotic surgery seems to be all but assured.

Food and Waterborne Cryptosporidiosis from a One Health Perspective: A Comprehensive Review

A sharp rise in the global population and improved lifestyles has led to questions about the quality of both food and water. Among protozoan parasites, Cryptosporidium is of great importance in this regard. Hence, Cryptosporidium’s associated risk factors, its unique characteristics compared to other protozoan parasites, its zoonotic transmission, and associated economic losses in the public health and livestock sectors need to be focused on from a One Health perspective, including collaboration by experts from all three sectors. Cryptosporidium, being the fifth largest food threat, and the second largest cause of mortality in children under five years of age, is of great significance. The contamination of vegetables, fresh fruits, juices, unpasteurized raw milk, uncooked meat, and fish by Cryptosporidium oocysts occurs through infected food handlers, sewage-based contamination, agricultural effluents, infected animal manure being used as biofertilizer, etc., leading to severe foodborne outbreaks. The only Food and Drug Administration (FDA)-approved drug, Nitazoxanide (NTZ), provides inconsistent results in all groups of patients, and currently, there is no vaccine against it. The prime concerns of this review are to provide a deep insight into the Cryptosporidium’s global burden, associated water- and foodborne outbreaks, and some future perspectives in an attempt to effectively manage this protozoal disease. A thorough literature search was performed to organize the most relevant, latest, and quantified data, justifying the title. The estimation of its true burden, strategies to break the transmission pathways and life cycle of Cryptosporidium, and the search for vaccine targets through genome editing technology represent some future research perspectives.

The Utilization of the Accelerated Approval Pathway in Oncology: A Case Study of Pembrolizumab.

The accelerated approval (AA) pathway was established by the United States Food and Drug Administration (FDA) to provide earlier access to therapies for patients with serious medical conditions and unmet medical needs. Since its inception, the AA pathway has been used for novel treatments across different therapeutic areas, but most prominently in oncology, including the immune checkpoint inhibitor class. This review article describes the history of regulatory approvals for pembrolizumab, an immunotherapy agent targeting programmed death receptor-1 (PD-1), and use of the AA pathway and the corresponding regulatory decisions made by the FDA. From its first AA in September 2014 to February 2024, pembrolizumab has used the accelerated pathway for roughly 40% of the approved indications listed in the US Prescribing Information and was the first oncology therapy to receive an AA for an alternate dosing regimen and a tissue-agnostic indication. As of February 2024, 14 of the 18 indication-specific AAs and 1 post-marketing requirement (PMR) for the alternate dosing regimen AA were converted to traditional approvals. Accelerated approvals for two indications were withdrawn, and the remaining ongoing PMRs are not due until later in 2024 or 2025. The median conversion time from AA to traditional approval was 2.6 years, which is roughly 6 months earlier than the median time reported for oncology AAs. While FDA was the first agency to establish an expedited approval pathway, regulators from other countries have established similar pathways. For pembrolizumab, approximately half of the datasets that supported US AAs also supported expedited approval, or sometimes full approval, in Canada, EU, Australia or Japan. Ultimately, the AA pathway balances the provision of earlier access to therapies with overcoming uncertainty about potential effectiveness, and therefore it is important to confirm treatment benefit and withdraw indications that do not confirm benefit in a timely manner. The regulatory strategy and use of this expedited program for pembrolizumab highlights the importance of the AA pathway in providing oncology patients with earlier access to life-saving medications.

An Analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience Database for MAGnetic Expansion Control Spinal Rods.

MAGnetic Expansion Control (MAGEC) rods can prevent repeated lengthening operations for scoliosis patients. However, there have been several Field Safety Notices issued, including a worldwide product recall due to actuator endcap separation. We aimed to review adverse events reported to the Food and Drug Administration (FDA) regarding MAGEC rods, focusing on MAGEC X. Reports submitted to the Manufacturer and User Facility Device Experience database in relation to MAGEC devices were accessed and analysed using R Statistical Software. Exclusion criteria included duplicate and literature review reports (n = 54). Free-text data were analysed using inductive content analysis. 1016 adverse events were reported to 11/30/2023. 99.0% (1006) were submitted by the manufacturer. Reports primarily arose from the UK (465, 45.8%) or US (421, 41.4%). From free-text data the most frequent adverse events were distraction mechanism failure (573), device wear (272), and actuator seal damage (180). Rod fracture (n = 48) was not significantly associated with rod diameter (≤ 5.0mm or > 5.0mm), p = 0.736. 234 reports referenced MAGEC X devices; actuator endcap separation was identified in 41.9% (99). Other events include failure of distraction (63), surface damage (31), and rod fracture (15). On 06/30/2020 MAGEC X2 received FDA approval. Twenty reports reference devices manufactured after this date, seven describe distraction mechanism failure; notably there are no reports of endcap separation. These data represent the largest series of adverse events reported for MAGEC rods, including significant new data regarding MAGEC X. As well as endcap separation, failure of distraction, surface damage, and rod fracture were reported.

Antibody–Drug Conjugates: A Start of a New Era in Gynecological Cancers

Antibody–drug conjugates (ADCs) are a new class of therapeutic agents designed to target specific antigens on tumor cells, combining the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy agents. ADCs have been available for over a decade, but in gynecological cancers, these agents are relatively new with great promise ahead. More than 80% of ongoing trials in gynecological cancers are evaluating ADCs’ safety and efficacy, of which 40% are early-phase trials. Around twenty ADCs are currently under investigation, either alone or in combination with chemotherapies or immune checkpoint inhibitors. Among them, mirvetuximab soravtansine has been recently approved by the Food and Drug Administration (FDA) in platinum-resistant ovarian cancer with high folate-α receptor expression, as a single agent or in combination. Tisotumab vedotin and trastuzumab deruxtecan are also now approved by the FDA in patients with pre-treated cervical and uterine cancers and further investigation is ongoing. Overall, the toxicity profiles of ADCs are acceptable. Ocular toxicity is one of the specific side effects of some ADCs, but most of the cases are manageable with the use of prophylactic steroids and dose adjustments. This review aims to provide an overview of the fundamental and operational features of ADCs and examine the latest and most promising data, with a particular focus on the Canadian viewpoint.

Ustekinumab Biosimilars

Ustekinumab is a fully human IgG1k monoclonal antibody that binds with high affinity and specificity to the p40 subunit of interleukins (IL-) 12 and 23, inhibiting their activity by preventing binding to their receptors. The European extension of the patent (Supplementary Protection Certificate) of ustekinumab expired on 20 July 2024. Biosimilar alternatives to ustekinumab are now an additional option for treating patients. The efficacy data for this drug in moderate-to-severe psoriasis obtained both from clinical trials and indirect comparisons through meta-analyses, are superior to those of etanercept and adalimumab, and its safety profile is more favorable than that of tumor necrosis factor (TNF) inhibitors. Several ustekinumab biosimilars have already been approved by regulatory agencies: between October 2023 and October 2024, Wezlana® (Amgen ABP 654), Uzpruvo® (Alvotech AVT04) and Pyzchiva® (Samsung/Bioepis SB17) have been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). SteQeyma® (Celltrion Healthcare CT-P43) was approved by the EMA in August 2024. Otulfi® (Fresenius Kabi/Formycon) was approved by the FDA in October 2024. Several other potential biosimilar candidates are under development, including BAT2206 (Bio-Thera), DMB-3115 (Dong-A ST), QX001S (Qyuns Therapeutic), BFI-751 (BioFactura), NeuLara (Neuclone), ONS3040 (Oncobiologics), and BOW090 (Epirus Biopharmaceuticals). In most cases, these monoclonal antibodies are expressed in cell lines (e.g., Chinese Hamster Ovary, CHO) different from those used for the originator (Sp2/0 spleen cell murine myeloma); of note, the cell line of origin is not a requirement for biosimilarity in the totality-of-evidence comparison exercise and may facilitate the production and reduce the immunogenicity of biosimilars originated in CHO cultures. This narrative review summarizes the available data on characteristics of the full comparability exercises and comparative clinical trials of these drugs.

Trop2-Targeted Molecular Imaging in Solid Tumors: Current Advances and Future Outlook.

Trophoblast cell surface antigen 2 (Trop2), a transmembrane glycoprotein, plays a dual role in physiological and pathological processes. In healthy tissues, Trop2 facilitates development and orchestrates intracellular calcium signaling. However, its overexpression in numerous solid tumors shifts its function toward driving cell proliferation and metastasis, thus leading to a poor prognosis. The clinical relevance of Trop2 is underscored by its utility as both a biomarker for diagnostic imaging and a target for therapy. Notably, the U.S. Food and Drug Administration (FDA) has approved sacituzumab govitecan (SG), a novel Trop2-targeted agent, for treating triple-negative breast cancer (TNBC) and refractory urothelial cancer, highlighting the significance of Trop2 in clinical oncology. Molecular imaging, a powerful tool for visualizing and quantifying biological phenomena at the molecular and cellular levels, has emerged as a critical technique for studying Trop2. This approach encompasses various modalities, including optical imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and targeted antibodies labeled with radioactive isotopes. Incorporating Trop2-targeted molecular imaging into clinical practice is vital for the early detection, prognostic assessment, and treatment planning of a broad spectrum of solid tumors. Our review captures the latest progress in Trop2-targeted molecular imaging, focusing on both diagnostic and therapeutic applications across diverse tumor types, including lung, breast, gastric, pancreatic, prostate, and cervical cancers, as well as salivary gland carcinomas. We critically evaluate the current state by examining the relevant applications, diagnostic accuracy, therapeutic efficacy, and inherent limitations. Finally, we analyze the challenges impeding widespread clinical application and offer insights into strategies for advancing the field, thereby guiding future research endeavors.

Prospective Screening of Cancer Syndromes in Patients with Mesenchymal Tumors

Background: The etiology of most mesenchymal tumors is unknown, and knowledge about syndromes with an increased risk of tumors in bone or soft tissue is sparse. Methods: We present a prospective germline analysis of 312 patients with tumors suspected of being sarcomas at a tertiary sarcoma center. Germline and tumor whole genome sequencing, tumor transcriptome, and methylome analyses were performed. Results: Germline pathogenic or likely pathogenic variants associated with an increased risk of tumors were detected in 24 patients (8%), of which 11 (4%) harbored a detectable second hit in the tumor. Second hits were confirmed in genes with (NF1, RB1, TP53, EXT2, and SDHC) and without (ATM, CDC73, MLH1, MSH6, POLG, and KCNQ1) known association with mesenchymal tumor predisposition. Sarcomas from two Lynch syndrome patients showed mismatch repair deficiency, predicting a treatment response to immune checkpoint inhibitors (Level 1 biomarker according to the FDA (Federal Drug Administration) and ESMO (European Society for Medical Oncology)). None of the three CHEK2 carriers had a second hit in the tumor, suggesting a weak link to sarcoma. Conclusions: We conclude that second-hit analyses can be used in standard of care to identify syndrome-related tumors. This approach can help distinguish true manifestations of tumor syndromes from unrelated germline findings and enhance the understanding of germline predisposition in soft tissue tumors. Prospective screening using germline whole genome sequencing should be considered when comprehensive somatic sequencing is introduced into clinical practice.

Abstract 4146315: Complications Associated With the 4798 Attain Stability Active Fixation Coronary Sinus Lead: Insights from the MAUDE Registry

Background: The Attain Stability Quad 4798 [Medtronic, Minneapolis, MN] lead was recently developed with a mechanism for active fixation into the venous wall, allowing for precise and secure placement in coronary venous branches. However, real-world data regarding complication rates are limited. Research Question: What are the real-world complications of the Medtronic 4798 lead? Goals: We reviewed the United States Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database for adverse events associated with the 4798 lead. Methods: We reviewed the MAUDE database on November 15, 2023, for all reported complications due to the 4798 lead from January 1, 2018 – a year before the lead was approved by the FDA – to the present. Results: A total of 2011 reports of adverse events occurred in mostly males (67.9%) patients with an average age of 70.86±12.1 years. Leads were used most frequently in 2023 (32.3%) for initial use (65.5%) but events commonly occurred intra-procedurally (73.7%). Device malfunction occurred in 43.4% of cases and included but was not limited to adverse events without an identified device problem (33.9%), device dislodgment (24.1%), infection (21.1%), and failure to capture (18.4%). In several cases, the guidewire was stuck (10.7%), or lead dislodgement (27.9%) occurred, resulting in direct helix damage (10.1%). Malfunctions resulted in injury and death in 55.8% and 1.1% of cases, respectively. Conclusions: The use of an active fixation CS lead has been associated with a significant incidence of intraprocedural helix mechanism malfunction. Further real-world surveillance and registry data can help clarify the true incidence of lead failure.