US Food Research Articles

Mechanism of protective actions of sparsentan in the kidney: lessons from studies in models of chronic kidney disease.

Simultaneous inhibition of angiotensin II AT1 and endothelin ETA receptors has emerged as a promising approach for treatment of chronic progressive kidney disease. This therapeutic approach has been advanced by the introduction of sparsentan, the first dual AT1 and ETA receptor antagonist. Sparsentan is a single molecule with high affinity for both receptors. It is US Food and Drug Administration approved for immunoglobulin A nephropathy (IgAN) and is currently being developed as a treatment for rare kidney diseases, such as focal segmental glomerulosclerosis. Clinical studies have demonstrated the efficacy and safety of sparsentan in these conditions. In parallel with clinical development, studies have been conducted to elucidate the mechanisms of action of sparsentan and its position in the context of published evidence characterizing the nephroprotective effects of dual ETA and AT1 receptor inhibition. This review summarizes this evidence, documenting beneficial anti-inflammatory, antifibrotic, and hemodynamic actions of sparsentan in the kidney and protective actions in glomerular endothelial cells, mesangial cells, the tubulointerstitium, and podocytes, thus providing the rationale for the use of sparsentan as therapy for focal segmental glomerulosclerosis and IgAN and suggesting potential benefits in other renal diseases, such as Alport syndrome.

Late-Onset Molybdenum Cofactor Deficiency Type A: A Treatable Cause of Developmental Delay.

Molybdenum cofactor deficiency classically presents in neonates with intractable seizures; however, milder cases generally present before age 2 years with developmental delays and may go undiagnosed. Early diagnosis, and safe, US Food and Drug Administration-approved substrate replacement are critical to preserve neurologic function. This article discusses 2 children who presented with late-onset molybdenum cofactor deficiency type A.

Safe Administration of Medication in School: Policy Statement.

Many youth with acute and chronic health conditions require medication to be administered during the school day. This policy statement offers guidance to school physicians, community prescribers, school nurses, other school health professionals, and groups providing oversight to school health activities and ensures patient safety and equity lenses are applied to administration of medications during school and for school-related activities. The American Academy of Pediatrics supports a robust collaborative model that allows all those involved in student health, including the student and family, to communicate, participate in effective medication management, inform delegated medication responsibilities, and promote safe medication storage and administration. School medication administration protocols are developed to help prevent medication administration errors specific to potential risks in the school setting and are responsive to the maturing students' evolving understanding of their health needs, growing autonomy, and responsibility. All protocols involving school nurses, unlicensed assistive personnel, and prescribers must be consistent with state and federal regulations on scope of practice, student privacy laws, and professional nursing organization guidelines. Consistent policies and messaging on safety of the patient and the entire school community enable school health teams to ensure equitable treatment of students prescribed therapeutic agents newly regulated by the US Food and Drug Administration, over-the-counter medications, or products that are currently not regulated by the US Food and Drug Administration.

Guaifenesin: The Ubiquitous Orphan.

Guaifenesin, a widely used ingredient in over-the-counter cough and cold medications, has been a subject of debate regarding its efficacy in treating respiratory conditions. Despite its historical use and US Food and Drug Administration approval, recent studies have questioned its claimed expectorant effect and its effectiveness in managing symptoms. This article examines the available evidence, highlighting the lack of significant benefits over placebo for upper respiratory disease. The rationale for clinical use is examined alongside the potential downside and alternatives to recommending guaifenesin as a treatment option.

Development and validation of a high-performance liquid chromatography with tandem mass spectrometry method for quantification of tofacitinib in human plasma

Introduction. The use of tofacitinib as a pharmacological treatment for rheumatoid arthritis remains relevant in the light of the predicted increase in prevalence of the disease. At the same time, due to the withdrawal of several foreign pharmaceutical companies from the Russian pharmaceutical market, there has been a heightened demand for domestically produced medications, including generic formulations of tofacitinib. Registration of generic drugs necessitates the conduct of bioanalytical studies. Development and validation of a method for quantifying the analyte in biosamples remains to be a crucial part of the bioequivalence studies.Aim. The aim of this research is to develop and validate a method for the quantitative determination of tofacitinib in human plasma using high-performance liquid chromatography as the separation system coupled with a tandem mass spectrometer for detection purposes.Materials and methods. Biosample preparation was based on plasma proteins precipitation using acetonitrile. Baricitinib was selected as an internal standard. The analytical range of the method was 1.00 to 200.00 ng/mL and was further expanded to 0.30 to 200.00 ng/mL during the analytical phase of the study. The mobile phase consisted of water and acetonitrile, both acidified with formic acid (0.1 % v/v). The stationary phase was a Phenomenex Kinetex C18 column [100 × 3.0 mm, with a particle size of 5 µm (Phenomenex, USA)]. Sample separation and detection were carried out using high-performance liquid chromatography coupled with a tandem mass spectrometry (HPLC-MS/MS), operating in positive ion mode. The multiple reaction monitoring (MRM) transitions selected for the analyte and the internal standard were 313.30 to 173.00 m/z and 371.90 to 186.00 m/z, respectively.Results and discussion. The developed assay was validated in accordance with the current requirements of regulatory documentation from the EAEU (Eurasian Economic Union), FDA (US Food and Drug Administration), and EMA (European Medicines Agency) with the following parameters being evaluated: selectivity, specificity, carry-over, matrix effect, recovery, calibration curve, lower limit of quantitation, accuracy, precision, stability. The validated method was applied in the analytical part of a bioequivalence study of domestically produced generic tofacitinib.Conclusion. A method for the quantitative determination of tofacitinib in human blood plasma with an analytical range of 0.30–200.00 ng/mL was developed and validated. Application of the assay during the analytical phase of bioequivalence study of generic tofacitinib confirms the possibility of using the method in similar bioanalytical investigations.

Comparison of the safety profiles for pirfenidone and nintedanib: a disproportionality analysis of the US food and drug administration adverse event reporting system

Comparison of the safety profiles for pirfenidone and nintedanib: a disproportionality analysis of the US food and drug administration adverse event reporting system

P.024 Sex and gender reporting in clinical trials among neurological US Food and Drug Administration approvals

Background: Sex and gender are related but distinct determinants of disease, treatment response, and research reproducibility whose consideration is increasingly required for research funding. Nevertheless, the quality of sex and gender reporting in neurological randomized controlled trials (RCTs) remains unknown. Methods: This ongoing study of RCTs associated with Food and Drug Administration neurological drug approvals aims to determine the frequency of accurate reporting of RCT participants’ sex and gender. Secondary outcomes include changes in reporting over time and RCT design characteristics. Results: Preliminary analysis included 145 RCTs (153,410 participants) associated with 77 medications approved in 1985-2023, most commonly for epilepsy (19%), migraine (16%), and multiple sclerosis (16%). Sixty-six RCTs (45.5%) used sex-related terms appropriately. Nine RCTs (6.2%) reported gender accurately. Fifty-three RCTs (37%) used sex- or gender-related terms interchangeably. There are no statistically significant differences in the proportions of studies reporting sex and/or gender accurately when comparing those published until versus after 2017. No RCT reported sex or gender collection methods, definitions of sex or gender, or including sex or gender minority participants. Conclusions: Preliminary results suggest shortcomings in reporting sex and, especially, gender accurately and inclusively among neurological drug RCTs and no significant improvement thereof in recent years.

Cost-effectiveness of treating relapsed or refractory 3L+ follicular lymphoma with axicabtagene ciloleucel vs mosunetuzumab in the United States

IntroductionNovel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective.MethodsA three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 and GO29781 trial data were used to inform progression-free survival (PFS) and overall survival (OS). Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel survival curves. The PFS HR value was estimated via a matching-adjusted indirect comparison (MAIC) based on mosun pseudo-individual patient data and adjusted axi-cel data to account for trial populations differences. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analyses (PSA) were conducted. Scenario analyses included: 1) the mosun HRs were applied to the weighted (adjusted) ZUMA-5 24-month data to most exactly reflect the MAIC, 2) mosun HR values were applied to axi-cel 48-month follow-up data, and 3) recent axi-cel health state utility values in diffuse large B-cell lymphoma patients.ResultsThe analysis estimated increases of 1.82 LY and 1.89 QALY for axi-cel compared to mosun. PFS for axi-cel patients was 6.42 LY vs. 1.60 LY for mosun. Increase of $257,113 in the progression-free state was driven by one-time axi-cel treatment costs. Total incremental costs for axi-cel were $204,377, resulting in an ICER of $108,307/QALY gained. The OWSA led to ICERs ranging from $240,255 to $75,624, with all but two parameters falling below $150,000/QALY. In the PSA, axi-cel had an 64% probability of being cost-effective across 5,000 iterations using a $150,000 willingness-to-pay threshold. Scenarios one and two resulted in ICERs of $105,353 and $102,695, respectively.DiscussionThis study finds that axi-cel is cost-effective compared to mosun at the commonly cited $150,000/QALY US willingness-to-pay threshold, with robust results across a range of sensitivity analyses accounting for parameter uncertainty.

#2459 Matching-adjusted indirect comparison of eGFR in patients with immunoglobulin A nephropathy treated with Nefecon (TRF budesonide) or sparsentan

Abstract Background and Aims Primary immunoglobulin A nephropathy (IgAN) is an immune-mediated disease that can lead to kidney failure, need for dialysis and kidney transplantation, and early death. IgAN is the most common type of primary glomerulonephritis globally, with an estimated worldwide incidence of 2.5 per 100 000 individuals per year. Estimated glomerular filtration rate (eGFR) is a measure of renal function and is accepted as a surrogate endpoint for clinical trials evaluating kidney function deterioration. In December 2023, the US Food and Drug Administration (FDA) granted full approval to Nefecon (marketed as Tarpeyo® by Calliditas Therapeutics), a targeted-release formulation of budesonide, to reduce the loss of kidney function in adults with IgAN at risk of disease progression, based on the Phase 3 NefIgArd clinical trial. In February 2023, sparsentan (marketed as Filspari™ by Travere Therapeutics) was granted accelerated approval by the FDA to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a urine protein–creatinine ratio (UPCR) ≥1.5 g/g, based on the Phase 3 PROTECT study. Matching-adjusted indirect comparison (MAIC) is a widely accepted and relevant methodology for comparing treatments across trials in the absence of head-to-head comparisons. In this analysis, we aimed to compare the effects of Nefecon and sparsentan on kidney function deterioration in patients with IgAN, as assessed by eGFR. Method An anchored MAIC was performed to estimate the relative effect of Nefecon and sparsentan on the absolute eGFR change from baseline at 9, 12 and 24 months, with common comparators of optimized renin–angiotensin system inhibition for NefIgArd and irbesartan for PROTECT. Patient-level data from NefIgArd were used to select a population matched to PROTECT, and the following baseline characteristics were used to determine the weights: mean age (years), sex (% male), race (% white), mean eGFR (mL/min/1.73 m2), mean UPCR (g/g), urine albumin–creatinine ratio (UACR) (% with UACR >1.1 g/g), and urinary protein excretion (% with urinary protein excretion >1.8 g/day). Absolute change in eGFR was analyzed using a mixed model for repeated measures (MMRM) method, including baseline, 3-, 6-, 9-, 12-, 18- and 24-month data, baseline eGFR, baseline eGFR-by-time interaction, treatment, and treatment-by-time interaction. The MAIC weights were incorporated into the MMRM. A Bayesian fixed-effects network meta-analysis was performed on the relative effect from PROTECT and the weighted relative effect from NefIgArd, measured by the estimated absolute change from baseline in eGFR. Results The matching-adjustment of the NefIgArd patient population to the PROTECT population is shown in Table 1. The weighted NefIgArd population exhibits very similar baseline characteristics to the PROTECT population. The effective sample size of the weighted NefIgArd population is 208. Results from the anchored MAIC showed statistically and clinically significant favorable effects of Nefecon versus sparsentan on eGFR for all time points analyzed (Fig. 1). Mean differences in the absolute change in eGFR of 5.68 mL/min/1.73 m2 (95% credible interval [Crl] 3.14, 8.20; p < 0.001), 3.48 mL/min/1.73 m2 (95% Crl 0.97, 5.97; p = 0.006) and 3.28 mL/min/1.73 m2 (95% Crl 0.02, 6.51; p = 0.048) were observed when comparing Nefecon with sparsentan at 9 months vs 36 weeks, 12 months vs 48 weeks, and 24 months vs 106 weeks, respectively. Conclusion After accounting for differences in the patient populations from the NefIgArd and PROTECT trials, the anchored MAIC showed that treatment with Nefecon 16 mg/day for 9 months was associated with greater eGFR benefit compared with continuous treatment with sparsentan 400 mg/day over 2 years, with significant differences observed as early as 9 months after treatment initiation and sustained up to 2-years of follow-up.

#861 Intradialytic oxygen saturation in chronic hemodialysis patients—results from a large U.S. population

Abstract Background and Aims The study of intradialytic oxygen saturation (SO2) in hemodialysis (HD) patients is a significant yet under-explored area. This study's objective was to evaluate the epidemiological aspects of SO2 during HD. Method SO2 levels during HD were measured using the Crit-Line Monitor (CLM; Fresenius Medical Care North America, Waltham, MA), a device certified by the US Food and Drug Administration (FDA) for the measurement of hematocrit and SO2 in the extracorporeal circuit. CLM measurements were recorded at 10-second intervals and transmitted into Amazon Web Services (AWS) via Apache KAFKA, a real time streaming software. Apache KAFKA was rolled out in phased approach, started early 2021. We extracted CLM data between January 14, 2021, and July 30, 2023. CLM values with the following characteristics were deemed implausible and hence, excluded: SO2 ≤ 0 or ≥99.9; hematocrit < 15% or >60%. We computed basic statistics of SO2 for every HD session. We then excluded the sessions with the standard deviation of SO2 < 0.1%, an interquartile range of zero, and sessions with less than 360 SO2 measurements (i.e., less than 60 minutes of recording). Results We collected data from over 5.6 million HD sessions. After data cleaning, we retained 4.9 million HD sessions from 72,656 patients treated in 727 dialysis clinics across the US. The average duration of a session was 204.5 (±42.8) minutes. Per HD session, on average 1,227 (±257) SO2 measurements were recorded. The distribution of the number of SO2 measurements per HD session is shown in Fig. 1A. The mean of the session-level average SO2 was 88% (±15%). The distribution of session-level average SO2 is shown in Fig. 1B. The bimodal distribution of SO2 is attributed to the use of arterio-venous and central venous vascular accesses, respectively. Conclusion We collected and analysed a substantial dataset of intradialytic SO2 in a large US HD population. These data provide a rich source for future research into SO2 and its clinical correlates. Exploring intradialytic SO2 in depth will offer valuable insights to improve patient care and optimize treatment procedures.

#157 UNI-494 Phase I tolerability and pharmacokinetics: trial in progress

Abstract Background and Aims Acute kidney injury (AKI) is a clinical syndrome defined by the sudden loss of kidney function, resulting in an inability to maintain electrolyte, acid-base and water balance. Currently, there are no effective treatments for AKI approved by the US Food and Drug Administration or the European Medicines Agency (EMA); management of the condition is primarily supportive. The most common cause of AKI was thought to be ischemia. However, more recently the focus has shifted from clinical causes to the underlying cellular processes inherent in these situations, in particular the dysfunction of mitochondria in AKI. UNI-494 is a novel nicotinamide ester derivative and selective mitochondrial ATP-sensitive potassium channel activator that improves mitochondrial function and may be beneficial for several disease states, including AKI. This study aims to evaluate the safety, tolerability, and pharmacokinetics of UNI-494. Method This is a single-center, double-blind, placebo-controlled, randomized single ascending dose (SAD) (Part 1) and multiple ascending dose (MAD) (Part 2) study in healthy male subjects and female subjects of non-childbearing potential. Part 1 will enroll up to approximately 40 subjects in 5 cohorts of 8 subjects each (randomized to a ratio of 6 active and 2 placebo per cohort). There will be an interim decision meeting after each cohort/period, to review the safety, tolerability, and PK data up to 48 h post-dose in order to decide the dose level for the subsequent cohort. Part 2 will enroll approximately 20 subjects in 2 cohorts of 10 subjects each, randomized to a ratio of 8 active treatment to 2 placebo who will be dosed for 5 days. The dose level for the Part 2 Cohort 1 will be selected based on the safety, tolerability and PK data from Part 1. Results We intend to present results elucidating safety, tolerability, and pharmacokinetics of UNI-494 in healthy subjects. Conclusion The safety, tolerability, and pharmacokinetics of UNI-494 in healthy subjects will be evaluated in this study.

DNA Barcoding Revealed a High Percentage of Mislabeling in Commercial Fish Products: The First Empirical Survey in South Texas

Seafood mislabeling is a widespread problem that have produced a growing distrust of seafood industry. In this study, we examined the prevalence of mislabeling in fish samples from regional markets in the greater Houston area and close-by coastal communities. A total of 63 fish fillet samples were purchased, labeled, and stored at -20˚C in individual packages until DNA extraction. DNA fragments of roughly 700 base pairs encoding cytochrome oxidase I (COI) were PCR-amplified from each DNA sample. With 99.6–100% nucleotide identity in the GenBank and BOLD databases, all samples were correctly identified at the species level. The scientific names identified by DNA barcoding were matched with legally acceptable market names using the US Food and Drug Administration (FDA) Seafood List. Out of the 63 samples examined, 13 samples (20.6%) were mislabeled. Moreover, 24 samples (38.1%) did not use the acceptable market names, indicating that the FDA policy is poorly implemented in seafood industry. The first DNA barcoding survey this area warranted the need of continuous monitoring and the dissemination of the regulation combined with taxonomic knowledge.

#1133 Kidney characteristics of belimumab-treated patients with SLE pre-lupus nephritis indication: identifying data for future comparative research

Abstract Background and Aims Lupus nephritis (LN) is a severe, renal manifestation occurring in approximately 40% of patients with the chronic autoimmune disease systemic lupus erythematosus (SLE) [1]. Belimumab (BEL), a human immunoglobulin G1λ monoclonal antibody that binds to and inhibits soluble B-lymphocyte stimulator, was indicated for SLE in 2011 and LN in 2020 by the US Food and Drug Administration [2]. BEL has proven efficacy for SLE and LN [2], but there are limited data regarding the effectiveness of BEL to delay LN onset due to lack of sufficient follow-up time. Evaluating the demographic, clinical and kidney characteristics of patients treated with BEL before its regulatory approval for LN allows for a longer follow-up period. This study describes the kidney characteristics of patients with SLE treated with BEL and/or standard therapy (ST) pre-LN indication. The objective was to evaluate whether there are sufficient data from BEL-treated patients with kidney impairment and available laboratory measurements for use in future comparative research regarding effectiveness of BEL to delay LN onset. Method This retrospective, real-world study (GSK Study 217532) used electronic health record (EHR) data to assess adult patients with SLE. Eligible patients received BEL with or without ST (BEL cohort) or ST only (ST cohort) during the study identification period (1 January 2017 to 31 December 2020) and had activity in the EHR 12 months pre-index (baseline period); the index date was the first prescription of BEL or ST. A diagnosis of SLE was defined as presence of International Classification of Diseases, 10th Revision, Clinical Modification codes (M32.1x, M32.8, M32.9) based on either ≥ 2 outpatient medical claims or ≥ 1 inpatient/emergency department claim during the baseline period (or index date). Patients were excluded if they received BEL during the baseline period. LN- and kidney-related characteristics were measured during the baseline period and after 36 months of follow-up. Results This study identified 32 017 patients with SLE: 1318 in the BEL cohort and 30 699 in the ST cohort. The mean (standard deviation) age of the BEL and ST cohorts was 43.9 (12.7) and 51.9 (15.2) years, respectively. Most patients were White (BEL: n = 804 [61.0%]; ST: n = 19,812 [64.5%]) and female (BEL: n = 1247 [94.6%], ST: n = 27 826 [90.6%]). At baseline, 13.1% of the BEL cohort and 10.0% of the ST cohort had an LN diagnosis; chronic kidney disease (CKD) was reported in 22.1% of the BEL cohort and 27.7% of the ST cohort (Table 1). End-stage kidney disease (ESKD) was observed at baseline in 1.0% of the BEL cohort and 4.0% of the ST cohort. Dialysis rate at baseline was 0.7% in the BEL cohort and 3.5% in the ST cohort. A smaller proportion of the BEL cohort had kidney impairment than the ST cohort. Overall, 32.1% of the BEL cohort (n = 423) and 46.1% of the ST cohort (n = 14,162) had 36 months of valid follow-up. The proportion of patients with available kidney laboratory characteristics was generally similar between baseline and 36 months follow-up, and between BEL and ST cohorts (Table 2). However, the proportion of the BEL cohort at baseline and at 36 months’ follow-up with a proteinuria laboratory measurement was >2-fold that of the ST cohort (baseline: BEL = 30.5%, ST = 12.9%; follow-up: BEL = 42.1%, ST = 20.2%). Conclusion This study demonstrates that there are adequate kidney value measurements for BEL and ST patients available to assess kidney outcomes over time in patients with SLE pre-LN indication of BEL. Observationally, the ST cohort displayed more impairment than the BEL cohort, which could indicate more advanced disease in this slightly older cohort. However, future studies should account for baseline differences between ST and BEL cohorts to assess kidney impairment–related outcome measures, by using matching and weighting procedures. Funding GSK.

A Review of Novel Medical Treatments for Thyroid Eye Disease.

Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves' disease. There has been no effective medication to prevent proptosis in thyroid eye disease until 2020 when the anti-IGF-1R receptor antibody, Teprotumumab, was approved by the US Food and Drug Administration (FDA), sparking increased interest in immune-based drug development. This study aims to review the newly developed drug therapy as well as conventional treatment for TED. Treatment of TED has traditionally been high-dose steroids and orbital radiotherapy, but recently there has been a paradigm shift in the treatment of TED in the US with the introduction of the therapeutic agent teprotumumab, which dramatically reduces proptosis. However, concerns remain about the development of hearing impairment as a potentially fatal complication and long-term safety. Recently, several clinical trials are underway to assess the efficacy and safety of novel drugs targeting mTORC1, IL-6, FcRN, and IGF-1R in treating TED. With the explosive increase in interest from academia and pharmaceutical companies in TED, there is anticipation for the development of drugs that are equivalent or superior to teprotumumab while being safer.

An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease

Friedreich ataxia (FRDA) is a life-threatening hereditary ataxia; its incidence is 1:50,000 individuals in the Caucasian population. A unique therapeutic drug for FRDA, the antioxidant Omaveloxolone, has been recently approved by the US Food and Drug Administration (FDA). FRDA is a multi-systemic neurodegenerative disease; in addition to a progressive neurodegeneration, FRDA is characterized by hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. Cardiomyopathy is the predominant cause of premature death. The onset of FRDA typically occurs between the ages of 5 and 15. Given the complexity and heterogeneity of clinical features and the variability of their onset, the identification of biomarkers capable of assessing disease progression and monitoring the efficacy of treatments is essential to facilitate decision making in clinical practice. We conducted an RNA-seq analysis in peripheral blood mononuclear cells from FRDA patients and healthy donors, identifying a signature of small non-coding RNAs (sncRNAs) capable of distinguishing healthy individuals from the majority of FRDA patients. Among the differentially expressed sncRNAs, microRNAs are a class of small non-coding endogenous RNAs that regulate posttranscriptional silencing of target genes. In FRDA plasma samples, hsa-miR-148a-3p resulted significantly upregulated. The analysis of the Receiver Operating Characteristic (ROC) curve, combining the circulating expression levels of hsa-miR-148a-3p and hsa-miR-223-3p (previously identified by our group), revealed an Area Under the Curve (AUC) of 0.86 (95%, Confidence Interval 0.77–0.95; p-value < 0.0001). An in silico prediction analysis indicated that the IL6ST gene, an interesting marker of neuroinflammation in FRDA, is a common target gene of both miRNAs. Our findings support the evaluation of combined expression levels of different circulating miRNAs as potent epi-biomarkers in FRDA. Moreover, we found hsa-miR-148a-3p significantly over-expressed in Intermediate and Late-Onset Friedreich Ataxia patients’ group (IOG and LOG, respectively) compared to healthy individuals, indicating it as a putative prognostic biomarker in this pathology.

Strengthening the use of artificial intelligence within healthcare delivery organizations: balancing regulatory compliance and patient safety.

Surface the urgent dilemma that healthcare delivery organizations (HDOs) face navigating the US Food and Drug Administration (FDA) final guidance on the use of clinical decision support (CDS) software. We use sepsis as a case study to highlight the patient safety and regulatory compliance tradeoffs that 6129 hospitals in the United States must navigate. Sepsis CDS remains in broad, routine use. There is no commercially available sepsis CDS system that is FDA cleared as a medical device. There is no public disclosure of an HDO turning off sepsis CDS due to regulatory compliance concerns. And there is no public disclosure of FDA enforcement action against an HDO for using sepsis CDS that is not cleared as a medical device. We present multiple policy interventions that would relieve the current tension to enable HDOs to utilize artificial intelligence to improve patient care while also addressing FDA concerns about product safety, efficacy, and equity.

Sustained Release Therapies with the Prostaglandin Analogues Intracameral Implants.

The travoprost intracameral implant was recently approved by the US Food and Drug Administration for sustained release medical treatment of open-angle glaucoma in the USA. The approval represents a substantial and progressive step forward in the area of sustained-release glaucoma therapy. Topical intraocular pressure-lowering medications for the treatment of glaucoma are faced with a host of challenges for long-term and usually lifelong care. A changing paradigm in glaucoma management involves first-line interventions with laser modalities, micro-invasive surgeries, and sustained-release treatment platforms. Future needs in the area of sustained-release therapy include a non-prostaglandin drug delivery platform and longer-term treatments that do not require surgical reintervention.

Data mining and safety analysis of avatrombopag: a retrospective pharmacovigilance study based on the US food and drug administration’s adverse event reporting system

With its increasing use in the treatment of thrombocytopenia, avatrombopag’s associated adverse events (AEs) pose a major challenge to its clinical application. This study aims to comprehensively study AEs associated with avatrombopag by using real-world evidence. We curated AE reports for avatrombopag from the first quarter of 2018 to the fourth quarter of 2023 in the US Food and Drug Administration’s Adverse Event Reporting System (FAERS) database. AEs were coded using the Medical Dictionary for Regulatory Activities of Preferred Terms and System Organ Classes. The reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item Gamma-Poisson Shrinker were used to investigate the relationship between avatrombopag and AE reports. Among 9,060,312 reported cases in the FAERS database, 1211 reports listed avatrombopag as “primary suspected” drug. Disproportionality analysis identified 44 preferred terms across 17 organ systems met the criteria for at least one of the four algorithms. The most commonly reported AEs were platelet count decreased (20.2%), headache (16.7%), platelet count increased (11.9%), platelet count abnormal (6.3%), contusion (2.7%), pulmonary embolism (2.3%), and deep vein thrombosis (2.1%). Unexpected AEs such as seasonal allergy, rhinorrhea, antiphospholipid syndrome, ear discomfort, and photopsia were also observed. Excluding the other serious outcomes, hospitalization (34.6%) was the most frequently reported serious outcome, followed by death (15.4%). Most reported AEs occurred within the first 2 days of initiating avatrombopag therapy, and the median onset time was 60 days. We identified new and unexpected AEs with clinical use of avatrombopag, and our results may provide valuable information for clinical monitoring and identifying risks associated with avatrombopag.

Clinical trial design and treatment effects: a meta-analysis of randomised controlled and single-arm trials supporting 437 FDA approvals of cancer drugs and indications.

This study aims to analyse the association between clinical trial design and treatment effects for cancer drugs with US Food and Drug Administration (FDA) approval. Cross-sectional study and meta-analysis. Data from Drugs@FDA, FDA labels, ClincialTrials.gov and the Global Burden of Disease study. Pivotal trials for 170 drugs with FDA approval across 437 cancer indications between 2000 and 2022. Treatment effects were measured in HRs for overall survival (OS) and progression-free survival (PFS), and in relative risk for tumour response. Random-effects meta-analyses and meta-regressions explored the association between treatment effect estimates and clinical trial design for randomised controlled trials (RCTs) and single-arm trials. Across RCTs, greater effect estimates were observed in smaller trials for OS (ß=0.06, p<0.001), PFS (ß=0.15, p<0.001) and tumour response (ß=-3.61, p<0.001). Effect estimates were larger in shorter trials for OS (ß=0.08, p<0.001) and PFS (ß=0.09, p=0.002). OS (ß=0.04, p=0.006), PFS (ß=0.10, p<0.001) and tumour response (ß=-2.91, p=0.004) outcomes were greater in trials with fewer centres. HRs for PFS (0.54 vs 0.62, p=0.011) were lower in trials testing the new drug to an inactive (placebo/no treatment) rather than an active comparator. The analysed efficacy population (intention-to-treat, per-protocol, or as-treated) was not consistently associated with treatment effects. Results were consistent for single-arm trials and in multivariable analyses. Pivotal trial design is significantly associated with measured treatment effects. Particularly small, short, single-centre trials testing a new drug compared with an inactive rather than an active comparator could overstate treatment outcomes. Future studies should verify results in unsuccessful trials, adjust for further confounders and examine other therapeutic areas. The FDA, manufacturers and trialists must strive to conduct robust clinical trials with a low risk of bias.

P37 Drug repurposing for treatment of recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma

Abstract Background Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disorder that leads to severe wounding and blistering of the skin. Patients with RDEB develop aggressive cutaneous squamous cell carcinoma (cSCC) with a mortality rate of approximately 90% by age 55 years. The current primary treatment is wide excision of tumours, often leading to amputations. Identifying new therapeutic avenues for RDEB cSCC remains a priority. Here, we approach this in two ways. Firstly, we identified a SMAD4-dependent sphingosine pathway response to endogenous transforming growth factor (TGF)-β, essential for RDEB cSCC proliferation which could be targeted as a potential therapeutic strategy. Secondly, we utilized a US Food and Drug Administration (FDA) screen of &amp;gt; 3000 drugs to identify potential druggable pathways that could be used to treat RDEB cSCC. Methods RDEB cSCC cell lines were used to test Siponimod, a sphingosine-1 receptor modulator, on proliferation, clonogenicity and invasion in vitro. Siponimod was used in vivo to test tumour growth effect of targeting the sphingosine pathway. We carried out an FDA-approved drug screen on four RDEB cSCC cell lines using the Opera Phenix high-throughput microscope to identify targets. Results Treatment of RDEB cSCC cell lines with Siponimod showed compromised proliferation compared with untreated cells in addition to significant reduction in colony formation. There was a significant decrease in the invasive capability of RDEB SCC cells. Treatment of normal human keratinocytes showed no effect on proliferation. Our FDA-approved screen identified multiple drugs that target MEK, mechanistic target of rapamycin complex, histone deacetylase, signal transducer and activator of transcription, and topoisomerase I/II in the top 50 hits. The most common target was DNA damage/repair pathways, but cytoskeletal signalling, transmembrane transporters and proteases were identified as other potential avenues for treatment of RDEB cSCC. Conclusions There is an unmet need for therapeutic options in RDEB cSCC. Here, we have demonstrated the potential of repurposing previously licensed drugs to identify treatment avenues for RDEB cSCC.