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Furoscix (furosemide injection) 80 mg/10 mL is a pH neutral formulation administered subcutaneously (SC) over 5 hours to treat edema in adults with chronic HF or chronic kidney disease. Furosemide 80 mg/mL is a novel concentrated formulation administered as a single 1.0-mL SC injection that could improve convenience for patients. This randomized, open-label, phase 1 study assessed the pharmacokinetics, bioavailability, pharmacodynamics, and safety of furosemide 80 mg/mL SC versus furosemide 80 mg administered intravenously (IV). Healthy volunteers were randomized 1:1 to furosemide 80 mg/mL SC or furosemide 80 mg IV (two 40-mg boluses, 2 hours apart), and after a 3-day washout, received the opposite treatment. Plasma furosemide pharmacokinetics, urine output, and urinary sodium and potassium excretion were measured through 12 hours post-dose. Bioavailability (the primary endpoint) was assessed as the least-squares mean ratio (LSMR) of area under the curve (AUC) from time 0-last (AUClast) and 0-infinity (AUCinf) between furosemide SC and furosemide IV. Plasma furosemide pharmacokinetics were assessed noncompartmentally. Pharmacodynamics were assessed using a repeated measures, mixed model analysis. Safety was assessed through end of study. Twenty-one participants were randomized (furosemide SC/IV, n = 10; furosemide IV/SC, n = 11). The furosemide SC/IV LSMR (90% confidence interval [CI]) AUClast was 106.1% (102.7%, 109.6%), and LSMR (90% CI) AUCinf was 107.3% (103.9%, 110.8%). Furosemide 80 mg/mL SC had bioavailability equivalent to furosemide 80 mg IV, as the CIs fell within 80.0%-125.0%. Mean (SD) Cmax was 4532.9 (1497.7) ng/mL with furosemide 80 mg/mL SC and 10,087.6 (2804.7) ng/mL with furosemide IV. The therapeutic effects of furosemide 80 mg/mL SC on diuresis, natriuresis, and kaliuresis occurred within 1 hour of treatment and were consistent with those of furosemide IV at all time points. There was no significant difference between furosemide 80 mg/mL SC versus furosemide IV in total urine output or urinary sodium or potassium excretion at 0-6 hours, 0-8 hours, or 0-12 hours. Adverse events (AEs) occurred in 14 (66.7%) participants (furosemide SC, n = 11 [52.4%]; furosemide IV, n = 7 [35.0%]) and were mild or moderate. Ten (47.6%) participants had injection site AEs, all of which were treatment-related, mild, non-serious, and resolved. Injection site pain scores graded on a Likert 11-point scale remained low (mean, <0.4; median, 0) at all time points, were similar between groups, and decreased over time. Furosemide 80 mg/mL SC injection was generally well tolerated and had bioavailability, diuresis, natriuresis, and kaliuresis consistent with those of furosemide IV.

Abstract Background: PRMT5 is an epigenetic enzyme that catalyzes symmetric di-methylation of arginine (SDMA) of multiple substrates that regulate biological processes including RNA splicing and cell cycle. The role of PRMT5 in controlling chromatin accessibility has been investigated in some cancer contexts, but its role in non-small cell lung cancer (NSCLC) global chromatin regulation is not known. AstraZeneca has developed an MTA-cooperative PRMT5 inhibitor (AZD3470) that selectively inhibits PRMT5 in MTAP-null tumors and currently is in Phase I clinical trial (NCT06130553, NCT06130553). Here we applied integrative dynamic MultiOMICs analysis upon AZD3470 treatment in six MTAP-null NSCLC cancer cell lines to inform on PRMT5’s function in maintaining tumor cell growth and survival. Methods: Utilizing an integrative approach, our study explored the effects of AZD3470 on human MTAP-deleted NSCLC cells. MultiOMICs analysis including SDMA post-translational modification (PTM) scans, ATAC-seq, RNA-seq, and mass spectrometry proteomics were employed to delineate the immediate effects and downstream phenotypes of AZD3470 PRMT5 inhibition. Results: AZD3470 induced significant SDMA modification of splicing factors consistent with known roles for PRMT5. PRMT5 inhibition by AZD3470 led to changes in global chromatin accessibility in NSCLC cells. Specific changes in genes involved in the cell cycle pathway were observed including CDK6. Integrative analysis of transcriptomics and proteomics data consistently showed alterations in cell cycle, DNA damage repair and splicing related pathways upon treatment, consistent with the established biological roles of PRMT5. Alternative splicing analysis showed that AZD3470 treatment induced a unique retained intron within the ATM gene and resulted in reduced ATM protein levels. Conclusion: Here we identify AZD3470-induced changes to protein post-translational modification, chromatin accessibility, gene expression and RNA splicing in MTAP-deficient NSCLC cancer cell lines. Different area of MultiOMICs data together pointed to changes in cell cycle and DNA repair pathways. Further, we identified alternative splicing of ATM as a consequence of AZD3470 PRMT5i treatment resulting in significant reduction of ATM protein expression. Keywords: AZD3470, NSCLC, PRMT5 Inhibition, Chromatin Accessibility, Alternative Splicing, DNA Repair, ATM Gene. Citation Format: Ted Hong, Steven Criscione, Andrew Jarnuczak, Jelena Urosevic, Stephanie Ashenden, Ghaith Hamza, Praveen Kumar, Nevena Cvetesic, Lauren Bradshaw, Shaun Moore, Daniel Karl, Tianhui Zhang, Abel Sousa, Jonathan Cairns, Anthony Iannetta, Andrew Zhang, Eric Miele, John Reicha, Chris Chambers, Ramy Elgendy, Julia Lindgren, Daniel Jachimowicz, Maryam Clausen, Graham Belfield, Tony Cheung, Michael Grondine, James T. Lynch, Ho Man Chan, Susan Critchlow, Emma Dean. Integrative dynamic MultiOMICs analysis identifies cell cycle and DNA damage response phenotypes as downstream consequences of using the PRMT5 inhibitor AZD3470 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB008.

Abstract BackgroundAmyloid‐directed therapies will increase the clinical use of amyloid PET. IDEAS captured &gt;17,000 clinical scan interpretations from local radiologists and nuclear medicine physicians. This study aimed to establish accuracy of these interpretations by comparison to expert readers across identical scans.MethodRandomly selected amyloid PET/CT scans performed using one of three FDA‐approved agents [18F‐Florbetaben (FBB), 18F‐Florbetapir (FBP), 18F‐Flutemetamol (FMM)] and previously interpreted by local readers from the Imaging Dementia ‐ Evidence for Amyloid Scanning (IDEAS) study were assigned to vendor‐selected panels of 3 expert readers for interpretation; 500 scans per agent and 1 panel per agent. Scans were stratified to match frequencies observed in the overall study by 1) participant age; 2) MCI vs dementia; 3) positive/negative interpretation; and 4) type of PET facility. Respective vendors performed quality control on attenuation‐corrected PET/CT images. Visual interpretations (positive or negative for Aß cortical deposition) were performed according to agent‐specific validated interpretation criteria. Expert panel readers were blinded to clinical and demographic data. Cohen’s kappa statistic with two‐sided 95% confidence interval estimates examined agreement between local reader and majority expert panel visual interpretation.ResultExpert panel readers’ visual interpretations totaled 4489. Median age for scanned participants was 75 (range 65‐96), 51.4% were female and 60.5% had MCI. Local readers interpreted 60.9% of scans positive and 39.1% negative (Table 1). Across all radiotracers, agreement between majority expert read and local readers was excellent (k coefficient 0.76; 95% CI 0.73 – 0.80, p&lt;.0001) with 86.6% (791/913) agreement for positive scans and 90.9% (532/585) agreement for negative scans (Figure 1). Agreement by individual radiopharmaceuticals was good to excellent: k coefficient 0.78 (95% CI 0.72 – 0.83, p&lt;.001) for FBB, k coefficient 0.72 (95% CI 0.66 – 0.78, p&lt;.001) for FBP, and k coefficient 0.78 (95% CI 0.73 – 0.84) for FMM (Figure 1). Agreement levels between local readers and individual experts varied from good to excellent (Figure 2).ConclusionWe found good to excellent agreement between local readers and majority assessment of three‐member expert panels for all combined scans and scans by individual agents. Visual interpretation of Aß PET can be performed in a clinical setting with high reliability.

Abstract BackgroundWe aimed to describe amyloid‐ and tau‐PET in patients with sporadic Early Onset AD (sEOAD) from the Longitudinal Early‐onset Alzheimer’s Disease Study. We focused on amyloid‐tau relationships and on the association between i) age, sex, and ii) cross‐sectional and longitudinal PET measures.MethodsIn December 2022, we selected patients who fulfilled the following criteria: 1) clinical diagnosis of MCI or mild dementia, 2) available amyloid‐PET (18F‐florbetaben), tau‐PET (18F‐fortaucipir), and structural MRI, 3) positive amyloid‐PET based on a process including visual read and quantification. Image acquisition, quality control, and processing followed ADNI procedures. Florbetaben‐PET Centiloids and mean cortical Flortaucipir‐SUVR were extracted in native space using FreeSurfer. Cross‐sectional analyses were performed using general linear models; longitudinal analyses (up to 4 scans/patient) were performed using linear mixed effect models with random intercepts.ResultsOut of the 372 cognitively impaired patients included in LEADS, 280 (75.3%) were amyloid‐positive patients with sEOAD (Table 1 for demographics and clinical characteristics). Cross‐sectionally, Centiloids and cortical Flortaucipir‐SUVR were correlated (r = 0.29, p&lt;.001; Fig 1a). Patient’s age was associated with cortical tau‐PET (older patients showing lower Flortaucipir‐SUVR, r = ‐0.47, p&lt;0.001, Fig 1b) but not amyloid‐PET (r = ‐0.02, p = 0.68). Females showed greater amyloid (d = 0.43, p&lt;0.001, Fig 1c) and tau‐PET burden (d = 0.35, p = 0.004), in the absence of sex differences in MMSE or CDR‐SB (d’s&lt;0.16, p’s&gt;0.37). Sex differences in tau‐PET remained significant (p = 0.04) when controlling for age and Centiloids. Both Centiloids and Flortaucipir‐SUVR increased longitudinally (p&lt;0.001, Figure 3a‐b). The rate of Centiloid change was not modulated by age (time*age, p = 0.79) or sex (time*sex, p = 0.91). Changes in tau‐PET were independent of sex (time*sex, p = 0.15), but younger patients tended to show greater FTP‐SUVR progression (time*age, p = 0.07). In a subsample of 123 patients with at least 2 timepoints for both amyloid and tau‐PET (Fig 3c), rates of amyloid and tau changes were correlated (r = 0.22, p = 0.013).ConclusionIn patients with sEOAD, amyloid‐ and tau‐PET are modestly correlated at baseline and continue to increase together over time. In EOAD, younger age is associated with higher tau‐PET burden, independent of amyloid. Females show greater amyloid and tau burden than males despite similar clinical severity measures.

Abstract BackgroundCompared with biofluid‐biomarkers, tau‐PET shows stronger association with cognitive impairment (Ossenkoppele,R‐2021) and decline, and better detects Alzheimer’s disease (AD) pathology (Coomans,EM‐2022; Smith,R‐2022). Conventionally, tau‐cognition relationship has been evaluated between global cortical tau‐PET and composite cognitive scores. However, tau‐PET binding patterns are heterogenous, with regional binding showing strong correlations with domain‐specific cognitive performance and decline. The goal of this study was to evaluate domain‐specific patterns of tau‐PET at baseline and in change‐from‐baseline (CFB) in symptomatic AD patients.MethodAmyloid‐positive participants (n = 172) with a clinical diagnosis of mild‐cognitive‐impairment (n = 97) or dementia due to AD (n = 76) and amyloid‐negative healthy‐controls (n = 68) underwent a 18Flortaucipir tau‐PET and neuropsychological testing (AV1451‐A05:NCT02016560) at baseline and 18months. Observed cognitive scores in impaired patients were normalized to age‐adjusted outcomes in healthy‐controls at baseline and 18months (Ossenkoppele,R‐2015). These scores were subsequently averaged within the episodic‐memory, semantic‐memory, language, visuospatial, and executive function cognitive domains (Malpetti,M‐2022). Standardized uptake value ratio (SUVr) in automated‐anatomical‐labelling regions (Tzourio‐Mazoyer,M‐2002) and AD‐specific region (MUBADA; Devous,M‐2017) was calculated in reference to cerebellum‐crus. The CFB (18months‐baseline) in SUVr and domain‐specific sub‐scores were calculated for all participants. Correlations between global SUVr versus composite cognitive score and regional SUVr versus domain‐specific scores at baseline and CFB were calculated.ResultDifferential cross‐sectional tau‐PET patterns showed significant negative associations with domain‐specific cognitive performance (Fig.1A). When evaluated longitudinally, higher global CFB in tau‐PET SUVr showed no‐to‐modest correlation with cognitive decline (Fig.2: ADAS‐Cog11 = 0.012, FAQ = ‐0.015, MMSE = ‐0.210, CDR‐SB = 0.014), however, heterogeneous associations were observed at the regional‐ and voxel‐level (Fig.1B,Fig.3), ranging from maximum of r = ‐0.45 (p&lt;0.001; frontal‐inferior and visuospatial) to minimum of r = ‐0.002 (p&lt;0.1; lingual and episodic). Increase in tau‐PET signal was associated with greater cognitive decline (i.e. visuospatial function: predominantly frontal; executive function: parietal and prefrontal; semantic‐memory: superior temporal region). An extensive and asymmetric tau‐PET pattern (L&gt;R) in frontal and occipital regions was related to language.ConclusionWe found associations between patterns of tau accumulation and domain‐specific cognitive decline in MCI and AD dementia. After validations using larger datasets, these relationships can supplement widely used associations between global tau‐PET and composite cognitive scores and, therefore, enhance tau PET‐guided and patient‐centered staging, prognosis, and response assessment.

PET-based radiomic metrics are increasingly utilized as predictive image biomarkers. However, the repeatability of radiomic features on PET has not been assessed in a test-retest setting. The prostate-specific membrane antigen-targeted compound 18 F-DCFPyL is a high-affinity, high-contrast PET agent that we utilized in a test-retest cohort of men with metastatic prostate cancer (PC). Data of 21 patients enrolled in a prospective clinical trial with histologically proven PC underwent two 18 F-DCFPyL PET scans within 7 days, using identical acquisition and reconstruction parameters. Sites of disease were segmented and a set of 29 different radiomic parameters were assessed on both scans. We determined repeatability of quantification by using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland-Altman analysis. In total, 230 lesions (177 bone, 38 lymph nodes, 15 others) were assessed on both scans. For all investigated radiomic features, a broad range of inter-scan correlation was found (r, 0.07-0.95), with acceptable reproducibility for entropy and homogeneity (wCOV, 16.0% and 12.7%, respectively). On Bland-Altman analysis, no systematic increase or decrease between the scans was observed for either parameter (±1.96 SD: 1.07/-1.30, 0.23/-0.18, respectively). The remaining 27 tested radiomic metrics, however, achieved unacceptable high wCOV (≥21.7%). Many common radiomic features derived from a test-retest PET study had poor repeatability. Only Entropy and homogeneity achieved good repeatability, supporting the notion that those image biomarkers may be incorporated in future clinical trials. Those radiomic features based on high frequency aspects of images appear to lack the repeatability on PET to justify further study.