Roche (Switzerland)

Current ICH guidelines, e.g.ICH E6 (R3), advocate a risk-based statistical review of clinical trial data to identify anomalies. The open-source R package, clinical trial anomaly spotter (CTAS) has been developed by Bayer and the Intercompany Quality Analytics (IMPALA) consortium, helps detect inconsistencies in subject time series data at both site and subject levels, facilitating timely intervention. CTAS analyzes time series of equal length. Each subject-level time series is summarized as six optional scalars: mean, standard deviation, range, relative unique value count, autocorrelation and local outlier factor. To detect site-level anomalies, sites can be scored using 3 different scoring methods. The performance of the CTAS algorithm was tested using simulations, artificially introducing site anomalies of various types and degrees into clinical trial data sets. We found that CTAS can reliably detect site anomalies depending on the degree of the anomaly introduced. Less complex anomalies such as mean were easier to detect than complex outlier such as local outlier factor. The three scoring methods differed in their ability to detect anomalous sites with a small number of patients and their false positive rates. CTAS is a valuable tool for timely detection of outliers in clinical data, suitable for integration into risk-based strategies. Choosing the appropriate site anomaly scoring method is crucial for handling sites with fewer subjects effectively.

The RHONE-X study (ClinicalTrials.gov identifier, NCT04432831) evaluated long-term safety and tolerability (primary end points), and efficacy (exploratory end points) of faricimab, a dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A) inhibitor, using a treat-and-extend (T&E) protocol in patients with diabetic macular edema (DME). Global phase 3, multicenter, nonrandomized, 2-year open-label extension study of the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) studies. Of 1622 patients who completed YOSEMITE and RHINE, 1474 patients (91%) were included in the RHONE-X trial. Patients transitioned from faricimab every 8 weeks (Q8W), faricimab T&E, or aflibercept 2.0 mg Q8W in YOSEMITE and RHINE to the RHONE-X study without requiring monthly initiation doses. All received faricimab T&E at up to 16-week intervals based on best-corrected visual acuity (BCVA) and central subfield thickness (CST), per YOSEMITE and RHINE criteria. Patients attended every month during the initial 4-month masked period, then only for T&E dosing visits (open-label arm). Analysis windows were defined for the RHONE-X study years 1, 1.5, and 2 to account for visit asynchronicity. The primary end point was incidence and severity of ocular and nonocular adverse events (AEs). Exploratory end points included change from baseline BCVA and CST, proportion of patients with absence of DME (CST < 325 μm), and treatment durability. Overall, 1204 patients (82%) completed the RHONE-X trial. The incidence of AEs leading to treatment discontinuation (1.5%) and rates of intraocular inflammation (1.3%) were low. Overall, faricimab T&E maintained visual and anatomic improvements achieved in YOSEMITE and RHINE. Adjusted mean BCVA improvements from YOSEMITE and RHINE baseline to the end of the RHONE-X trial were +10.1 letters (faricimab T&E), +11.4 letters (faricimab T&E [prior Q8W]), and +9.5 letters (faricimab T&E [prior aflibercept]); CST reductions were -198.3 μm, -202.5 μm, and -204.9 μm, respectively. At study end, more than 90% of patients achieved DME absence, regardless of prior treatment. Median number of injections over the RHONE-X trial (2 years) were 7 (faricimab T&E), 8 (faricimab T&E [prior Q8W]), and 8 (faricimab T&E [prior aflibercept]). By the RHONE-X trial completion, approximately 80% of patients received faricimab at ≥Q12W intervals. Faricimab, a dual Ang-2 and VEGF-A inhibitor, provided long-term safety, efficacy, and durability in patients with DME treated using a T&E regimen. Sustained visual and anatomic improvements were observed, with extended dosing intervals and reduced treatment burden. Faricimab was well tolerated, with a safety profile consistent with the YOSEMITE and RHINE trials. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

To evaluate the association of hyperreflective foci contiguous with the retinal pigment epithelium (rpeHRF) with visual function impairment in aged normals, early age-related macular degeneration (eAMD), and intermediate AMD (iAMD). Prospective cohort study. Participants of the MACUSTAR study. MACUSTAR participants underwent color fundus photography, optical coherence tomography (OCT) imaging, best corrected visual acuity (BCVA), low-luminance VA (LLVA), rod-mediated dark adaptation (RMDA) at 12°, contrast sensitivity (CS), mesopic (mesPSD), and scotopic pointwise sensitivity deviation (scPSD) testing. rpeHRF presence and count were determined using custom FiJi software. Group comparisons and associations with visual function were analyzed using analysis of variance, linear regression, and Spearman correlation. Presence, burden, and topographic distribution of rpeHRF, as well as association with functional parameters, were determined. Fifty-six normal aged (33 female, mean age 68.1 ± 6.4 years), 34 eAMD (27 female, 71.7 ± 6.4 years), and 583 iAMD eyes (387 female, 72.0 ± 7.0 years) were included. rpeHRF counts were 0.16 ± 0.85 in normals, 0.33 ± 0.96 in eAMD, and 1.61 ± 2.49 in iAMD (P < .001). BCVA, LLVA, CS (all P < .001), and scPSD (P = .001) differed between disease groups, whereas RMDA and mesPSD did not. In iAMD, eyes with rpeHRF showed worse BCVA, LLVA, CS, scPSD (all P < .001), and mesPSD (P = .02). rpeHRF was found to be associated modestly with only CS, scPSD, LLVA, and BCVA. Presence and burden of rpeHRF were independently associated with impaired visual function and may thus serve as a prognostic biomarker for disease progression and enrichment criterion for future interventional trials.

The liver is a primary target for recombinant adeno-associated viral (rAAV) vectors, yet the influence of serotype, sex, and liver zonation on transduction and transcriptomic changes remains incompletely understood. This proof-of-concept study employs spatial transcriptomics alongside single-nucleus RNA sequencing to map the spatial distribution and impacts of rAAV2- and rAAV9-CMV-EGFP vectors in male and female mouse livers. Spatial transcriptomics provided precise transgene mapping and highlighted that CMV-EGFP rAAV vectors deregulate hepatocellular lipid metabolism, the circadian clock, and the immune/stress response with sex specific differences. Lipid metabolism genes (Elovl3, Chka, Irs2, Ppard), were consistently deregulated across all zones of the liver lobule in male and female rAAV2- and rAAV9-CMV-EGFP-treated mice, while Srebf1, Tlcd4, Cpt2, and Acot1 exhibited sex-specific patterns. Circadian clock modulators (Dbp, Tef, Arntl, Nfil3, Nr1d1/Nr1d2) were altered independently of zonation. The study found sex-specific downregulation of immune and stress-response genes and pathways, including Gadd45g and hypoxia pathways. TGF-β and EGFR pathways were upregulated sex-independently. Spatial transcriptomics further enabled examination of transgene and rAAV entry factor co-expression, identifying known and novel factors like Rpsa, Dpp4, Sdc1, and solute carrier proteins, highlighting its role in supporting targeted screening. Our findings demonstrate spatial transcriptomics as a powerful tool in gene therapy research and reveal novel rAAV vector effects on liver biology.