Kyowa Kirin (France)

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a novel therapeutic alternative to erythropoiesis-stimulating agents (ESAs) for anemia in chronic kidney disease. Evidence regarding their real-world effectiveness is still limited. We analyzed data from the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS, 2019–2022) to assess the real-world effectiveness of HIF-PHIs among maintenance hemodialysis patients. We compared patients who transitioned from ESAs to HIF-PHIs with those who continued ESAs, focusing on baseline characteristics and changes in anemia-related, iron metabolism, and inflammatory parameters. Among 1433 patients on ESAs, only 56 (3.9%) were switched to HIF-PHIs. Compared with the ESA continuation group, patients in the HIF-PHI group had poorer nutritional status (albumin: 3.3 vs. 3.6 g/dL; cholesterol: 142 vs. 156 mg/dL; respectively) and greater ESA resistance (erythropoietin resistance index: 18.4 vs. 8.5 IU/kg/week/g/dL, respectively), despite higher ESA doses and iron prescription rates. After switching, a significant increase in hemoglobin was observed at 1 month (+0.44 g/dL; 95% confidence interval: 0.05–0.82; p = 0.025). Serum iron and total iron-binding capacity levels also increased, while transferrin saturation and ferritin remained unchanged. A subgroup analysis suggested greater hemoglobin response in patients with high C-reactive protein levels (p for interaction = 0.074), but no difference by erythropoietin resistance index (p for interaction = 0.372). In routine clinical practice, HIF-PHIs were selectively prescribed to patients with treatment-refractory anemia. Treatment increased hemoglobin levels, with a suggestive trend toward greater effect among those with inflammation, supporting the potential utility of HIF-PHIs in complex anemia management.

Abstract Disclosure: A.A. Khan: Ascendis, Alexion Pharmaceuticals, Inc., Amolyt, Bridge Bio, Takeda. T.O. Carpenter: Kyowa Kirin, Ultragenyx. J. Simmons: Kyowa Kirin, Ultragenyx. H. Cassinelli: None. E.A. Imel: Kyowa Kirin, Ultragenyx. P.F. Florenzano: Kyowa Kirin, Ultragenyx. B. Johnson: Kyowa Kirin, Kyowa Kirin. E. Yang: Ultragenyx. H.M. Heerssen: Kyowa Kirin. J. Li: Kyowa Kirin. L.M. Ward: Kyowa Kirin, Ultragenyx. Introduction: Burosumab, a fully human FGF23-neutralizing antibody, improved outcomes in adults and children with X-linked hypophosphatemia (XLH) in 24- and 64-week randomized controlled trials, respectively. This analysis describes real-world changes in patient-reported outcomes (PROs) over ≤3 years (y) in burosumab-treated individuals with XLH, including age groups with previously limited data (13-17 and >65y). Methods: Participants (pts) initiating burosumab after enrollment and before the Year (Y) 1 visit in the XLH Disease Monitoring Program (DMP); NCT03651505, a multi-country observational study) were evaluated. In children, change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) T-scores at Y1 and 3 were evaluated to assess fatigue, pain interference, and physical function (PF) mobility. In adults, change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and PROMIS PF T-scores at Y1 and 3 visits were evaluated to assess pain severity, joint stiffness, and PF. Results: At baseline (N=116) and Y1 (n=108), most groups included >10 pts, but the >65y group included 3. Y3 (n=76) group sample size range was 3-22. In children (n=83), mean ± standard deviation (SD) PROMIS pain interference improved significantly at Y1 (n=36: −3.6 ± 8.5, P=0.016) and Y3 (n=29: −4.8 ± 10.1, P=0.017). Mean PROMIS fatigue and PF mobility improved descriptively at Y1 and 3. The 5-12y group showed descriptive improvements in all PROMIS domains at Y1 and 3, with a significant change for pain at Y1 (n=25: −4.2 ± 7.3, P=0.008). The 13-17y group showed descriptive improvements in fatigue and pain interference at Y1 and 3. In adults (n=72), mean ± SD WOMAC scores improved significantly at Y1 (pain: −7.5 ± 18.8, P=0.001; stiffness: −12.2 ± 23.6, P<0.0001; PF: −6.3 ± 15.5, P=0.001), and Y3 (n=47) (pain: −11.3 ± 16.9, P<0.0001; stiffness: −16.8 ± 21.7, P<0.0001; PF: −10.8 ± 16.6; P<0.0001). Mean ± SD PROMIS PF score improved significantly at Y1 (1.5 ± 5.6, P=0.025) and remained stable at Y3 (1.6 ± 5.8). All adult groups had descriptive reductions from baseline in all WOMAC domains at Y1 and 3. Significant improvements in mean ± SD scores were seen at Y1 and 3 for pain in the 30-39y (Y1: −7.5 ± 11.3, P=0.0036; Y3: −10.3 ± 12.2, P=0.0054) and 50-64y (Y1: −13.3 ± 18.9, P=0.0333; Y3: −21.9 ± 13.1, P=0.0021) groups, stiffness in the 18-29y (Y1: −22.1 ± 28.5, P=0.057; Y3: −25.0 ± 23.2, P=0.0185) and 30-39y (Y1: −10.4 ± 17.9, P=0.0092; Y3: −13.3 ± 19.2, P=0.175) groups, and PF in the 50-64y (Y1: −8.7 ± 13.5, P=0.0467; Y3: −14.9 ± 9.1, P=0.0023) group. Conclusion: Children with XLH showed early and sustained improvement in pain interference. Adults with XLH also showed significant improvements at DMP Y1 and 3 in all WOMAC domains. Despite small sample sizes, this analysis provides real-world data on the positive impact of burosumab treatment on PROs. Presentation: Sunday, July 13, 2025

Objective To evaluate the efficacy of istradefylline in Parkinson’s disease patients experiencing motor fluctuations with and without dyskinesia and characterize potential predictors for treatment-emergent dyskinesia with istradefylline.Methods Pooled analysis of 8 phase 2b/3 trials of istradefylline (20 or 40 mg/day) versus placebo.Results Data from 2,719 patients, 56% of whom presented with baseline dyskinesia, were analyzed post hoc. The presence of baseline dyskinesia did not affect the mean decrease in “OFF” time with dyskinesia, increase in “ON” time without troublesome dyskinesia, or improvement in the Unified Parkinson’s Disease Rating Scale motor score associated with istradefylline treatment. Dyskinesia was reported in 17% of patients receiving istradefylline, with higher rates for women (21%), patients with a BMI <18.5 kg/m2 (22%), and patients receiving catechol-o-methyltransferase inhibitors plus dopamine agonists (22%) and monoamine oxidase B inhibitors (25%).Conclusion Istradefylline treatment resulted in greater reductions in total “OFF” hours/day and increases in “ON” time without troublesome dyskinesia than did placebo, regardless of the presence or absence of preexisting dyskinesia.

Bardoxolone methyl, also known as CDDO-Me or RTA 402, was a new investigational drug that improves the estimated glomerular filtration rate by activating the Keap1-Nrf2 pathway. Bardoxolone methyl is a synthetic triterpenoid compound derived from oleanolic acid (OA). OA-mediated cholestasis has not been reported in the clinical treatment of treat liver disorders but has been reported in mice. Cholestasis can be transient (e.g., during pregnancy) but can also be chronic and is a risk factor for hepatobiliary carcinoma. Therefore, it is important to evaluate and understand the risk of drug-induced cholestasis and its mechanisms, including species differences. We evaluated the effects of bardoxolone methyl on the in vivo hepatobiliary systems in rats and monkeys, as well as sandwich-cultured hepatocytes. Bardoxolone methyl was administered daily to rats and monkeys for 26 or 52 weeks, respectively. As a result, bardoxolone methyl was associated with the development of cholestasis and cholangioma in rats but not in monkeys. In an in vitro evaluation using sandwich-cultured hepatocytes treated with bardoxolone methyl, cholestasis was observed in rat hepatocytes, but not in monkey or human hepatocytes. A gene expression analysis showed that rat-specific cholestasis was caused by the reduction of the bile salt export pump gene expression after treatment with bardoxolone methyl. These results strongly suggest that the effects of bardoxolone methyl on the hepatobiliary system differ among animal species, especially between rodents and non-rodents. In conclusion, the risk of cholestasis and cholestasis-derived carcinogenicity associated with bardoxolone methyl are expected to be quite low in humans.

To evaluate the safety of istradefylline vs. other PD adjuncts based on randomized controlled trials (RCTs) available at the time of US approval.

In the rapidly evolving field of speech generative models, there is a pressing need to ensure audio authenticity against the risks of voice cloning. We present AudioSeal, the first audio watermarking technique designed specifically for localized detection of AI-generated speech. AudioSeal employs a generator/detector architecture trained jointly with a localization loss to enable localized watermark detection up to the sample level, and a novel perceptual loss inspired by auditory masking, that enables AudioSeal to achieve better imperceptibility. AudioSeal achieves state-of-the-art performance in terms of robustness to real life audio manipulations and imperceptibility based on automatic and human evaluation metrics. Additionally, AudioSeal is designed with a fast, single-pass detector, that significantly surpasses existing models in speed - achieving detection up to two orders of magnitude faster, making it ideal for large-scale and real-time applications.

In order to reduce out of plane deformation of dry wall by lateral force, connecting method of stud end to runner by screw is employed as one of the simple measures. Loading tests are conducted using real size stud-runner systems with/without stiffen measure at stud end. Stiffen effect is quantified through elastic curve equation comparing measured results of with/without stiffen model. Calculated results are obtained as rotational spring which connects deflection angle and fixed end moment at stud end. The stiffening effect is not remarkable large as roughly 10% reduction. If larger effect is required more heavy measures are needed.