Bayer (Finland)

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.

Abstract Rationale: Mosliciguat is a first-in-class, small-molecule soluble guanylate cyclase (sGC) activator designed for lung-targeted delivery via dry powder inhalation. sGC is in the nitric oxide (NO) pathway; NO binds the prosthetic heme group of sGC, catalyzing production of cyclic guanosine monophosphate (cGMP), resulting in increased vasodilation, reduced inflammation/apoptosis, reverse vascular remodelling, and antifibrotic effects. sGC is redox sensitive, losing heme in pulmonary hypertension (PH) conditions of oxidative stress, and resulting in the formation of oxidized-heme sGC and heme-free, apo-sGC. The loss of heme in apo-sGC abrogates NO-induced activation of the enzyme, resulting in reduced responsiveness to NO and impaired production of cGMP. Phosphodiesterase 5 inhibitors and riociguat, an sGC stimulator, are approved for PH, but highly synergistic with functional, NO-responsive, heme-containing sGC. New approaches are needed to restore function to pathologic sGC variants. Mosliciguat has a novel mechanism, directly binding to the heme-binding pocket in sGC and mimicking the NO-bound heme moiety to directly increase cGMP production. Through mosliciguat's unique ability to restore activity to the pathologic NO-insensitive apo-sGC, it may provide more effective vasodilation under conditions of NO depletion, including in patients with increased oxidative stress seen with PH. Thus, mosliciguat could address the unmet need for treatment of PH irrespective of oxidative stress. Here we report the results of the Phase 1 ATMOS trial of inhaled mosliciguat in patients with untreated pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Open-label, single-dose escalation (5 doses up to 4mg) multicenter trial. Per Protocol Set (PPS) consisted of the NO-nonresponsive pts with PVR≥5 Wood units at baseline (N=4/dose). Peak percent change (PPC) from baseline in pulmonary vascular resistance (PVR), safety, pharmacodynamics, and pharmacokinetics were assessed. Results: 38 patients received mosliciguat. For PPS (N=20), mean PPC of PVR from baseline [95%CI] was -21.0%[-31.6%,-10.4%], -16.1%[-32.8%,0.7%], -25.9%[-60.3%,8.4%], -38.1%[-55.9%,-20.3%] and -36.3%[-48.3%,-24.4%] for the 5 increasing doses, respectively. Reduced PVR persisted over the 3-hour RHC period at the highest doses. Pulmonary artery pressure decreased, plasma cGMP increased and, at the highest dose, mean cardiac output increased by ∼25% from baseline. Effects were similar including non-PPS patients (N=37). Most adverse events were mild, with headache (n=3; 7.9%), decreased oxygen saturation and fatigue (n=2; 5.3% each) reported most frequently (N=38). No safety relevant changes were seen in systemic vascular resistance or blood pressure. Conclusion: Mosliciguat had favorable tolerability and resulted in a sustained, substantial reduction in PVR after a single inhaled dose.

Abstract Myocardial infarction (MI) is the leading cause of death worldwide. However, current therapies are unable to restore the function of the injured myocardium. Advanced approaches, such as stimulation of cardiomyocyte (CM) proliferation are promising, but suffer from poor pharmacokinetics and possible systemic adverse effects. Nanomedicines can be a solution to the above‐mentioned drawbacks. However, targeting the cardiac tissue still represents a challenge. Herein, a MI‐selective precision nanosystem is developed, that relies on the heart targeting properties of atrial natriuretic peptide (ANP) and lin‐TT1 peptide‐mediated hitchhiking on M2‐like macrophages. The system based on pH‐responsive putrescine‐modified acetalated dextran (Putre‐AcDEX) nanoparticles, shows biocompatibility with cultured cardiac cells, and ANP receptor‐dependent interaction with CMs. Moreover, treatment with nanoparticles (NPs) loaded with two pleiotropic cellular self‐renewal promoting compounds, CHIR99021 and SB203580, induces a 4‐fold increase in bromodeoxyuridine (BrdU) incorporation in primary cardiomyocytes compared to control. In vivo studies confirm that M2‐like macrophages targeting by lin‐TT1 peptide enhances the heart targeting of ANP. In addition, NP administration does not alter the immunological profile of blood and spleen, showing the short‐term safety of the developed system in vivo. Overall, the study results in the development of a peptide‐guided precision nanosystem for delivery of therapeutic compounds to the infarcted heart.

Since its introduction in 1990, the levonorgestrel‐releasing intrauterine system (LNG‐IUS) has played a key role in shaping the healthcare landscape of women. Here we explore the development of the first LNG‐IUS (Mirena®) and the early clinical trials that demonstrated its potential. We highlight the contraceptive and therapeutic benefits of Mirena®, and discuss how clinical practice has been changed since the introduction of LNG‐IUS and other long‐acting reversible contraceptive methods. The history of Mirena® is rich in innovation and has also paved the way to the development of smaller intrauterine systems with lower hormone doses. Along with Mirena®, these newer LNG‐IUS contribute to improving contraceptive choices for women, allowing them to select the option that is right for them and that meets their needs no matter their age, parity or circumstances.

Objective: The aim of the study was to provide an additional, detailed description of early bleeding patterns with the 19.5 mg levonorgestrel-releasing intrauterine system (LNG-IUS).Methods: We conducted a pooled analysis of the bleeding diaries of participants in a previously reported phase II randomised controlled study (n = 741) and a phase III study (n = 2904), with 2-year extension phase (n = 707), of the 19.5 mg LNG-IUS. Main outcome measures were the median number of bleeding and/or spotting days per 30-day reference period for 12 months and the influence of the previous contraceptive method and levonorgestrel dose on bleeding patterns.Results: The pooled analysis comprised 1697 women. There was a progressive decline in the number of bleeding and/or spotting days from month 1: the proportion of women with ≤4 bleeding and/or spotting days per month increased from 6.2% in month 1 to 15.8% in month 2, 26.0% in month 3, 39.3% in month 6 and 54.1% in month 12. The median number of bleeding and/or spotting days in month 1 was lowest in women who had previously been using an LNG-IUS.Conclusion: Analysis of bleeding diaries using 30-day reference periods provides detailed insight into bleeding changes in the first months following placement of the 19.5 mg LNG-IUS. This insight may prove useful when counselling women about contraceptive choice and method continuation.

The Colorectal Oral Novel therapy For the Inhibition of angiogenesis and Retarding of Metastases (CONFIRM)-randomized trials, investigating the role of the VEGF-receptor inhibitor PTK787/ZK 222584 (vatalanib) in colorectal cancer (FOLFOX 4 ± vatalanib), showed some benefit in patients with high serum lactate dehydrogenase (LDH) levels. Here, we investigated the expression of LDH5 (encoded entirely by the LDHA gene, regulated by the hypoxia inducible factors) in cancer tissues from patients recruited in the CONFIRM trials and relationship to response. Paraffin-embedded materials from 179 patients recruited in the CONFIRM trials were analyzed by immunohistochemistry for the expression of the LDH5 protein. Correlations with serum LDH, response, and survival were assessed. A significant association of tumor burden and of poor performance status (PS) with serum LDH was noted. Poor PS and high tumor LDH5 expression predicted for poor response rates. High tissue LDH5 was related to poor progression-free survival (PFS) only in the placebo group of patients, whereas the addition of vatalanib seemed to improved response and PFS in this subgroup. High serum LDH levels were linked with significantly poorer overall survival, which however was not sustained in multivariate analysis. Serum LDH and tissue LDH5 levels are complementary features that help to characterize the activity of LDH in colorectal cancer and have a potent value in predicting response to chemotherapy. The addition of vatalanib diminished the impact of LDH expression on the prognosis of patients.