The Merck Group, branded and commonly known as Merck, is a German multinational science and technology company headquartered in Darmstadt, with about 57,000 employees and present in 66 countries. The group includes around 250 companies; the main company is Merck KGaA in Germany. The company is divided into three Businesses: Healthcare, Life Sciences and Performance Materials. Merck was founded in 1668 and is the world's oldest operating chemical and pharmaceutical company, as well as one of the largest pharmaceutical companies in the world.Merck operates in Europe, Africa, Asia, Oceania and the Americas. It has major research and development centres in Darmstadt, Boston, Tokyo and Beijing, as well as other Research and Development units in Taiwan, France, Israel, South Korea and in the UK. Merck pioneered the commercial manufacture of morphine in the 19th century and for a time held a virtual monopoly on cocaine. Merck was privately owned until going public on the Frankfurt Stock Exchange in 1995 and is listed on the DAX index of Germany's top companies. The Merck family still controls a majority of 70.3% of the company's shares. The Merck Group includes around 250 companies in 180 countries; the current main parent company of the group, since 1995, is named Merck KGaA, and is itself mainly owned by the former main parent company, E. Merck oHG, which now operates as a holding company. The American pharmaceutical company Merck & Co. was established as a subsidiary of Merck in 1891, but was nationalized by the United States in 1917, before being privatized again when George W. Merck purchased back the stock in 1919. It is known as MSD (Merck Sharp and Dohme) outside of North America. The original Merck of Darmstadt holds the rights to the name Merck in all countries except the U.S. and Canada, where it is known as EMD (Emanuel Merck, Darmstadt). In 2015 Merck adopted a new uniform brand identity for all its subsidiaries, and the company has stressed its intention to protect the brand of "the real Merck" globally and initiated litigation against its former subsidiary over use of the name.In 2018, the company celebrated their 350th anniversary. Merck has formed a strategic alliance with the Technische Universität Darmstadt, which is located in the same town as Merck.
Fluorosurfactants are an integral part of many industrial processes due to their unparalleled surface activity and high water and oil repellency and can be found in a wide range of consumer products. However, their lack of biodegradability causes great environmental concern and has led to increased regulatory action in recent years. In the search for alternatives, perfluoropropyl vinyl ether was recently identified as a promising building block with an improved ecological profile regarding degradation and accumulation. Here, we utilized short-chain perfluoropropyl vinyl ether (PPVE) or perfluoromethyl vinyl ether (PMVE) as precursors to construct polyether-based fluorosurfactants through copolymerization with hydrophilic comonomers. Surfactant properties and overall fluorine content per molecule could be easily adjusted by changing the comonomer feed. The surface activity was investigated in aqueous solution via tensiometry and was found to be competitive with both legacy PFAS such as perfluorooctanesulfonic acid and current state-of-the-art small molecule fluorosurfactants (gamma stat >= 20.35 mN m-1). These findings illustrate the potential of amphiphilic copolymers as a modular, straightforward, and versatile platform for next-generation fluorosurfactants as an alternative to long-chain legacy PFAS.
A novel active pharmaceutical ingredient (API) exhibiting needlelike morphology displayed variable and poor solid-state bulk properties, including low flowability, strong adhesion, and high electrostatic charge, which negatively impacted formulation manufacturing. Applying a quality-by-design methodology, an improved API with enhanced flowability and reduced adhesion and electrostatic charge was obtained through batch-seeded cooling crystallization. A robust crystallization process was developed using statistical design of experiments, chemical engineering calculation-driven crystallization experiments, and process analytical technology. This process, combined with delumping via comilling, was demonstrated at the pilot scale. The solid-state properties of the API were comprehensively characterized, and it was successfully integrated into the drug product workflow. The crystallization process was optimized within approximately 9 months.
BACKGROUND:Toll-like receptors (TLR) 7 and 8 (TLR7/8) are activators of innate and adaptive immunity contributing to lupus pathogenesis. In Cohort B of WILLOW, a phase 2, randomised, placebo-controlled, double-blind, basket, dose-finding study, enpatoran, an oral small molecule inhibitor of TLR7/8, was evaluated in participants with active systemic lupus erythematosus (SLE). METHODS:Participants were eligible if they were aged 18-75 years with moderate-to-severe SLE, with or without cutaneous manifestations, had a disease duration of at least 6 months, and were receiving a stable dose of medication before the screening period. Participants were recruited from 132 centres in 22 countries. In Part 1, participants were randomly allocated in a 1:2 ratio to receive either placebo or 100 mg enpatoran, both twice-daily. Following the enrolment of 60 participants, Part 2 was activated and additional participants were randomly allocated in a 1:1:1:1 ratio to 25 mg, 50 mg, or 100 mg of enpatoran or placebo, all twice-daily, for 24 weeks. Random allocation was stratified by region, biomarker status, and hybrid Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index score. The primary objective was to evaluate the dose-response relationship of enpatoran, using British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate at week 24, based on multiple comparison procedure-modelling analysis. Study visits were scheduled from week 0 to week 24, followed by a 2-week safety follow-up period for participants who chose not to enter the long-term extension. From weeks 2 to 12, glucocorticoid doses were tapered to a prednisone-equivalent dose of no more than 5 mg/day, as clinically tolerated. Adverse events were monitored continuously throughout the study; safety parameters (including physical examination, vital signs, and routine chemistry and haematology) were assessed at all study visits. The trial was registered at ClinicalTrials.gov (NCT05162586) and a long-term extension study is ongoing. FINDINGS:Between May 4, 2022, and Feb 6, 2024, participants were screened for eligibility for WILLOW cohorts A and B; 715 participants were screened and 354 were randomly allocated and included in the Cohort B safety population (95 to placebo, 71 to 25 mg enpatoran, 74 to 50 mg enpatoran, and 114 to 100 mg enpatoran). One patient allocated to the placebo group was found to be ineligible and was excluded from the full analysis set for the efficacy analyses. 335 (95%) of 353 participants were female, 18 (5%) were male, and median age was 41 years (IQR 33-51). At week 24, the study did not meet its primary objective of identifying a statistically significant dose-response relationship for enpatoran in BICLA response rate (p=0·14). BICLA response rates at week 24 were higher with all doses of enpatoran (25 mg: 41 [58%] of 71; odds ratio [OR] vs placebo 2·2 [95% CI 1·1-4·0], 50 mg: 36 [49%] of 74; OR 1·5 [95% CI 0·8-2·8], and 100 mg: 56 [49%] of 114; OR 1·6 [95% CI 0·9-2·8]) versus placebo (37 [39%] of 94). The most common treatment-emergent adverse event was diarrhoea, in four (6%) of 71, two (3%) of 74, and two (2%) of 114 participants in the 25 mg, 50 mg, and 100 mg enpatoran groups, respectively, and seven (7%) of 95 participants in the placebo group. Serious adverse events were reported in one (1%) of 71, three (4%) of 74, five (4%) of 114, and three (3%) of 95 participants treated with 25 mg, 50 mg, and 100 mg enpatoran and placebo, respectively. INTERPRETATION:In this study of participants with moderate-to-severe SLE, enpatoran improved BICLA response rates versus placebo; however, the primary objective of a statistically significant dose-dependent effect on disease activity based on BICLA response was not met. Enpatoran was well tolerated across all dose groups. FUNDING:Merck Healthcare (Darmstadt, Germany).
Oral cladribine, a highly effective pulsed selective immune reconstitution therapy (SIRT) for relapsing multiple sclerosis (RMS) is characterised by extended treatment-free periods following brief exposure to medication. Since approval in 2017, long-term real-world data have become available which provide insight into the management of patients treated with cladribine tablets beyond year 4. Most patients remained without additional therapy, which may hint at stable disease control. However, the absence of further treatment must not necessarily be interpreted as absence of any disease activity, as MRI data are often incomplete in watch-and-wait cohorts. The observed long-term remission is likely linked to the unique mode of action, which involves rapid repopulation of lymphocytes with different dynamics amongst subsets and sustained reduction of memory B cells. The recovery of the immune system and lymphocytes preserves long-term therapeutic options with existing or upcoming drugs. In cases of mild recurring disease activity, retreatment with cladribine tablets has been shown to be effective and tolerable within the known safety profile. Unrestricted long-term management options associated with cladribine tablets include a switch to other DMTs in cases of insufficient disease control. Overall, cladribine tablets show potential of a paradigmatic shift in MS management that may enable treatment-free remission over 6 years as an achievable treatment goal in a substantial proportion of RMS patients.
Robust text-to-SQL over complex, real-world databases remains brittle even with modern LLMs: iterative refinement often introduces syntactic and semantic drift, corrections tend to be non-transferable across queries, and naive use of large context windows scales poorly. We propose a controlled text-to-SQL framework built around reflective refinement. Instead of repeatedly rewriting the current SQL instance, the system decomposes generation into typed stages and applies feedback as persistent updates to the stage-level generation mechanism. A Reflection-Refinement Loop localizes violations to the responsible stage maximize preservation of previously validated constraints and support monotonic improvement over a query set. The method operates without gold SQL by combining interpreter-based checks with LLM-based semantic coverage verification as epistemic judges. Experiments on Spider and BIRD demonstrate consistent gains over strong prompting baselines, robust convergence within a small refinement budget, and improved execution accuracy across both frontier and open-weight model families.
