Drugs最新文献

Tasurgratinib succinate (TASFYGO^®; Eisai Co., Ltd.) is an orally active, small molecule inhibitor of fibroblast growth factor receptors (FGFRs) 1, 2, and 3 being developed for the treatment of solid tumors, including cholangiocarcinoma (i.e., bile duct cancer) and breast cancer. Tasurgratinib succinate received its first approval on 24 September 2024 in Japan, for the treatment of FGFR2 fusion-positive unresectable biliary tract cancer that has progressed after chemotherapy. The approval was based on the positive results of an open-label, single-arm, multicenter, phase II study conducted in Japan and China. This article summarizes the milestones in the development of tasurgratinib succinate leading to this first approval for biliary tract cancer.

Zenocutuzumab (zenocutuzumab-zbco; BIZENGRI^®), an IgG1 bispecific human epidermal growth factor receptor (HER)2- and HER3-directed antibody, is being developed by Merus for the treatment of solid tumours with neuregulin 1 (NRG1) gene fusions. On 4 December 2024, zenocutuzumab received its first approval in the USA for the treatment of adults with advanced, unresectable or metastatic pancreatic adenocarcinoma or non-small cell lung cancer (NSCLC) harbouring an NRG1 gene fusion with disease progression on or after prior systemic therapy. This article summarizes the milestones in the development of zenocutuzumab leading to this first approval for the second-line treatment of NRG1+ pancreatic adenocarcinoma or NSCLC.

Glucocorticoids (GCs) possess potent anti-inflammatory and immunosuppressive properties and are used to treat various diseases, including systemic autoimmune rheumatic diseases, rheumatoid arthritis, and systemic lupus erythematosus (SLE). However, GCs are associated with several adverse events and are considered risk factors for infections and cardiovascular disorders; furthermore, their application as therapeutics has changed with recent progress in molecular-targeted therapies. Although GCs have been the mainstay of SLE treatment for more than 50 years, the latest European Alliance of Association for Rheumatology recommendations for the management of SLE in 2023 has significantly relegated the use of GCs and recommended that these be used as "bridging therapy" during periods of SLE disease activity. They also recommended the use of GC pulse therapy followed by relatively low doses of GCs even in patients with high disease-activity lupus nephritis, with a focus on the appropriate use of hydroxychloroquine, immunosuppressive drugs, and biological agents. This combination is essential for improving renal survival, minimizing flares, and reducing the side effects of GC. The GC dose was tapered to < 5 mg/day of prednisolone within half a year, maintained for 3 years, and then discontinued with the concomitant use of combination therapies. In contrast to non-renal SLE, the development of more potent molecular targeted therapies for lupus nephritis is required.

Background: Bimatoprost implant 10 µg is an intracameral, biodegradable implant that slowly releases bimatoprost to lower intraocular pressure (IOP). This study was designed to evaluate safety and the duration of the IOP-lowering effect after single and as-needed repeat administration of the bimatoprost implant in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT).

Patients and methods: This study is an interim analysis of an ongoing, prospective, open-label, multicenter study in patients with OAG or OHT who are inadequately managed with topical IOP-lowering medication for reasons other than efficacy. IOP-lowering rescue treatment is allowed if implant retreatment criteria are not met. The primary endpoint is time to retreatment/rescue after the initial implant administration analyzed with the Kaplan-Meier method. Key safety measures include treatment-emergent adverse events (TEAEs) and reading-center evaluation of central corneal endothelial cell density (CECD). Analysis of data collected through 15 September 2023 focused on outcomes after a single or two implants.

Results: In total, 441 patients received the 10-µg bimatoprost implant in the study eye on day 1 (cycle 1), 179 patients received a second administration (cycle 2), and 378 patients had at least 12 months of follow-up data available. The median time (95% confidence interval) from the first administration to a second administration or rescue was 392 (369, 485) days; the probability of not requiring retreatment or rescue by day 360 was 57.5%. A second implant administration similarly provided a long duration of IOP control. The baseline mean (standard error, SE) IOP was 25.6 (0.14) mmHg; the mean (SE) change from baseline IOP in unrescued eyes after a single administration was - 7.5 (0.21) mmHg at week 24 and - 6.4 (0.28) mmHg at month 12. Conjunctival hyperemia, typically associated with the administration procedure, was the most common ocular TEAE (cycle 1, 14.3%; cycle 2, 12.8%). Mean (SE) percentage change in CECD from baseline at 12 months after administration was - 4.3 (0.81)% in cycle 1 and - 8.5 (2.22)% in cycle 2. The cycle 1 implant was no longer visible or ≤ 25% of initial size in 66.3% and 94.3% of study eyes at months 12 and 24, respectively.

Conclusions: In this interim analysis based on available data, the IOP-lowering effect of the initial administration of the 10-µg bimatoprost implant was well maintained for > 1 year in most patients. Results after a second administration were comparable. The safety profile of initial and repeat administration was acceptable.

Trial registry: ClinicalTrials.gov identifier NCT03850782; registered 20 February 2019.

Osteoporosis and osteoarthritis are key diseases of musculoskeletal ageing and are increasing in prevalence and burden with the progressively ageing population worldwide. These conditions are thus particularly common in 'the oldest old', and there are complexities of managing them within the context of extensive multimorbidity, physical and mental disability, and polypharmacy, the rates for all of which are high in this population. In this narrative review, we explore the epidemiology of osteoporosis and osteoarthritis in the oldest old before examining trials and real-world data relating to the pharmacological treatment of these diseases in older adults, including anti-resorptives and bone-forming agents in osteoporosis and symptomatic slow-acting drugs for osteoarthritis, paracetamol, and non-steroidal anti-inflammatory drugs in osteoarthritis, recognising that the oldest old are usually excluded from clinical trials. We then review the potential benefits of nutritional interventions and exercise therapy before highlighting the health economic benefits of interventions for osteoporosis and osteoarthritis. The high prevalence of risk factors for both disease and adverse events associated with treatment in the oldest old mean that careful attention must be paid to the potential benefits of intervention (including fracture risk reduction and improvements in osteoarthritis pain and function) versus the potential harms and adverse effects. Further direct evidence relating to such interventions is urgently needed from future research.

The complex pathophysiology of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) is reflected in the heterogeneity of the presenting clinical syndromes caused by these diseases but also provides a variety of conceivable molecular and cellular targets that can be therapeutically manipulated. The last decade has seen an expansion of established and potential therapies for treating AAV, some of which target the dysfunctional autoreactive immune response and others aim to ameliorate the downstream consequences of local vascular inflammation and necrosis. The success and widespread adoption of the anti-CD20 monoclonal antibody, rituximab, as an agent to both induce and maintain remission, has heralded a change in the standard-of-care management of AAV, replacing the "old guard" combination of cyclophosphamide and high-dose corticosteroids established in the 1970s. The development and approval of avacopan, a first-in-class small-molecule antagonist to the main receptor for the complement anaphylatoxin C5a, has the potential to reduce the corticosteroid burden experienced by patients with AAV and may also improve outcomes for those with AAV kidney disease. It marks the culmination of almost 20 years of international collaboration, from understanding the pathological role of complement in basic murine models of AAV through to a phase III clinical trial, and emphasises the importance of following promising translational discoveries through to drug development and clinical deployment. This article summarises how recent progress in our understanding of the basic pathophysiology of AAV has resulted in the development of new and effective treatments and, reciprocally, how studying the impact of these treatments in patients has advanced our understanding of dysfunctional immunobiology in disease.

Background and objective: Bimatoprost implant 10 µg (Durysta) is an intracameral biodegradable implant that releases bimatoprost to lower intraocular pressure (IOP). The purpose of this study was to prospectively collect effectiveness and safety data after administration of the implant in patients with open-angle glaucoma or ocular hypertension.

Methods: This phase IV, multicenter, prospective, observational, open-label, 18-month study (ARGOS) enrolled adult patients with open-angle glaucoma or ocular hypertension who were scheduled to receive the bimatoprost implant in one or both eyes. Data collected included IOP, use of topical IOP-lowering medications, treatment-emergent adverse events, and central corneal endothelial cell density. The primary endpoint was the proportion of primary (first-treated) eyes that received no additional (new) IOP-lowering treatment per standard medical care through month 6 after the implant administration.

Results: A total of 217 patients (341 eyes) were enrolled, and 132 patients (60.8%) and 203 eyes (59.5%) completed the study. Most patients were on topical IOP-lowering medication before receiving the implant. After implant administration, the proportion of primary eyes that had received no additional treatment was 88.6% (95% confidence interval 86.6-90.6) at month 6 (primary endpoint) and remained high throughout the follow-up: 83.7% (95% confidence interval 80.2-87.3) at month 12 and 77.7% (95% confidence interval 73.4-82.1) at month 18. Intraocular pressure was reduced after implant administration, with mean changes in IOP from baseline at follow-up visits ranging from - 1.0 to - 2.0 mm Hg. The mean number of topical IOP-lowering medications used was also reduced, from 1.8 at baseline to 0.9 at month 12 and 1.0 at month 18. Increased IOP and dry eye were the most common ocular treatment-emergent adverse events. The mean percentage change in central corneal endothelial cell density from baseline at month 18 (central reading center evaluation) was - 3.47%. In qualitative interviews, most patients (84%, 21/25) reported overall satisfaction with their treatment outcomes.

Conclusions: The bimatoprost implant helped control IOP and decrease topical medication use. Throughout the 18 months after implant administration, an estimated 77.7% of eyes required no new added medication for IOP management. Patient-reported outcomes were favorable, and the safety profile of the implant was acceptable.

Clinical trial registration: ClinicalTrials.gov identifier NCT04647214, registered 23 November, 2020.

One dose does not fit all, especially in oncolytic drugs, where side effects and therapy failures highlight the need for personalized dosing approaches. In recent years, the quest to apply model-informed precision dosing to oncology drugs has gained significant momentum, reflecting its potential to revolutionize patient care by tailoring treatments to individual pharmacokinetic profiles. Despite this progress, model-informed precision dosing has not (yet) become widely integrated into routine clinical care. We aimed to explain model-informed precision dosing from a clinical viewpoint while addressing all prospective model-informed precision dosing implementation and validation studies in the field of oncology. We identified 16 different drugs for which prospective model-informed precision dosing validation/implementation has been performed. Although these studies are mostly focused on attaining adequate drug exposures and reducing inter-individual variability, improved clinical outcomes after performing model-informed precision dosing were shown for busulfan, and high-dose methotrexate. Toxicities were significantly reduced for busulfan and cyclophosphamide treatment. In contrast, for carboplatin, for which model-informed precision dosing has been used in the Calvert formula, no prospective validation on outcomes was deemed necessary as the therapeutic window had been extensively validated. Model-informed precision dosing has shown to be of added value in oncology and is expected to significantly change dosing regimens in the future.

Risperidone in situ microparticles (risperidone ISM^®) is a novel long-acting prolonged-release formulation approved in the EU and USA for treating schizophrenia in adults. Once-monthly intramuscular injections of risperidone ISM^® provide immediate and sustained therapeutic levels of risperidone, eliminating the need for loading doses or oral supplementation. In the pivotal PRISMA-3 trial in patients with acute schizophrenia exacerbation, risperidone ISM^® significantly improved Positive and Negative Syndrome Scale (primary endpoint) and Clinical Global Impression-Severity of Illness (key secondary endpoint) total scores over the 12-week double-blind phase, with improvements observed as early as day 8. Continued treatment sustained efficacy over the 12-month open-label extension phase. Risperidone ISM^® also improved social functioning and had a positive impact on health-related quality of life. Patients stable on daily oral risperidone maintained their treatment benefits after switching to monthly risperidone ISM^®. Risperidone ISM^® was generally well tolerated in clinical trials, with a safety profile consistent with that of oral risperidone. Its fast onset of action, without the need for oral supplementation or loading doses, makes risperidone ISM^® a promising long-acting injectable that could enhance treatment adherence.