Despite substantial agreement between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on new drug approval in the past decades, a few new drugs for the treatment of some of the most prevalent and severe neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as much rarer neurogenetic disorders, were handled differently by the two regulatory agencies. The possible reasons for the differing behaviors of the FDA and EMA are several and wide-ranging, and they will be examined in this opinion-based analysis. How patients’ perceptions of the complex approaches to drug approval and commercialization may create disappointment and confusion will also be reappraised.
Human African trypanosomiasis (HAT), also known as sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei species. Fexinidazole, an oral treatment for HAT, has shown efficacy in both hemo-lymphatic and meningo-encephalitic stages of the disease. After oral administration, only a small fraction of fexinidazole is eliminated unchanged via the renal route; therefore, hepatic metabolic clearance represents a significant portion of the total clearance of fexinidazole. Consequently, in patients with hepatic impairment (HI), total clearance may be decreased, potentially resulting in overexposure of fexinidazole and could lead to modification of the exposures of its two metabolites. This study aims to evaluate the effect of mild and moderate HI on the pharmacokinetics (PK) of fexinidazole and its active metabolites compared with that in participants with normal hepatic function. This Phase I, multicentric, open-label, non-randomised study included 21 participants divided into three groups: mild HI (n = 7), moderate HI (n = 7) and normal hepatic function (n = 7). Each participant received a single oral dose of 1200 mg fexinidazole under fed conditions. PK parameters, including the maximum plasma concentration (Cmax), area under the plasma concentration–time curve (AUCinf) and terminal half-life (t½z), of fexinidazole and its metabolites M1 (sulfoxide metabolite) and M2 (sulfone metabolite) were assessed. Safety and tolerability were evaluated through adverse events, laboratory tests and vital signs. In participants with mild HI, the mean Cmax and AUCinf of fexinidazole, M1 and M2 were similar to or slightly higher (up to 1.40-fold; 90
Biologics have significantly enhanced treatment for psoriasis but data regarding their treatment patterns and economic burden are limited. The aim of this study was to evaluate adherence, persistence, switching, health-care resource utilization (HCRU) and costs among secukinumab, adalimumab, ustekinumab, and ixekizumab in China. This retrospective observational study identified adult patients with psoriasis who initiated biologics between 1 January 2020 and 30 June 2022, from the Regional Medical Big Data of Tianjin, China (comprising hospital information system data from 43 tertiary and 39 secondary hospitals). Treatment adherence was assessed using the Proportion of Days Covered (PDC) and PDC ≥ 80
Cancer has a substantial health and economic impact on the populations of the Gulf countries—the United Arab Emirates (UAE), Kuwait, and Oman; however, uncertainty remains among decision-makers, payers, and stakeholders regarding their clinical and economic advantages. Hence, this study aims to evaluate the potential health and economic impact of programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitor immunotherapies to reduce uncertainty and inform coverage, reimbursement, and treatment decisions across the Gulf region. The Health Impact Projection (HIP) model, a partitioned survival model, was adapted from a payer perspective for the UAE, Oman, and Kuwait to explore the health and economic impact of the anti-PD-1/PD-L1 class over 2022–2026 among key indications, including: first line non-squamous non-small cell lung cancer (1LNSCLC), neo-adjuvant triple-negative breast cancer (TNBC), metastatic TNBC, head and neck cancer, 1L metastatic urothelial carcinoma, metastatic renal cell carcinoma (RCC), second line endometrial cancer, 1L cervical cancer, and colorectal cancer. The model adopted a 1-to-5-year time horizon, structured in weekly cycles, with a new cohort joining yearly. Model inputs were based on publicly available data, literature, and expert advice. The model estimated that, over 5 years, 3763 patients across the UAE, Kuwait, and Oman would receive anti-PD-1/PD-L1s treatments, resulting in total gains of 1745 life years, 2791 progression-free survival (PFS) years, and 1625 quality adjusted life-years (QALYs). The introduction of anti-PD-1/PD-L1s would have an average annual impact of 149 million and a 0.17
Postmenopausal osteoporosis is a major public health concern, imposing a substantial economic burden on healthcare systems. Teriparatide is one of the key pharmacological treatments; however, its cost effectiveness remains controversial. This systematic review aimed to evaluate the cost effectiveness of teriparatide in the treatment of postmenopausal women with osteoporosis. A comprehensive literature search was conducted in PubMed, Scopus, Embase, and Web of Science up to October 2024. The included studies comprised cost-effectiveness and cost-utility analyses conducted from healthcare system/payer and societal perspectives. Studies that met the inclusion criteria were assessed using the Quality of Health Economic Studies (QHES) checklist. A total of 22 economic evaluations were included. Most studies found that teriparatide was not cost effective under general conditions, except in specific scenarios such as reduced drug prices, the use of generic alternatives, or under sensitivity analysis assumptions. The variability in willingness-to-pay thresholds and regional drug costs contributed substantially to differing incremental cost-effectiveness ratio outcomes across countries. Only a few studies accounted for indirect costs, and the limited geographic distribution highlighted the need for research in underrepresented regions such as the Middle East and Africa. Furthermore, a funding disclosure analysis suggested a potential bias in industry-sponsored studies, although no definitive conclusions could be drawn. Our findings suggest that teriparatide is generally not cost effective for the treatment of postmenopausal osteoporosis, although its economic value may vary depending on contextual and policy-related factors. Further robust economic evaluations are needed, incorporating both direct and indirect costs, and covering understudied regions. The findings of this review can support informed resource allocation and policy making in osteoporosis management. Limitations include heterogeneity across the included studies, potential language bias due to the inclusion of only English-language publications, and methodological variations that limited cross-study comparability
Viloxazine (extended-release [ER] capsules) is a nonstimulant medication approved for the treatment of pediatric (aged ≥ 6 years) and adult attention deficit hyperactivity disorder. This study assessed the effect of hepatic impairment (HI) on the pharmacokinetics, safety, and tolerability of viloxazine ER. In this open-label, multicenter study, adults (18–78 years) with mild (n = 8), moderate (n = 8), or severe (n = 8) HI (Child–Pugh classification) and a demographically matched control cohort with normal hepatic function received a single oral dose of viloxazine ER (200 or 400 mg), following a ≥ 10-h overnight fast. Blood samples were collected for 72 h post-administration and analyzed for viloxazine and its primary metabolite 5-hydroxy-viloxazine glucuronide. The potential for HI to impact pharmacokinetics was evaluated using relative bioavailability analysis of viloxazine maximum measured plasma concentration (Cmax) and area under the concentration–time curve (AUC) parameters and comparison of time to Cmax (Tmax) and terminal elimination half-life (t1/2). Safety and tolerability were also evaluated. In adults with versus without HI (any severity), there were no significant differences in viloxazine Cmax (mean ± standard deviation [SD] for mild HI, 3.1 ± 1.0 µg/mL versus 2.4 ± 0.4 µg/mL; moderate HI, 2.5 ± 0.8 µg/mL versus 2.5 ± 0.6 µg/mL; severe HI, 1.3 ± 0.4 µg/mL versus 1.5 ± 0.2 µg/mL) and AUC (from time 0 to infinity; mean ± SD for mild HI, 70.5 ± 19.3 h·µg/mL versus 56.8 ± 8.6 h·µg/mL; moderate HI, 62.8 ± 28.9 h·µg/mL versus 60.4 ± 20.5 h·µg/mL; severe HI, 42.0 ± 16.4 h·µg/mL versus 33.1 ± 9.7 h·µg/mL), and mean exposure for those with HI was within 25
Janus kinase (JAK) inhibitors are a new class of medications that are changing how we treat inflammatory skin diseases. Even though these drugs are increasingly being approved for various skin conditions, there is still limited detailed comparison of their effectiveness, safety, and long-term effects across different diseases. In this study, we systematically evaluated the use of JAK inhibitors in atopic dermatitis, psoriasis, vitiligo, alopecia areata, and hidradenitis suppurativa across both trial and real-world settings. We conducted a systematic review following PRISMA 2020 guidelines and searched major databases for randomized controlled trials (RCTs), open-label extensions, and real-world cohort studies published through May 2025. The main effectiveness outcomes included disease-specific measures: Eczema Area and Severity Index (EASI) for atopic dermatitis, Psoriasis Area and Severity Index (PASI) for psoriasis, Severity of Alopecia Tool (SALT) for alopecia areata, Vitiligo Area Scoring Index (VASI) for vitiligo, and Hidradenitis Suppurativa Clinical Response (HiSCR) for hidradenitis suppurativa. Safety outcomes included rates of adverse events, infections, thromboembolism, and cancer. Patient-centered outcomes included quality of life (DLQI) and pruritus reduction. Risk of bias was assessed using the Cochrane Risk of Bias tool 2.0 (RoB 2). We included 68 studies (42 RCTs, 14 open-label extensions, and 12 real-world cohorts) with 15,427 patients across five inflammatory skin diseases. Oral JAK inhibitors demonstrated efficacy across multiple conditions compared with placebo, with EASI-75 response rates ranging from 38 to 73
Background and Objectives To better inform clinical and public health decision-making on the use of antiviral drugs for mild/moderate SARS-CoV-2 infection in Hong Kong, we sought to assess effectiveness of the approved nirmatrelvir/ritonavir and molnupiravir treatment regimens.Methods We conducted a cohort study of patients aged 18-64 years with laboratory-confirmed SARS-CoV-2 infection in Hong Kong between April 2022 and January 2023. We utilised a conditional logistic regression model with a 5-strata propensity score-matched analysis adjusted for potential confounders such as age, sex, SARS-CoV-2 vaccination status, and chronic conditions. The outcomes were disease progression (development/worsening of clinical symptoms/conditions), intensive care unit (ICU) admission among hospitalised persons, and mortality at 28 days (infection-related) and 90 days (all-cause) following the recommended 5-day treatment course commencing within 5 days of symptom onset or laboratory confirmation and excluding persons who had a contraindication for the drugs. Results were expressed as adjusted odds ratios with associated 95% confidence intervals.Results We included 206,418 individuals, of which 53% were symptomatic at infection confirmation. About 33.3% of the individuals were treated with nirmatrelvir/ritonavir whereas only about 6.1% were treated with molnupiravir. Compared with no treatment, treatment with either nirmatrelvir/ritonavir or molnupiravir was associated with significantly reduced odds of disease progression in patients aged 18-44 years [0.20 (0.09-0.42) and 0.10 (0.04-0.26), respectively] and patients aged 45-64 years [0.14 (0.10-0.20) and 0.19 (0.14-0.25), respectively]. Whereas mostly no significant associations were observed with these drugs for the other outcomes in patients aged 18-44 years, they were associated with significantly reduced odds of the outcomes in patients aged 45-64 years. There was no significant difference in the head-to-head comparison between nirmatrelvir/ritonavir and molnupiravir against all the outcomes in patients aged 18-44 years, and against ICU admission in patients aged 45-64 years, but compared with molnupiravir in those aged 45-64 years, nirmatrelvir/ritonavir was associated with significantly reduced odds of disease progression, SARS-CoV-2 infection-related mortality, and all-cause mortality [0.39 (0.22-0.70), 0.20 (0.10-0.38), and 0.33 (0.21-0.53), respectively]. We made these observations mostly irrespective of symptom status.Conclusions Nirmatrelvir/ritonavir and molnupiravir treatment regimens seemed effective against clinically relevant outcomes in patients aged 18-64 years with laboratory-confirmed SARS-CoV-2 infection in Hong Kong, particularly in those aged 45-64 years for whom nirmatrelvir/ritonavir seemed better than molnupiravir.
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intensely pruritic episodes and eczematous lesions. This disease is prevalent in up to 25
Antipsychotic drugs, long established in the management of psychotic disorders, are increasingly recognized as modulators of autophagy with potential implications for cancer therapy. A growing body of evidence demonstrates that several antipsychotics, such as phenothiazines and penfluridol, can regulate autophagic flux in tumor cells, thereby affecting cell survival, apoptotic signaling, and responsiveness to anticancer treatments. Autophagy is a fundamental homeostatic process that enables tumor cells to meet heightened metabolic demands and adapt to diverse cellular stresses; however, its dysregulation can also facilitate therapeutic resistance. Pharmacological modulation of this pathway by antipsychotics may therefore enhance tumor sensitivity to conventional therapies and contribute to overcoming drug resistance. Importantly, the effects of these agents on autophagy are context dependent, varying with drug class, concentration, and tumor type, and can lead to divergent outcomes in tumor growth and progression. Drawing on accumulating preclinical and emerging clinical evidence, the current review delineates the molecular basis of antipsychotic-autophagy crosstalk and highlights the promise of repurposing these agents as adjunctive strategies in cancer treatment, while underscoring the need for rigorous mechanistic and translational investigations.
Deuruxolitinib (LEQSELVI), a deuterated analogue of the Janus kinase (JAK) 1/2 inhibitor ruxolitinib, is being developed by Sun Pharmaceuticals Industries for the treatment of alopecia areata. In July 2024, deuruxolitinib received its first global approval for the treatment of severe alopecia areata in adults in the USA. Additionally, in March 2026, deuruxolitinib received approval in the same indication in the UK. This article summarizes the milestones in the development of deuruxolitinib leading to the approval for severe alopecia areata in adults.
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that disproportionately affects children, often causing significant physical, psychological, and social burdens. While biologic therapies have transformed AD management in adults, pediatric-specific evidence remains limited. Dupilumab, an interleukin (IL)-4 receptor α antagonist that inhibits IL-4 and IL-13 signaling, is currently the only US Food and Drug Administration (FDA)-approved biologic for pediatric AD. To systematically review the efficacy, safety, quality of life, and adherence of dupilumab in children (0–12 years) with moderate-to-severe AD. This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed, Embase, and Cochrane Library were searched from inception to August 10, 2024, for studies involving biologic use in pediatric AD. Eligible designs included randomized controlled trials (RCTs), open-label extensions, observational studies, case series, and case reports reporting validated efficacy, safety, quality of life, or adherence outcomes. Risk of bias was assessed using the Mixed Methods Appraisal Tool (MMAT). Results were synthesized narratively, stratified by study design and age group; meta-analysis was not performed due to heterogeneity in study designs, outcome measures, and follow-up durations. Of 1576 records screened, 20 studies (n= around 1200; age range: 5 months to 12 years) met inclusion criteria. Across study designs, dupilumab produced rapid and sustained improvements in disease severity, with mean Eczema Area and Severity Index (EASI) reductions of 62–92
The accumulation of N-desethylamiodarone (DEA), an active metabolite of amiodarone, is a recognized risk factor for interstitial pneumonia. However, predictors of DEA accumulation, particularly during the initiation phase of amiodarone therapy, remain unclear. We aimed to identify predictors of DEA accumulation using classification and regression tree analysis and to verify their association with interstitial pneumonia in patients receiving amiodarone. We conducted a retrospective analysis of 80 patients who underwent therapeutic drug monitoring of amiodarone and DEA levels at Kitasato University Hospital. Potential risk factors for elevated DEA levels (≥ 0.6 mg/L) were identified using classification and regression tree analysis with 20 variables. To prevent overfitting, strict pruning parameters were implemented (minimum bucket size = 7, maximum depth = 2). N-desethylamiodarone levels were compared between patients with and without interstitial pneumonia, and the findings were validated through Monte Carlo simulations based on published pharmacokinetic models. Elevated DEA levels (≥ 0.6 mg/L) were observed in 23 patients (29
Ketamine has revolutionized the treatment of mood disorders by offering rapid antidepressant effects, particularly in individuals with treatment-resistant depression. Unlike traditional monoaminergic antidepressants, ketamine acts primarily through antagonism of the N-methyl-D-aspartate (NMDA) receptor, initiating a cascade of glutamatergic signaling that promotes synaptic plasticity, neurogenesis, and rapid symptom relief. However, while its mechanisms are increasingly understood, the temporal trajectory of these neuroplastic changes-and their behavioral correlates-remain poorly defined. This review synthesizes both preclinical and clinical evidence on the time-dependent effects of ketamine across molecular, cellular, and behavioral domains. Preclinical studies are examined to characterize rapid molecular and synaptic changes, including brain-derived neurotrophic factor (BDNF) signaling, activation of the mechanistic target of rapamycin (mTOR) pathway, and modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which collectively drive early phases of synaptic remodeling. In parallel, clinical studies are reviewed to evaluate how these biological processes correspond to changes in mood, motivation, cognition, and functional outcomes in patients, with particular emphasis on the timing of antidepressant response and durability of effects. Special attention is given to how ketamine-induced neuroplasticity unfolds over hours to days, and how this temporal progression links mechanistic findings from preclinical models with observed clinical recovery. By framing ketamine's action within a plasticity-centered model of antidepressant response, this review provides a novel perspective that integrates neuroscience and clinical psychiatry. It also identifies critical gaps in translational research and offers a roadmap for optimizing the therapeutic use of ketamine and future fast-acting antidepressants.
Anti-amyloid monoclonal antibodies have emerged as disease-modifying therapies for Alzheimer's disease. However, their broader clinical adoption is limited by amyloid-related imaging abnormalities, a key safety concern. Traditionally viewed as an unavoidable and dose-dependent adverse effect, amyloid-related imaging abnormalities often lead to treatment interruption or the exclusion of high-risk patients from therapy. Emerging evidence now suggests that amyloid-related imaging abnormalities may instead reflect a transient modifiable cerebrovascular response, primarily influenced by the kinetics of amyloid clearance rather than the absolute magnitude of amyloid removal. Recent data from titration-based dosing strategies demonstrate that gradual amyloid mobilization can significantly reduce the incidence of amyloid-related imaging abnormalities without compromising amyloid positron emission tomography responses or downstream biomarkers. This kinetic perspective may support a more nuanced re-evaluation of patient groups previously deemed unsuitable for therapy, including APOE ε4 carriers, individuals with cerebral microbleeds, and patients on antithrombotic treatment. In this Current Opinion, we propose a pragmatic clinical framework that integrates amyloid clearance kinetics, magnetic resonance imaging-based risk stratification, and individualized protocols for treatment interruption and re-challenge. By reframing amyloid-related imaging abnormalities as a modifiable clinical decision-making challenge rather than an inherent toxicity, anti-amyloid therapies may be optimized for safer use; however, whether such approaches can enable broader and more inclusive treatment strategies remains to be established in prospective studies, particularly in high-risk populations.
Cancer diagnoses impact adherence to antidiabetic medications, but limited research has focused on patients with prostate cancer and type 2 diabetes (T2DM). We investigated adherence trajectories to oral antidiabetic medications one year before and after a prostate cancer diagnosis and identified risk factors. This retrospective cohort study used the 2011–2021 MarketScan Commercial and Medicare Supplemental databases. We included newly diagnosed prostate cancer patients with T2DM with continuous insurance enrollment. We applied group-based trajectory modeling with a beta distribution to evaluate adherence patterns before and after prostate cancer diagnosis. Model covariates included age, total number of medications, number of antidiabetic medications, the Charlson Comorbidity Index (CCI), cost, insurance type, and complicated diabetes from the year before diagnosis. Metastasis and cancer treatments were included in the model after diagnosis. The study included 7864 patients (mean age = 74.5 ± 7.1). Three adherence trajectories were identified before diagnosis: consistently high adherence, steady decliners, and consistently low adherence. After diagnosis, a fourth trajectory revealing a moderate decline emerged. Over half (61.2
Background and ObjectiveNusinersen, onasemnogene abeparvovec-xioi, and risdiplam are disease-modifying therapies that have demonstrated clinical benefits for patients with spinal muscular atrophy. However, their high costs pose significant challenges for healthcare payers. This study evaluated the potential budget impact of these treatments compared with best supportive care from a US healthcare payer perspective.MethodsA budget impact analysis was conducted over a 5-year time horizon using a state-transition model to estimate direct healthcare costs associated with each disease-modifying therapy and best supportive care in a cohort of children with infantile-onset spinal muscular atrophy. A scenario analysis also assessed the budget impact over a lifetime horizon. Model inputs for transitions and costs were derived from clinical trials, observational registries, and administrative databases.ResultsCompared with best supportive care, the added 5-year per-patient budget impact was $2.18 million for onasemnogene abeparvovec-xioi, $1.51 million for nusinersen, and $1.17 million for risdiplam. When modeled over a lifetime horizon, the incremental per-patient budget impact versus best supportive care was $5.86 million for risdiplam, $3.16 million for onasemnogene abeparvovec-xioi, and $3.05 million for nusinersen.ConclusionsDisease-modifying therapies for the management of infantile-onset spinal muscular atrophy have a substantial budget impact on US healthcare payers, primarily driven by high drug acquisition costs. The impact (per year) becomes less pronounced when evaluated over a longer time horizon, with the largest lifetime budget impact observed for risdiplam.
Tyrosine kinase inhibitors are widely used targeted anti-cancer agents. They may induce pigmentary alterations that, although often benign, can have meaningful clinical and psychosocial implications. This study aimed to investigate pigmentation changes in the use of all tyrosine kinase inhibitors and to explain their underlying mechanisms. This narrative review is based on studies identified through searches of PubMed, Scopus, and Web of Science up to 1 September, 2025, encompassing clinical trials, case reports, original research articles, and relevant review articles on tyrosine kinase inhibitor-associated pigmentary changes. Tyrosine kinase inhibitor therapy was associated with a wide spectrum of pigmentary outcomes. Skin hypopigmentation and hair depigmentation were more frequently observed, largely attributed to direct inhibition of stem cell factor/c-Kit signaling and its downstream mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/protein kinase B pathways, leading to reduced melanocyte survival and function. Conversely, hyperpigmentation, though rare and unpredictable, was reported in association with paradoxical mitogen-activated protein kinase activation, melanocortin 1 receptor reactivation, or drug–melanin–iron complex formation. Patient-specific factors, including genetic polymorphisms (c-KIT, melanocortin 1 receptor, microphthalmia-associated transcription factor), immune and cytokine milieu, ethnicity, and concomitant therapies, were identified as modifiers of clinical outcomes. Pigmentary alterations induced by tyrosine kinase inhibitors are multifactorial, patient dependent, and reflect the interplay of genetic, immunologic, environmental, and pharmacologic factors. While hypopigmentation predominates, hyperpigmentation remains an uncommon but clinically relevant phenomenon. Larger multicenter studies, functional experimental models, and pharmacogenetic investigations are needed to elucidate predictive factors, clarify molecular mechanisms, and develop preventive or therapeutic strategies. Understanding these pigmentary changes may also provide valuable insights into drug activity and pave the way toward personalized medicine.
Anti-programmed cell death-(ligand) 1 (anti-PD-[L]1) agents are approved for advanced and early-stage cancers. While they may offer clinical and economic benefits in the neoadjuvant and/or adjuvant setting, their population-level impact in Italy has not been thoroughly evaluated. This study aims to estimate health and productivity outcomes of introducing anti‑PD‑(L)1 agents for neoadjuvant and/or adjuvant therapy in early‑stage cancers in Italy (melanoma Stage IIB/C, melanoma Stage III, renal cell carcinoma, triple‑negative breast cancer and resectable non‑small‑cell lung cancer) over a 10-year horizon. We developed a model synthesising outputs from five indication-specific Markov models comparing two worlds: one without anti-PD-(L)1 agents use in the neoadjuvant and/or adjuvant settings versus one with their use. Italian-specific population and incidence inputs were used, with clinical and quality-of-life data from individual trials, from a societal perspective with 3
