Leo Pharma (Australia)

The rigorous identification, quantification, and control of impurities are fundamental to ensuring the safety, efficacy, and quality of pharmaceutical products throughout the drug development lifecycle. As unavoidable byproducts of complex synthesis and manufacturing processes, impurities span a diverse range of compounds-including organic, inorganic, residual solvent, and genotoxic species-all of which require meticulous characterization using a suite of analytical techniques. This review synthesizes best practices for impurity classification, source mapping, and alignment of control strategies with global regulations (ICH Q3A/B, Q3C, Q3D, and M7), distinguishing phase-appropriate profiling, stress testing, and fully validated, stability-indicating methods. Advanced structural-elucidation tools (LC-MS/MS, HRMS, NMR) are surveyed alongside key strategies for lifecycle change management. Special emphasis is placed on mutagenic impurities, especially nitrosamines, highlighting how recent industry experience and regulatory actions have reshaped risk management and analytical sensitivity requirements. The discussion extends to emerging trends-green analytical chemistry, AI-driven prediction and interpretation, and real-time monitoring via Process Analytical Technology (PAT) and Real-Time Release Testing (RTRT)-that are redefining impurity control from reactive detection to proactive prevention. Collectively, this review provides scientists, regulators, and quality professionals with actionable frameworks for robust impurity management, facilitating compliance and accelerating pharmaceutical development.

With a limited number of traditional virulence factors, the success of the nosocomial pathogen Acinetobacter baumannii is largely attributed to its ability to persist and resist. The niches encountered during infection vary significantly from the more commonly studied laboratory setting, and consequently, the genes responsible for in vivo pathogenesis have yet to be fully elucidated. This study utilized the A. baumannii AB5075-UW transposon mutant library with unbiased genome-wide transposon sequencing to identify the genetic basis for survival and fitness during pneumonia and septicaemia infections. We identified 128 genes essential for in-host survival, including 22 required for survival in all tissues. Additionally, 302 genes with significantly altered fitness in vivo were also identified. Tissue specificity was observed, highlighting the importance of genes associated with aa biosynthesis in the lungs, cell shape and structure in the kidneys and metal acquisition during septicaemia. The majority (89%) of the genes with aberrant fitness were constituents of the core A. baumannii genome. The findings were validated using a subset of targeted mutants, including those required for infection (phoB, cysI and hom) or specifically septicaemia (corA, lepA and purN) or pneumonia (argC, hisC and leuD), confirming that these observations were a result of specific in vivo fitness defects rather than aberrant in vitro growth. Taken together, these data provide the first global profile of genes required for in vivo fitness of A. baumannii during different disease states and growth in different tissues.

The current management of psoriasis does not differentiate between younger and older patients in selecting the safest and/or most effective biologic. To explore the effect of age at treatment initiation in response to biologics in patients with moderate-to-severe psoriasis in the UK and Eire. Data from patients registered in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) from 2007 to 2024 on a first course of tumour necrosis factor (TNF), interleukin (IL)-12/IL-23, IL-17 and IL-23 inhibitors with at least 6 months' follow-up were included. Patients aged ≥ 16 years at registration were organized into the following cohorts: 16-24 years, 25-34 years, 35-44 years, 45-54 years, 55-64 years, 65-74 years and ≥ 75 years. The 45-54 years age group was used as the reference cohort. Biologic survival was defined as the time between treatment initiation to its discontinuation associated with ineffectiveness or the occurrence of adverse events (AEs). Adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) was estimated using a flexible parametric model to compare discontinuing treatment between the age groups. Each model included exposure (biologic class), effect modifier (age groups), interaction terms, baseline demographics and clinical and disease severity covariates. In total, 14 294 patients were included and organized into the following age groups: 16-24 years, n = 847 (5.9%); 25-34 years, n = 2502 (17.5%); 35-44 years, n = 3575 (25.0%); 45-54 years, n = 3863 (27.0%); 55-64 years, n = 2338 (16.4%); 65-74 years, n = 954 (6.8%); and ≥ 75 years, n = 215 (1.5%). The interaction effects model showed that individuals aged 16-24 years were more likely to discontinue TNF inhibitors (TNFi) due to ineffectiveness than those in the reference cohort (aHR 1.30, 95% CI 1.10-1.55). For survival associated with AEs, individuals aged 55-64 years were at higher risk of discontinuing TNFi and IL-12/IL-23 inhibitors [IL-12i/IL-23i; aHR 1.33 (95% CI 1.13-1.56) and aHR 1.34 (95% CI 1.03-1.75), respectively]; those aged 65-74 years were more likely to discontinue TNFi, IL-12i/IL-23i and IL-17 inhibitors [aHR 1.89 (95% CI 1.54-2.31), aHR 2.00 (95% CI 1.47-2.73) and aHR 1.69 (95% CI 1.08-2.64), respectively], whereas individuals aged ≥ 75 years were at higher risk of discontinuing the four biologic classes. Patients aged 16-24 years with psoriasis are more likely to stop TNFi due to ineffectiveness, whereas those aged ≥ 55 years are more likely to stop biologics due to AEs. These real-world findings provide important information for clinicians treating people with moderate-to-severe psoriasis across all age groups.

Introduction: Contact sensitization to topical drugs, a frequent cause of allergic contact dermatitis, may hinder their topical or even systemic use. The EDEN fragrance study assessed the prevalence of contact sensitization to topical drugs in the general population of five European countries.<br/><br/>Objectives: To report the crude prevalence of contact allergy to topical drugs and identify the clinical relevance.<br/><br/>Methods: Within a sample of individuals from the general population who were patch tested with T.R.U.E. Test®, we evaluated the crude prevalence of contact sensitization to wool alchools (1000 mcg/cm2), neomycin (600 mcg/cm2), caine mix 630 mcg/cm2 (benzocaine, tetracaine and dibucaine), quinoline mix 190 mcg/cm2 and three different topical corticosteroids (budesonide 1 mcg/cm2, tixocortol pivalate 3 mcg/cm2 and hydrocortisone butyrate 20 mcg/cm2). Combining patch test results with reported avoidance of topical drugs in their lifetime or a previous diagnosis of contact dermatitis, we assessed the possible clinical relevance of positive reactions.<br/><br/>Results: Among 3119 patch tested individuals (54.9% females, mean age 44.2 ± 16.0 years), the crude prevalence of contact sensitization for topical drugs was 2.1%, with 0.8% occurring within the group of topical steroids and 0.4% with neomycin, caine mix or wool alchools. Reactivity to topical drugs was not associated with avoidance of topical drugs, but significantly associated with a previous diagnosis of contact dermatitis (3.7%), especially for wool alchools (1.1%), neomycin (1.3%) and tixocortol pivalate (0.9%). When controlling for sex, a previous diagnosis of atopic dermatitis or psoriasis there was no significant difference.<br/><br/>Conclusions: Our results indicate that, although relatively low, sensitization to topical drugs may be significant, especially in individuals who have had contact dermatitis, whom we may assume have relevant reactions. Sensitization to neomycin, an antibiotic that may crossreact with other aminoglicosides for systemic use may not be irrelevant, suggesting the need to further restrict its topical use.

This study aimed to determine the optimal threshold iodine density to distinguish enhancing and nonenhancing renal masses with dual-layer dual-energy CT (dlDECT). In this retrospective, HIPAA-compliant, institutional review board-approved study, 383 consecutive renal mass dlDECT studies from September 5, 2018, through December 15, 2022, were reviewed for enhancing solid renal masses with ≥∆20 HU. Studies with simple cysts in the same interval served as controls. Lesion ROI HU measurements on unenhanced and nephrographic phases and ROI iodine density measurements of each lesion and the abdominal aorta for normalization were recorded. The mean lesion HU values and absolute and normalized iodine densities were compared with enhancing and nonenhancing renal lesions using a two-sample t test. The diagnostic accuracy of iodine thresholds was assessed by calculating sensitivity and specificity, with receiver operating characteristic curve and AUC analysis. There were 38 enhancing and 39 nonenhancing renal lesions. The mean (standard deviation [SD]) ∆HU was 73.5 (38.7) and 3.9 (5.1) HU for enhancing and nonenhancing lesions, respectively. The mean absolute iodine density was significantly different for enhancing and nonenhancing lesions (3.2 [1.7] mg/mL and 0.20 [0.22] mg/mL, respectively; P < 0.0001). Normalized mean iodine density was significantly different for enhancing and nonenhancing lesions (0.62 [0.33] mg/mL and 0.04 [0.04] mg/mL, respectively; P < 0.0001). The optimal absolute iodine density threshold of 0.70 mg/mL (AUC, 0.999) and normalized iodine density threshold of 0.11 mg/mL (AUC, 0.999) were 100% sensitive and 97.4% specific for discriminating enhancing and nonenhancing renal lesions. This study provides absolute and normalized iodine density thresholds to distinguish enhancing and nonenhancing renal lesions with high sensitivity and specificity using dlDECT.

The review systematizes and analyzes the literature data about the pharmacodynamic effects alongside the established antibacterial properties of the antibiotic substance — fusidic acid from the fusidane class. According to several sources, the substance is characterized with its anti-inflammatory, immunosuppressive, anticancer, and antiviral activities. It has been proven that fusidic acid can inhibit lymphocyte activation and the production of pro-inflammatory cytokines in lymphocytes, mononuclear cells, and leukocyte chemotaxis. It inhibits the activation and proliferation of T-lymphocytes in response to phytohemagglutinin and the development of septic shock in response to S. aureus enterotoxin and LPS. The cytoprotective action of fusidic acid on pancreatic islet cells is demonstrated in a model of insulin and glial cells exposed to a cytotoxic substance. When applied externally, its anti-inflammatory effect is comparable to that of low- and moderately-active glucocorticosteroids. The efficacy of fusidic acid in reducing inflammation-induced edema of epidermal proliferation and decreasing the synthesis of critical pro-inflammatory cytokines is comparable to that of dexamethasone at equivalent concentrations. The immunomodulatory and anti-inflammatory properties of this antibiotic substance are clinically significant, enhancing its antibacterial effect, facilitating quicker relief of inflammation, resolution of inflammatory infiltrates, improvement of patient’s quality of life by expediting the removal of unpleasant sensations associated with inflammation and mitigating the repercussions of the inflammatory process.

BackgroundBDMARD treatments in patients with psoriatic arthritis (PsA) are initiated after insufficient response to csDMARD either in monotherapy or by in parallel continuing csDMARDs. Here, the value of MTX in combination with bDMARDs in PsA is still unclear. We designed an investigator-initiated, randomized, placebo-controlled trial (IIT) in active PsA to examine the potential impact of MTX-continuation or -initiation parallel to newly started UST on different outcomes beyond clinical examination (MSUS; PsASon22 score [1]).ObjectivesTo compare sensitive imaging efficacy outcomes measured by MSUS changes [PsASon22] from week 4 and 24 to baseline in UST+PBO vs UST+MTX (stratified to ongoing or new onset of MTX treatment).MethodsA total of 186 patients with active PsA (defined as TJC≥4, SJC≥4 [68/66 joint count] and DAS28≥3.2) were screened for eligibility. 173 patients were randomized to UST+MTX (new or ongoing) or UST+PBO. 84 patients were included in the subgroup analysis with MSUS scoring of PsASon22 at BL, weeks 4 and 24. Results were compared between the groups with prior MTX treatment (UST+ ongoing MTX or UST+PBO) and with new initiation of MTX to UST (UST+ new MTX or UST+PBO) according to the study design.ResultsBL data were well-balanced between treatment groups (UST+MTX, n=44; UST+PBO, n=40) and subgroups with exception of slightly higher age (mean age 53.3 years) and more (45%) female patients in the UST with ongoing MTX group. All baseline data are shown in Table 1. After UST initiation, improvement of inflammatory activity measured by MSUS using PsASon22 score was seen early at week 4 in all treatment groups. The improvement was delayed in patients with previous MTX failure (“prior MTX”) and, in overall less pronounced compared to the patients without previous MTX treatment (Figure 1). At week 24, clinical meaningful changes in PsASon22 score were seen in all treatment groups but with most prominent differences in both treatment groups with UST+PBO.ConclusionIL12/23 inhibition with UST is an effective treatment for active PsA independent of MTX use. Data from this IIT indicate that additional MTX has no positive impact on UST efficacy for musculoskeletal manifestations such as arthritis and enthesitis measured sensitively by PsASon22 ultrasound score validated for PsA monitoring. Moreover, by monitoring in MSUS, patients on UST monotherapy seem to benefit best from the treatment.Reference[1]Ficjan, A., et al., Ultrasound composite scores for the assessment of inflammatory and structural pathologies in Psoriatic Arthritis (PsASon-Score). Arthritis Res Ther, 2014. 16(5): p. 476.Table 1.Baseline Characteristics: Subgroup analysis on MSUSParameterswith prior MTX, UST + MTXwith prior MTX, UST + Placebowithout MTX, UST + MTXwithout MTX, UST + PlaceboN=20N=17N=24N=23Age [years]53.3 (SD 10.0)46.8 (SD 15.8)45.5 (SD 14.6)45.2 (SD 15.6)Sex [Female]9 (45.0%)6 (35.3%)9 (37.5%)8 (34.8%)BMI [kg/m²]28.0 (SD 6.1)28.5 (SD 5.5)30.4 (SD 4.7)28.1 (SD 4.8)Age at PsA diagnosis [years]47.8 (SD 12.2)42.5 (SD 15.0)42.0 (SD 14.0)40.6 (SD 16.2)PsASon225.0 (1.5 to 13.0)2.0 (1.0 to 8.0)3.0 (1.0 to 7.0)6.0 (3.0 to 10.0)Presence of Enthesitis [LEI > 0]9 (45.0%)7 (41.2%)16 (66.7%)11 (47.8%)Presence of Dactylitis [LOCF]1 (5.0%)1 (5.9%)13 (54.2%)9 (39.1%)TJC68 [LOCF]14.5 (9.0 to 23.5)13.0 (9.0 to 16.0)10.5 (8.0 to 15.0)13.0 (9.0 to 18.0)SJC66 [LOCF]8.5 (6.5 to 20.5)8.0 (6.0 to 10.0)8.0 (7.0 to 12.0)8.0 (5.0 to 10.0)Nail involvement [mtNAPSI > 0]7 (35.0%)9 (52.9%)17 (70.8%)14 (60.9%)BSA [%]2.0 (1.0 to 6.0)1.0 (1.0 to 3.0)5.5 (1.0 to 12.1)2.0 (1.0 to 5.0)PASI2.5 (0.7 to 5.8)1.8 (0.6 to 3.8)7.1 (2.5 to 10.4)4.2 (0.8 to 8.2)HAQ-DI [LOCF]0.8 (0.4 to 1.4)0.9 (0.3 to 1.5)1.1 (0.4 to 1.6)1.0 (0.4 to 1.3)DLQI [LOCF]5.5 (3.0 to 12.5)6.0 (1.0 to 9.0)11.5 (3.0 to 15.5)6.0 (3.0 to 11.0)EQ5D Health Scale VAS100 [LOCF]47.7 (SD 24.1)50.2 (SD 20.2)54.2 (SD 22.9)59.1 (SD 16.0)Figure 1.Improvement in PsASon22 score from baseline to week 4 and 24 (mITT population)Acknowledgements:NIL.Disclosure of InterestsMichaela Köhm Speakers bureau: Janssen, UCB, Pfizer, Novartis, Consultant of: Janssen, UCB, Pfizer, Novartis, Grant/research support from: Janssen, Pfizer, GSK, BMS, Ann Christina Foldenauer Grant/research support from: Janssen, GSK, BMS, Pfizer, Tanja Rossmanith Grant/research support from: Janssen, GSK, Leo, Pfizer, BMS, Siegfried Wassenberg: None declared, Stephanie Finzel: None declared, Arnd Kleyer: None declared, Raoul Bergner: None declared, Rieke Alten: None declared, Herbert Kellner: None declared, Jochen Walter: None declared, Peter Kästner: None declared, Frank Behrens Speakers bureau: Janssen, Pfizer, UCB, Novartis, Consultant of: Janssen, Pfizer, UCB, Novartis, Grant/research support from: Janssen, Pfizer, UCB, Novartis, GSK, BMS.