Search Results (784)

Background/Objectives: Elevated lipoprotein(a) [Lp(a)] is an independent cardiovascular risk factor associated with atherosclerotic cardiovascular disease and calcific aortic valve disease. Historically, therapeutic options for reducing Lp(a) have been limited. This study aimed to characterize the clinical development landscape of emerging Lp(a)-targeted therapies, evaluate endpoint assessment strategies, and summarize available efficacy evidence from investigational agents. Methods: A qualitative clinical trial landscape review was conducted using ClinicalTrials.gov. Interventional Phase I–III studies evaluating therapies specifically targeting Lp(a) were identified through a structured registry search performed on 5 November 2025. Eligible studies were screened according to predefined inclusion and exclusion criteria. Extracted data included trial characteristics, therapeutic class, endpoint methodologies, and published efficacy outcomes. Data were synthesized narratively. Results: Twenty clinical trials met the eligibility criteria. Three therapeutic classes were identified: antisense oligonucleotides (ASOs), small interfering RNA (siRNA)-based therapies, and small-molecule inhibitors. Pelacarsen represented the sole ASO program, whereas siRNA-based therapies constituted the largest therapeutic category. Five studies were designed as cardiovascular outcomes trials. Percent change from baseline in circulating Lp(a) concentration was the most frequently used efficacy endpoint. Published data demonstrated substantial reductions in Lp(a) concentrations across all major therapeutic platforms. Available non-head-to-head published evidence showed substantial Lp(a) reductions across several investigational agents, including siRNA-based therapies, pelacarsen, and muvalaplin, although differences between studies preclude direct comparison between therapeutic platforms. Conclusions: The Lp(a) therapeutic landscape has rapidly evolved, with RNA-based therapies demonstrating unprecedented reductions in circulating Lp(a) concentrations. Ongoing cardiovascular outcomes trials will determine whether these reductions translate into meaningful cardiovascular benefits, establish Lp(a) as a therapeutic target in cardiovascular prevention and clarify the long-term safety and risk–benefit profile of Lp(a)-targeted therapies. Full article

MET pathway alterations have evolved from a niche translational interest into one of the most clinically actionable axes in non-small cell lung cancer (NSCLC). Three biologically distinct lesions—MET exon 14 (METex14) skipping mutations, focal high-level MET amplification, and c-Met protein overexpression—are now individually targetable, each with its own diagnostic prerequisites and therapeutic class. Selective type Ib MET tyrosine kinase inhibitors (capmatinib, tepotinib) anchor first-line therapy for METex14, while next-generation agents and type II inhibitors are being developed to address on-target D1228 and Y1230 resistance mutations. In parallel, MET amplification has emerged as a leading mechanism of acquired resistance to osimertinib in EGFR-mutated NSCLC, with the SAVANNAH, SACHI, and INSIGHT 2 trials providing biomarker-guided combination strategies. The 2025 accelerated approval of telisotuzumab vedotin for c-Met-overexpressing tumors expanded the therapeutic armamentarium beyond kinase inhibition. Despite these advances, lineage plasticity, polyclonal bypass signaling, and inconsistent diagnostic thresholds for MET amplification continue to limit durable benefit. This review integrates the molecular biology, current clinical evidence, resistance mechanisms, and a proposed 2025 treatment algorithm for MET-altered NSCLC, with emphasis on the translational interface between mutation class, drug class, and emerging combinatorial approaches. As a narrative review, it synthesizes peer-reviewed literature and pivotal trial and regulatory data through early 2026, identified by structured searches of PubMed and major oncology congress proceedings, and prioritizes sources that link mutation class to drug class and resistance mechanism. Full article

Background: Outcomes in chronic myeloid leukemia (CML) remain heterogeneous despite effective BCR::ABL1 tyrosine kinase inhibitors (TKIs). Somatic mutations in epigenetic regulators, particularly additional sex combs-like 1 (ASXL1), have been implicated in adverse prognosis, but their clinical impact in CML has not been systematically defined. Methods: A systematic review was conducted using CINAHL, EMBASE, MEDLINE Ultimate, and PubMed from inception through August 2025. A total of 1339 records were identified; the eligible studies included adult and pediatric patients with chronic and advanced-phase (accelerated or blast) CML. After duplicate removal and screening, 11 studies met the inclusion criteria; these included adult patients only and were included in a qualitative synthesis and meta-analysis. ASXL1 mutation status was assessed using validated molecular methods. The outcomes included the molecular response, cytogenetic response, survival, and treatment resistance. Random-effects models were used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. Results: Across the included studies, ASXL1 mutations were detected in approximately 15% of patients. At 12 months, patients with ASXL1 mutations had significantly lower odds of achieving a major molecular response (MMR) compared with ASXL1-wildtype patients (OR 0.29; 95% CI 0.16–0.51; p < 0.0001; I² = 30%). No statistically significant difference was observed in the complete cytogenetic response (CCyR) (OR 0.30; 95% CI 0.02–5.31; p = 0.41; I² = 68%). Compared with patients harboring other non-ASXL1 somatic mutations, an ASXL1 mutation was not associated with a significant difference in MMR (OR 0.49; 95% CI 0.23–1.05; p = 0.067; I² = 0%). Conclusions: ASXL1 mutations may be associated with an inferior molecular response to TKI therapy in CML, supporting their role as an adverse prognostic biomarker. These findings highlight the potential value of incorporating myeloid mutation profiling into future CML risk-stratification strategies. Full article

Background: Treatment-resistant obsessive–compulsive disorder (TR-OCD) remains a major therapeutic challenge. Although current guidelines recommend optimized serotonin reuptake inhibitor (SRI) therapy, clomipramine switching, exposure and response prevention, and antipsychotic augmentation, a substantial proportion of patients continue to experience severe and disabling symptoms. In such cases, clinicians may consider pharmacological intensification strategies beyond guideline-endorsed algorithms. Methods: This study combines a structured narrative synthesis of pharmacological strategies for TR-OCD with a retrospective observational case series from a tertiary OCD referral clinic. Treatment resistance was defined as failure to achieve at least a 35% reduction in Yale–Brown Obsessive Compulsive Scale (Y-BOCS) score after at least two adequate SRI trials, including clomipramine, and optimized exposure and response prevention when available. Five patients treated with pharmacological intensification strategies were included. The primary outcome was percentage change in Y-BOCS score at 12 weeks. Results: The case series illustrates five strategies used in highly refractory OCD: supratherapeutic SSRI dosing, SSRI plus mirtazapine augmentation, dual SSRI therapy, serotonergic intensification in a clozapine-treated patient, and glutamatergic/GABAergic augmentation with topiramate. Baseline Y-BOCS scores ranged from 28 to 32. At 12 weeks, symptom reduction ranged from 23% to 36%. One patient met criteria for response, three showed near-response, and one demonstrated partial improvement. No cases of serotonin toxicity or clinically significant cardiac complications occurred. Conclusions: These cases suggest that carefully monitored pharmacological intensification may be feasible in selected specialist settings, but efficacy and safety require confirmation in prospective controlled studies. Recommendations: Pharmacological intensification should be reserved for highly refractory patients managed in specialist services, implemented with gradual titration, structured serotonin toxicity and electrocardiographic monitoring, and explicit individualized risk–benefit discussion; dual SSRI therapy should be regarded as the most experimental and highest-risk serotonergic option; and prospective controlled studies incorporating standardized functional outcomes are needed to refine patient-selection criteria and clarify which patients may benefit. Full article

Background: Ferrocene-containing compounds have gained attention in medicinal chemistry due to their unique redox and structural properties. This study investigates ferrocene-based analogues of imatinib and nilotinib to define their binding determinants within the ABL1 kinase domain using an integrated in silico approach, in relation to their previously reported cytotoxic activity. Methods: Ligand geometries were optimized at the B3LYP/def2-TZVP level with D3(BJ) dispersion and SMD solvation. Molecular docking against ABL1 (PDB ID: 2HYY) was performed using Glide SP, validated by re-docking and enrichment screening. Docked poses were refined using MM-GBSA (Prime, VSGB 2.1/OPLS4). The most active compounds (9 and 15a), together with the inactive control 15e, were subjected to three independent 500 ns molecular dynamics simulations (Desmond, OPLS4), followed by trajectory analysis including RMSD, RMSF, radius of gyration, SASA, and polar surface area. Results: Compounds 9 and 15a maintained stable binding within the ATP-binding pocket despite lacking the canonical hinge interaction with Met318, indicating hinge-independent binding. Their binding was mainly driven by interactions with Asp381 (DFG motif) and cation–π contacts with Lys271. In contrast, the compound 15e showed unstable binding, increased conformational flexibility, reduced pocket burial, and loss of key stabilizing interactions. Active compounds also preserved stable P-loop dynamics, with Tyr253 engagement suggesting a role in loop stabilization. Compound 9 exhibited the most constrained and reproducible binding mode among all analogues. Conclusions: Ferrocene-based analogues can sustain stable ABL1 binding via non-classical interaction networks independent of hinge recognition. The clear distinction between active compounds and the inactive analogue 15e supports the robustness of the proposed binding mode and provides a structural basis for their reported cytotoxic activity. These findings support further experimental evaluation of ferrocene-containing scaffolds as potential BCR-ABL1 inhibitors. Full article

Multidrug resistance (MDR) is defined as resistance to apparently unrelated drugs with different mechanisms of action, a phenomenon that seriously decreases the efficacy of many anticancer therapeutic regimens. MDR is mainly associated with a high expression of ATP-binding cassette (ABC) transporters, including ABCB1, ABCG2, and members of the ABCC subfamily, which actively extrude many anticancer drugs of various classes out of the cells. Protein kinase inhibitors (PKIs) were developed as therapies targeting oncogenic kinases but later appeared to be both substrates and inhibitors of ABC transporters and thus can potentially reverse MDR. This comprehensive review evaluates how PKIs regulate ABC transporters through three key mechanisms: altering expression, modifying subcellular localization, and inhibiting the efflux function. We evaluated the effect of PKIs that target tyrosine and serine/threonine kinases, such as EGFR/ErbB, JAK, VEGFR, BCR-Abl, ALK, FGFR, MEK1/2, B-RAF, BTK, CDK4/6, MET, RET, PDGFR and SYK. We have collected both computational studies and experimental reports, including functional assays, mechanistic studies of inhibition, and structural approaches that have evaluated PKIs’ effects on ABC transporters. We conclude that although PKIs can be ABC substrates, they mainly inhibit drug efflux, with minimal and context-dependent effects on transporter expression or localization. Full article

Ribosome-inactivating proteins are a class of toxins that target eukaryotic ribosomes, inhibit protein synthesis, and ultimately induce cell death. Several of these toxins pose significant clinical and public health threats. Among these, ricin, derived from the castor bean plant (Ricinus communis), is a highly potent biotoxin with recognized bioterrorism potential. Other ribosome-inactivating proteins, including Shiga toxin produced by pathogenic Shigella and Escherichia coli, as well as mucoricin from Mucorales fungi, contribute to disease severity and can lead to life-threatening complications. Despite these risks, no approved therapeutics are currently available. The development of effective inhibitors depends on robust and well-defined strategies to identify and validate small molecules that disrupt toxin–ribosome interactions. Efforts to target the catalytic active site have met with limited success, largely due to its broad, shallow, and highly polar architecture, which is not conducive to high-affinity binding by drug-like molecules. In contrast, the ribosome-binding interface represents a more tractable target, as it is essential for toxin recruitment and offers more structurally defined and druggable features. Inhibitors targeting this interface can also exert allosteric effects by disrupting long-range conformational coupling between the ribosome-binding region and the active site, thereby attenuating catalytic activity without directly engaging the catalytic pocket. In this review, we compile and evaluate biophysical and biochemical assays for the discovery and characterization of small-molecule inhibitors that target toxin–ribosome interactions. We examine in vitro binding approaches, including surface plasmon resonance-based fragment screening and fluorescence anisotropy assays for ranking inhibitory activity. We further review biochemical and molecular assays that assess ribosome protection from toxin-mediated depurination, along with complementary cell-based assays that evaluate functional rescue in cellular systems. Collectively, this review consolidates current screening methodologies and highlights opportunities to refine assay strategies, thereby supporting the advancement of targeted therapeutics. Full article

Background: Pathogenic BRCA1 and BRCA2 mutations confer a homologous recombination deficiency that underlies PARP inhibitor sensitivity. While BRCA1 mutation carriers more frequently develop triple-negative breast cancer (TNBC) and BRCA2 carriers hormone receptor-positive (HR+) disease, whether the specific protein domain harboring a pathogenic somatic mutation differs systematically between breast cancer subtypes remains uncertain. Apparent domain enrichment in earlier unfiltered analyses may be confounded by missense variants of uncertain significance (VUSs), which lack clinical actionability. Methods: We assembled three independent breast cancer cohorts via cBioPortal: TCGA-BRCA (brca_tcga_pub2015), METABRIC (brca_metabric), and MSK-CHORD (msk_chord_2024). All somatic BRCA1/2 mutations were mapped to UniProt-annotated functional domains and to Rebbeck-defined breast/ovarian cancer cluster regions (BCCR/OCCR). Per ENIGMA/ACMG guidance, pathogenic mutations (nonsense, frameshift, and canonical splice site) were analyzed inferentially, while missense and in-frame variants—predominantly VUSs—were only reported descriptively. Fisher’s exact tests with Benjamini–Hochberg FDR correction were applied across domain × subtype contingencies. Cohort heterogeneity was assessed via Cochran’s Q and I² statistics; pooled effect estimates were computed using inverse-variance fixed-effects meta-analysis. Results: A total of 394 somatic BRCA1/2 mutations were identified across the three cohorts (BRCA1 n = 166; BRCA2 n = 228), of which 147 (37.3%) met pathogenic criteria. Among 131 pathogenic mutations in HR+/HER2− or TNBC subtypes, 84 (64.1%) occurred in HR+/HER2− disease and 47 (35.9%) in TNBC. Domain-level distributions did not differ significantly between subtypes for any BRCA1 domain (BRCT: TNBC 20.0% vs. HR+ 18.8%, OR = 1.08, 95% CI 0.31–3.78, and FDR-adjusted p = 1.00) or BRCA2 domain (DBD: TNBC 17.6% vs. HR+ 30.8%, OR = 0.48, and FDR-adjusted p = 1.00). Cluster-region analyses (nine Rebbeck BCCR/OCCRs) similarly showed no significant enrichment. Post hoc power analysis indicated that the study could only reliably detect large effects (OR ≥ ~3.0 for the principal BRCT contrast), and formal equivalence testing (TOST) demonstrated equivalence within a prespecified ±20% margin for BRCA1 BRCT (TOST p = 0.031). Heterogeneity across cohorts was minimal (Cochran’s Q = 0.62, I² = 0.0%). Descriptive analyses of VUSs suggested the apparent enrichment of BRCA1 BRCT-localized missense variants in TNBC (31.8% vs. 17.9% in HR+), but this signal did not extend to pathogenic mutations. Conclusions: Within the statistical power available, our three-cohort analysis shows no evidence of large subtype-specific enrichment of pathogenic BRCA1/2 somatic mutations across protein domains or cluster regions; small to moderate effects cannot be excluded. Notably, the majority (64%) of pathogenic mutations occurred in HR+/HER2− disease, underscoring that BRCA1/2 testing should not be deprioritized in non-TNBC subtypes. The apparent BRCT enrichment observed in earlier unfiltered analyses appears to be driven by VUSs rather than pathogenic variants, highlighting the methodological necessity of pathogenicity filtering for clinically actionable inference. These findings provide cohort-scale supportive evidence for emerging clinical guidelines that recommend broader BRCA1/2 testing across breast cancer subtypes. Full article

Metformin (MET) plays crucial regulatory roles in mammalian oocyte meiosis, yet the concentration-dependent biphasic impacts of MET on porcine oocyte in vitro maturation (IVM) and the related molecular mechanisms remain poorly clarified. This study aimed to explore the distinct effects and underlying pathways of low- and high-dose MET in porcine oocytes. Different concentrations of MET (0, 7.5, 15, 30, 150, and 300 μM) were supplemented during oocyte IVM, with phenotypic detection, untargeted metabolomic analysis, and Nrf2 inhibitor (ML385) intervention performed for mechanism exploration. Results showed that 15 μM low-dose MET facilitated oocyte maturation, mitochondrial function and redox balance, while 300 μM high-dose MET caused obvious developmental damage. Mechanistically, low-dose MET triggered noncanonical AMPK activation independent of the AMP/ATP ratio and enhanced AMPK–Nrf2 antioxidant signaling, whereas high-dose MET induced energy stress and oxidative injury via inhibiting mitochondrial complex I. Blockade of Nrf2 further abolished the protective effects of low-dose MET. Collectively, this finding illustrates the biphasic actions of MET on porcine oocytes and provides a theoretical reference for optimizing porcine in vitro embryo production. Full article

Background—Generalized pustular psoriasis (GPP) is a rare and severe inflammatory skin disorder—and evidence regarding relative impact of treatments thereof is currently scant. Objective—We aimed to systematically review and narratively synthesize comparative interventional therapies for GPP and secondarily explore their relative effectiveness through exploratory network meta-analyses (NMAs). Methods—Comprehensive searches were performed in PubMed and EMBASE to identify comparative interventional studies that investigated the impact of biologics in GPP. Bayesian NMAs were conducted only for exploratory analyses. Results—Eleven studies met our inclusion criteria and data from 4 of the 11 were used for NMAs. Methodological heterogeneity was evident; the various biologics demonstrated effectiveness in treating GPP. Inhibitors of interleukin (IL)-36 (e.g., spesolimab) resulted in rapid pustular clearance within one week and sustained reductions in flare occurrence. Inhibitors targeting IL-17, IL-23, TNF, and IL-12/23 also demonstrated high response rates, durable disease control, and improvements in quality of life among diverse patient populations. Results from our exploratory NMAs revealed patterns of relative effectiveness with IL-17 and IL-36 inhibitors that are consistent with the existing literature. However, methodological limitations across the four studies deterred us from making conclusive inferences. Conclusions—Biologic therapies provide significant clinical benefit in patients with GPP. Our narrative syntheses highlight the need for future quantitative syntheses. Full article

Non-small cell lung cancer (NSCLC) accounts for up to 85% of lung cancer cases, with activating EGFR mutations present in 10–15% of Western and up to 35% of Asian patients. EGFR tyrosine kinase inhibitors (TKIs) have transformed management, with first-line osimertinib demonstrating a median progression-free survival (PFS) of 18.9 months and overall survival (OS) of 38.6 months in the FLAURA trial. However, resistance inevitably develops, most commonly via T790M mutations (~50% of cases after first- and second-generation TKIs), and after osimertinib, through diverse mechanisms including C797S mutations, MET/HER2 amplification, and histologic transformation. Emerging strategies to overcome resistance include next-generation TKIs, combination targeted therapies, downstream pathway inhibitors, immunotherapy approaches, and antibody–drug conjugates. Understanding these mechanisms is critical for optimizing patient outcomes and guiding personalized therapeutic approaches. This review discusses current strategies to delay or overcome resistance and highlights emerging therapeutic avenues with the potential to reshape the management of EGFR-mutant NSCLC. Full article

Objective: Insulin resistance is a key pathophysiological driver linking obesity and type 2 diabetes (T2D) with cardiovascular risk. Composite surrogate indices derived from routine clinical parameters, such as the Metabolic Score for Insulin Resistance (METS-IR) and the Single Point Insulin Sensitivity Estimator (SPISE), may provide a practical means of capturing multidimensional metabolic changes. Given that comparative data are limited, we aimed to evaluate the effects of sodium–glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) on these indices in individuals with T2D and overweight or obesity. Methods: In this retrospective observational study, 100 individuals with T2D treated with either GLP-1RA (n = 54) or SGLT2i (n = 46) were evaluated over 6 months. Strict inclusion criteria ensured treatment stability without initiation or modification of concomitant pharmacotherapy. Changes in METS-IR and SPISE were assessed alongside body mass index (BMI) and glycated hemoglobin (HbA1c). Multivariable regression and exploratory analyses, including stratification by BMI and correlation analyses, were performed. Results: Both treatment groups demonstrated significant improvements in METS-IR (GLP-1RA: −3.9 ± 5.9; SGLT2i: −2.5 ± 2.6; both p < 0.001) and SPISE (GLP-1RA: +0.46 ± 0.52; SGLT2i: +0.44 ± 0.61; both p < 0.001), with no significant between-group differences. In the GLP-1RA group, changes in METS-IR correlated with changes in BMI (r = 0.48, p < 0.001) and HbA1c (r = 0.29, p = 0.030), whereas no significant correlations were observed in the SGLT2i group. Stratified analyses indicated greater reductions in METS-IR among individuals with BMI ≥30 kg/m² treated with GLP-1RA. Conclusions: Both SGLT2i and GLP-1RA improve composite surrogate markers of insulin resistance, with distinct associations with weight and glycemic changes. METS-IR and SPISE may serve as practical tools for monitoring multidimensional metabolic responses in clinical practice. Full article

Background: Difficult-to-treat anatomical areas in atopic dermatitis (AD), including the head and neck, hands, genital and intertriginous regions, are frequently associated with therapeutic refractoriness, persistent pruritus, and substantial functional and psychosocial burden. Real-world evidence (RWE) regarding the effectiveness of Janus kinase (JAK) inhibitors in these site-dominant phenotypes remains fragmented. This structured narrative review aimed to synthesize available RWE on abrocitinib, baricitinib, and upadacitinib in AD involving difficult-to-treat areas. Methods: A comprehensive search of PubMed, Ovid MEDLINE, Scopus, Embase, and the Cochrane Library was conducted up to 31 December 2025. Real-world observational studies reporting site-specific outcomes in patients with AD treated with JAK inhibitors were included. Primary randomized controlled trial efficacy analyses were excluded, while relevant post hoc regional analyses were considered. A total of 22 studies met eligibility criteria for qualitative synthesis. Results: Across heterogeneous real-world cohorts, JAK inhibitors demonstrated clinically meaningful improvement in difficult anatomical regions, particularly the head and neck and hands. Rapid pruritus reduction was a consistent and clinically relevant finding. Safety profiles were broadly aligned with clinical trial data. Conclusions: Real-world data support JAK inhibitors as effective options for anatomically complex AD phenotypes, warranting further standardized regional assessment. Full article

In prokaryotes, translation initiation orchestrates protein synthesis through a network of dynamic interactions among the ribosome, mRNA, initiator tRNA^fMet, and initiation factors (IFs). Traditional approaches that rely on radioactive labeling or surface immobilization are hindered by inherent safety risks and methodological constraints. We present a fluorescence-based analytical platform that integrates microscale thermophoresis (MST) as a unified, multiparametric toolkit for comprehensive interrogation of bacterial translation initiation at the molecular level. By systematically applying MST to a panel of fluorescently labeled components—initiator tRNA^fMet, mRNAs, and initiation factors—we quantify assembly pathways and equilibria as initiation progresses from simple bimolecular interactions to higher-order, multicomponent complexes. To broaden the fluorescence toolbox for ribosomal studies, we developed a robust BODIPY-labeling protocol for 70S ribosomes and confirmed preservation of structural integrity and function by nano differential scanning fluorimetry, stopped-flow kinetic assays, and peptide-synthesis activity tests. Our microscale fluorescent system facilitates probing initiation at a variety of steps, since the role of magnesium ions and initiation factors upon 30S initiation complex formation. The same platform can be applied to investigate the effects of different compounds on translation initiation, as demonstrated for a number of antibiotics, aptamers, and antimicrobial peptides. Using this approach, we determined the antibiotic streptomycin dissociation constant for both 30S and 70S ribosomes, which proved identical at 0.3 ± 0.1 μM, and demonstrated the effect of the antimicrobial peptide rumicidin-1 on translation initiation. Offering a cost-effective and high-sensitivity alternative to conventional methods, this approach advances mechanistic understanding of prokaryotic translation and provides a versatile framework for the discovery of novel protein synthesis inhibitors. Full article

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by complement-mediated hemolytic anemia and thrombosis. The first treatments approved were complement 5 inhibitors (C5is), eculizumab and ravulizumab. Recently approved treatments include pegcetacoplan, iptacopan, danicopan (as an add-on to a C5i), and crovalimab. Methods: A systematic literature review (SLR) was conducted to identify clinical evidence on all available treatments. Outcomes evaluated were hemoglobin and lactate dehydrogenase (LDH) levels, transfusion avoidance, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and safety. Results: In total, 133 records met the inclusion criteria. Of these, 54 records reporting on 11 Phase 3 trials and 2 extension studies are summarized. Eight trials and one extension study evaluated complement inhibitor (CI)-naïve patients, three trials evaluated CI-experienced patients with residual anemia, and one extension study evaluated both groups. In both patient groups, all treatments led to improved outcomes. Conclusions: This SLR is the first to provide an overview of clinical trials assessing the efficacy and safety of all currently approved PNH treatments, which could help inform clinical decisions. Although some head-to-head trials are available, direct comparative evidence remains limited for several comparators, necessitating an indirect treatment comparison (ITC) to assess the efficacy and safety across the treatment landscape. Full article