Drugs

Nardone, Olga Maria; Vuyyuru, Sudheer K.; Yuan, Yuhong; Hanzel, Jurij; Jairath, Vipul

doi: 10.1007/s40265-025-02183-zpmid: 40323342

Interleukin-23 (IL-23), a member of the IL-12 family of cytokines, plays a critical role in intestinal homeostasis and inflammation and is strongly implicated in the pathogenesis of inflammatory bowel disease (IBD). Therapies targeting the p19 subunit of IL-23 have recently expanded the therapeutic options for IBD demonstrating efficacy and safety for the treatment of moderate to severe Crohn’s disease (CD). Thus, in this review, we provide an overview of agents targeting the IL-23 pathway in CD, highlighting similarities and differences of specific IL-23 inhibitors. Furthermore, we summarize key phase 3 trials and head-to-head trials, focusing on design features and interpretation. Finally, we discuss the positioning of selective IL-23 agents for CD treatment along with areas of unmet clinical needs. However, real-world data will offer additional comparative effectiveness information, data for disease subtypes, and insights into the long-term outcomes of IL-23 inhibition. Looking ahead, ongoing phase 3 studies testing p19-specific selective IL-23 inhibitors are expected to expand the therapeutic options for patients with complex phenotypes, including those with extraintestinal manifestations (EIMs), fistulas, and strictures. Advances in molecular and cellular characterization, including the development of predictive molecular biomarkers, may help guide clinical decision-making, enabling more personalized treatment approaches. Precision medicine studies may further enhance our understanding of the molecular biology of IL-23, shedding light on how these agents work in complex CD and clarify their potential complementary or synergistic effects with other therapies.

Cazzola, Mario; Page, Clive; Rogliani, Paola; Calzetta, Luigino; Matera, Maria Gabriella

doi: 10.1007/s40265-025-02179-9pmid: 40214902

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) share a complex and multifactorial relationship characterized by overlapping risk factors, systemic inflammation, and intertwined pathophysiological mechanisms, with atherosclerosis emerging as a central inflammatory process connecting COPD and CVD, driven by systemic inflammation, oxidative stress, and endothelial dysfunction. While systemic inflammation is recognized as a critical link between these conditions, the precise pathways through which inflammation arises remain under investigation. There is therefore a need for therapeutic strategies to mitigate cardiovascular risks in patients with COPD. Among the pathways contributing to this interplay, the phosphoinositide 3-kinase (PI3K) signaling pathway has gained significant attention. Dysregulated PI3K signaling contributes to inflammation, oxidative stress, and endothelial dysfunction, which are key drivers of both COPD and CVD. Consequently, PI3K inhibitors have emerged as a promising therapeutic approach to mitigate inflammation and oxidative damage, offering a targeted strategy to address the shared pathological mechanisms underlying these diseases. A comprehensive understanding of the role of PI3K signaling and its inhibitors could facilitate the development of novel interventions to reduce cardiovascular risk in patients with COPD.

Tramontano, Daniele; Bini, Simone; Maiorca, Carlo; Di Costanzo, Alessia; Carosi, Martina; Castellese, Jacopo; Arizaj, Ina; Commodari, Daniela; Covino, Stella; Sansone, Giorgia; Minicocci, Ilenia; Arca, Marcello; D’Erasmo, Laura

doi: 10.1007/s40265-025-02158-0pmid: 40106181

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Quantitative and qualitative changes in plasma lipoprotein profiles are frequently associated with CKD and represent a significant risk factor for CVD in patients with CKD. Guidelines from the European Society of Cardiology and the European Atherosclerosis Society classify CKD as a condition with high or very high cardiovascular risk and set specific low-density lipoprotein cholesterol targets. Conventional lipid-lowering therapies (LLTs), such as statins, ezetimibe, and fibrates, can control CKD-associated dyslipidemia and, to some extent, prevent major atherosclerotic events in patients with CKD, but their use in clinical practice presents challenges because of the potential renal safety concerns. In recent years, novel therapies with the ability to lower both low-density lipoprotein cholesterol and triglycerides have been introduced to the market (e.g., proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, lomitapide, volanesorsen) to improve our ability to control lipid abnormalities. However, their impact on kidney functionality has not been fully elucidated. The aim of this review was to examine the renal safety profiles of various LLTs, with special reference to novel medications, and to highlight important considerations and guidance for the use of these medications in overt CKD or in patients with some degree of renal function impairment. We underscore the lack of a comprehensive understanding of kidney safety, particularly for novel LLT therapies, and strongly emphasize the importance of future dedicated research to fully assess the safety and efficacy of these agents in patients with kidney abnormalities.

Legrand, Matthieu; Ranjan, Amaresh; Rammohan, Shruthi; De Backer, Daniel; Ostermann, Marlies; Gulati, Anil; Vincent, Jean-Louis; Khanna, Ashish K.

doi: 10.1007/s40265-025-02176-ypmid: 40253656

Shock is a life-threatening condition marked by inadequate tissue perfusion and organ dysfunction with high morbidity and mortality. Activation of the sympatho-adrenergic system is pivotal in response to all four major categories (i.e., hypovolemic, distributive, cardiogenic, and obstructive). In addition, exogenous vasopressors are often used to maintain organ perfusion pressure and decrease the size of the intravascular compartment. These agents preferentially constrict the arterial system but may lead to microcirculatory failure, especially at higher doses. This review outlines the sympatho-adrenergic system response after shock, discusses various vasopressors currently used as resuscitative agents, and reports the rationale for using a predominant venous vasopressor in shock. We also discuss the preliminary evidence for and ongoing research into a novel venous vasopressor, centhaquine citrate.

Baratta, Francesco; Moscucci, Federica; Lospinuso, Ilaria; Cocomello, Nicholas; Colantoni, Alessandra; Di Costanzo, Alessia; Tramontano, Daniele; D’Erasmo, Laura; Pastori, Daniele; Ettorre, Evaristo; Del Ben, Maria; Arca, Marcello; Desideri, Giovambattista

doi: 10.1007/s40265-025-02182-0pmid: 40338434

The global population aged 80 years and older will reach approximately half a billion in the coming years, and cardiovascular prevention in this group of patients will become a global health challenge. In the era of evidence-based medicine, the use of lipid-lowering therapies (LLTs) in the elderly, particularly in primary and secondary cardiovascular prevention, remains an area of active research. Although there is broad consensus on the use of LLTs in the elderly to prevent recurrent cardiovascular events in secondary prevention, there is considerable debate about their use in primary prevention. Many efforts have been made to improve cardiovascular risk stratification in patients over 75 years of age in primary prevention. In recent years, some specific risk scores have been developed, including the Systematic Coronary Risk Evaluation 2 for Older Persons (SCORE2-OP). While there are very few specific warnings to consider for LLTs in the elderly, an important challenge in this patient population is to identify the turning point at which the disutility risk outweighs the potential benefits. However, despite the widespread recognition of the importance of this issue, there is a lack of guidance on how to identify patients who should be withdrawn from therapy. The aim of this narrative review is to examine the current state of knowledge regarding the indications for LLT in elderly patients, identify outstanding issues, and discuss future developments.

Al-Moussally, Feras; Khan, Saud; Katukuri, Vinay; Kinaan, Mustafa; Mansi, Ishak A.

doi: 10.1007/s40265-025-02177-xpmid: 40223043

AimIn recent years, use of glucagon-like peptide-1 receptor agonists (GLP-1RA) has exponentially increased due to their beneficial effects on weight loss and cardiovascular outcomes. Lately, some animal studies and observational data suggested that GLP-1RA may be useful in the treatment of alcohol use disorder (AUD). We aim to compare the risk of progression to liver cirrhosis and alcohol-related hospital admission after initiation of GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP4i), as the active comparator, in patients with type 2 diabetes mellitus and AUD.MethodsWe conducted a retrospective propensity score-matched cohort study, utilizing new-user and active comparator design. The study used data from the Veterans Health Administration during fiscal years 2006 to 2021 encompassing adults with AUD who initiated either GLP-1RA or DPP4i prescriptions. Our two co-primary outcomes were progression to cirrhosis (compensated and decompensated cirrhosis) and alcohol-related hospital admission.ResultsThe eligible cohort included 9965 GLP-1RA users and 19,688 DPP4i users. After propensity score matching, 7302 pairs were matched on 79 characteristics without residual imbalances. In the propensity score-matched cohort, progression to cirrhosis occurred in 6.6% of GLP-1RA users and 6.0% DPP4i users; odds ratio (OR): 1.1, 95% confidence interval (95% CI): 0.97–1.26. Alcohol-related hospital admission occurred in 1.4% of GLP-1RA users and in 1.7% of DPP4i users (OR: 0.85; 95% CI: 0.65–1.11).ConclusionsUse of GLP-1RA in patients with AUD was not associated with beneficial effect on progression to cirrhosis or alcohol-related hospital admission.

Fung, Simon

doi: 10.1007/s40265-025-02180-2pmid: 40261472

Garadacimab (Andembry®) is a fully human IgG4/lambda recombinant monoclonal anti-activated Factor XII antibody being developed by CSL Behring for the prevention of hereditary angioedema attacks. In January 2025, garadacimab received its first approval in Australia and the UK for prevention of hereditary angioedema attacks in adult and adolescent patients aged ≥ 12 years. Additionally, in February 2025, garadacimab was approved for the same indication in the EU, Japan and Switzerland. In the USA and Canada, regulatory review of garadacimab is currently underway. This article summarizes the milestones in the development of garadacimab leading to this first approval for prevention of recurrent hereditary angioedema attacks in adult and adolescent patients aged ≥ 12 years.

Lee, Arnold

doi: 10.1007/s40265-025-02159-zpmid: 40180779

Disassociation of transthyretin (TTR) has been identified as a key step in the pathology of TTR amyloid cardiomyopathy, which is characterised by the presence of amyloid fibrils in cardiac tissue. Acoramidis (ATTRUBY™) is a small molecule TTR stabiliser being developed by BridgeBio Pharma, Inc. and is the first drug to demonstrate near-complete (> 90%) stabilisation of TTR. This article summarizes the milestones in the development of acoramidis leading to its first approval in the USA for the treatment of the cardiomyopathy of wild-type or variant TTR-mediated amyloidosis in adults to reduce cardiovascular death and cardiovascular-related hospitalization. In the EU, a positive opinion has been adopted for the treatment of wild-type or variant transthyretin amyloidosis in adult patients with cardiomyopathy.

Lee, Arnold

doi: 10.1007/s40265-025-02165-1pmid: 40240539

Crinecerfont (CRENESSITY™) is a corticotropin releasing factor type 1 (CRF1) receptor antagonist developed by Neurocrine Biosciences for the treatment of classic congenital adrenal hyperplasia (CAH) in adult and paediatric patients. In patients with classic CAH, circulating levels of adrenocorticotropic hormone (ACTH), androstenedione and 17-hydroxyprogesterone are elevated, which traditionally has required supraphysiologic doses of glucocorticoids to manage. As a CRF1 receptor antagonist, crinecerfont acts by reducing systemic ACTH secretion to subsequently decrease elevated levels of steroid precursors and adrenal androgens, thereby reducing the dosage of glucocorticoids required to manage androgen levels in patients. This article summarizes the milestones in the development of crinecerfont leading to this first approval as an adjunctive treatment to glucocorticoid replacement to control androgens in adults and paediatric patients aged ≥ 4 years with classic CAH.

Keam, Susan J.

doi: 10.1007/s40265-025-02178-wpmid: 40323340

Suzetrigine (JOURNAVX™), an oral, non-opioid analgesic that is highly selective for the voltage-gated sodium channel NaV1.8 relative to other NaV channels, is being developed by Vertex Pharmaceuticals Inc. for the management of acute and neuropathic pain. NaV1.8 is expressed in peripheral pain-sensing neurons but is not expressed in the brain. Suzetrigine prevents transmission of pain signals by blocking NaV1.8 channels located along peripheral pain-sensing neurons, inhibiting the normal action potential. On 30 January 2025, suzetrigine was approved for the treatment of moderate to severe acute pain in adults in the USA. Suzetrigine is the first NaV inhibitor to be approved in this new therapeutic class of non-opioid analgesics. This article summarizes the milestones in the development of suzetrigine leading to this first approval for the treatment of moderate to severe acute pain.