Drugs

Chang, Ming-Ling; Liaw, Yun-Fan

doi: 10.1007/s40265-023-01843-2pmid: 36906663

Worldwide, an estimated 296 million people are living with chronic hepatitis B virus (HBV) infection, with a significant risk of morbidity and mortality. Current therapy with pegylated interferon (Peg-IFN) and indefinite or finite therapy with nucleoside/nucleotide analogues (Nucs) are effective in HBV suppression, hepatitis resolution, and prevention of disease progression. However, few achieve hepatitis B surface antigen (HBsAg) loss (functional cure), and relapse often occurs after the end of therapy (EOT) because these agents have no direct effect on durable template: covalently closed circular DNA (cccDNA) and integrated HBV DNA. Hepatitis B surface antigen loss rate increases slightly by adding or switching to Peg-IFN in Nuc-treated patients and this loss rate greatly increases up to 39% in 5 years with finite Nuc therapy with currently available Nuc(s). For this, great effort has been made to develop novel direct-acting antivirals (DAAs) and immunomodulators. Among the DAAs, entry inhibitors and capsid assembly modulators have little effect on reducing HBsAg levels; small interfering RNA, antisense oligonucleotides, and nucleic acid polymers in combination with Peg-IFN and Nuc may reduce HBsAg levels significantly, even a rate of HBsAg loss sustained for > 24 weeks after EOT up to 40%. Novel immunomodulators, including T-cell receptor agonists, check-point inhibitors, therapeutic vaccines, and monoclonal antibodies may restore HBV-specific T-cell response but not sustained HBsAg loss. The safety issues and the durability of HBsAg loss warrant further investigation. Combining agents of different classes has the potential to enhance HBsAg loss. Compounds directly targeting cccDNA would be more effective but are still in the early stage of development. More effort is required to achieve this goal.

Jayabalan, Nanthini; Oronsky, Bryan; Cabrales, Pedro; Reid, Tony; Caroen, Scott; Johnson, Aishwarya M.; Birch, Natalia A.; O’Sullivan, John D.; Gordon, Richard

doi: 10.1007/s40265-023-01838-zpmid: 36920652

Chronic unresolving inflammation is emerging as a key underlying pathological feature of many if not most diseases ranging from autoimmune conditions to cardiometabolic and neurological disorders. Dysregulated immune and inflammasome activation is thought to be the central driver of unresolving inflammation, which in some ways provides a unified theory of disease pathology and progression. Inflammasomes are a group of large cytosolic protein complexes that, in response to infection- or stress-associated stimuli, oligomerize and assemble to generate a platform for driving inflammation. This occurs through proteolytic activation of caspase-1-mediated inflammatory responses, including cleavage and secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and initiation of pyroptosis, an inflammatory form of cell death. Several inflammasomes have been characterized. The most well-studied is the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, so named because the NLRP3 protein in the complex, which is primarily present in immune and inflammatory cells following activation by inflammatory stimuli, belongs to the family of nucleotide-binding and oligomerization domain (Nod) receptor proteins. Several NLRP3 inflammasome inhibitors are in development, all with multi-indication activity. This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology.

Blais, Joseph E.; Huang, Xin; Zhao, Jie V.

doi: 10.1007/s40265-023-01841-4pmid: 36941490

BackgroundBerberine is a nutraceutical that can improve lipid metabolism. Berberine may also affect sex hormones and exert sex-specific lipid-modifying effects, which have been overlooked. This study aimed to comprehensively review the efficacy and safety of berberine in adults for the treatment of dyslipidemia with consideration of potential sex disparity.Data Sources We searched Medline, Embase, Wanfang, CNKI, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform from inception to 13 December 2022. No language restrictions were applied. This study was registered in PROSPERO (CRD42021293218) prior to completing the literature search.Study Selection Two blinded reviewers assessed studies for inclusion. Eligible studies were randomized controlled trials in adults that compared berberine versus placebo, and measured blood lipids or lipoproteins.Data Extraction and Synthesis Data extraction was performed by two blinded reviewers using a structured form in Covidence. Risk of bias was assessed using the Cochrane risk of bias tool for randomized trials. Mean differences (MD) were estimated using inverse variance weighting with random effects models for lipid outcomes using R. Adverse events (AEs) were described narratively.Main Outcomes Primary outcomes were low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoprotein B. Secondary outcomes were gastrointestinal and muscle-related AEs.ResultsEighteen studies (n = 1788 participants), conducted mainly in mainland China and Hong Kong (15 studies [83%]), were included with treatment durations ranging from 4 to 24 weeks. Berberine reduced LDL cholesterol (− 0.46 mmol/L, 95% CI − 0.62 to − 0.30, 14 studies, n = 1447), total cholesterol (− 0.48 mmol/L, 95% CI − 0.63 to − 0.33, 17 studies, n = 1637), triglycerides (− 0.34 mmol/L, 95% CI − 0.46 to − 0.23, 18 studies, n = 1661) and apolipoprotein B (− 0.25 g/L, 95% CI − 0.40 to − 0.11, 2 studies, n = 127). Berberine increased HDL cholesterol by 0.06 mmol/L (95% CI 0.00 to 0.11, 15 studies, n = 1471). Notably, the effect on HDL cholesterol was different in women (0.11 mmol/L, 95% CI 0.09 to 0.13) from that in men (− 0.07 mmol/L, 95% CI − 0.16 to 0.02). Among 16 studies that reported AEs, no serious AEs were reported for berberine. Gastrointestinal AEs were reported in 12 studies and tended to be more frequent in participants allocated to berberine versus placebo (2–23% vs 2–15%).ConclusionsBerberine produces small reductions in LDL cholesterol, triglycerides, and apolipoprotein B, with potential sex-specific effects on HDL cholesterol. Large-scale trials that consider sex disparity and assess clinical outcomes are required.Graphical Abstract[graphic not available: see fulltext]

Lailler, Grégory; Grave, Clémence; Gabet, Amélie; Regnault, Nolwenn; Deneux-Tharaux, Catherine; Kretz, Sandrine; Tsatsaris, Vassilis; Plu-Bureau, Geneviève; Blacher, Jacques; Olie, Valérie

doi: 10.1007/s40265-023-01842-3pmid: 36867398

BackgroundMany clinical trials have reported that low-dose aspirin decreases the risk of pre-eclampsia in women with prior pre-eclampsia. However, its impact in a real-world population has not been fully assessed.ObjectivesTo assess the rates of low-dose aspirin initiation during pregnancy in women with a history of pre-eclampsia, and to evaluate the impact of low-dose aspirin in prevention of pre-eclampsia recurrence in a real-world population.Study DesignCONCEPTION is a French nationwide cohort study which uses data from the country’s National Health Data System database. We included all women in France who gave birth at least twice between 2010–2018, and who had pre-eclampsia during their first pregnancy. Every dispensing of low-dose aspirin (75–300 mg) between the beginning of their second pregnancy and 36 weeks of gestation (WG) was identified. We used Poisson regression models to estimate the adjusted incidence rate ratios (aIRRs) of receiving aspirin at least once during their second pregnancy. In women who had early and/or severe pre-eclampsia during their first pregnancy, we estimated the IRRs of pre-eclampsia recurrence during their second pregnancy according to the aspirin therapy.ResultsIn 28,467 women who were included in the study, the aspirin initiation rate during the second pregnancy ranged from 27.8% for women in whose first pregnancy the pre-eclampsia was mild and late, to 79.9% for those women whose pre-eclampsia was severe and early. Just over half (54.3%) of those treated with aspirin-initiated treatment before 16 WG and adhered to treatment. Compared with women with mild and late pre-eclampsia, the aIRRs (95% CI) for receiving aspirin at least once during the second pregnancy were 1.94 (1.86–2.03) for women with severe and late pre-eclampsia, 2.34 (2.17–2.52) for those with early and mild pre-eclampsia, and 2.87 [2.74–3.01] for those with early and severe pre-eclampsia E. Social deprivation was associated with a lower initiation of aspirin (IRR = 0.74 [0.70–0.78]). Aspirin was not associated with a lower risk of mild and late pre-eclampsia, severe and late pre-eclampsia, or mild and early pre-eclampsia during the second pregnancy. The aIRRs for severe and early pre-eclampsia during the second pregnancy were 0.77 (0.62–0.95) for women who received prescribed aspirin at least once, 0.71 (0.5–0.89) for those who initiated aspirin therapy before 16 WG, and 0.60 (0.47–0.77) for those who adhered to aspirin treatment throughout their second pregnancy. The risk of severe and early pre-eclampsia was lower only when the prescribed mean daily dose was ≥ 100 mg/day.ConclusionIn women with a history of pre-eclampsia, aspirin initiation during a second pregnancy and adherence to the prescribed dosage were largely insufficient, especially for women experiencing social deprivation. Aspirin initiated before 16 WG at a dose ≥ 100 mg/day was associated with a lower risk of severe and early pre-eclampsia.

Keam, Susan J.

doi: 10.1007/s40265-023-01847-ypmid: 36877454

Teplizumab (teplizumab-mzwv; TZIELD™) is a CD3-directed monoclonal antibody (humanized IgG1κ) that is being developed by Provention Bio, Inc. for the treatment of type 1 diabetes (T1D). In November 2022, teplizumab was approved in the USA to delay the onset of Stage 3 T1D in adults and pediatric patients 8 years of age and older with Stage 2 T1D, based on results of a clinical trial in high-risk relatives of individuals with T1D. This article summarizes the milestones in the development of teplizumab leading to this first approval in the treatment of T1D.

Hoy, Sheridan M.

doi: 10.1007/s40265-023-01848-xpmid: 36867399

Bexagliflozin (BRENZAVVY™) is an orally administered potent inhibitor of sodium–glucose transporter 2 (SGLT-2). It is being developed by TheracosBio for the treatment of type 2 diabetes (T2D) and essential hypertension, and in January 2023 it received its first approval in the USA for use as an adjunct to diet and exercise to improve glycaemic control in adults with T2D. Bexagliflozin is contraindicated in patients receiving dialysis and is not recommended in patients with type 1 diabetes or in those with an estimated glomerular filtration rate of < 30 mL/min/1.73 m2. Bexagliflozin is undergoing clinical development for the treatment of essential hypertension in the USA. This article summarizes the milestones in the development of bexagliflozin leading to this first approval for the treatment of T2D.

Lee, Arnold

doi: 10.1007/s40265-023-01854-zpmid: 36920653

Ublituximab (ublituximab-xiiy; BRIUMVI™) is a glycoengineered anti-CD20 monoclonal antibody developed by TG Therapeutics, Inc. for the treatment of multiple sclerosis (MS). The mechanism of action of ublituximab involves the depletion of B cells via antibody-dependent cellular cytotoxicity, as B cells have a key role in the pathogenesis of MS. Ublituximab is the first anti-CD20 treatment that is administered twice-yearly as one hour infusions, following the initial doses. In December 2022, ublituximab received its first global approval in the USA for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. This article summarizes the milestones in the development of ublituximab leading to this first approval in this indication.

Huang, Jin-Xian; Zhang, Guo-Wen

doi: 10.1007/s40265-023-01849-wpmid: N/A

Tong, Qiang; Wang, Shiow-Ing; Wei, James Cheng-Chung; Dai, Sheng-Ming

doi: 10.1007/s40265-023-01850-3pmid: N/A