Drugs

Prince, David Stephen; Nash, Emily; Liu, Ken

doi: 10.1007/s40265-023-01939-9pmid: 37747685

Alcohol is a prominent cause of liver disease worldwide with higher prevalence in developed nations. The spectrum of alcohol-associated liver disease (ALD) encompasses a diverse range of clinical entities, from asymptomatic isolated steatosis to decompensated cirrhosis, and in some cases, acute or chronic liver failure. Consequently, it is important for healthcare practitioners to maintain awareness and systematically screen for ALD. The optimal evaluation and management of ALD necessitates a collaborative approach, incorporating a multidisciplinary team and accounting for concurrent medical conditions. A repertoire of therapeutic interventions exists to support patients in achieving alcohol cessation and sustaining remission, with complete abstinence being the ultimate objective. This review explores the existing therapeutic options for ALD acknowledging geographical discrepancies in accessibility. Recent innovations, including the inclusion of alcohol consumption biomarkers into clinical protocols and the expansion of liver transplantation eligibility to encompass severe alcohol-associated hepatitis, are explored.

Rajasekaran, Arun; Green, Todd J.; Renfrow, Matthew B.; Julian, Bruce A.; Novak, Jan; Rizk, Dana V.

doi: 10.1007/s40265-023-01940-2pmid: 37747686

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a frequent cause of kidney failure. Currently, the diagnosis necessitates a kidney biopsy, with routine immunofluorescence microscopy revealing IgA as the dominant or co-dominant immunoglobulin in the glomerular immuno-deposits, often with IgG and sometimes IgM or both. Complement protein C3 is observed in most cases. IgAN leads to kidney failure in 20–40% of patients within 20 years of diagnosis and reduces average life expectancy by about 10 years. There is increasing clinical, biochemical, and genetic evidence that the complement system plays a paramount role in the pathogenesis of IgAN. The presence of C3 in the kidney immuno-deposits differentiates the diagnosis of IgAN from subclinical glomerular mesangial IgA deposition. Markers of complement activation via the lectin and alternative pathways in kidney-biopsy specimens are associated with disease activity and are predictive of poor outcome. Levels of select complement proteins in the circulation have also been assessed in patients with IgAN and found to be of prognostic value. Ongoing genetic studies have identified at least 30 loci associated with IgAN. Genes within some of these loci encode complement-system regulating proteins that can interact with immune complexes. The growing appreciation for the central role of complement components in IgAN pathogenesis highlighted these pathways as potential treatment targets and sparked great interest in pharmacological agents targeting the complement cascade for the treatment of IgAN, as evidenced by the plethora of ongoing clinical trials.

Terkeltaub, Robert

doi: 10.1007/s40265-023-01944-ypmid: 37819612

Hyperuricemia with consequent monosodium urate crystal deposition leads to gout, characterized by painful, incapacitating inflammatory arthritis flares that are also associated with increased cardiovascular event and related mortality risk. This narrative review focuses on emerging pharmacologic urate-lowering treatment (ULT) and management strategies in gout. Undertreated, gout can progress to palpable tophi and joint damage. In oral ULT clinical trials, target serum urate of < 6.0 mg/dL can be achieved in ~ 80–90% of subjects, with flare burden reduction by 1–2 years. However, real-world ULT results are far less successful, due to both singular patient nonadherence and prescriber undertreatment, particularly in primary care, where most patients are managed. Multiple dose titrations commonly needed to optimize first-line allopurinol ULT monotherapy, and substantial potential toxicities and other limitations of approved, marketed oral monotherapy ULT drugs, promote hyperuricemia undertreatment. Common gout comorbidities with associated increased mortality (e.g., moderate–severe chronic kidney disease [CKD], type 2 diabetes, hypertension, atherosclerosis, heart failure) heighten ULT treatment complexity and emphasize unmet needs for better and more rapid clinically significant outcomes, including attenuated gout flare burden. The gout drug armamentarium will be expanded by integrating sodium-glucose cotransporter-2 (SGLT2) inhibitors with uricosuric and anti-inflammatory properties as well as clinically indicated antidiabetic, nephroprotective, and/or cardioprotective effects. The broad ULT developmental pipeline is loaded with multiple uricosurics that selectively target uric acid transporter 1 (URAT1). Evolving ULT approaches include administering selected gut anaerobic purine degrading bacteria (PDB), modulating intestinal urate transport, and employing liver-targeted xanthine oxidoreductase mRNA knockdown. Last, emerging measures to decrease the immunogenicity of systemically administered recombinant uricases should simplify treatment regimens and further improve outcomes in managing the most severe gout phenotypes.

Chen, Qiuzhe; Maher, Chris G.; Han, Christopher S.; Abdel Shaheed, Christina; Lin, Chung-Wei Christine; Rogan, Eileen M.; Machado, Gustavo C.

doi: 10.1007/s40265-023-01941-1pmid: 37768540

BackgroundThe prevalence of continued opioid use or serious adverse events (SAEs) following opioid therapy in the emergency department (ED) for musculoskeletal pain is unclear. The aim of this review was to examine the prevalence of continued opioid use and serious adverse events (SAEs) following the provision of opioids for musculoskeletal pain in the emergency department (ED) or at discharge.MethodsRecords were searched from MEDLINE, EMBASE and CINAHL from inception to 7 October 2022. We included randomised controlled trials and observational studies enrolling adult patients with musculoskeletal pain who were administered and/or prescribed opioids in the ED. Continued opioid use and opioid misuse data after day 4 since ED discharge were extracted. Adverse events were coded using the Common Terminology Criteria for Adverse Events (CTCAE), and those rated as grades 3–4 (severe or life-threatening) and grade 5 (death) were considered SAEs. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool.ResultsSeventy-two studies were included. Among opioid-naïve patients who received an opioid prescription, 6.8–7.0% reported recent opioid use at 3–12 months after discharge, 4.4% filled ≥ 5 opioid prescriptions and 3.1% filled > 90-day supply of opioids within 6 months. The prevalence of SAEs was 0.02% [95% confidence interval (CI) 0, 0.2%] in the ED and 0.1% (95% CI 0, 1.5%) within 2 days. One study observed 42.9% of patients misused opioids within 30 days after discharge.ConclusionsAround 7% of opioid-naïve patients with musculoskeletal pain receiving opioid therapy continue opioid use at 3–12 months after ED discharge. SAEs following ED administration of an opioid were uncommon; however, studies only monitored patients for 2 days.Protocol Registration10.31219/osf.io/w4z3u.

Syed, Yahiya Y.

doi: 10.1007/s40265-023-01947-9pmid: 37843754

Lotilaner ophthalmic solution 0.25% (XDEMVY™), a gamma-aminobutyric acid-gated chloride channel (GABA-Cl) inhibitor selective for mites, is being developed by Tarsus Pharmaceuticals for the treatment of Demodex blepharitis and meibomian gland dysfunction in patients with Demodex lid infestation (Demodex-induced meibomianitis). On 24 July 2023, lotilaner ophthalmic solution 0.25% received its first approval in the USA for the treatment of Demodex blepharitis. The agent is also currently in phase 3 development for Demodex blepharitis in China and phase 2 development for Demodex-induced meibomianitis in the USA. This article summarizes the milestones in the development of lotilaner ophthalmic solution 0.25% leading to this first approval for the treatment of Demodex blepharitis in the USA.

Syed, Yahiya Y.

doi: 10.1007/s40265-023-01965-7pmid: 37906372

Keam, Susan J.

doi: 10.1007/s40265-023-01952-ypmid: 37847461

Tafolecimab (SINTBILO®), a subcutaneously administered anti-proprotein convertase subtilisin/kexin type 9 enzyme (PCSK9) monoclonal antibody, is being developed by Innovent for the treatment of hypercholesterolemia and mixed hyperlipidemia. Tafolecimab was approved in August 2023 in China as an adjunct to diet, in combination with a statin or statin with other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, for the treatment of adults with primary hyperlipidemia [including heterozygous familial hypercholesterolemia (HeFH) and non-familial hypercholesterolemia (non-FH)] and mixed dyslipidemia who have failed to achieve LDL-C goals despite moderate or higher doses of statins, to reduce LDL-C, total cholesterol (TC), and apolipoprotein B (ApoB) levels. This article summarizes the milestones in the development of tafolecimab leading to this first approval for the treatment of adults with primary hyperlipidemia and mixed dyslipidemia.

Hoy, Sheridan M.

doi: 10.1007/s40265-023-01955-9pmid: 37856038

Pozelimab (pozelimab-bbfg; VEOPOZ™) is a fully human immunoglobulin (Ig) G4P (i.e. IgG4 with a proline substitution to promote stabilization of the disulfide bonds between the two heavy chains) monoclonal antibody developed by Regeneron Pharmaceuticals Inc., to block the activity of complement factor 5 (C5) and prevent diseases mediated by the complement pathway. In August 2023, pozelimab received its first approval for the treatment of adults, and paediatric patients aged ≥ 1 year with CD55-deficient protein-losing enteropathy (PLE), also known as CHAPLE disease, in the USA. It is the first US FDA-approved treatment for this disease. In the USA, pozelimab has been granted orphan drug designations for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) [both as a monotherapy and in combination with cemdisiran] and for the treatment of myasthenia gravis (in combination with cemdisiran). Pozelimab is also undergoing clinical development in several other countries worldwide for the treatment of CD55-deficient PLE, PNH and myasthenia gravis. This article summarizes the milestones in the development of pozelimab leading to this first approval for the treatment of adults, and paediatric patients aged ≥ 1 year with CD55-deficient PLE, also known as CHAPLE disease, in the USA.

Heo, Young-A

doi: 10.1007/s40265-023-01953-xpmid: 37882942

Zuranolone (ZURZUVAE™) is an oral neuroactive steroid and a positive allosteric modulator of the gamma aminobutyric acid A (GABAA) receptor being developed by Sage Therapeutics and Biogen for the treatment of mood disorders. In August 2023, zuranolone received its first approval in the USA for the treatment of adults with postpartum depression [pending scheduling by the US Drug Enforcement Administration (DEA)]. This article summarizes the milestones in the development of zuranolone leading to this first approval.

Hoy, Sheridan M.

doi: 10.1007/s40265-023-01960-ypmid: 37861882