Drugs

Vignon, Philippe; Laterre, Pierre-François; Daix, Thomas; François, Bruno

doi: 10.1007/s40265-020-01402-zpmid: 32951149

Sepsis is a syndrome which is defined as a dysregulated host response to infection leading to organ failure. Since it remains one of the leading causes of mortality worldwide, numerous drug candidates have already been tested, and continue to be developed, as potential adjunct therapies. Despite convincing mechanisms of action and robust pre-clinical data, almost all drug candidates in the field of sepsis have failed to demonstrate clinical efficacy in the past two decades. Accordingly, the development of new sepsis drugs has markedly decreased in the past few years. Nevertheless, thanks to a better understanding of sepsis pathophysiology and pathways, new promising drug candidates are currently being developed. Instead of a unique sepsis profile as initially suspected, various phenotypes have been characterised. This has  resulted in the identification of multiple targets for new drugs together with relevant biomarkers, and a better understanding of the most appropriate time to intervention. Within the entire sepsis drugs portfolio, those targeting the immune response are probably the most promising. Monoclonal antibodies targeting either cytokines or infectious agents are undoubtedly part of the potential successful therapeutic classes to come.

Cernea, Simona; Dima, Lorena; Correll, Christoph U.; Manu, Peter

doi: 10.1007/s40265-020-01393-xpmid: 32930957

Fasting hyperglycemia, impaired glucose tolerance, prediabetes, and diabetes are frequently present in patients treated with second-generation antipsychotics (SGAPs) for schizophrenia, bipolar disorder, and other severe mental illnesses. These drugs are known to produce weight gain, which may lead to insulin resistance, glucose intolerance, and metabolic syndrome, which constitute important risk factors for the emergence of diabetes. The aim of this review was to formulate therapeutic guidelines for the management of diabetes in patients treated with SGAPs, based on the association between SGAP-induced weight gain and glucose dysregulation. A  systematic search in PubMed from inception to March 2020 for randomized controlled trials (RCTs) of diabetes or prediabetes in patients treated with SGAPs was performed. PubMed was also searched for the most recent clinical practice guidelines of interventions for co-morbid conditions associated with diabetes mellitus (DM) (arterial hypertension and dyslipidemia), lifestyle interventions and switching from high metabolic liability SGAPs to safer SGAPs. The search identified 14 RCTs in patients treated with SGAPs. Drug therapy using metformin as first-line therapy and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or perhaps sodium–glucose cotransporter-2 (SGLT2) inhibitors as add-on therapy, might be preferred in these patients as well, as they favorably influence glucose metabolism and body mass index, and provide cardio-renal benefits in general to the DM population, although for the SGLT-2 inhibitors there are no RCTs in this specific patient category so far. Metformin is also useful for treatment of prediabetes. Arterial hypertension should be treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and statins should be used for correction of dyslipidemia. The outcome of lifestyle-changing interventions has been disappointing. Switching from clozapine, olanzapine, or quetiapine to lower cardiometabolic-risk SGAPs, like aripiprazole, brexpiprazole, cariprazine, lurasidone, or ziprasidone, has been recommended.

Ackermann, Christoph Jakob; Adderley, Helen; Ortega-Franco, Ana; Khan, Adeel; Reck, Martin; Califano, Raffaele

doi: 10.1007/s40265-020-01409-6pmid: 32986224

The advent of PD-(L)1 and CTLA-4 immune check point inhibitors (CPIs) has dramatically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC). For up to a quarter of patients with advanced NSCLC, CPIs have the potential to induce durable responses with long-term survival outcomes. Since the approval of first-line pembrolizumab for patients whose tumors express a PD-L1 ≥ 50%, several pivotal first-line CPI-based phase 3 studies have been conducted investigating combination treatments combining CPIs with chemotherapy (ChT) or combining different CPIs with or without ChT. As a result, there has been an increase in front-line treatment options for advanced NSCLC, and treatment algorithms are changing very quickly. In fit patients with advanced NSCLC, combination treatments including CPI and ChT are considered the new standard of care with improved clinical outcomes. CPI combination treatments are well tolerated and quality of life also seems to be better when CPIs are implemented in the first-line setting. The aim of this review is to provide a summary of the recently published first-line phase 3 studies investigating CPIs as monotherapy or in combination with other CPIs or ChT in advanced NSCLC, and to suggest possible treatment algorithms.

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

doi: 10.1007/s40265-020-01412-xpmid: 33025535

Erdosteine is a drug approved for the treatment of acute and chronic pulmonary diseases, originally developed as a mucolytic agent. It belongs to the thiol-based family of drugs that are known to also possess potentially important antioxidant and anti-inflammatory properties, and exhibit antibacterial activity against a variety of medically important bacterial species. Erdosteine is a prodrug that is metabolized to the ring-opening compound metabolite M1 (MET 1), which has mucolytic properties. Experimental studies have documented that erdosteine prevents or reduces lung tissue damage induced by oxidative stress and, in particular, that Met 1 also regulates reactive oxygen species production. The RESTORE study, which has been the only trial that investigated the effects of a thiol-based drug in chronic obstructive pulmonary disease (COPD) frequent exacerbators, documented that erdosteine significantly reduces the risk of acute exacerbations of COPD (AECOPDs), shortens their course, and also decreases the risk of hospitalization from COPD. The preventive action of erdosteine on AECOPDs was not affected by the presence or absence of inhaled corticosteroids (ICSs) or blood eosinophil count. These findings clearly contrast with the Global Initiative for Chronic Obstructive Lung Disease strategy’s approach to use erdosteine only in those COPD patients not treated simultaneously with an ICS. Furthermore, they support the possibility of using erdosteine in a step-down approach that in COPD is characterized by the withdrawal of the ICS.

Tesch, Megan E.; Gelmon, Karen A.

doi: 10.1007/s40265-020-01411-ypmid: 33021725

Approximately 20% of all breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). Targeting breast cancer through this vital oncogenic protein has been a major step towards improved patient outcomes. Today, several anti-HER2 agents are in clinical use including: the monoclonal antibodies trastuzumab and pertuzumab; the small molecule inhibitors lapatinib, neratinib, and tucatinib; and the antibody–drug conjugates ado-trastuzumab emtansine and trastuzumab deruxtecan, in some jurisdictions. In addition, several trastuzumab biosimilars have recently been granted regulatory approval in North America and the EU, and are enhancing patient access to HER2-directed therapy. The various agents differ greatly in their side-effect profiles and approved indications, from neoadjuvant and adjuvant use in early disease, to first- and later-line use in metastatic disease. This review discusses the current treatment recommendations for the use of anti-HER2 agents alone and in combination, examines the latest advances in HER2-targeted drugs and how they may be best applied in clinical practice, and provides guidance on optimal sequencing of the growing array of therapeutic options for HER2-positive breast cancer.

Krishnamoorthy, Madhusudhan; Mohd Noor, Norhayati; Mat Lazim, Norhafiza; Abdullah, Baharudin

doi: 10.1007/s40265-020-01406-9pmid: 32915441

BackgroundIn treating allergic rhinitis, montelukast has the potential to be used as an alternative or addition to an oral antihistamine or intranasal corticosteroid.ObjectiveThe objective of this systematic review was to assess the effectiveness of montelukast in treating allergic rhinitis.MethodsAn electronic literature search was performed using the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE from 1966 to 21 January 2019. The eligibility criteria were randomized controlled trials comparing montelukast with placebo or other standard treatments. The primary outcomes assessed were daytime nasal symptom score (DNS) and night-time nasal symptom score (NNS). The secondary outcomes assessed were composite nasal symptom score (CSS), daytime eyes symptom score (DES), and rhinoconjunctivitis quality-of-life questionnaires (RQLQ). The meta-analysis was conducted using Review Manager 5.3 software based on the random-effects model.ResultsFifteen studies of 10387 participants met the inclusion criteria. Montelukast was more effective than placebo in improving DNS (mean difference [MD] − 0.12, 95% confidence interval [CI] − 0.15 to − 0.08; p < 0.001), NNS (MD − 0.09, 95% CI − 0.13 to − 0.05; p < 0.001), CSS (MD − 0.08, 95% CI − 0.11 to − 0.06; p < 0.001), DES (MD − 0.17, 95% CI − 0.33 to − 0.02; p < 0.030), and RQLQ (MD − 0.34, 95% CI − 0.49 to − 0.20; p < 0.001). Oral antihistamine was superior to montelukast in improving DNS (MD 0.08, 95% CI 0.03–0.13; p = 0.002), CSS (MD 0.03, 95% CI − 0.02 to 0.07; p = 0.27), DES (MD 0.06, 95% CI 0–0.12; p = 0.040), and RQLQ (MD 0.03, 95% CI − 0.05 to 0.12; p = 0.430). Montelukast was superior to oral antihistamine in improving NNS (MD -0.03, 95% CI − 0.08 to 0.03; p = 0.330). Intranasal fluticasone spray was superior to montelukast in improving DNS (MD 0.71, 95% CI 0.44–0.99; p < 0.001) and NNS (MD 0.63, 95% CI 0.29–0.97; p < 0.001). Combined montelukast and oral antihistamine was superior to oral antihistamine in improving DNS (MD − 0.15, 95% CI − 0.27 to − 0.03; p = 0.010), NNS (MD − 0.16, 95% CI − 0.28 to − 0.05; p = 0.006), CSS (MD − 0.12, 95% CI − 0.25 to − 0.01; p = 0.070), DES (MD − 0.12, 95% CI − 0.30 to 0.06; p = 0.180), and RQLQ (MD − 0.10, 95% CI − 0.28 to 0.08; p = 0.290). Combined montelukast and OAH was superior to montelukast in improving DNS (MD 0.15, 95% CI 0.08–0.21; p < 0.001), NNS (MD 0.05, 95% CI − 0.09 to 0.19; p = 0.510), CSS (MD 0.1, 95% CI 0.03–0.17; p = 0.007), DES (MD 0.18, 95% CI 0–0.36; p = 0.050), and RQLQ (MD 0.07 95% CI − 0.15 to 0.29; p = 0.530).ConclusionsMontelukast is more effective than placebo in treating the overall symptoms of allergic rhinitis while the combined therapy of montelukast and an oral antihistamine is superior to either montelukast or an oral antihistamine alone.

Dhillon, Sohita

doi: 10.1007/s40265-020-01410-zpmid: 33044711

Risdiplam (Evrysdi™) is an orally administered, survival motor neuron 2 (SMN2)-directed RNA splicing modifier being developed by Roche, PTC Therapeutics Inc and the SMA Foundation for the treatment of the spinal muscular atrophy. The small molecule is designed to treat spinal muscular atrophy caused by mutations in chromosome 5q leading to SMN protein deficiency. The drug boosts the ability of an alternative gene SMN2 to produce full-length and functional SMN protein. In August 2020, Evrysdi™ (risdiplam) received its first approval in the USA for the treatment of spinal muscular atrophy in patients 2 months of age and older. Risdiplam is in pre-registration for this indication in numerous countries worldwide, including the European Union, Brazil, Chile, China, Indonesia, Russia, South Korea and Taiwan. This article summarizes the milestones in the development of risdiplam leading to this first approval for spinal muscular atrophy.

Al-Salama, Zaina T.

doi: 10.1007/s40265-020-01418-5pmid: 33058042

Imlifidase (IdefirixTM), a cysteine protease derived from the immunoglobulin G (IgG)‑degrading enzyme of Streptococcus (S.) pyogenes is being developed by Hansa Biopharma AB for treatment of transplant rejection and rare IgG-mediated autoimmune conditions. In August 2020, intravenous imlifidase received its first global approval in the EU for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor. Imlifidase is currently undergoing clinical evaluation for the prevention of kidney transplant rejection in the USA, Australia, France and Austria, and clinical development is underway for anti-glomerular basement membrane disease, and for Guillain–Barre syndrome in France, the UK and the Netherlands. This article summarizes the milestones in the development of imlifidase leading to this first approval for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor.

Markham, Anthony

doi: 10.1007/s40265-020-01427-4pmid: 33136236

Pralsetinib (GAVRETO™, Blueprint Medicines Corporation) is a selective rearranged during transfection (RET) inhibitor being developed for the treatment of various solid tumours. RET is a well described proto-oncogene present in multiple cancers including non-small cell lung cancer (NSCLC), papillary thyroid cancer, and medullary thyroid carcinoma (MTC). Pralsetinib was recently granted accelerated approval for the treatment of metastatic RET fusion-positive NSCLC in the USA and is under regulatory review in the USA for RET fusion-positive thyroid cancer and RET mutation-positive MTC; pralsetinib is under regulatory review in the EU for RET fusion-positive NSCLC. This article summarizes the milestones in the development of pralsetinib leading to this first approval.

Markham, Anthony

doi: 10.1007/s40265-020-01425-6pmid: 33074439

The original article can be found online.