The metabolic interplay between dietary carbohydrate and exercise and its role in acute appetite regulation in males: a randomized controlled study.

An understanding of the metabolic determinants of postexercise appetite regulation would facilitate development of adjunctive therapeutics to suppress compensatory eating behaviours and improve the efficacy of exercise as a weight-loss treatment. Metabolic responses to acute exercise are, however, dependent on pre-exercise nutritional practices, including carbohydrate intake. We therefore aimed to determine the interactive effects of dietary carbohydrate and exercise on plasma hormonal and metabolite responses and explore mediators of exercise-induced changes in appetite regulation across nutritional states. In this randomized crossover study, participants completed four 120 min visits: (i) control (water) followed by rest; (ii) control followed by exercise (30 min at ∼75% of maximal oxygen uptake); (iii) carbohydrate (75 g maltodextrin) followed by rest; and (iv) carbohydrate followed by exercise. An ad libitum meal was provided at the end of each 120 min visit, with blood sample collection and appetite assessment performed at predefined intervals. We found that dietary carbohydrate and exercise exerted independent effects on the hormones glucagon-like peptide 1 (carbohydrate, 16.8 pmol/L; exercise, 7.4 pmol/L), ghrelin (carbohydrate, -48.8 pmol/L; exercise: -22.7 pmol/L) and glucagon (carbohydrate, 9.8 ng/L; exercise, 8.2 ng/L) that were linked to the generation of distinct plasma 1 H nuclear magnetic resonance metabolic phenotypes. These metabolic responses were associated with changes in appetite and energy intake, and plasma acetate and succinate were subsequently identified as potential novel mediators of exercise-induced appetite and energy intake responses. In summary, dietary carbohydrate and exercise independently influence gastrointestinal hormones associated with appetite regulation. Future work is warranted to probe the mechanistic importance of plasma acetate and succinate in postexercise appetite regulation. KEY POINTS: Carbohydrate and exercise independently influence key appetite-regulating hormones. Temporal changes in postexercise appetite are linked to acetate, lactate and peptide YY. Postexercise energy intake is associated with glucagon-like peptide 1 and succinate levels.

The acute effect of fasted exercise on energy intake, energy expenditure, subjective hunger and gastrointestinal hormone release compared to fed exercise in healthy individuals: a systematic review and network meta-analysis.

OBJECTIVE: To determine the acute effect of fasted and fed exercise on energy intake, energy expenditure, subjective hunger and gastrointestinal hormone release. METHODS: CENTRAL, Embase, MEDLINE, PsycInfo, PubMed, Scopus and Web of Science databases were searched to identify randomised, crossover studies in healthy individuals that compared the following interventions: (i) fasted exercise with a standardised post-exercise meal [FastEx + Meal], (ii) fasted exercise without a standardised post-exercise meal [FastEx + NoMeal], (iii) fed exercise with a standardised post-exercise meal [FedEx + Meal], (iv) fed exercise without a standardised post-exercise meal [FedEx + NoMeal]. Studies must have measured ad libitum meal energy intake, within-lab energy intake, 24-h energy intake, energy expenditure, subjective hunger, acyl-ghrelin, peptide YY, and/or glucagon-like peptide 1. Random-effect network meta-analyses were performed for outcomes containing ≥5 studies. RESULTS: 17 published articles (23 studies) were identified. Ad libitum meal energy intake was significantly lower during FedEx + Meal compared to FedEx + NoMeal (MD: -489 kJ; 95% CI, -898 to -80 kJ; P = 0.019). Within-lab energy intake was significantly lower during FastEx + NoMeal compared to FedEx + NoMeal (MD: -1326 kJ; 95% CI, -2102 to -550 kJ; P = 0.001). Similarly, 24-h energy intake following FastEx + NoMeal was significantly lower than FedEx + NoMeal (MD: -2095 kJ; 95% CI, -3910 kJ to -280 kJ; P = 0.024). Energy expenditure was however significantly lower during FastEx + NoMeal compared to FedEx+NoMeal (MD: -0.67 kJ/min; 95% CI, -1.10 to -0.23 kJ/min; P = 0.003). Subjective hunger was significantly higher during FastEx + Meal (MD: 13 mm; 95% CI, 5-21 mm; P = 0.001) and FastEx + NoMeal (MD: 23 mm; 95% CI, 16-30 mm; P < 0.001) compared to FedEx + NoMeal. CONCLUSION: FastEx + NoMeal appears to be the most effective strategy to produce a short-term decrease in energy intake, but also results in increased hunger and lowered energy expenditure. Concerns regarding experimental design however lower the confidence in these findings, necessitating future research to rectify these issues when investigating exercise meal timing and energy balance. PROSPERO REGISTRATION NUMBER: CRD42020208041. KEY POINTS: Fed exercise with a standardised post-exercise meal resulted in the lowest energy intake at the ad libitum meal served following exercise completion. Fasted exercise without a standardised post-exercise meal resulted in the lowest within-lab and 24-h energy intake, but also produced the lowest energy expenditure and highest hunger. Methodological issues lower the confidence in these findings and necessitate future work to address identified problems.

The acute effect of glucagon on components of energy balance and glucose homoeostasis in adults without diabetes: a systematic review and meta-analysis.

OBJECTIVE: Using a systematic review and meta-analysis, we aimed to estimate the mean effect of acute glucagon administration on components of energy balance and glucose homoeostasis in adults without diabetes. METHODS: CENTRAL, CINAHL, Embase, MEDLINE, PubMed, and Scopus databases were searched from inception to May 2021. To be included, papers had to be a randomised, crossover, single- or double-blind study, measuring ad libitum meal energy intake, energy expenditure, subjective appetite, glucose, and/or insulin following acute administration of glucagon and an appropriate comparator in adults without diabetes. Risk of bias was assessed using the Revised Cochrane Risk of Bias Tool for Randomized trials with additional considerations for cross-over trials. Certainty of evidence was assessed using the GRADE approach. Random-effect meta-analyses were performed for outcomes with at least five studies. This study is registered on PROSPERO (CRD42021269623). RESULTS: In total, 13 papers (15 studies) were considered eligible: energy intake (5 studies, 77 participants); energy expenditure (5 studies, 59 participants); subjective appetite (3 studies, 39 participants); glucose (13 studies, 159 participants); insulin (12 studies, 147 participants). All studies had some concerns with regards to risk of bias. Mean intervention effect of acute glucagon administration on energy intake was small (standardised mean difference [SMD]: -0.19; 95% CI, -0.59 to 0.21; P = 0.345). Mean intervention effect of acute glucagon administration on energy expenditure (SMD: 0.72; 95% CI, 0.37-1.08; P < 0.001), glucose (SMD: 1.11; 95% CI, 0.60-1.62; P < 0.001), and insulin (SMD: 1.33; 95% CI, 0.88-1.77; P < 0.001) was moderate to large. CONCLUSIONS: Acute glucagon administration produces substantial increases in energy expenditure, and in circulating insulin and glucose concentrations. However, the effect of acute glucagon administration on energy intake is unclear. Insufficient evidence was available to evaluate the acute effect of glucagon on subjective appetite.

Differential effects of L- and D-phenylalanine on pancreatic and gastrointestinal hormone release in humans: A randomized crossover study.

AIM: To investigate the effects of L-phenylalanine on gastroenteropancreatic hormone release, glucose levels, subjective appetite and energy intake in humans, and to determine whether these effects were stereoisomer-specific by comparing them with D-phenylalanine. MATERIALS AND METHODS: A dose-finding, non-randomized, unblinded, crossover study was conducted during October-December 2017 at the NIHR Imperial Clinical Research Facility in five participants, in which the tolerability of escalating doses of oral L-phenylalanine was assessed (0, 3, 6 and 10 g). Also, an acute, randomized, double-blind, placebo-controlled crossover study was conducted during January-May 2018 at the NIHR Imperial Clinical Research Facility in 11 participants, in which the effects of oral 10 g L-phenylalanine relative to D-phenylalanine and placebo on gastroenteropancreatic hormone (insulin, glucagon, glucose-dependent insulinotropic polypeptide [GIP], peptide tyrosine tyrosine [PYY], glucagon-like peptide-1) and glucose concentrations, visual analogue scales for subjective appetite and energy intake at an ad libitum meal served 70 minutes postingestion, were investigated. RESULTS: L-phenylalanine was well-tolerated and increased insulin and glucagon concentrations prior to meal ingestion at several time points relative to placebo and D-phenylalanine (P < .05). L-phenylalanine also increased GIP concentrations relative to D-phenylalanine (P = .0420) and placebo (P = .0249) 70 minutes following ingestion. L-phenylalanine reduced postprandial glucose area under the curve (AUC)70-150mins relative to placebo (P = .0317) but did not affect subjective appetite or energy intake (P > .05). D-phenylalanine increased postprandial PYY AUC70-150mins concentrations relative to placebo (P = .0002). CONCLUSIONS: Ingestion of L-phenylalanine, but not D-phenylalanine, increases insulin, glucagon and GIP concentrations without appearing to have a marked effect on appetite.

Effects of mycoprotein on glycaemic control and energy intake in humans: a systematic review.

Mycoprotein is a food high in both dietary fibre and non-animal-derived protein. Global mycoprotein consumption is increasing, although its effect on human health has not yet been systematically reviewed. This study aims to systematically review the effects of mycoprotein on glycaemic control and energy intake in humans. A literature search of randomised controlled trials was performed in PubMed, Embase, Web of Science, Google Scholar and hand search. A total of twenty-one studies were identified of which only five studies, totalling 122 participants, met the inclusion criteria. All five studies were acute studies of which one reported outcomes on glycaemia and insulinaemia, two reported on energy intake and two reported on all of these outcomes. Data were extracted, and risk-of-bias assessment was then conducted. The results did not show a clear effect of acute mycoprotein on blood glucose levels, but it showed a decrease in insulin levels. Acute mycoprotein intake also showed to decrease energy intake at an ad libitum meal and post-24 h in healthy lean, overweight and obese humans. In conclusion, the acute ingestion of mycoprotein reduces energy intake and insulinaemia, whereas its impact on glycaemia is currently unclear. However, evidence comes from a very limited number of heterogeneous studies. Further well-controlled studies are needed to elucidate the short- and long-term effects of mycoprotein intake on glycaemic control and energy intake, as well as the mechanisms underpinning these effects.

Postprandial suppression of appetite is more reproducible at a group than an individual level: Implications for assessing inter-individual variability.

Individual differences in appetite are increasingly appreciated. However, the individual day-to-day reliability of appetite measurement is currently uncharacterised. This study aimed to assess the reliability of appetite following ingestion of mixed-macronutrient liquid meals at a group and individual level. Two experiments were conducted with identical protocols other than meal energy content. During each experiment, 10 non-obese males completed four experimental trials constituting high- and low-energy trials, each performed twice. Experiment one employed 579 kJ (138 kcal) and 1776 kJ (424 kcal) liquid meals. Experiment two employed 828 (198 kcal) and 4188 kJ (1001 kcal) liquid meals. Visual analogue scales were administered to assess appetite for 60 min post-ingestion. The typical error (standard error of measurement) of appetite area under the curve was 6.2 mm⋅60 min-1 (95%CI 4.3-11.3 mm⋅60 min-1), 6.5 mm (95%CI 4.5-11.9 mm⋅60 min-1), 7.1 mm⋅60 min-1 (95%CI 4.9-12.9 mm⋅60 min-1) and 6.5 mm⋅60 min-1 (95%CI 4.5-11.8 mm⋅60 min-1) with the 579, 828, 1776 and 4188 kJ meals, respectively. A systematic bias between first and second exposure was detected for all but the 4188 kJ meal. The change in appetite with high-vs. low-energy meals did not differ at a group level between first and second exposure (mean difference: -0.97 mm⋅60 min-1; 95%CI -6.48-4.53 mm⋅60 min-1), however, ∼50% of individuals differed in their response with first vs second exposure by more than the typical error. Appetite responses are more reliable when liquid meals contain a higher-vs lower-energy content. Appetite suppression with high-vs low-energy meals is reproducible at the group- but not individual level, suggesting that multiple exposures to an intervention are required to understand true individual differences in appetite.

Test-meal palatability is associated with overconsumption but better represents preceding changes in appetite in non-obese males.

Single-course, ad libitum meals are recommended for the assessment of energy intake within appetite research. This study represents the first investigation of the comparative sensitivity of two single-course, ad libitum meals designed to differ in palatability. We conducted two experiments using a preload study design. All protocols were identical except for the energy content of the preloads (Expt 1: 579 and 1776 kJ; Expt 2: 828 and 4188 kJ). During each experiment, ten healthy men completed four experimental trials constituting a low- or high-energy preload beverage, a 60-min intermeal interval and consumption of a pasta-based or a porridge-based, ad libitum meal. Appetite ratings were measured throughout each trial, and palatability was assessed after food consumption. Preload manipulation did not influence appetite (P=0·791) or energy intake (P=0·561) in Expt 1. Palatability and energy intake were higher for the pasta meal than for the porridge meal in both experiments (palatability P≤0·002; energy intake P≤0·001). In Expt 2, consumption of the high-energy preload decreased appetite (P=0·051) and energy intake (P=0·002). Energy compensation was not significantly different between pasta and porridge meals (P=0·172), but was more strongly correlated with preceding changes in appetite at the pasta meal (r -0·758; P=0·011) than the porridge meal (r -0·498; P=0·143). The provision of a highly palatable, pasta-based meal produced energy intakes that were more representative of preceding appetite ratings, but the moderately palatable, porridge-based meal produced more ecologically valid energy intakes. Ad libitum meal selection and design may require a compromise between sensitivity and ecological validity.

Pemigatinib: A Review in Advanced Cholangiocarcinoma.

Pemigatinib (Pemazyre®), a selective, potent, reversible, oral inhibitor of fibroblast growth factor receptor (FGFR) 1-3, has received conditional (in the EU) or accelerated (in the USA) approval for the treatment of adults with previously treated, unresectable locally-advanced or metastatic cholangiocarcinoma (CCA) with an FGFR2 gene fusion or rearrangement. Over the course of a single-arm, phase 2 study (FIGHT-202), just over a third of patients with pretreated, advanced CCA [almost exclusively intrahepatic CCA (iCCA)] harbouring an FGFR2 fusion or rearrangement who received pemigatinib once daily (2 weeks on, 1 week off) had an objective response; nearly half had stable disease. Median progression-free survival and overall survival at the time of the final analysis were 7.0 months and 17.5 months, respectively. Pemigatinib was generally well tolerated and had a manageable safety profile. The most common treatment-related adverse event, hyperphosphataemia, was exclusively grade 1-2 in severity and, similarly, observed ocular and nail toxicities were rarely grade ≥ 3 in severity. Pending confirmation of its clinical benefits in an ongoing cisplatin plus gemcitabine-controlled, phase 3 study (FIGHT-302), pemigatinib provides a valuable targeted therapy for pretreated patients with advanced (i)CCA harbouring a FGFR2 fusion or rearrangement.

Bile duct cancer or cholangiocarcinoma (CCA) has a very poor prognosis, partly because the majority of patients are first diagnosed at an advanced stage when they are no longer eligible for potentially curative surgery and are therefore limited to receiving systemic (palliative) chemotherapy, which results in only modest survival gains. 10­20% of CCAs arise inside the liver [intrahepatic CCAs (iCCAs)]; ≈ 10­20% of patients with advanced iCCAs are eligible to receive fibroblast growth factor receptors (FGFR) inhibitors, as the development of their tumours depends, in part, on FGFRs that have been inappropriately activated due to underlying genetic abnormalities. Pemigatinib (Pemazyre^®) is a selective, potent, once-daily oral FGFR 1­3 inhibitor. In a phase 2 trial in patients with advanced CCA (almost exclusively iCCA) containing an abnormal FGFR2 fusion or rearrangement who had already received systemic chemotherapy, more than a third receiving pemigatinib experienced partial or complete shrinkage of their tumours, while almost half had neither growth nor shrinkage of their tumours. Pemigatinib was generally well tolerated with a manageable safety profile. Pending completion of a phase 3 study designed to confirm its clinical benefits, pemigatinib represents a valuable targeted therapy for pretreated patients with advanced (i)CCA harbouring a FGFR2 fusion or rearrangement.

Inclisiran: A Review in Hypercholesterolemia.

Inclisiran (Leqvio®) is a first-in-class, subcutaneously administered, small interfering RNA (siRNA) that prevents hepatic synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9), thereby decreasing circulating low-density lipoprotein cholesterol (LDL-C). In the EU, inclisiran is indicated in adults with primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet. It is intended for use in patients unable to reach LDL-C goals on maximally tolerated statin therapy, with or without other lipid-lowering therapies (LLTs). In patients who are statin intolerant or for whom a statin is contraindicated, it can be used with or without other LLTs. In clinical trials, twice-yearly injections of inclisiran (after initial doses at days 1 and 90) approximately halved LDL-C levels in patients with, or at high risk of developing, atherosclerotic cardiovascular disease (ASCVD) who had hypercholesterolemia, irrespective of whether or not their existing treatment included a statin. The safety and tolerability profile of the drug was similar to placebo, although mild to moderate, transient injection-site adverse reactions were more frequent with inclisiran. Pending confirmation of the expected reduction in cardiovascular (CV) events with inclisiran, it is a valuable additional/alternative antihyperlipidemic agent to a statin, as its infrequent maintenance dosing regimen confers a convenience advantage over other non-statin LLTs.

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death and disability. 'Statins' are the drugs of choice for reducing elevated levels of low-density lipoprotein cholesterol (LDL-C) in patients with, or at risk of developing, ASCVD. However, due to multiple factors, including adverse events and/or poor adherence, many patients don't achieve their guideline target LDL-C level on conventional (statin-based) therapy and novel, non-statin lipid-lowering therapies (LLTs) are needed. Inclisiran (Leqvio^®) is a small interfering RNA (siRNA) drug that works as an LLT by stopping the liver from making an enzyme [proprotein convertase subtilisin/kexin type 9 (PCSK9)] that otherwise reduces its ability to remove LDL-C from the blood. Subcutaneously injecting inclisiran every 6 months (after initial doses at days 1 and 90) was generally well tolerated and approximately halved LDL-C levels in patients with, or at high risk of developing, ASCVD who had hypercholesterolemia, regardless of whether or not their conventional therapy included a statin. Inclisiran is a potentially valuable additional/alternative antihyperlipidemic agent to a statin because of its infrequent, and therefore more convenient, dosing schedule versus other non-statin LLTs, including anti-PCSK9 monoclonal antibodies.

Epcoritamab: First Approval.

Epcoritamab (epcoritamab-bysp; Epkinly™; Tepkinly®) is a subcutaneously administered CD3×CD20 T-cell-engaging bispecific antibody being co-developed by Genmab and AbbVie for the treatment of mature B-cell non-Hodgkin lymphoma subtypes (B-NHLs), including diffuse large B-cell lymphoma (DLBCL). Epcoritamab received its first (conditional) approval on 19 May 2023, in the USA, for the treatment of adult patients with relapsed or refractory (R/R) DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥ 2 lines of systemic therapy. Elsewhere, epcoritamab has received a positive opinion in the EU as a monotherapy for the treatment of adults with R/R DLBCL after ≥ 2 lines of systemic therapy, and is currently under regulatory review in Japan for the treatment of adults with R/R large B-cell lymphoma after ≥ 2 lines of systemic therapy. Clinical development of epcoritamab as monotherapy and in combination with standard of care agents for the treatment of mature B-NHLs is ongoing globally. This article summarizes the milestones in the development of epcoritamab leading to this first approval for R/R DLBCL.

Fenfluramine: A Review in Dravet and Lennox-Gastaut Syndromes.

Fenfluramine (Fintepla®) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive allosteric modulation effects at sigma-1 receptors. Originally approved for use at high doses as an appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before being investigated for use at low doses as an adjunctive ASM in patients with developmental epileptic encephalopathies, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) who have pharmacoresistant seizures. In clinical trials, treatment with adjunctive fenfluramine markedly reduced convulsive seizure frequency in patients with DS that were sustained for up to 3 years, and reduced drop seizure frequency in patients with LGS that were sustained for up to 1 year. Notably, fenfluramine was also associated with clinically meaningful improvements in aspects of everyday executive functioning (EF) not entirely explainable by seizure reduction alone. Furthermore, it was generally well tolerated with, importantly, no reports of VHD or PAH. Thus, adjunctive fenfluramine is a novel and effective treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.

Emerging in infancy and childhood, respectively, Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are severe developmental and epileptic encephalopathies. They are characterized by seizures that are frequently 'pharmacoresistant' [i.e. cannot be controlled by ≥ 2 anti-seizure medications (ASMs)] and that, along with cognitive and behavioural comorbidities, can have a major impact on the quality of life of patients (and their caregivers/family members) as they grow. Fenfluramine (Fintepla^®) is an oral ASM with a distinctive dual mechanism of action, that is used at low doses. In clinical trials in patients with DS or LGS, adding fenfluramine to the existing ASM regimen produced significant and sustained reductions in pharmacoresistant seizures and was associated with clinically meaningful improvements in aspects of everyday executive functioning (EF; i.e. the ability to regulate cognition, emotions and/or behaviour). Importantly, there was no evidence of the heart complications previously observed with the use of high doses of fenfluramine as an appetite suppressant. Adjunctive fenfluramine is an effective and generally well-tolerated treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.

Ivosidenib: A Review in Advanced Cholangiocarcinoma.

Ivosidenib (Tibsovo®), a first-in-class, oral small molecule, potent and selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), is approved in the EU and USA for the treatment of adults with pretreated, advanced, mIDH1 cholangiocarcinoma (CCA). It is presumed to exert its cytostatic effects in this setting by suppressing 2-hydroxyglutarate, an oncometabolite produced by mIDH1 that impairs cellular differentiation and promotes tumorigenesis. In the multinational phase 3 ClarIDHy study in patients with pretreated, advanced mIDH1 CCA, monotherapy with ivosidenib once daily significantly prolonged progression-free survival (PFS) and almost doubled the disease control rate compared with placebo. Moreover, it had a favourable effect on overall survival (OS), which was also significantly prolonged after correcting for a high rate of crossover from the placebo group (permitted by the trial protocol). Ivosidenib treatment preserved health-related quality of life (HRQOL) relating to physical function, pain and appetite loss/eating and was generally well tolerated, with the most common treatment-emergent adverse events being low-grade diarrhoea, nausea and fatigue. Thus, ivosidenib represents a novel and valuable targeted therapy for the subset of patients with pretreated, advanced CCA tumors harbouring mIDH1.

Cholangiocarcinoma (CCA) is often diagnosed at an advanced stage when the prognosis is poor due to limited treatment options, including standard-of-care (palliative) chemotherapy. Around 40% of patients with CCA have a tumor that can be targeted for treatment due to the presence of a molecular abnormality implicated in tumor formation and/or maintenance. One such abnormality (present in ≈14% of patients with intrahepatic CCA), is a mutated form of the isocitrate dehydrogenase 1 (IDH1) enzyme ('mutant IDH1') that inappropriately catalyses the production of 2-hydroxyglutarate (2-HG), an oncometabolite that promotes tumorigenesis. Ivosidenib (Tibsovo^®), a first-in-class, small molecule, oral inhibitor of mIDH1, exerts a cytostatic (stabilizing) effect on mIDH1 CCA tumors, presumably by suppressing the production of 2-HG. Compared with placebo, ivosidenib resulted in a statistically significant, near-doubling of progression-free survival and, similarly, a near doubling of the disease control rate in a pivotal study in patients with pretreated, advanced, mIDH1 CCA. Overall survival was also significantly improved after controlling for the high rate of crossover. Health-related quality of life was maintained and ivosidenib treatment was generally well tolerated. Ivosidenib represents a novel and valuable targeted therapy for patients with advanced mIDH1 CCA tumors.

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC.

Osimertinib (TAGRISSO®) is an orally administered, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is approved for the adjuvant treatment of adults with completely resected, stage IB-IIIA, EGFR sensitizing mutation (exon 19 deletion or exon 21 [L858R] substitution)-positive non-small cell lung cancer (NSCLC). In the pivotal ADAURA trial in adults with completely resected, early-stage, EGFR mutation-positive (EGFRm+) NSCLC, osimertinib adjuvant therapy significantly prolonged disease-free survival (DFS) compared with placebo in the overall population of patients with stage IB-IIIA disease, as well as in the primary population of patients with stage II-IIIA disease. A DFS benefit of osimertinib was seen irrespective of whether or not patients received prior adjuvant chemotherapy. Overall survival (OS) data were very immature at the time of the analysis of DFS, and more mature OS data are awaited with interest. Osimertinib adjuvant therapy did not adversely affect health-related quality of life and was generally well tolerated, with a manageable safety profile and no new safety signals identified. Based on the available evidence, osimertinib is thus an appropriate targeted option for the adjuvant treatment of adults with completely resected, stage IB-IIIA, EGFRm+ NSCLC.

Almost a third of patients with non-small cell lung cancer (NSCLC) have early-stage disease at diagnosis. Surgical resection is the primary treatment option, with adjuvant chemotherapy also recommended for select individuals with stage IB disease and those with stage II­IIIA disease. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are oral drugs that target and inhibit cancer-driving EGFR sensitizing mutations when present in patients with NSCLC. Osimertinib (TAGRISSO^®) is the first EGFR TKI to be approved for adjuvant use in adults with completely resected, stage IB­IIIA, EGFR mutation-positive (EGFRm+) NSCLC. In a trial in the intended patient population, adjuvant osimertinib reduced the risk of disease recurrence or death by ≈ 80% versus placebo, regardless of whether or not patients received adjuvant chemotherapy. The effect of adjuvant osimertinib on overall survival is being evaluated. The safety profile of osimertinib in the early-stage disease setting was consistent with that seen in the advanced disease setting. Based on the available evidence, osimertinib is an appropriate targeted option for the adjuvant treatment of adults with completely resected, stage IB­IIIA, EGFRm+ NSCLC.

Darinaparsin: First Approval.

Darinaparsin (Darvias®), an organoarsenic drug, is a novel mitochondrial-targeted anticancer agent currently being developed by Solasia Pharma K.K for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). An intravenous formulation of darinaparsin has been approved for the treatment of relapsed or refractory PTCL in Japan, and preparation for the next stage of the clinical development program for this indication is currently underway in China, the USA and the EU. This article summarizes the milestones in the development of darinaparsin leading to this first approval for relapsed or refractory PTCL.

Empagliflozin: A Review in Symptomatic Chronic Heart Failure.

Empagliflozin (Jardiance®), a sodium-glucose cotransporter 2 inhibitor (SGLT2i) initially developed to treat type 2 diabetes mellitus (T2DM), has also been approved in the EU and USA for the treatment of all adults with symptomatic chronic heart failure (CHF), regardless of their left ventricular ejection fraction (LVEF). In pivotal phase III trials in ambulant patients with symptomatic CHF and mildly-reduced or preserved ejection fraction (EMPEROR-Preserved; LVEF > 40%) or those with symptomatic CHF and reduced ejection fraction (EMPEROR-Reduced; LVEF ≤ 40%), the addition of oral empagliflozin 10 mg/day to standard of care significantly reduced the risk of cardiovascular (CV) death or hospitalization for HF (HHF), as well as that of a number of other outcomes indicative of worsening HF, compared with placebo. The beneficial effect of empagliflozin on CV death/HHF was seen irrespective of the presence or absence of T2DM and regardless of background HF therapies. In addition, empagliflozin significantly improved health-related quality of life (HRQOL) and was generally well tolerated, with an adverse event profile that was generally consistent with that seen in patients with T2DM. Thus, empagliflozin is a valuable treatment option for ambulant patients with symptomatic CHF across a broad LVEF spectrum.

Categorizing chronic heart failure (CHF) according to left ventricular ejection fraction (LVEF) is central to the management of this condition. CHF with a reduced ejection fraction (HFrEF) is characterized by a LVEF ≤ 40%; CHF with a mildly reduced ejection fraction (HFmrEF) is characterized by a LVEF of 41­49%; and CHF with a preserved ejection fraction (HFpEF) is characterized by a LVEF of ≥ 50%. Historically, standard of care treatments for HFrEF have not been effective against HFpEF, which is becoming the most common form of HF. Empagliflozin (Jardiance^®) is the first sodium-glucose cotransporter type 2 inhibitor to be approved for the treatment of adults with symptomatic CHF, regardless of their LVEF. Empagliflozin significantly reduced the risk of hospitalization for HF or cardiovascular death in nonhospitalized patients with HFpEF, HFmrEF or HFrEF, regardless of diabetes status and the standard HF therapies they were already taking. Empagliflozin also improved health-related quality of life and was generally well tolerated. Empagliflozin is a valuable treatment option for patients with symptomatic CHF associated with a broad range of LVEFs.

Varenicline Solution Nasal Spray: A Review in Dry Eye Disease.

Increasing endogenous tear film production via pharmacological neuroactivation of the nasolacrimal reflex [NLR; also known as the trigeminal parasympathetic pathway (TPP)] is a novel therapeutic approach to treating dry eye disease (DED). An intranasal formulation of the water-soluble, small-molecule, nicotinic acetylcholine receptor (nAChR) agonist varenicline (Tyrvaya™) has been approved in the USA for the treatment of DED. Twice-daily administration of varenicline solution nasal spray resulted in rapid, statistically significant and clinically meaningful improvements in the signs and symptoms of DED over a period of 4 weeks in two pivotal studies (ONSET-1 and -2). The efficacy of varenicline solution was maintained over a longer-term period of 12 weeks in a third study (MYSTIC). Consistent with the nasal route of delivery, the most common adverse events reported by varenicline solution recipients were non-ocular in nature (mild and transient sneezing and cough). Thus, varenicline solution nasal spray is a rapidly-acting, effective and generally well tolerated treatment for DED that offers several potentially useful advantages over existing topical ocular therapies in terms of increasing endogenous tear secretion and reducing ophthalmic treatment burden.

Dry eye disease (DED) is a common, often chronic, condition characterized by symptoms, such as irritation and blurred vision, that can negatively impact on quality of life. DED occurs due to the production of insufficient or unstable tear films and is typically treated with topically applied artificial tears and medications that reduce accompanying inflammation of the ocular surface. Using an intranasal formulation of the nicotinic acetylcholine receptor (nAChR) agonist varenicline (Tyrvaya™) to enhance natural tear production represents a novel approach to DED treatment. Varenicline solution nasal spray led to fast and sustained improvements in the signs and symptoms of DED in clinical trials of up to 12 weeks' duration. Varenicline solution was also generally well tolerated, with the most common adverse events being mild and transient sneezing and cough. Varenicline solution nasal spray is a new type of treatment for DED that may increase natural tear production, have better ocular tolerability and, for some patients, be easier and/or more convenient to use compared with traditional topical therapies.

Teserpaturev/G47Δ: First Approval.

Teserpaturev/G47Δ (Delytact®) is a third-generation (triple-mutated) recombinant oncolytic herpes simplex virus type 1 being developed by Daiichi Sankyo Co., Ltd. for the treatment of certain solid cancers. Teserpaturev/G47Δ has been approved for the treatment of malignant glioma in Japan and is currently in clinical development for the treatment of prostate cancer (phase II), malignant pleural mesothelioma (phase I) and recurrent olfactory neuroblastoma (phase I). This article summarizes the milestones in the development of teserpaturev/G47Δ leading to this first approval for the treatment of malignant glioma.

Finerenone: First Approval.

Finerenone (Kerendia®), a first-in-class, orally administered, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA), is being developed by Bayer HealthCare Pharmaceuticals for the treatment of diabetic kidney disease (DKD) and heart failure (HF), including chronic HF (CHF). Finerenone has been approved in the USA to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, end stage renal disease (ESRD), cardiovascular death, nonfatal myocardial infarction (MI), and hospitalization for HF in adults with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). Finerenone is undergoing regulatory assessment in the EU and in China. A phase III trial is investigating finerenone in patients who have HF with preserved ejection fraction. This article summarizes the milestones in the development of finerenone leading to this first approval to reduce the risk of serious kidney and heart complications in adults with CKD and T2D.

Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC.

Entrectinib (Rozlytrek®) is an orally active, CNS-penetrant, small-molecule, selective inhibitor of the tropomyosin receptor tyrosine kinases TRKA/B/C [encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1/2/3, respectively], the proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and the anaplastic lymphoma kinase gene (ALK). It is approved for the treatment of adults and paediatric patients aged ≥ 12 years with NTRK fusion-positive (NTRK+) solid tumours and adults with ROS1 fusion-positive (ROS1+) non-small-cell lung cancer (NSCLC). In trials in adults, entrectinib induced clinically meaningful and durable systemic responses in tyrosine kinase inhibitor (TKI)-naïve patients with locally-advanced or metastatic NTRK+ solid tumours or ROS1+ NSCLC, irrespective of the presence or absence of CNS metastases at baseline. Moreover, entrectinib demonstrated substantial intracranial efficacy in patients with baseline CNS metastases. Entrectinb efficacy in paediatric patients was established on the basis of extrapolation of clinical trial data from adults with NTRK+ solid tumours and children and adolescents aged < 21 years with recurrent or refractory NTRK+ CNS/solid tumours. Entrectinib was generally well tolerated, with a manageable safety profile. Thus, entrectinib expands the range of treatment options for advanced NTRK+ solid tumours and ROS1+ NSCLC, and may be of particular value in patients with existing CNS metastases and those who are at risk of developing CNS metastases.