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A needle-free device for delivering a 6 mg fixed dose of sumatriptan into subcutaneous tissues has been developed and approved for the acute treatment of migraine and cluster headache in the US and some EU countries. In a pivotal registration study in healthy adult volunteers, a single dose of needle-free subcutaneous sumatriptan 6 mg demonstrated bioequivalence to a single dose of traditional, needle-based subcutaneous sumatriptan 6 mg when delivered into the abdomen or the thigh, but not the arm. In a noncomparative, multicentre, phase IV study, the administration of (one or two doses of) needle-free subcutaneous sumatriptan 6 mg consistently provided rapid and sustained relief from migraine pain and associated symptoms during the treatment of up to four migraine attacks over a period of up to 60 days among current triptan users. Moreover, the use of needle-free subcutaneous sumatriptan was associated with a significant improvement in treatment satisfaction in these patients who were less than 'very satisfied' with their usual symptomatic therapy. Needle-free subcutaneous sumatriptan was generally well tolerated in the phase IV study. Although the overall adverse event profile of the needle-free delivery system was similar to that previously reported for the needle-based delivery system, it was associated with a numerically higher incidence of administration/injection-site reactions in clinical trials that enrolled healthy adult volunteers. [ABSTRACT FROM AUTHOR]

Vilazodone, a novel antidepressant agent that combines selective serotonin reuptake inhibitor (SSRI) activity and serotonin 5-HT(1A) receptor partial agonist activity in a single molecule, is indicated for the treatment of major depressive disorder (MDD) in the US. It is administered orally, once daily, with food. At the recommended dosage of 40 mg/day, vilazodone was effective in the short-term treatment of MDD in adults, as evidenced by significant improvements versus placebo on multiple measures of depression, including the Montgomery-Åsberg Depression Rating Scale (MADRS) and the 17-item Hamilton Rating Scale for Depression (HAM-D-17), in two pivotal, 8-week, randomized, double-blind, phase III studies. Significant differences between vilazodone and placebo on the MADRS and HAM-D-17 were seen after 1 week of treatment (first efficacy timepoint) in one of the two studies. Long-term treatment with vilazodone 40 mg/day was associated with an improvement from baseline in depressive symptoms in a 52-week, noncompar-ative, phase III study. Vilazodone was generally well tolerated in the short- and long-term treatment of MDD, with diarrhoea and nausea being the most frequently occurring treatment-emergent adverse events. Vilazodone had a minimal impact on sexual functioning in the three phase III studies. [ABSTRACT FROM AUTHOR]

Vinflunine is a novel bifluorinated vinca alkaloid that appears to differ from other class members in terms of its tubulin-binding properties and inhibitory effects on microtubule dynamics. Notably, it demonstrated superior in vivo antitumour activity to that of vinorelbine in a range of transplantable murine and human tumours. In a randomized, open-label, multicentre phase III trial in adult patients with advanced transitional cell carcinoma of the urothelium who experienced progression after first-line platinum-containing chemotherapy (n = 370), median overall survival (OS; primary endpoint) was 6.9 months for intravenous vinflunine plus best supportive care (BSC) recipients versus 4.6 months for BSC alone recipients in the intent to treat (ITT) population. The difference in OS between treatment groups was not significant in the ITT population; however, there was a significant improvement in OS for vinflunine plus BSC recipients in the ITT population after adjusting for prespecified prognostic factors, and in the analysis of the eligible population (ITT population excluding baseline protocol violations). In the latter, median OS was 6.9 months with vinflunine plus BSC versus 4.3 months with BSC alone after a median follow-up of ~ 1.8 years and again after a median follow-up of ~ 3.6 years. Progression-free survival, objective response rate and disease control rate were significantly improved with vinflunine plus BSC versus BSC alone. The most frequent treatment-related adverse events in vinflunine recipients included myelosuppression (e.g. neutropenia) and gastrointestinal symptoms (e.g. constipation). In general, adverse events with vinflunine were noncumulative and medically manageable. [ABSTRACT FROM AUTHOR]

Hylan G-F 20, a cross-linked hyaluronic acid derivative, is an elastoviscous, high-molecular-weight (average 6000 kDa) fluid with rheological properties similar to those of knee synovial fluid of healthy young individuals. In a 26-week, randomized, double-blind, multicentre study in patients with symptomatic primary osteoarthritis of the knee (n = 253), one intra-articular injection of hylan G-F 20 (single-injection formulation) into the target knee significantly relieved pain (as measured by the Western Ontario and McMaster Universities Osteoarthritis Index pain [WOMAC A] subscale), including pain while walking on a flat surface (as assessed by the WOMAC A1 subscore), compared with placebo. Observer-reported disease status and patient-reported health status were also significantly improved in hylan G-F 20-treated patients compared with placebo-treated patients. A single intra-articular injection of hylan G-F 20 was generally well tolerated, with an adverse event profile similar to that of placebo. Repeat administration of hylan G-F 20 after 6 months had a similar tolerability profile to that of the initial injection. However, no patient who developed a target-knee adverse event after their first injection experienced such an event following their second injection. [ABSTRACT FROM AUTHOR]

Prucalopride, a first-in-class dihydrobenzofurancarboxamide derivative, is a potent, selective and specific serotonin 5-HT4 receptor agonist with enterokinetic properties. Over a 12-week treatment period, prucalopride 2 and 4mg once daily significantly improved bowel habit assessments (based on patient diary data) relative to placebo in three large, randomized, doubleblind, multicentre trials in patients (aged 17-95 years) with severe chronic constipation, the majority of whom were women who experienced inadequate relief with previous therapies. There was no additional benefit with the 4mg/day over the 2mg/day dosage of prucalopride. Patient assessments of constipation symptoms and severity, treatment efficacy, satisfaction with bowel habit and treatment, and health-related quality of life were also significantly improved with prucalopride compared with placebo. The improvement in patient satisfaction with bowel habit and treatment was maintained for up to 24 months in open-label, multicentre, long-term follow-up studies. Prucalopride therapy was generally well tolerated; most adverse events in the 12-week studies were transient and of mild to moderate severity. In terms of cardiovascular tolerability, the incidence of QT interval prolongation with prucalopride at dosages of 2 and 4mg/day was low and similar to that with placebo. Moreover, prucalopride at dosages up to 20mg/day (10-fold higher than the recommended therapeutic dosage) had no clinically relevant effects on cardiovascular parameters in healthy volunteers. [ABSTRACT FROM AUTHOR]

Degarelix is a gonadotropin-releasing hormone (GnRH) receptor antagonist that, in common with GnRH receptor agonists (e.g. leuprolide, goserelin and triptorelin), is indicated for use as an androgen-deprivation therapy in patients with advanced prostate cancer. In 1-year, randomized, open-label, phase II or III trials in patients with all stages of prostate cancer, subcutaneous degarelix was associated with rapid, profound and sustained suppression of serum testosterone and prostate-specific antigen (PSA), without evidence of testosterone surges or microsurges. In the phase III trial, degarelix (240 mg initially followed by 80 mg every 28 days) was considered to be effective and noninferior to intramuscular leuprolide (7.5 mg every 28 days) with regard to inducing and maintaining suppression of serum testosterone to castrate levels (i.e.

black triangle Risedronate, an orally administered pyridinal bisphosphonate, is effective in the treatment and prevention of postmenopausal osteoporosis. Efforts to optimize patient adherence and persistence with, and hence the effectiveness of, therapy have led to the development of a 75 mg tablet to be taken on two consecutive days each month (2CDM). black triangle After 1 year of treatment, risedronate 75 mg 2CDM was noninferior to risedronate 5 mg once daily in improving lumbar spine bone mineral density (BMD) in an ongoing (2-year) randomized, double-blind, parallel-group, multinational trial in 1229 postmenopausal women with osteoporosis. Mean percentage increases in BMD from baseline at 12 months were 3.4% and 3.6% in the 75 mg 2CDM and 5 mg once-daily groups; the upper limit of the 95% confidence interval for the treatment difference (5 mg once daily - 75 mg 2CDM; -0.19%, 0.62%) did not exceed the predefined noninferiority margin (1.5%). black triangle In general, improvements in hip BMD and reductions in bone turnover markers with the 75 mg 2CDM regimen were not significantly different from those with the 5 mg once-daily regimen; there was no significant between-group difference in the incidence of new vertebral fractures at 12 months. black triangle The tolerability profile (including the incidence of upper gastrointestinal tract adverse events) of risedronate 75 mg 2CDM in postmenopausal women with osteoporosis was similar to that of risedronate 5 mg once daily. [ABSTRACT FROM AUTHOR]

Romiplostim is an Fc-peptide fusion protein (or 'peptibody') that stimulates megakaryopoiesis and thrombopoiesis by binding to, and activating, the thrombopoietin receptor. Because it has no sequence homology to thrombopoietin, romiplostim theoretically avoids the risk of eliciting cross-reacting, neutralizing antibodies to thrombopoietin. In well designed, 24-week, phase III trials, subcutaneous romiplostim was significantly more effective than placebo in achieving the primary endpoint of a protocol-defined durable platelet response in nonsplenectomized (61% vs 5%) or splenectomized (38% vs 0%) adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP). Romiplostim was also significantly more effective than placebo with regard to a number of secondary endpoints, including the proportions of patients with an overall (durable plus transient) platelet response or who required ITP rescue medications. The majority of romiplostim-treated patients receiving concurrent ITP drugs were able to reduce or discontinue these therapies. Platelet response was maintained by most patients during longer-term treatment with romiplostim for up to 3 or 4 years in an open-label extension study. Romiplostim was generally well tolerated. Almost all adverse events in the phase III studies were of mild-to-moderate intensity; most were unrelated to treatment. Longer-term treatment with romiplostim had an adverse event profile consistent with that observed in the phase III studies. [ABSTRACT FROM AUTHOR]

Topically administered dorzolamide 2%/timolol 0.5% (dorzolamide/timolol ophthalmic solution; Cosopt(R)) is a fixed combination of two ocular hypotensive drugs (the carbonic anhydrase inhibitor dorzolamide and the beta-adrenoceptor antagonist timolol) that have an additive effect on lowering intraocular pressure (IOP) when administered together. This product is indicated for the treatment of elevated IOP in patients with open-angle glaucoma or ocular hypertension (OH) who are insufficiently responsive to topical beta-adrenoceptor antagonist monotherapy. As such, it can be considered for use in individuals who, as a consequence of failing to achieve target IOP with beta-adrenoceptor antagonist monotherapy, require the addition or substitution of another class of topical antiglaucoma medication. Clinical trials have demonstrated that dorzolamide/timolol (1 drop per eye twice daily) is an effective and generally well tolerated fixed combination for lowering IOP in patients with open angle glaucoma or OH, including individuals uncontrolled on beta-adrenoceptor antagonist monotherapy. Compared with concomitant therapy with the individual components, the primary advantage of fixed combination dorzolamide/timolol is convenience. [ABSTRACT FROM AUTHOR]

Tigecycline is the first member of a new class of broad-spectrum antibacterials, the glycylcyclines, that has been specifically developed to overcome the two major mechanisms of tetracycline resistance (ribosomal protection and efflux). In vitro, tigecycline was active against a wide range of Gram-positive and -negative aerobic and anaerobic bacteria implicated in complicated skin and skin structure infections (cSSSIs) and complicated intra-abdominal infections (cIAIs). Intravenously administered tigecycline (recommended dosage regimen 100 mg initially, followed by 50 mg every 12 hours for 5-14 days) has been approved by the US FDA for the treatment of cSSSIs and cIAIs. In well designed, pivotal phase III studies, tigecycline monotherapy was noninferior to combination therapy with vancomycin 1 g plus aztreonam 2 g every 12 hours in hospitalised adult patients with cSSSIs (two trials; pooled clinical cure rates, 86.5% vs 88.6%) or broad-spectrum therapy with imipenem/cilastatin 200-500 mg/200-500 mg every 6 hours in hospitalised adult patients with cIAIs (two trials; pooled clinical cure rates, 86.1% vs 86.2%). Tigecycline was generally well tolerated in phase III studies; nausea, vomiting and diarrhoea were the most frequent adverse events in patients treated with tigecycline or an active comparator (vancomycin plus aztreonam or imipenem/cilastatin). [ABSTRACT FROM AUTHOR]

Pregabalin, the pharmacologically active S-enantiomer of 3-aminomethyl-5-methyl-hexanoic acid, has a similar pharmacological profile to that of its developmental predecessor gabapentin, but showed greater analgesic activity in rodent models of neuropathic pain. The exact mechanism of action of pregabalin is unclear, although it may reduce excitatory neurotransmitter release by binding to the alpha2-delta protein subunit of voltage-gated calcium channels. Oral pregabalin at fixed dosages of 300 and 600 mg/day, administered three times daily, was superior to placebo in relieving pain and improving pain-related sleep interference in three randomised, double-blind, multicentre studies of 5-8 weeks' duration in a total of 724 evaluable patients with painful diabetic peripheral neuropathy (DPN). Significant reductions in weekly mean pain scores (primary endpoint) and sleep interference scores were observed at 1 week and sustained thereafter. A significant reduction in pain was apparent on the first day of treatment with pregabalin 300 mg/day. Twice daily fixed (600 mg/day) or flexible (150-600 mg/day) pregabalin was also effective in reducing pain and sleep interference in two 12-week placebo-controlled trials in a total of 733 randomised DPN patients. Pregabalin was well tolerated in DPN patients; mild-to-moderate dizziness, somnolence and peripheral oedema were the most common adverse events. [ABSTRACT FROM AUTHOR]

Icodextrin (Extraneal) is a high molecular weight glucose polymer developed specifically for use as an alternative osmotic agent to dextrose during the once-daily long-dwell exchange in peritoneal dialysis (PD). Isosmotic 7.5% icodextrin solution induces transcapillary ultrafiltration (UF) by a mechanism resembling 'colloid' osmosis (unlike hyper-osmolar dextrose-based solutions, which induce UF by crystalline osmosis). In addition, absorption of icodextrin from the peritoneal cavity is relatively slow compared with that of dextrose; this results not only in UF of longer duration, but also a lower carbohydrate load compared with medium (2.5%) and strong (4.25%) dextrose exchanges. In randomised clinical trials of up to 2 years in duration, administration of icodextrin for the long (8- to 16-hour) overnight exchange in continuous ambulatory peritoneal dialysis (CAPD) or daytime exchange in automated peritoneal dialysis (APD) produced net UF which exceeded that with 1.5% and 2.5% dextrose solutions (thereby improving fluid balance), and was equivalent to that with 4.25% dextrose solution. Icodextrin also increased peritoneal clearances of creatinine and urea nitrogen compared with 2.5% dextrose solution. The increase in UF volume with icodextrin was enhanced in CAPD patients with high peritoneal membrane permeability (i.e. high and high-average transporters), maintained in the small number of patients followed-up for 2 years and sustained during episodes of peritonitis. Icodextrin reduced the percentage of patients with net negative UF in contrast to 1.5% and 2.5% dextrose and, in noncomparative studies, extended PD technique survival in patients who had failed dextrose-based dialysis. The use of icodextrin was also associated with some symptomatic improvements and health-related quality of life advantages, and no adverse effect on patient survival, compared with dextrose, although confirmation of these findings is ideally required in appropriately designed studies. The tolerability of icodextrin was generally similar to that of dextrose-based solutions in controlled clinical trials, although there was an approximate three-fold increase in the risk of new skin rash (5.5% vs 1.7%). However, reports of severe cutaneous hypersensitivity reactions remain rare; this possibility should not preclude the use of the polymer. CONCLUSION: 7.5% icodextrin solution offers the first feasible alternative to conventional dextrose solutions for the once-daily long-dwell exchange in PD. It is effective, generally well tolerated and appears to be most useful in situations of reduced or inadequate UF with dextrose, including in high and high-average transporters, during episodes of peritonitis and patients who have failed dextrose-based dialysis. [ABSTRACT FROM AUTHOR]

Alemtuzumab is an unconjugated, humanised, monoclonal antibody directed against the cell surface antigen CD52 on lymphocytes and monocytes. In noncomparative phase I/II studies in patients with B-cell chronic lymphocytic leukaemia (B-CLL) relapsed after or refractory to alkylating agents and fludarabine, intravenous (IV) administration of alemtuzumab 30 mg/day three times weekly for up to 12 weeks was associated with overall objective response (OR) rates of 21-59%. Combining alemtuzumab with fludarabine resulted in ORs >80%. In noncomparative studies in patients with previously untreated B-CLL, subcutaneous (SC) administration of alemtuzumab alone, or IV in combination with fludarabine, was highly effective, achieving OR rates of around 90%. IV alemtuzumab was active in patients with chemotherapy-resistant/relapsed T-cell prolymphocytic leukaemia, with reported OR rates of 24-76%. Alemtuzumab has been incorporated in novel conditioning regimens designed to facilitate stem cell transplantation in haematological malignancies. Adverse events with alemtuzumab are predictable and manageable. 'First-dose' flulike symptoms, frequently seen after IV infusion, can be managed by (pre)medication and minimised by dose escalation (or SC injection). Anti-infective prophylaxis is mandatory. Cytopenias are transient, although red blood cell and platelet support may be required. [ABSTRACT FROM AUTHOR]

The treatment of irritable bowel syndrome with constipation (IBS-C) has historically been based on the severity of symptoms, with education, reassurance, dietary advice, bulking agents and laxative therapy offered as appropriate. Tegaserod (Zelnorm, Zelmac) is the first selective serotonin 5-HT(4) receptor partial agonist to be approved for the treatment of this syndrome. Tegaserod is active against multiple irritable bowel syndrome (IBS) symptoms; it stimulates gut motility and reduces visceral sensitivity and pain. The drug does not cure IBS and was not designed to treat the diarrhoea-predominant version. Its efficacy in men has not been established. Three large well designed clinical trials of tegaserod 6 mg twice daily for 12 weeks in patients (mainly women) with IBS-C have demonstrated superiority versus placebo in global relief from symptoms. Global relief response rates were 38.4-46.8% with tegaserod 6 mg twice daily and 28.3-38.8% with placebo (p < 0.05-0.0001 vs placebo). The relative increases in response rates with tegaserod 6 mg twice daily over the already high responses in the placebo groups ranged from 12-65% after 4-12 weeks of treatment. A response was seen within the first week. The proportion of patients with satisfactory relief from symptoms fell over the 4-week period following withdrawal of tegaserod and placebo, but did not reach baseline levels during this time. Diarrhoea has been associated with tegaserod in clinical trials (an incidence of about 10% versus 5% with placebo, usually occurring in the first week of treatment), but the drug is otherwise well tolerated. There were no apparent changes in the tolerability profile with extended tegaserod treatment (

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., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Efmoroctocog alfa (Elocta ® , Eloctate ® , Eloctate™), an extended half-life (EHL) recombinant factor VIII (rFVIII)-Fc fusion protein, is approved for the treatment and prophylaxis of bleeding in patients with haemophilia A. The efficacy of efmoroctocog alfa in the prevention and treatment of bleeding in previously treated patients (PTPs) and previously untreated patients (PUPs) with severe haemophilia A has been demonstrated in phase III studies; this includes its use in the perioperative setting (in PTPs). Furthermore, the effectiveness of efmoroctocog alfa in clinical practice has been confirmed in numerous real-world studies; compared with conventional, standard half-life (SHL) FVIII products, prophylaxis with this EHL FVIII product achieved similar or reduced bleeding rates with fewer injections. Efmoroctocog alfa was generally well tolerated; inhibitors occurred in approximately one-third of PUPs in a phase III study. Efmoroctocog alfa is an established and effective EHL FVIII replacement therapy for the management of haemophilia A. Compared with SHL FVIII products, EHL FVIII products such as efmoroctocog alfa have the potential to optimise prophylactic outcomes by decreasing the burden of treatment or increasing the level of bleed protection., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Isatuximab (Sarclisa ® ; isatuximab-irfc in the USA) is an anti-CD38 monoclonal antibody (mAb) approved for use in the treatment of adults with multiple myeloma (MM): in combination with pomalidomide and dexamethasone for those with relapsed and refractory MM (RRMM) who have received ≥ 2 prior therapies, including lenalidomide and a proteasome inhibitor; and in combination with carfilzomib and dexamethasone for those with relapsed MM who have received ≥ 1 prior therapy. In phase III studies, the addition of isatuximab to pomalidomide and dexamethasone significantly prolonged progression-free survival (PFS) and improved the depth of tumour response in patients with RRMM, as did the addition of isatuximab to carfilzomib and dexamethasone in patients with relapsed or refractory MM. Health-related quality of life was maintained when isatuximab was combined with these other therapies. Isatuximab-based combination therapies were generally well tolerated and demonstrated a manageable safety profile with no new safety signals. Although mature overall survival data are awaited, available evidence indicates that the combinations of isatuximab with pomalidomide and dexamethasone and isatuximab with carfilzomib and dexamethasone are important additional treatment options for RRMM and relapsed MM, respectively., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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.

OnabotulinumtoxinA (Botox ® ; a formulation of botulinum toxin type A (BoNT/A)] is indicated for the prevention of headaches in adults with chronic migraine (CM) in numerous countries, including those of Europe. In clinical trials, intramuscular administration of BoNT/A (155-195 units at 12-week intervals) to patients with CM was generally well tolerated and associated with sustained and clinically meaningful improvements in multiple assessments of headache symptoms, headache-related impact and/or disability and migraine-specific health-related quality of life over a period of 1 year (in the pivotal PREEMPT 1 and 2 studies) and 2 years (in the phase IV COMPEL study). The efficacy and safety of BoNT/A therapy have been confirmed in a number of large, prospective, real-world studies conducted in Europe, including the 2-year REPOSE study. Intramuscular BoNT/A has also demonstrated greater clinical utility than the oral prophylactic medication topiramate in a clinical practice setting (FORWARD study).

Atezolizumab (Tecentriq ® ), a fully humanized, monoclonal anti-programmed cell death ligand-1 (PD-L1) antibody, is the first immune checkpoint inhibitor to be approved, in combination with carboplatin and etoposide, for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). Approval was based on primary data from the multinational phase I/III IMpower133 trial in PD-L1-unselected patients with previously untreated ES-SCLC. In this trial, induction therapy with atezolizumab plus carboplatin and etoposide followed by maintenance therapy with atezolizumab alone significantly prolonged overall survival (OS) and progression-free survival (PFS) compared with carboplatin and etoposide alone. The addition of atezolizumab to chemotherapy was generally well tolerated, with no new safety signals being identified beyond those previously reported for the individual agents. The most common grade 3-4 treatment-related adverse events with this regimen were haematological; the most common immune-related adverse events included rash and hypothyroidism. Importantly, the addition of atezolizumab to chemotherapy improved survival outcomes without adversely impacting patient-reported health-related quality of life (HRQOL). Thus, atezolizumab in combination with carboplatin plus etoposide has emerged as a valuable option for the first-line treatment of ES-SCLC and is being accepted as a standard of care in this setting.

Inebilizumab (Uplizna™; inebilizumab-cdon in the USA) is a humanised anti-CD19 monoclonal antibody being developed by Viela Bio for the treatment of a range of autoimmune diseases associated with CD19-expressing B cells. Inebilizumab targets and depletes CD19-expressing B cells through antibody-dependent cell-mediated cytotoxicity. In June 2020, inebilizumab received its first global approval in the USA for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are seropositive for immunoglobulin G autoantibodies against aquaporin-4 (AQP4-IgG). The drug is also undergoing clinical evaluation for kidney transplant desensitization, myasthenia gravis, and IgG4-related disease. This article summarizes the milestones in the development of inebilizumab leading to this first approval for the treatment of AQP4-IgG seropositive NMOSD.

The article Liposomal Irinotecan: A Review in Metastatic Pancreatic Adenocarcinoma, written by James E. Frampton, was originally published Online First without Open Access.

Liposomal irinotecan (nal-IRI; Onivyde ® ; also known as pegylated liposomal irinotecan) has been developed with the aim of maximising anti-tumour efficacy while minimising drug-related toxicities compared with the conventional (non-liposomal) formulation of this topoisomerase 1 inhibitor. In combination with 5-fluorouracil and leucovorin (5-FU/LV), nal-IRI is the first agent to be specifically approved for use in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who have progressed following gemcitabine-based therapy. In the pivotal, phase III NAPOLI-1 trial, intravenous administration of nal-IRI + 5-FU/LV to gemcitabine-pretreated patients with mPDAC (as a second-line treatment in approximately two-thirds of cases) was associated with a significant ≈ 2-month median overall survival advantage compared with 5-FU/LV alone. Moreover, adding nal-IRI to 5-FU/LV extended survival with a manageable safety profile and without adversely affecting health-related quality of life, thereby producing significant and clinically meaningful gains in quality-adjusted survival relative to 5-FU/LV alone. Complementing the observed efficacy and safety of nal-IRI in NAPOLI-1 are an increasing number of real-world studies, which provide evidence of the effectiveness of this combination therapy in the treatment of mPDAC that has progressed following gemcitabine-based therapy in contemporary clinical practice in Europe, the USA and East Asia. Thus, nal-IRI, in combination with 5-FU/LV, is the first regimen specifically approved for use as a second- or subsequent-line therapy in gemcitabine-pretreated patients with mPDAC and, as such, represents a valuable treatment option in this setting.

The terminal complement protein (C5) inhibitor eculizumab (Soliris ® ) is the first agent to be specifically approved in the EU, USA, Canada and Japan for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive and (in the EU only) for those with a relapsing course of disease. In the phase III PREVENT trial, eculizumab significantly reduced the risk of adjudicated relapse relative to placebo in patients with AQP4-IgG-seropositive NMOSD, approximately a quarter of whom did not receive concomitant immunosuppressive therapies. The beneficial effect of eculizumab was seen across all patient subgroups analysed and was accompanied by improvements in neurological and functional disability assessments, as well as generic health-related quality of life measures; it was sustained through 4 years of treatment, according to combined data from the PREVENT trial and an interim analysis of its ongoing open-label extension study. The safety profile of eculizumab in AQP4-IgG-seropositive NMOSD was consistent with that seen for the drug in other approved indications. Thus, eculizumab provides an effective, generally well tolerated and approved treatment option for this rare, disabling and potentially life-threatening condition.

The article Eculizumab: A Review in Neuromyelitis Optica Spectrum Disorder, written by James E. Frampton, was originally published electronically in SpringerLink on 7 April 2020 without Open Access. After publication Alexion Pharmaceuticals, Inc., requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by Alexion Pharmaceuticals, Inc.

Rituximab (MabThera ® , Rituxan ® ), a chimeric murine/human anti-CD20 monoclonal antibody administered by intravenous infusion, is indicated for the treatment of moderate to severe pemphigus vulgaris (PV), in combination with a tapering course of corticosteroids. Approval in the EU and USA was based on data for the subset of patients with newly-diagnosed, previously untreated PV participating in the randomized, controlled RITUX 3 study; rituximab plus short-course prednisone resulted in a > 3-fold higher rate of complete remission off prednisone therapy and a > 2-fold decrease in the rate of moderate/severe relapse compared with standard-dose prednisone in this patient subpopulation. In addition, rituximab plus short-term prednisone was steroid-sparing and resulted in fewer patients experiencing grade 3 or 4 corticosteroid-related adverse events compared with standard-dose prednisone. The adverse event profile of rituximab in patients with PV was consistent with that observed for the drug in other approved autoimmune disorders; no new safety concerns were identified. Notwithstanding there is some uncertainty over the optimum dosing schedule to achieve and maintain disease control, rituximab is a highly effective and generally well tolerated, steroid-sparing treatment for moderate to severe PV.

Stiripentol (Diacomit ® ) is an orally-active, structurally unique anti-epileptic drug (AED) with multiple potential mechanisms of action, including enhancement of central γ-aminobutyric acid transmission. In the EU, stiripentol is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with Dravet syndrome (DS; previously known as severe myoclonic epilepsy of infancy), whose seizures are not adequately controlled with clobazam and valproate. This approval (and similar DS indications in the USA, Canada and Japan), reflect the results of the STICLO studies, two small, randomized controlled trials in which stiripentol as adjunctive therapy was associated with a markedly superior response rate after 2 months compared with placebo in patients aged between 3 and ≈ 21 years with DS that was inadequately controlled with clobazam and valproate. These short-term results have subsequently been supported and extended by findings from longer-term, open-label, observational studies, including a retrospective longitudinal cohort study, which showed that the efficacy of combining stiripentol with clobazam and valproate when started at paediatric age was maintained in mid-adulthood with up to 24 years of exposure, and up to 40 years of age. Drowsiness, appetite loss, weight loss, ataxia and tremor are the most common adverse events associated with the addition of stiripentol to clobazam and valproate. Based on the available evidence, stiripentol, as an adjunct to clobazam and valproate, is a demonstrably beneficial and generally well-tolerated second-line treatment for patients with DS.

Glycopyrronium/formoterol (Bevespi Aerosphere ® ) is a fixed-dose combination of the long-acting muscarinic antagonist glycopyrronium bromide and the long-acting β 2 -agonist formoterol fumarate delivered via a pressurized metered dose inhaler (pMDI) and formulated using co-suspension delivery technology. It is approved in the USA and EU for use as maintenance treatment in patients with chronic obstructive pulmonary disease (COPD) and in Japan to relieve symptoms in patients with COPD. In the PINNACLE trials in patients with moderate to very severe COPD, glycopyrronium/formoterol was associated with significantly greater improvements in lung function than its monocomponents and placebo at 24 weeks and its monocomponents and open-label tiotropium over 52 weeks. In the AERISTO trial, glycopyrronium/formoterol was non-inferior to umeclidinium/vilanterol dry powder inhaler for peak change in forced expiratory volume in 1 s (FEV 1 ) within 2 h postdose, but not for the change in morning predose trough FEV 1 , over 24 weeks. Glycopyrronium/formoterol was generally well tolerated in patients with moderate to very severe COPD, with most adverse events (AEs) being of mild or moderate severity. Thus, glycopyrronium/formoterol pMDI formulated using co-suspension delivery technology is a useful new addition that extends treatment options for patients with COPD.

Rotigotine (Neupro ® ), a non-ergolinic dopamine agonist (DA), is administered once daily via a transdermal patch (TP) that delivers the drug over a 24-h period. In the EU, the rotigotine TP is approved as monotherapy for the treatment of early Parkinson's disease (PD) and as combination therapy with levodopa throughout the course of the disease. It is also approved for the treatment of PD in numerous other countries, including Australia, the USA, China and Japan. Rotigotine TP effectively improved motor and overall functioning in clinical trials in Caucasian and Asian patients with early PD (as monotherapy) or advanced PD (in combination with levodopa); treatment benefits appeared to be maintained in open-label extensions that followed patients for up to 6 years. Rotigotine TP was not consistently non-inferior to ropinirole and pramipexole in studies that included these oral non-ergolinic DAs as active comparators. Rotigotine TP variously improved some non-motor symptoms of PD, in particular sleep disturbances and health-related quality of life (HRQOL), based on findings from individual studies and/or a meta-analysis. Rotigotine TP was generally well tolerated, with an adverse event profile characterized by adverse events typical of dopaminergic stimulation and transdermal patch application. Available for more than a decade, rotigotine TP is a well-established, once-daily DA formulation for use in the short- and longer-term treatment of PD. It offers a convenient alternative when non-oral administration of medication is preferred and may be particularly useful in patients with gastrointestinal disturbances that reduce the suitability of oral medication.

Tildrakizumab (tildrakizumab-asmn in the USA) [Ilumetri ® ; Ilumya™] is a humanized monoclonal antibody (mAb) that selectively targets the p19 subunit of interleukin (IL)-23, thereby inhibiting the IL-23/IL-17 axis, the signalling pathway primarily implicated in the immunopathogenesis of psoriasis. Administered subcutaneously, it is approved for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy (e.g. in the EU and Australia) and those who are candidates for systemic therapy or phototherapy (in the USA). In the pivotal phase III reSURFACE 1 and 2 trials, tildrakizumab was superior to placebo and efficacious compared with etanercept, in terms of the proportion of patients achieving a response [≥ 75% improvement from baseline in Psoriasis Area and Severity index score (PASI 75) and a Physician's Global Assessment score of 0/1] at week 12. Response rates peaked at week 22 and the vast majority of patients achieving PASI 75 at week 28 maintained this response after a total of 3 years of treatment in the reSURFACE trials and their ongoing open-label extension studies. In addition, patients with a partial or no response to etanercept at week 28 benefitted from switching to the highest approved dose of tildrakizumab in the reSURFACE 2 trial and its ongoing extension. Treatment with tildrakizumab improved health-related quality of life and was generally well tolerated, both in the short- and longer-term. Tildrakizumab thus expands the range of useful therapeutic options for patients with moderate-to-severe plaque psoriasis, particularly those with an inadequate response to phototherapy and conventional systemic agents.

Brexpiprazole (Rxulti ® , Rexulti ® ) is an oral atypical antipsychotic agent approved for the treatment of schizophrenia in the EU (in adult patients) and the USA, as well as in some other countries, including Japan. Like aripiprazole, it is a partial agonist at dopamine D 2 and serotonin 5-HT 1A receptors and an antagonist at serotonin 5-HT 2A receptors. However, brexpiprazole displays less intrinsic activity at D 2 receptors and, coupled with actions at 5HT 1A , 5HT 2A and noradrenaline α 1B receptors that are at least as potent as its action at D 2 receptors, is predicted to demonstrate a lower propensity for activating adverse events and extrapyramidal symptoms than aripiprazole. Brexpiprazole 2-4 mg/day produced statistically significant and clinically meaningful improvements in overall symptomatology and psychosocial functioning compared with placebo in adults with acute exacerbation of schizophrenia. As maintenance treatment, brexpiprazole 1-4 mg/day significantly delayed the time to relapse compared with placebo in patients who were already stabilized on the drug and was associated with stabilization or continued improvement in patients' symptoms and functioning. Brexpiprazole was generally well tolerated, exhibiting an adverse event profile characterized by a relatively low incidence of activating and sedating adverse effects, small changes in QT interval and metabolic parameters that were not clinically significant, and moderate weight gain. Clinical evidence to date suggests it usefully extends the range of therapeutic options for schizophrenia.

SB5 (Imraldi ® ) is a biosimilar of the reference anti-TNF monoclonal antibody adalimumab. It is approved for use in the following indications for which reference adalimumab is approved: rheumatoid arthritis (RA), juvenile idiopathic arthritis [polyarticular juvenile idiopathic arthritis (pJIA) and enthesitis-related arthritis (ERA)], axial spondyloarthritis [ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)], psoriatic arthritis (PsA), psoriasis, pediatric plaque psoriasis, hidradenitis suppurativa (HS), Crohn's disease, pediatric Crohn's disease, ulcerative colitis (UC), and non-infectious uveitis. SB5 has similar physicochemical and pharmacodynamic properties to those of reference adalimumab, and the pharmacokinetic similarity of these agents has been shown in healthy volunteers and patients with RA. SB5 demonstrated clinical efficacy considered equivalent to that of reference adalimumab in patients with RA, and was generally well tolerated in this population. The safety and tolerability profile of SB5 was similar to that of reference adalimumab, as was the immunogenicity profile. Switching from reference adalimumab to SB5 had no impact in terms of efficacy, safety or immunogenicity. The role of reference adalimumab in the management of RA, pJIA, ERA, AS, nr-axSpA, PsA, psoriasis, pediatric plaque psoriasis, HS, Crohn's disease, UC and non-infectious uveitis is well established and SB5 provides an effective biosimilar alternative for patients requiring adalimumab therapy.

Tafenoquine (Krintafel™, Arakoda™), an orally-active 8-aminoquinoline anti-malarial drug, is a long-acting analogue of primaquine with activity against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of Plasmodium species that include Plasmodium vivax (P. vivax) and Plasmodium falciparum. It has been developed by GlaxoSmithKline (formerly SmithKline Beecham) for the radical cure of P. vivax malaria and by 60 Degrees Pharmaceuticals for the prophylaxis of malaria. The exact mechanism(s) of action underlying the anti-Plasmodium activity of tafenoquine are unknown, although it may exert its effect by inhibiting haematin polymerization and, additionally, by inducing mitochondrial dysfunction leading to the apoptotic-like death of the organism. In July 2018, tafenoquine was approved in the USA for the radical cure of P. vivax malaria in patients aged ≥ 16 years who are receiving appropriate antimalarial therapy for acute P. vivax malaria. Subsequently, in August 2018, tafenoquine was approved in the USA for the prophylaxis of malaria in patients aged ≥ 18 years. This article primarily summarizes the milestones in the development of tafenoquine leading to its first global approval for the radical cure of P. vivax malaria.