Benefit:Risk Profile of Budesonide in Obstructive Airways Disease Page 5, Fig. 2 Key milestones in the development of budesonide.

Correction to: As-needed ICS-LABA in Mild Asthma: What Does the Evidence Say? Abstract, fourth to last sentence, which currently reads:

Correction to: Polatuzumab Vedotin: First Global Approval The article Polatuzumab Vedotin: First Global Approval, written by Emma D. Deeks, was originally published Online First without Open Access. After publication in volume 79, issue 13, pages 1467–1475 Roche/GCC requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by Roche/GCC. The article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial.

Targeting Granulocyte-Monocyte Colony-Stimulating Factor Signaling in Rheumatoid Arthritis: Future Prospects Abstract Rheumatoid arthritis (RA) is a systemic, autoimmune disease that affects joints and extra-articular structures. In the last decade, the management of this chronic disease has dramatically changed with the introduction of several targeted mechanisms of action, such as tumor necrosis factor-α inhibition, T-cell costimulation inhibition, B-cell depletion, interleukin-6 blockade, and Janus kinase inhibition. Beyond its well-known hematopoietic role on the proliferation and differentiation of myeloid cells, granulocyte-monocyte colony-stimulating factor (GM-CSF) is a proinflammatory mediator acting as a cytokine, with a proven pathogenetic role in autoimmune disorders such as RA. In vitro studies clearly demonstrated the effect of GM-CSF in the communication between resident tissue cells and activated macrophages at chronic inflammation sites, and confirmed the elevation of GM-CSF levels in inflamed synovial tissue of RA subjects compared with healthy controls. Moreover, a pivotal role of GM-CSF in the perception of pain has been clearly confirmed. Therefore, blockade of the GM-CSF pathway by monoclonal antibodies directed against the cytokine itself or its receptor has been investigated in refractory RA patients. Overall, the safety profile of GM-CSF inhibitors seems to be very favorable, with a particularly low incidence of infectious complications. The efficacy of this new mechanism of action is comparable with main competitors, even though the response rates reported in phase II randomized controlled trials (RCTs) appear to be numerically lower than the response rates observed with other biological disease-modifying antirheumatic drugs already licensed for RA. Mainly because of this reason, nowadays the development program of most GM-CSF blockers for RA has been discontinued, with the exception of otilimab, which is under evaluation in two phase III RCTs with a head-to head non-inferiority design against tofacitinib. These studies will likely be useful for better defining the potential role of GM-CSF inhibition in the therapeutic algorithm of RA. On the other hand, the potential role of GM-CSF blockade in the treatment of other rheumatic diseases is now under investigation. Phase II trials are ongoing with the aim of evaluating mavrilimumab for the treatment of giant cell arteritis, and namilumab for the treatment of spondyloarthritis. Moreover, GM-CSF inhibitors have been tested in osteoarthritis and diffuse subtype of systemic sclerosis. This review aims to describe in detail the available evidence on the GM-CSF blocking pathway in RA management, paving the way to a possible alternative treatment for RA patients. Novel insights regarding the potential use of GM-CSF blockers for alternative indications will be also addressed.

Stiripentol: A Review in Dravet Syndrome Abstract 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.

Upadacitinib: First Approval Abstract Upadacitinib (Rinvoq™), an orally-administered Janus kinase 1 (JAK-1) inhibitor, is being developed by AbbVie for the treatment of rheumatoid arthritis. In August 2019, based on positive results from multinational phase III trials conducted in patients with rheumatoid arthritis, upadacitinib received marketing approval in the USA for the treatment of moderately to severely active rheumatoid arthritis and an inadequate response or intolerance to methotrexate. This article summarizes the milestones in the development of upadacitinib leading to this first approval for the treatment of rheumatoid arthritis.

As-needed ICS-LABA in Mild Asthma: What Does the Evidence Say? Abstract For the last three decades, the guidelines for asthma management have supported a stepwise therapeutic approach, based on the administration of controller medications (especially inhaled corticosteroids) complemented by on-demand use of rescue medication. Classically, the rescue medication recommended comprised short-acting β agonists (SABA). Some years ago, the use of Symbicort Maintenance and Reliever Therapy (SMART) demonstrated the benefits of a combination of budesonide-formoterol, an inhaled corticosteroid, and a long-acting β agonist (ICS-LABA) as rescue medication in moderate and severe asthma. The results were enthusiastically received, and this therapeutic option was adopted in the guidelines for moderate to severe asthma patients. Recently, four trials (two randomised placebo control trials under the auspices of the SYGMA project and two real-life studies, Novel START, and the PRACTICAL trial) have explored the potential benefits of substituting SABA with budesonide-formoterol as rescue medication in mild asthma patients. The SYGMA 1 and 2 studies showed that the combination with formoterol-budesonide as rescue medication provides better asthma control than short-acting β-agonists alone in GINA step 2 patients, although the superiority was slight. Compared to budesonide maintenance therapy, the fixed combination of ICS-LABA on demand provides poorer asthma control. Regarding exacerbations, the fixed dose ICS-LABA combination on demand showed the same benefits for the prevention of exacerbations as chronic ICS treatment in mild asthma patients. The Novel START study, which assessed a population with milder symptoms, concluded that the fixed dose ICS-LABA combination used as needed was superior to SABA (albuterol) as needed for the prevention of asthma exacerbations. These results in fact show that, in undertreated GINA step 2 with only SABA as needed, ICS-LABA is more effective than SABA. The authors of PRACTICAL concluded that the study provided modest evidence that the ICS-LABA combination used as-needed for symptom relief reduces the rate of severe exacerbations compared with maintenance low-dose budesonide plus terbutaline as needed, although the study was not limited to mild asthma since according to the treatment consumed, it was evident that they had recruited some moderate asthma patients. Despite this poor evidence, and ignoring the clinical histological benefits of chronic inhaled corticosteroids (especially when administered promptly), GINA 2019 recently recommended daily low dose ICS or ICS-LABA as needed as a first option for step 2 patients. For step 1, symptom-driven or as-needed treatment with ICS-LABA is recommended rather than SABA alone (the preferred option until the last GINA update). Finally, the SIENA study showed that 73% of patients with mild asthma do not have an eosinophilic phenotype and that these patients have a similar clinical response to ICS (mometasone) and antimuscarinic drugs (tiotropium), results that challenge the indication of a drug combination that incorporates ICS as a first option. Overall, we believe there is insufficient evidence for the systematic recommendation of as-needed ICS-LABA instead of SABA on request for GINA step 1 or as a replacement for chronic ICS in GINA step 2.

Pretomanid: First Approval Abstract Pretomanid, an oral nitroimidazooxazine antimycobacterial agent administered as part of the BPaL (bedaquiline, pretomanid and linezolid) and BPaMZ (bedaquiline, pretomanid, moxifloxacin and pyrazinamide) regimens, has been developed by the Global Alliance for TB Drug Development (TB Alliance) under license from Novartis, for the treatment for tuberculosis (TB). TB Alliance has licensed Mylan to manufacture and commercialize pretomanid for use as part of the BPaMZ and BPaL regimens. The license is non-exclusive in low- and middle-income countries and exclusive in high-income markets. Pretomanid, as part of the BPaL regimen, was recently approved in the USA under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) pathway for the treatment of adults with pulmonary extensively drug-resistant (XDR) or treatment-intolerant or non-responsive multidrug-resistant (MDR) TB. Pretomanid is also under regulatory review in the EU. This article summarizes the milestones in the development of pretomanid leading to this first regulatory approval.

Benefit:Risk Profile of Budesonide in Obstructive Airways Disease Abstract Airway inflammation is a major contributing factor in both asthma and chronic obstructive pulmonary disease (COPD) and represents an important target for treatment. Inhaled corticosteroids (ICS) as monotherapy or in combination therapy with long-acting β2-agonists or long-acting muscarinic antagonists are used extensively in the treatment of asthma and COPD. The development of ICS for their anti-inflammatory properties progressed through efforts to increase topical potency and minimise systemic potency and through advances in inhaled delivery technology. Budesonide is a potent, non-halogenated ICS that was developed in the early 1970s and is now one of the most widely used lung medicines worldwide. Inhaled budesonide’s physiochemical and pharmacokinetic/pharmacodynamic properties allow it to reach a rapid and high airway efficacy due to its more balanced relationship between water solubility and lipophilicity. When absorbed from the airways and lung tissue, its moderate lipophilicity shortens systemic exposure, and its unique property of intracellular esterification acts like a sustained release mechanism within airway tissues, contributing to its airway selectivity and a low risk of adverse events. There is a large volume of clinical evidence supporting the efficacy and safety of budesonide, both alone and in combination with the fast- and long-acting β2-agonist formoterol, as maintenance therapy in patients with asthma and with COPD. The combination of budesonide/formoterol can also be used as an as-needed reliever with anti-inflammatory properties, with or without regular maintenance for asthma, a novel approach that is already approved by some country-specific regulatory authorities and currently recommended in the Global Initiative for Asthma (GINA) guidelines. Budesonide remains one of the most well-established and versatile of the inhaled anti-inflammatory drugs. This narrative review provides a clinical reappraisal of the benefit:risk profile of budesonide in the management of asthma and COPD.

Darolutamide: First Approval Abstract Darolutamide (NUBEQA™) is a structurally distinct non-steroidal androgen receptor antagonist being developed by Orion and Bayer as a treatment for prostate cancer. Based on positive results in the phase III ARAMIS trial, darolutamide was recently approved in the USA for the treatment of men with non-metastatic castration-resistant prostate cancer. This article summarizes the milestones in the development of darolutamide leading to this first approval.