**1. Introduction**

The 2022 Global Initiative for Asthma (GINA) report [1] describes asthma as a heterogeneous disease, often characterised by chronic airway inflammation, with a history of respiratory symptoms, including wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, along with variable expiratory airflow limitation.

The long-term goals of asthma management are to achieve symptom control, reduce the risk of exacerbations and mortality, preserve lung function, and minimise drug-related side effects [1]. The stepwise approach used for pharmacological treatment in asthma mandates an iterative cycle of assessment, adjustment of pharmacological and nonpharmacological treatment, and review of the therapeutic response [1].

Over the last 30 years, inhaled corticosteroids (ICS) have been the mainstay of asthma treatment, with the long-acting β2-adrenoceptor agonist (LABA) formoterol/ICS combination serving as the preferred controller and/or reliever therapy, depending on asthma severity [2]. Nevertheless, this therapeutic option has become increasingly unattractive due to its inability to alter the natural course of the disease, including asthma progression [3]. Although ICS are clinically efficacious in most asthmatics, a considerable subset of patients (3–10%) remain uncontrolled despite optimal therapeutic adherence and proper

**Citation:** Calzetta, L.; Aiello, M.; Frizzelli, A.; Pistocchini, E.; Ritondo, B.L.; Rogliani, P.; Chetta, A. Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma. *Biomedicines* **2022**, *10*, 2330. https://doi.org/10.3390/ biomedicines10092330

Academic Editor: Stanislawa Bazan-Socha

Received: 27 July 2022 Accepted: 14 September 2022 Published: 19 September 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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inhaler technique [4]. Even after using the highest dosage of ICS, such individuals do not achieve control over their symptoms, and often need to step up to treatment with oral corticosteroids (OCS) in order to avert future episodes of life-threatening exacerbations [5].

This variability in the therapeutic response is the result of the highly heterogeneous nature of asthma [6] in terms of pathogenesis, disease severity, and outcomes [7]. Asthma is nowadays referred to as an umbrella diagnosis encompassing a plethora of endotypes and clinical phenotypes that vary from mild to severe forms [8].

More recently, the management of asthma has evolved from a blockbuster approach of "one size fits all" to a more personalised one, which treats the patient rather than the disease. In the early 2000s, the introduction of biological therapies directed towards specific inflammatory pathways advanced the improvement of asthma outcomes, initially with the anti-IgE monoclonal antibody (mAb) omalizumab [9], followed 10 years later by the approval of the mAbs anti-interleukin (IL)-5 mepolizumab and reslizumab, and the anti-IL-5Rα benralizumab [10]. The newest treatment options for severe uncontrolled asthma include the mAbs anti-IL-4/IL-13 dupilumab [11] and the anti-thymic stromal lymphopoietin (TSLP) tezepelumab [12]. Such mAbs have noteworthy properties, reducing asthma exacerbations with an OCS sparing effect [10].

In recent years, a lot of effort has been put into the development of a more personalised approach [13]. The ability to target specific inflammatory mediators and cellular pathways via highly selective therapeutic agents has progressively revolutionised the treatment of a complex, heterogeneous disorder such as asthma [14]. Although current medications may improve symptom control, QoL, and the frequency and severity of exacerbations, they do not really induce asthma remission [3].

Therefore, the aim of this review was to systematically assess the investigational agents in Phase I and II under development in the last five years, in order to understand whether there is some emerging drug and/or formulation that might be developed in the future for effective treatment of asthmatic patients.
