Designing inhaled small molecule drugs for severe respiratory diseases: an overview of the challenges and opportunities

ABSTRACT

Introduction

Inhaled drugs offer advantages for the treatment of respiratory diseases over oral drugs by delivering the drug directly to the lung, thus improving the therapeutic index. There is an unmet medical need for novel therapies for lung diseases, exacerbated by a multitude of challenges for the design of inhaled small molecule drugs.

Areas covered

The authors review the challenges and opportunities for the design of inhaled drugs for respiratory diseases with a focus on new target discovery, medicinal chemistry, and pharmacokinetic, pharmacodynamic, and toxicological evaluation of drug candidates.

Expert opinion

Inhaled drug discovery is facing multiple unique challenges. Novel biological targets are scarce, as is the guidance for medicinal chemistry teams to design compounds with inhalation-compatible features. It is exceedingly difficult to establish a PK/PD relationship given the complexity of pulmonary PK and the impact of physical properties of the drug substance on PK. PK, PD and toxicology studies are technically challenging and require large amounts of drug substance. Despite the current challenges, the authors foresee that the design of inhaled drugs will be facilitated in the future by our increasing understanding of pathobiology, emerging medicinal chemistry guidelines, advances in drug formulation, PBPK models, and in vitro toxicology assays.

KEYWORDS:

• Inhalation
• inhaled drugs
• lung
• respiratory diseases
• drug discovery

Article highlights

• There is a big unmet medical need for respiratory diseases.

• Inhaled drugs are often more efficacious, act faster, and have less side effects than orally taken medications.

• Discovery of novel inhaled drugs is facing a number of challenges, for example, a scarcity of novel targets, complexity of pulmonary PK and dependence of PK and PD on preclinical routes of administration, limited guidance for the design of compounds suitable for inhalation, challenges to establish PK/PD relationships, and the need for large quantities of drug substance for preclinical testing.

• In vivo testing can provide medicinal chemists with guidelines for the design of new compounds, early solid-state characterization is critical to avoid compound attrition in development, and PBPK methods are emerging as powerful tools for dose projection.

• Increased understanding of disease drivers and analysis of real-world data together with better devices for preclinical dosing, PBPK models, engineered particle formulations, and novel ways to assess toxicity risk will fuel future advances in the field.

Declaration of interest

The authors are all employees of Genentech and own Roche stock. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was not funded.