Elarekibep (PRS-060/AZD1402), a new class of inhaled Anticalin medicine targeting IL-4Ra for type 2 endotype asthma.

BACKGROUND: Type 2 endotype asthma is driven by IL-4 and IL-13 signaling via IL-4Ra, which is highly expressed on airway epithelium, airway smooth muscle, and immunocytes in the respiratory mucosa, suggesting potential advantages of an inhalable antagonist. Lipocalin 1 (Lcn1), a 16 kDa protein abundant in human periciliary fluid, has a robust drug-like structure well suited to protein engineering, but it has never been used to make an inhaled Anticalin protein therapeutic. OBJECTIVES: We sought to reengineer Lcn1 into an inhalable IL-4Ra antagonist and assess its pharmacodynamic/kinetic profile. METHODS: Lcn1 was systematically modified by directed protein mutagenesis yielding a high-affinity, slowly dissociating, long-acting full antagonist of IL-4Ra designated PRS-060 with properties analogous to dupilumab, competitively antagonizing IL-4Ra-dependent cell proliferation, mucus induction, and eotaxin expression in vitro. Because PRS-060 displayed exquisite specificity for human IL-4Ra, with no cross-reactivity to rodents or higher primates, we created a new triple-humanized mouse model substituting human IL-4Ra, IL-4, and IL-13 at their correct syntenic murine loci to model clinical dosing. RESULTS: Inhaled PRS-060 strongly suppressed acute allergic inflammation indexes in triple-humanized mice with a duration of action longer than its bulk clearance, suggesting that it may act locally in the lung. CONCLUSION: Lcn1 can be reengineered into the Anticalin antagonist PRS-060 (elarekibep), exemplifying a new class of inhaled topical, long-acting therapeutic drugs with the potential to treat type 2 endotype asthma.

The role of animal models in the pharmacological evaluation of emerging anti-inflammatory agents for the treatment of COPD.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that has been relatively under researched compared to other inflammatory diseases. Indeed, thus far there have been no anti-inflammatory therapies specifically approved for COPD and the available anti-inflammatory therapies were originally developed for asthma. The challenges facing research in COPD are multi-faceted; the mechanisms underlying the complex and heterogeneous pathology of this disease require unravelling; the role of inflammation in disease progression needs to be confirmed and new drugs with potential to successfully treat COPD need to be identified. Many of the compounds in the clinic today have been identified through the work performed in a range of animal models of COPD. These models have provided us with an understanding of disease pathology and potential mechanistic pathways and have given us the means to prioritise new chemical entities before entry into the clinic. This review will summarise currently available models of COPD and highlight how they have been used to take a first generation of anti-inflammatory therapies for COPD into clinical development. The predictive nature of these animal models will become clear as these therapies are clinically evaluated. The recurring challenge will be to take emerging pre-clinical and clinical data and use it to continually improve animal models so that they remain a valuable tool in the drug discovery process.

p38alpha-selective mitogen-activated protein kinase inhibitor SD-282 reduces inflammation in a subchronic model of tobacco smoke-induced airway inflammation.

Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation, which is relatively insensitive to inhaled corticosteroids. The extent of the pulmonary inflammation in COPD correlates with disease severity, and it is thought to play a significant role in disease progression. We have evaluated a selective p38alpha-selective mitogen-activated protein kinase (MAPK) inhibitor, indole-5-carboxamide (ATP-competitive inhibitor of p38 kinase) (SD-282), in an 11-day model of tobacco smoke (TS)-induced pulmonary inflammation in A/J mice, by using dexamethasone as a reference steroid. Two oral treatment paradigms were evaluated in this TS model: prophylactic with daily pretreatment before each daily exposure, and therapeutic with daily treatment for 6 days commencing after 5 days of smoke exposure. Bronchoalveolar lavage and histological evaluation of lung sections taken after exposure to TS revealed an inflammatory response composed of increased numbers of macrophages and neutrophils and enhanced mucin staining. Phospho-p38 staining in macrophages and type II epithelial cells after TS exposure was also observed. Given prophylactically or therapeutically, dexamethasone failed to inhibit any of the TS-induced inflammatory changes. By contrast, SD-282 inhibited TS-induced increases in macrophages and neutrophils. Furthermore, SD 282 reduced TS-induced increases in cyclooxygenase-2 and interleukin-6 levels, and phospho-p38 expression in the lungs. In conclusion, SD-282 markedly reduced TS-induced inflammatory responses when given prophylactically or therapeutically whereas dexamethasone was ineffective. This is the first evidence that a p38alpha-selective MAPK inhibitor can exert pulmonary anti-inflammatory activity in a TS exposure model when given in a therapeutic mode, establishing the potential of p38 MAPK inhibitors as a therapy for COPD.

Emerging trends in the therapy of COPD: bronchodilators as mono- and combination therapies.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that is characterized by progressive airway obstruction that, unlike asthma, is relatively insensitive to bronchodilators and to the classic anti-inflammatory therapy, corticosteroids. In this review we consider the potential of bronchodilator drugs and corticosteroid drugs that are in clinical development for COPD and discuss how the best treatments might be achieved with combinations of drugs that are either already launched or close to launch.

Emerging trends in the therapy of COPD: novel anti-inflammatory agents in clinical development.

During the past ten years, the pharmaceutical industry has focussed on treating chronic obstructive pulmonary disease (COPD) as distinct to asthma, and no novel anti-inflammatory agents have been launched as therapies for this disease. As our understanding of the pathology of COPD has increased it has been established that the progressive pulmonary inflammation that is associated with COPD relates to disease severity. Thus, it is anticipated that drugs that reduce pulmonary inflammation will provide effective, disease-modifying therapies. Here, we consider the potential of anti-inflammatory drugs that are currently in clinical development for COPD and discuss how these might reduce pulmonary inflammation in this disease.

Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY†85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases.

Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.

Etiologics ltd.

Etiologics is an innovative drug discovery company that, unlike most new companies in this sector, has a balanced portfolio of ethylnitrosourea (ENU) technology, animal models of disease, in vitro cell function models, and expertise in drug discovery, which spans the whole drug discovery process. The aim of the company is to identify and develop novel effective therapies for respiratory and metabolic diseases where there is a high unmet medical need. Etiologics also offers partners access to its ENU technology and/or preclinical respiratory models/expertise to enable them to identify/validate new targets and enhance the value of in-house programs.