Elsevier

Advanced Drug Delivery Reviews

Volume 54, Issue 11, 5 December 2002, Pages 1463-1474
Advanced Drug Delivery Reviews

Inhaled P2Y2 receptor agonists as a treatment for patients with Cystic Fibrosis lung disease

https://doi.org/10.1016/S0169-409X(02)00154-0Get rights and content

Abstract

P2Y2 receptor agonists are a new class of compounds that are being evaluated as a treatment for the pulmonary manifestations of Cystic Fibrosis (CF). Results of preclinical research suggest that these compounds inhibit sodium absorption, restore chloride conductance and rehydrate the CF airway surface. In addition, P2Y2 receptor agonists have been shown to enhance ciliary beat frequency and increase mucociliary clearance in animals and subjects with impaired mucociliary clearance. The normalization of airway surface liquid and enhancement of lung clearance is expected to provide a clinical benefit to CF patients. A number of P2Y2 agonist compounds have been evaluated in healthy subjects and patients with CF. Most recently, INS37217, a metabolically stable and potent P2Y2 agonist has been developed and studies have shown it to be well-tolerated when given via inhalation. This compound is currently being evaluated in children and adults with CF lung disease.

Introduction

Cystic fibrosis (CF) is the most common genetic disease that results in premature death, affecting approximately 30 000 individuals in the USA and 75 000 worldwide [1]. Much of the morbidity from CF occurs from respiratory complications, such as mucus plugging, frequent bacterial infections and declining lung function over time [2]. In CF patients, the most common cause of death is respiratory failure secondary to infections from Pseudomonas aeruginosa [3]. The mean life expectancy for individuals with CF is currently about 32 years [4].

The pulmonary manifestations of CF are related to the defect in the gene that codes for the cystic fibrosis transmembrane regulator (CFTR) protein [1], [5], [6]. This defect results in abnormalities in sodium, chloride and water transport across the respiratory epithelial cells and thickened airway mucus, impaired mucociliary clearance and, ultimately, susceptibility to bacterial colonization and infection [7], [8].

Current therapies for CF lung disease focus either on attempts to change the consistency of mucus or treat the bacterial infection, including selective agents against P. aeruginosa. Inhaled recombinant DNAse (dornase alfa, Pulmozyme®) has been demonstrated to be beneficial presumably by reducing viscosity of respiratory secretions. In clinical trials, DNAse was shown to reduce the frequency of pulmonary exacerbations and improve lung function [9]. Inhaled tobramycin (TOBI®) has been shown to slow the decline in lung function in patients with CF [10] and reduce the P. aeruginosa content in sputum [10]. Although both products are beneficial, neither is targeted at the basic ionic transport defect, which is the underlying cause of the pulmonary manifestations of basic CF.

Since the pulmonary manifestation of CF are related to the impairment of salt and fluid transport in respiratory epithelia, a product aimed at correcting this defect could have significant clinical benefit for CF patients. A key discovery in the early 1990s demonstrated that triphosphate nucleotides such as adenosine-5′-triphosphate (ATP) and uridine-5′-triphosphate (UTP) activate chloride secretion in normal and CF airway epithelia. The Cl secretory response was initiated via a vise in intracellular Ca2+ activated Cl channel (CaCC) [11], [12], [13]. This stimulated chloride transport, coupled with an inhibitor of Na+ transport [14], was associated with increased liquid transport across the apical surface [12]. This physiologic response is known to be mediated via specific ‘purinergic receptors’, known as the P2Y2 receptors [11], [12], [13]. Therapies designed to normalize airway surface liquid composition and volume are highly desired [15]. Since P2Y2 receptor agonists have the potential for correcting the fundamental pulmonary defect of CF patients, there is considerable interest in their development. This review focuses on the development, to date, of P2Y2 agonists, including results of clinical studies with the most promising compounds.

Section snippets

Pharmacology of P2Y2 receptor agonists

The role of purinergic receptors and their pharmacology was originally proposed by Burnstock to describe responses previously defined as nonadrenergic and noncholineric [16]. Adenosine-5′-triphosphate (ATP) was proposed as the natural ligand of these receptors. Upon further study, it was proposed that purinergic receptors should be subdivided into P1 receptors, responding to nucleosides and P2 receptors responding to purine and pyrimidine nucleotides (Fig. 1). The P2 class has been subsequently

Clinical studies with P2Y2 agonists

The promising results in preclinical models led to a number of clinical pharmacology studies evaluating effects of inhaled P2Y2 receptor agonists on sputum expectoration and mucociliary clearance in smokers and patients with a variety of airway disorders including CF and primary ciliary dyskinesia (PCD). Initial studies were performed using the endogenous ligand compound, UTP. Administration of UTP in doses varying from 20 mg to 180 mg in the nebulizer cup resulted in significant increases in

Clinical studies of INS365 in lung disease

The initial evaluation of INS365 in humans was a rising dose evaluation in 75 healthy non-smokers and cigarette smokers [27]. Single nebulized doses were administered and volunteers were monitored for tolerability. INS365 doses of up to 400 mg in the nebulizer cup were generally well-tolerated in non-smokers. The cigarette smokers were only able to tolerate doses up to 100 mg, suggesting that tolerability may be lower in individuals with damaged airways. There were no serious adverse events

Initial clinical studies of INS37217

The initial phase 1 evaluation of INS37217 solution by nebulization has been completed in healthy non-smokers and smokers [30]. This study provided evidence of tolerability and set the stage for the current study in CF patients, which is ongoing.

The objectives of this Phase 1 study were to:

  • 1.

    Evaluate the safety and tolerability of escalating single doses of inhaled INS37217 in healthy adult male non-smokers and smokers.

  • 2.

    Determine a safe and tolerable dose (or doses) of inhaled INS37217 for use in

Discussion

P2Y2 agonists are a new and exciting class of compounds for the treatment of CF lung disease. With the availability of INS37217, which is more metabolically stable than the natural ligand UTP, a compound is now available which should allow testing of the potential utility of P2Y2 agonists as a chronic treatment for CF. The phase 1/2 study in children and adults with CF described previously will be completed by summer, 2002. A phase 2 program is being planned in collaboration with the

Conclusions

In conclusion, P2Y2 receptor agonists are a new class of compounds that are being developed for the treatment of CF lung disease. Early research to date shows promise that these products can inhibit Na+ absorption, restore chloride ion conductance, rehydrate the airway surface, and produce dose-related increases in mucociliary clearance. While high doses can greatly enhance sputum expectoration in patients with lung disease, lower doses that normalize airway surface liquid and enhance

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