Somatostatin Receptor Agonists and Non-Cancer Respiratory Hypersecretion - A Critical Assessment

Based on a review of the literature regarding the pathophysiology of hypersecretion across various conditions involving respiratory dysfunction, it would appear there are three main underlying causes for excessive sputum production: hypersecretion of mucus glycoprotein and other glandular products from mucus-producing cells, increased transepithelial chloride secretion, mediated via PGE2, PGF2α, TxB2, excessive transudation of plasma proteins into the respiratory tract. These factors may operate independently or in combination. Asthma is characterised by inflammation, increased luminal mucus, with an increased ratio of MUC5B/MUC5AC and MUC2 present in the mucus, epithelial fragility with loss of ciliated cells, goblet cell hyperplasia, submucosal gland hypertrophy, ‘tethering’ of mucus to goblet cells and plasma exudation. COPD and CF have a similar presentation but with a higher MUC5B/MUC5AC ratio and susceptibility to infection. In contrast with the copious sputum production commonly seen in bronchioalveolar carcinoma, bronchorrhoea is not a common feature of CF, asthma, COPD or other conditions with bronchiectasis, where sputum volumes are lower, and the clinical issue may be related more to the viscosity of mucus than to its quantity. Although dramatic positive effects on the BAC-related bronchorrhoea were seen with octreotide and gefitinib treatment, it is therefore doubtful whether agonist of the SST receptor is of clinical usefulness in these other conditions. The reduction in sputum production in BAC seen with both octreotide and gefitinib is likely a result of modu­lation of the EGF receptor, which is known to be involved in goblet cell metaplasia, even if other mechanisms of action cannot be ruled out.  As such, the mechanism of action is potentially relevant also for other pathologies, although currently available EGF-R inhibitors (gefitinib, erlotinib) and somatostatin are perhaps less well adapted for chronic therapy. In conclusion, bronchorrhoea appears to be a sporadic rather than characterising manifestation of asthma, COPD, cystic fibrosis and non-CF bronchiectasis. As a therapeutic target, therefore, bronchorrhoea is not perceived as a high value proposition in these indications, considering existing treatment options and the clinical and regulatory complexities inherent in demonstrating a favourable risk/benefit ratio in a medically plausible subset of patients.