Understanding host pathogenesis in leprosy patients with ENL informed the development of a host directed therapy that reduces disease and improves control of the infection in leprosy and tuberculosis
Gilla Kaplan1, Joseph Camardo, Danielle J. Smith2 and Mark Sullivan2
Affiliations: 1Dept. Medicine, University of Cape Town, South Africa; 2Medicines development for Global Health, Southbank, VIC Australia.
The observation that thalidomide treatment of lepromatous leprosy patients with Erythema Nodosum Leprosum (ENL) efficiently eliminates the clinical manifestations of the reactional state, by reducing systemic tumor necrosis factor alpha (TNF-) levels, informed a drug discovery and development program. By screening a library of thalidomide congeners, we identified a non-teratogenic non-embriotoxic small molecule that reduced monocyte/macrophage TNF- production via phosphodiesterase 4 inhibition (PDE4i). Treatment with the molecule (CC-11050) for 28 days reduced the symptoms of ENL in 10/10 patients tested, as evaluated by a composite semi quantitative disease score that included multiple manifestations of ENL. No sever adverse events (SAE) were noted and the drug was well tolerated by all patients. Studies in rabbits with experimental pulmonary tuberculosis (TB) demonstrated a CC-11050 mediated acceleration in INH killing of M. tuberculosis in association with reduced lung fibrosis and accelerated granuloma resorption. When CC-11050 was tested for anti-inflammatory activity, as an adjunct to antibiotic treatment in TB patients with advanced disease, significant (p=0.05) lung function improvement, measured by increased forced exhaled volume of air (FEV-1) was observed. Bacillary clearance from sputum was accelerated (p=0.15) and no SAE were observed in any of the treated patients. Lung function improvement continued beyond the duration of CC-11050 adjunctive treatment reaching clinically significant levels by the end of TB therapy. Going forward, we plan to continue the development of CC-11050 to meet stringent regulatory authority requirements, including generation of additional non-clinical safety data, formulation development and manufacture scale up. The absorption, distribution, metabolism and excretion (ADME) of CC-11050 have been well characterized and will be used to establish a population pharmacokinetic model to inform pharmacokinetic/pharmacodynamics response parameters. Confirmation of clinical response will be assessed in further clinical studies in ENL and tuberculosis (Word count 286).