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Clinical Trial Design for Orphan Indications - A Pilot Study of Aerosolized Liposomal Cyclosporine A for Chronic Rejection in Lung Transplant Patients

Iacono AT.

RDD Europe 2013. Volume 1, 2013: 101-110.

Abstract:

Lung transplantation offers a unique clinical opportunity to study immunosuppressive drug delivery by inhalation and the potential to change the evolution of a pivotal clinical syndrome manifesting as post-transplant bronchiolitis obliterans syndrome (BOS). There are no effective treatments and because oral immunosuppression has limited efficacy, we believe that aerosolized liposomal cyclosporine A (AL-CsA) may delay disease progression of BOS. Transplant subjects studied previously, using aerosolized cyclosporine in propylene glycol solution plus standard oral immunosuppressive therapy, have experienced long-term improvement or stabilization of both lung function and histologic rejection criteria. However, use of that formulation was associated with airway irritability manifesting as cough, wheezing and transient dyspnea and lung function declines in about half the subjects making differentiation between progressive BOS, defined as decline in FEV1, versus irritation of the airways due to aerosolized cyclosporine A in propylene glycol (A-CsA-PG) is problematic with FEV1 as the primary end point. Therefore, patients are now being enrolled into a randomized, controlled open-label trial of AL-CsA for BOS with 30 subjects expected over three years. Since September 2012, four lung recipients with BOS (Stage 1 or 2) have been randomly assigned to receive AL-CsA plus standard triple drug immunosuppression or triple drug immunosuppression alone (standard of care, SOC). While no patient or group has yet reached the efficacy end-point, no patients have had or reported adverse effects related to AL-CsA with 100% compliance. We are encouraged by the safety profile and stability in FEV1 after AL-CsA treatment delivered by PARI Pharma’s investigational eFlow® nebulizer system. Thus far, our experience has shown that AL-CsA may prove to be a superior formulation for experimental use in future studies of safety and efficacy and as a recommended treatment for rejection after lung transplantation.