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Evaluation of Apremilast as a Novel Therapeutic Agent in Cystic Fibrosis
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A3883 - Evaluation of Apremilast as a Novel Therapeutic Agent in Cystic Fibrosis
Author Block: T. Bono1, L. W. Rasmussen2, K. Patel2, M. Mazur2, L. Tang2, G. Bolger2, S. M. Rowe2, S. Raju2; 1UABSOM, Birmingham, AL, United States, 2UAB, Birmingham, AL, United States.
INTRODUCTION: Cystic fibrosis (CF) lung disease is caused by genetic mutations in the CFTR protein. Defective CFTR function results in pathogenic mucus accumulation in the lungs due to insufficient epithelial anion transport. CFTR-mediated ion transport is tightly regulated by cAMP-dependent signaling pathways suggesting drugs that increase cellular cAMP levels may offer clinical benefits in CF, particularly patients with residual CFTR function or using pharmacologic CFTR modulators. Apremilast is an inhibitor of phosphodiesterase 4 (PDE4) enzymes that degrade cAMP and it is used for the treatment of psoriasis and psoriatic arthritis due its anti-inflammatory properties. Here, we test whether apremilast can activate CFTR in epithelia derived from CF patients, including those on currently approved CFTR modulators.
METHODS: Primary human bronchial epithelial (HBE) cells isolated from CF patients homozygous for F508del CFTR and wild type 16HBE cells were cultured at air-liquid interface until terminal differentiation. CFTR activity was measured by short-circuit current (Isc) in modified Ussing chambers.
RESULTS: In 16HBE cells, apremilast enhanced cAMP levels by 4-fold compared to Vehicle (Veh) and robustly increased CFTR activity (Isc in µA/cm2, ΔVeh: 0.15, ΔApr: 22.6, P≤0.0001). In CF cells, apremilast moderately increased CFTR function, confirming the uncorrected genetic defect (Isc in µA/cm2, ΔVeh: 0.23, ΔApr: 2.1, P≤0.001). Currently, many CF patients homozygous for F508del CFTR use the drug combination lumacaftor/ivacaftor, which includes VX-809, a corrector that increases F508del CFTR surface protein levels and VX-770, a potentiator that activates channels present on the cell surface. When apremilast was tested in CF cells pre-treated with VX-809 and VX-770, CFTR function was dramatically increased (ΔApr mediated Isc, in µA/cm2, Veh-treated: 1.6, VX-809-treated: 7.9, P≤0.01). Interestingly, in CF cells pretreated with VX-809 alone, apremilast effects on CFTR function were observed even when it was tested immediately following maximal acute activation of CFTR by VX-770 (ΔApr mediated Isc, in µA/cm2, No prior activation with VX770: 7.9 prior activation with VX770: 7.4). These data suggest that despite presence of VX-770, apremilast may offer additional CFTR activation.
CONCLUSIONS: Apremilast is a potent activator of CFTR function in HBE cells expressing either normal CFTR or the F508del mutation by increasing cAMP. The increased function of F508del-CFTR function was observed both in the absence and the presence of VX809 and VX770. Thus, apremilast may offer moderate benefits in CF patients with Fdel508 mutations when used individually and in those on lumacaftor/ivacaftor therapy it can significantly augment CFTR activity and offer additional clinical benefits.
Author Block: T. Bono1, L. W. Rasmussen2, K. Patel2, M. Mazur2, L. Tang2, G. Bolger2, S. M. Rowe2, S. Raju2; 1UABSOM, Birmingham, AL, United States, 2UAB, Birmingham, AL, United States.
INTRODUCTION: Cystic fibrosis (CF) lung disease is caused by genetic mutations in the CFTR protein. Defective CFTR function results in pathogenic mucus accumulation in the lungs due to insufficient epithelial anion transport. CFTR-mediated ion transport is tightly regulated by cAMP-dependent signaling pathways suggesting drugs that increase cellular cAMP levels may offer clinical benefits in CF, particularly patients with residual CFTR function or using pharmacologic CFTR modulators. Apremilast is an inhibitor of phosphodiesterase 4 (PDE4) enzymes that degrade cAMP and it is used for the treatment of psoriasis and psoriatic arthritis due its anti-inflammatory properties. Here, we test whether apremilast can activate CFTR in epithelia derived from CF patients, including those on currently approved CFTR modulators.
METHODS: Primary human bronchial epithelial (HBE) cells isolated from CF patients homozygous for F508del CFTR and wild type 16HBE cells were cultured at air-liquid interface until terminal differentiation. CFTR activity was measured by short-circuit current (Isc) in modified Ussing chambers.
RESULTS: In 16HBE cells, apremilast enhanced cAMP levels by 4-fold compared to Vehicle (Veh) and robustly increased CFTR activity (Isc in µA/cm2, ΔVeh: 0.15, ΔApr: 22.6, P≤0.0001). In CF cells, apremilast moderately increased CFTR function, confirming the uncorrected genetic defect (Isc in µA/cm2, ΔVeh: 0.23, ΔApr: 2.1, P≤0.001). Currently, many CF patients homozygous for F508del CFTR use the drug combination lumacaftor/ivacaftor, which includes VX-809, a corrector that increases F508del CFTR surface protein levels and VX-770, a potentiator that activates channels present on the cell surface. When apremilast was tested in CF cells pre-treated with VX-809 and VX-770, CFTR function was dramatically increased (ΔApr mediated Isc, in µA/cm2, Veh-treated: 1.6, VX-809-treated: 7.9, P≤0.01). Interestingly, in CF cells pretreated with VX-809 alone, apremilast effects on CFTR function were observed even when it was tested immediately following maximal acute activation of CFTR by VX-770 (ΔApr mediated Isc, in µA/cm2, No prior activation with VX770: 7.9 prior activation with VX770: 7.4). These data suggest that despite presence of VX-770, apremilast may offer additional CFTR activation.
CONCLUSIONS: Apremilast is a potent activator of CFTR function in HBE cells expressing either normal CFTR or the F508del mutation by increasing cAMP. The increased function of F508del-CFTR function was observed both in the absence and the presence of VX809 and VX770. Thus, apremilast may offer moderate benefits in CF patients with Fdel508 mutations when used individually and in those on lumacaftor/ivacaftor therapy it can significantly augment CFTR activity and offer additional clinical benefits.
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