moli1901 and Cystic-Fibrosis

Although cystic fibrosis (CF) patients display multiorgan dysfunction (e.g. pancreas, gut, and lung) it is lung disease that is the leading cause of premature death in these patients. CF lung disease is characterized by persistent pulmonary infection and mucus plugging of the airways initiated by the failure of solute transport across the airway epithelium. Many drug therapies aim to alleviate the secondary characteristics of CF lung disease; however, new therapies in development are targeted at correcting the ion transport deficiency of CF. The goal is to hydrate airway surfaces by stimulating secretion (through activation of the CF transmembrane conductance regulator and calcium-activated chloride channels), and/or inhibiting absorption (through the epithelial sodium channel) thereby stimulating healthy mucociliary clearance. If mucociliary clearance can be stimulated sufficiently from an early age, then there is the possibility that secondary lung infection may be eradicated from the syndrome of CF disease.

Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Deoxycytosine Nucleotides; Humans; Ion Transport; Lung; Mannitol; Peptides, Cyclic; Saline Solution, Hypertonic; Sodium Channel Blockers; Uridine

Lancovutide activates a chloride channel (TMEM-16A) other than the cystic fibrosis (CF) transmembrane conductance regulator protein and could benefit CF patients.. In this randomized, multi-center, double-blind, placebo-controlled, parallel-group trial 161 patients ≥12 years with a confirmed diagnosis of CF were randomized to either placebo (saline) or active drug in 3 different dosing schemes of 2.5mg inhaled lancovutide (once daily, every other day or twice a week) for eight weeks. The primary endpoint was the change in the forced expiratory volume in 1 second (FEV1) percent predicted. Secondary endpoints included further lung function parameters (FEV1 (absolute), functional vital capacity percent predicted, forced expiratory flow percent predicted, pulse oximetry), quality of life assessment, pulmonary exacerbations, hospitalization due to pulmonary exacerbations, time to first pulmonary exacerbation, duration of anti-inflammatory, mucolytic or antibiotic treatment, and safety.. There was no significant difference in the change in FEV1 percent predicted, quality of life, other lung function parameters, pulmonary exacerbations or requirement of additional treatment between groups. Overall, the inhalation of lancovutide was safe although a higher rate of adverse events, especially related to the respiratory system, occurred as compared to placebo.. Lancovutide did not improve FEV1 percent predicted when compared to placebo (NCT00671736).

Topics: Adult; Aerosols; Cystic Fibrosis; Double-Blind Method; Female; Humans; Male; Peptides, Cyclic; Young Adult

In cystic fibrosis (CF) patients, the absence or dysfunction of the chloride channel CF transmembrane conductance regulator (CFTR) results in reduced chloride ion transport in respiratory epithelial cells. Moli1901 stimulates an alternative chloride channel and may thus compensate for the CFTR deficiency in the airway epithelium of CF patients.. A phase II, placebo-controlled, double-blinded, single-center, multiple (5 consecutive days), rising-dose (daily dose, 0.5, 1.5, or 2.5 mg of Moli1901) study was conducted to investigate the safety and tolerability of multiple doses of aerosolized inhaled Moli1901 in 24 patients with CF and stable lung disease.. Moli1901 was well tolerated in all but one CF patient, in whom a transient significant decrease in FEV(1) developed following inhalation, which resolved spontaneously, and in a second patient in whom transient throat numbness developed during drug inhalation. A significant improvement of FEV(1) was observed in the group receiving treatment with 2.5 mg/d Moli1901 compared to the group receiving placebo (p = 0.01 [Wilcoxon test]). Moli1901 was not detected in the plasma of the highest dose group.. The inhalation of Moli1901 up to a total cumulative dose of 12.5 mg appears to be safe in adult patients with CF. In addition, Moli1901 had a sustained beneficial effect on pulmonary function, which supports further studies of its efficacy in CF patients.

Topics: Administration, Inhalation; Adolescent; Adult; Chloride Channels; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Peptides, Cyclic; Respiratory Mucosa

The peptide drug Moli1901 activates an alternative chloride channel that is present in cystic fibrosis (CF) nasal and airway epithelia. Doing so bypasses the dysfunctional CF transmembrane regulator.. To determine whether intranasal Moli1901 is safe, tolerable, and will induce chloride transport in healthy volunteers and CF subjects.. A single-blind (to the participant), randomized, placebo-controlled, dose-escalation study of intranasal Moli1901 was performed in four healthy non-CF participants and four participants with CF. Drug or placebo was administered by intranasal superfusion, and nasal potential difference responses were continuously monitored during sequential dose escalations at 1-min intervals from 0.01 through 10 micro mol/L.. Neither Moli1901 nor placebo were associated with visible changes such as edema, erythema, drainage, secretions, or ulcer formation. No elevations in lactate dehydrogenase, albumin, or cell counts were observed in nasal lavage fluid after administration. No clinically significant changes in FEV(1) or other toxicity parameters occurred. Changes in the nasal potential difference (NPD) induced by chloride-free, amiloride-containing Ringers solution and by subsequent superfusion with the same solution plus 10 micro mol/L isoproterenol were consistent with both an acute and a sustained change in chloride transport in response to Moli1901. A similar analysis of NPD in the four CF participants demonstrated an acute response that resolved more quickly. A dose-response relationship to Moli1901 was observed in non-CF participants, but a greater range of variability within the CF participants contributed to the lack of a clear dose-response relationship in this group.. Moli1901 stimulates chloride transport in normal and CF nasal epithelia in vivo, but may have a shorter duration of action in CF participants.

Topics: Administration, Intranasal; Adolescent; Adult; Amiloride; Biological Transport; Chloride Channels; Cystic Fibrosis; Dose-Response Relationship, Drug; Female; Humans; Isoproterenol; Male; Membrane Potentials; Nasal Mucosa; Peptides, Cyclic; Single-Blind Method

Moli1901 is a 19 residue polycyclic peptide antibiotic which increases chloride transport and water mobilization in airway epithelium. These properties suggest that it may be a useful treatment for cystic fibrosis (CF). In this study, we used accelerator mass spectrometry (AMS) to quantify Moli1901 following administration of only 0.045 microCi of 14C-Moli1901 per dog. Limits of quantitation of AMS were 0.03 (urine) to 0.3 (feces) ng equiv. Moli1901/g. Administration of 14C-Moli1901 by intratracheal instillation (approximately 100 microg) into the left cranial lobe of the lung of beagle dogs resulted in retention of 64% of the dose in the left cranial lobe for up to 28 days. Whole blood and plasma concentrations of 14C were <5 ng/ml at all times after the dose. Concentrations of 14C in whole blood and plasma declined over the first day after the dose and rose thereafter, with the rise in plasma concentrations lagging behind those in whole blood. During the first 3 days after the dose, plasma accounted for the majority of 14C in whole blood, but after that time, plasma accounted for only 25-30% of the 14C in whole blood. Tissue (left and right caudal lung lobe, liver, kidney, spleen, brain) and bile concentrations were low, always less than 0.25% the concentrations found in the left cranial lung lobe. Approximately 13% of the dose was eliminated in urine and feces in 28 days, with fecal elimination accounting for about 10% of the dose. The data presented here are consistent with that obtained in other species. Moli1901 is slowly absorbed and excreted from the lung, and it does not accumulate in other tissues. Moli1901 is currently in the clinic and has proven to be safe in single dose studies in human volunteers and cystic fibrosis patients by the inhalation route. No information on the disposition of the compound in humans is available. This study in dogs demonstrates the feasibility of obtaining that information using 14C-Moli1901 and AMS.

Topics: Animals; Carbon Radioisotopes; Cystic Fibrosis; Dogs; Intubation, Intratracheal; Lung; Male; Mass Spectrometry; Particle Accelerators; Peptides, Cyclic