RVT-1601

In 1960s, cromolyn sodium (CS) has been introduced as the first non-steroidal anti-inflammatory drug for the treatment of allergic and mast-cell driven diseases. Its applicability has been limited due to a poor bioavailability. Here we present pharmacokinetic data of a novel high concentration formulation of CS (PA101) delivered via a high-efficiency nebulizer (eFlow®) in healthy volunteers (HVs), allergic asthmatics and patients with indolent systemic mastocytosis (ISM). In HVs, PA101 40 mg and 80 mg (30 L) and PA101 40 mg (40 L), Intal^TM (via LC® Plus) 20 mg and Nalcrom® (oral suspension) 200 mg showed maximum measured plasma concentration (C_max) of 156, 236, 88.6, 17.8 and 5.23 ng/mL, respectively, with respective areas under the plasma time-concentration curve (AUC) of 338, 526, 212, 40.6 and 33.3 h·ng/mL. Systemic exposure (AUC) to CS with PA101 40 mg was approximately 8-fold and 11-fold higher compared to Intal^TM and Nalcrom® in HVs, respectively. PA101 via eFlow® yielded comparable PK profiles in HVs and patients. Systemic bioavailability of PA101 was approximately 25% compared to approximately 1% for Nalcrom® and approximately 10% for Intal^TM, respectively. These data warrant further research on the therapeutic potential of PA101 (via eFlow®) in allergic and mast-cell driven diseases.

Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied.

This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants.

Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48-0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78-2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported.

This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation.

Patara Pharma.