Safety, tolerability, and pharmacokinetics of single and repeat ascending doses of CHF6001, a novel inhaled phosphodiesterase-4 inhibitor: two randomized trials in healthy volunteers

Abstract

PurposeThe purpose of this study was to evaluate safety, tolerability, and pharmacokinetics (PK) of CHF6001, an inhaled phosphodiesterase-4 inhibitor.Materials and methodsTwo healthy volunteer, randomized, double-blind, placebo-controlled studies were conducted. In each, Part 1 evaluated single ascending doses, with PK sampling up to 48 hours post-dose; Part 2 evaluated multiple ascending doses (Study 1, 7 days; Study 2, 14 days), with PK sampling up to 24 hours post-dose on first and last day of each period. In Study 1, treatments were administered via single-dose dry-powder inhaler (SDDPI; Aerolizer): Part 1, 20, 100, 200, 400, 800, 1,600, and 2,000 µg or placebo; Part 2, 100, 300, 600, 1,200, and 1,600 µg or placebo once daily (OD). In Study 2, treatments were administered via multi-dose dry-powder inhaler (MDDPI; NEXThaler): Part 1, 2,400, 4,000, and 4,800 µg or placebo; Part 2, 1,200, 2,000, or 2,400 µg twice daily (BID) or placebo. Modeling and simulation then compared OD and BID dosing via MDDPI.ResultsThere was a clear correlation between CHF6001 dose and plasma concentration, following single and multiple doses and using SDDPI and MDDPI. CHF6001 plasma concentration area under the curve (AUC) was dose proportional, with steady state slopes of the fitted line of 0.95 (90% CI: 0.86, 1.04) for AUC0–24 h in Study 1, and 0.85 (90% CI: 0.38, 1.32) for AUC0–12 h in Study 2. Bioavailability waŝ30% higher with MDDPI than SDDPI. The PK simulation confirmed dose proportionality; the same total daily dose OD or BID via MDDPI resulted in similar 24 hours exposure, with BID dosing providing smaller fluctuation and lower maximum concentration. CHF6001 was well tolerated with no relationship between dose and adverse events.ConclusionCHF6001 demonstrated a good safety profile. There was a clear dose proportionality for systemic exposure, with higher bioavailability via MDDPI, suggesting that the MDDPI provides better pulmonary drug deposition. BID dosing was associated with a better exposure profile.

COPD patients with chronic bronchitis and higher sputum eosinophil counts show increased type‐2 and PDE4 gene expression in sputum

“…6 In preclinical studies and RCTs, tanimilast showed a potent topical anti-inflammatory effect which was devoid of class-related systemic adverse effects. [5][6][7][8][9][10] In recent post hoc analyses, it was shown that tanimilast significantly reduced the exacerbation rate in the subgroup of COPD patients with chronic bronchitis and eosinophil count ≥ 150cells/µl after 24 weeks of treatment. 10 In a biomarker RCT conducted in COPD patients with chronic bronchitis receiving triple therapy (ICS/ long-acting β 2 agonist therapy (LABA) / long-acting muscarinic antagonist (LAMA)), tanimilast showed clear anti-inflammatory effects by modulating a range of airway biomarkers and inflammation pathways after 32 days of treatment.…”

“…3 CHF6001 (international non-proprietary name (INN): tanimilast) is a novel PDE4 inhibitor currently in clinical development, specifically formulated as an extrafine formulation to be delivered by inhalation. 5 PDE4s are a family of cAMP-specific enzymes encoded by four genes (PDE4A, PDE4B, PDE4C and PDE4D) that are abundantly expressed in leucocytes. Tanimilast can inhibit all A-D isoforms with equal potency exerting a broad spectrum of anti-inflammatory effects in almost all cells of the immune system.…”

CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in Mice

“…CHF6001 is a PDE4 inhibitor optimized for inhaled delivery with the goal of achieving maximal efficacy in airways while reducing systemic exposure and side effects (Moretto et al, 2015; Villetti et al, 2015). When administered by dry powder inhalation, CHF6001 is well tolerated up to 4,800 µg in humans (Mariotti et al, 2018) and is currently in phase IIb clinical trials for the treatment of COPD (clinicaltrials.gov).…”

Inhaled Phosphodiesterase 4 (PDE4) Inhibitors for Inflammatory Respiratory Diseases

“…CHF 6001 is a highly potent PDE4 inhibitor (IC 50 = 0.026 nM) that showed preclinical efficacy in a variety of species (Moretto et al, 2015;Villetti et al, 2015). It is well tolerated in humans (Mariotti et al, 2018). In a double blind, placebo controlled, three-way crossover study, 36 atopic asthmatics received CHF 6001 doses of 400 or 1200 µg inhaled once daily for 9 days.…”