Lung function, pharmacokinetics, and tolerability of inhaled indacaterol maleate and acetate in asthma patients.

BACKGROUND: Indacaterol maleate delivered with the Breezhaler® inhalation device is a long-acting ß2-agonist approved for chronic obstructive pulmonary disease. In the development of a once daily, inhaled fixed dose combination (FDC) of indacaterol, glycopyrronium bromide (a long-acting muscarinic antagonist), and mometasone furoate (an inhaled corticosteroid [ICS]) for the treatment of patients with asthma, the acetate salt of indacaterol is used instead of the maleate salt. Here, we investigated the lung function, pharmacokinetics (PK) and safety of indacaterol maleate 150 µg once daily (o.d.) and indacaterol acetate 150 µg o.d. in comparison with placebo. METHODS: This was a randomised, double-blind, three-period crossover study (ClinicalTrials.gov identifier, NCT03257995) in patients with asthma on background ICS therapy. Patients with percent predicted pre-bronchodilator forced expiratory volume per second (FEV1) ≥50% and ≤ 90% were included in the study. Patients received indacaterol maleate 150 µg o.d., indacaterol acetate 150 µg o.d., or placebo on top of stable background ICS in randomised sequence. Trough FEV1 was assessed after 14 days of treatment. PK of indacaterol salts were assessed at steady state after 14 days of treatment; peak expiratory flow (PEF) rate and rescue medication use were collected with a combined PEF-meter/electronic diary throughout the study. RESULTS: Of the 54 adult patients (median age of 48 years), 51 patients completed the study. Both indacaterol salts demonstrated statistically significant improvements in trough FEV1 of 186 mL (maleate) and 146 mL (acetate) compared with placebo (both P < 0.001). FEV1 AUC0-4h improved by 248 mL (maleate) and 245 mL (acetate), and PEF by 33 L/min (maleate) and 30.8 L/min (acetate) versus placebo. Systemic exposure of indacaterol (AUC0-24h,ss and Cmax,ss on Day 14) was comparable after administration of both salt forms. Both salt forms demonstrated a good safety profile and were well tolerated, with a difference in the reporting frequency of AEs of coughing (maleate, 23.5%; acetate, 0%). CONCLUSIONS: In patients with asthma, indacaterol maleate and acetate elicited comparable and significant improvements in lung function compared with placebo and achieved comparable systemic exposure. Both indacaterol salts were safe and well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov NCT03257995 June 06, 2017.

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate following once-daily inhalation as a combination in healthy subjects.

Indacaterol (IND), is co-formulated with glycopyrronium (GLY), and mometasone furoate (MF) as a once-daily (o.d.) inhaled fixed-dose combination (IND/GLY/MF) delivered via the Breezhaler® device for maintenance treatment of asthma. We evaluated the steady state plasma pharmacokinetics (PK) of IND, GLY and MF following inhalation of IND/GLY/MF or as monotherapies. This was a randomized, open-label, four-way crossover study. Subjects received IND/GLY/MF 150/50/160 µg (high-dose), IND 150 µg, GLY 50 µg or MF 190 µg (in vitro fine particle mass comparable to 160 µg MF in IND/GLY/MF) via the Breezhaler® device, o.d. for 14 days in each period, with a washout of at least 7 days. PK was characterized on Day 14, up to 24 h post-dose. In total, 36 healthy subjects were randomized. For IND, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.922 (0.878, 0.969) and 1.02 (0.967, 1.08), respectively for the IND/GLY/MF versus IND monotherapy comparison. For GLY, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 0.986 (0.944, 1.03) and 1.21 (1.09, 1.34), respectively for the IND/GLY/MF versus GLY comparison. For MF, the geometric mean ratios (90% CI) for AUC0-24h,ss and Cmax,ss were 1.16 (1.09, 1.24) and 1.17 (1.09, 1.25), respectively for IND/GLY/MF versus MF comparison. Similar systemic exposure was noted for IND/GLY/MF versus monotherapy for all three mono-components, indicating a lack of PK interaction. Multiple inhaled doses of IND, GLY and MF were safe and well tolerated, when administered alone or in combination. There was no clinically relevant pharmacokinetic interaction between IND, GLY and MF when administered as IND/GLY/MF.

Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor.

Background CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110ß, p110δ and p110γ isoforms with an IC50 of 89 ± 29 nM, 56 ± 35 nM, 39 ± 10 nM and 230 ± 31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (n = 11), 3 (27.3%) patients had DLTs and all patients (100%) experienced ≥ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicities-51.6% patients experienced ≥ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms.

Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia.

PURPOSE: This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53-MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers. PATIENTS AND METHODS: Initial dosing regimens were: 1A (day 1; 21-day cycle; dose 12.5-350 mg) and 2A (days 1-14; 28-day cycle; dose 1-20 mg). Alternative regimens included 1B (days 1 and 8; 28-day cycle) and 2C (days 1-7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLT) during cycle 1. RESULTS: Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% [95% confidence interval (CI), 2.2-27.4] in solid tumors and 4.2% (95% CI, 0.1-21.1), 20% (95% CI, 4.3-48.1), and 22.2% (95% CI, 8.6-42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively. CONCLUSIONS: A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies.