Dose-dependent inactivation of airway tryptase with a novel dissociating anti-tryptase antibody (MTPS9579A) in healthy participants: A randomized trial

Abstract

Tryptase is the most abundant secretory granule protein in human lung mast cells and plays an important role in asthma pathogenesis. MTPS9579A is a novel monoclonal antibody that selectively inhibits tryptase activity by dissociating active tetramers into inactive monomers. The safety, tolerability, pharmacokinetics (PKs), and systemic and airway pharmacodynamics (PDs) of MTPS9579A were assessed in healthy participants. In this phase I single-center, randomized, observer-blinded, and placebo-controlled study, single and multiple ascending doses of MTPS9579A were administered subcutaneously (s.c.) or intravenously (i.v.) in healthy participants. In addition to monitoring safety and tolerability, the concentrations of MTPS9579A, total tryptase, and active tryptase were quantified. This study included 106 healthy participants (82 on active treatment). Overall, MTPS9579A was well-tolerated with no serious or severe adverse events. Serum MTPS9579A showed a dose-proportional increase in maximum serum concentration (C_max ) values at high doses, and a nonlinear increase in area under the curve (AUC) values at low concentrations consistent with target-mediated clearance were observed. Rapid and dose-dependent reduction in nasosorption active tryptase was observed postdose, confirming activity and the PK/PD relationship of MTPS9579A in the airway. A novel biomarker assay was used to demonstrate for the first time that an investigative antibody therapeutic (MTPS9579A) can inhibit tryptase activity in the upper airway. A favorable safety and tolerability profile supports further assessment of MTPS9579A in asthma. Understanding the exposure-response relationships using the novel PD biomarker will help inform clinical development, such as dose selection or defining patient subgroups.

FIGURE 1

Observed serum concentrations after single or multiple doses of MTPS9579A. Mean (+SD) serum MTPS9579A concentrations were analyzed over time. (a) A single ascending dose was administered on day 1 and pharmacokinetic concentrations were analyzed for 84 days post‐dose. (b) Multiple ascending doses were administered on days 1, 29, and 57, and serum MTPS9579A concentrations were analyzed through day 141. Samples below LLOQ (250 ng/ml) were not included. LLOQ, lower limit of quantification

FIGURE 2

Dose‐dependent increases in serum total tryptase after single or multiple doses of MTPS9579A. Participants received a single dose on day 1 (a) or multiple doses on days 1, 29, and 57 (b). On dosing days, serum was collected pre‐dose

FIGURE 3

Increase in nasosorption total tryptase after single or multiple doses of MTPS9579A demonstrates target engagement in the airway. Participants received a single dose on day 1 (a) or multiple doses on days 1, 29, and 57 (b). On dosing days, nasosorption was collected predose. Data is missing for some timepoints because of insufficient sample volumes available

FIGURE 4

Dose‐dependent reduction of nasosorption active tryptase after single or multiple doses of MTPS9579A demonstrates activity of MTPS9579A in the airway. Active tryptase levels were evaluated throughout study duration (a, b). Participants received a single dose on day 1 (a) or multiple doses on days 1, 29, and 57 (b). On dosing days, nasosorption was collected predose. Samples below LLOQ were imputed as LLOQ/2. BL, baseline; LLOQ, lower limit of quantification. Dashed line indicates LLOQ

FIGURE 5

High MTPS9579A exposures correspond with no detectable nasosorption active tryptase. The relationship between serum MTPS9579A concentrations and nasosorption active tryptase at (a) 28 days post‐single dose (SAD) or (b) 28 days post‐third dose (MAD) were analyzed. Samples below LLOQ for active tryptase were imputed as LLOQ/2. SAD, single‐ascending dose; LLOQ, lower limit of quantification; MAD, multiple‐ascending dose; PK, pharmacokinetics