A recent Phase 2a clinical trial evaluating the efficacy of MTPS9579A, an anti-tryptase antibody, in reducing asthma exacerbations did not meet its primary endpoint. The study, published in Allergy, found no significant difference in the time to first composite exacerbation event between patients treated with MTPS9579A and those receiving a placebo. This outcome challenges the immediate potential of this specific tryptase inhibitor in managing uncontrolled asthma.
The Phase 2a study, conducted from October 2019 to May 2022, involved 134 patients with moderate-to-severe asthma, with a mean age of 54 years (55% female). Participants were randomized 1:1 to receive either 1800 mg of MTPS9579A or a placebo every four weeks for 48 weeks. The primary endpoint was the time to the initial composite exacerbation event. The results indicated a hazard ratio of 0.90 (95% CI, 0.55-1.47; P = 0.6835), demonstrating no statistically significant difference between the two groups.
A parallel Phase 1c trial assessed the pharmacokinetics of MTPS9579A and tryptase levels in the upper and lower airways. This trial enrolled patients aged 18 to 65 years with moderate-to-severe asthma on daily inhaled corticosteroids and a second controller medication. Results from the Phase 1c trial (n=27 patients) showed that MTPS9579A concentrations at the 1800-mg dose on day 22 were 6.8-fold lower in bronchial lining fluid (BLF) compared to nasal lining fluid (NLF). Baseline measurements revealed significantly elevated levels of active (119-fold) and total (30-fold) tryptase in BLF versus NLF (P < .05).
Researchers suggest that the lack of efficacy may be attributed to insufficient drug concentrations in the lower airway to effectively inhibit the high levels of tryptase present during asthma exacerbations. "The lack of impact on active or total tryptase levels in the lower airway, even with 1800 mg IV likely indicates that drug concentrations were not sufficient to completely saturate the high tryptase levels," the investigators noted.
Tryptase as a Therapeutic Target
Despite the negative outcome of this trial, the study investigators maintain that tryptase remains an important therapeutic target for asthma. Tryptase, a mast cell protease released during asthma exacerbations, is associated with airway inflammation and hyperresponsiveness, key pathophysiological processes in asthma. "While this was a negative study, tryptase inhibition has shown promise as a druggable target in another study," the investigators stated. "Tryptase remains an important target due to its association with airway inflammation and hyperresponsiveness, pathophysiological processes in asthma that may potentially be mitigated by anti-tryptase therapeutics."
Study Limitations
The researchers acknowledged limitations in the Phase 1c study, including the relatively small number of patients enrolled and potential differences in the surface area sampled by the nasosorption and bronchosorption filters. These factors may have influenced the assessment of drug concentrations and tryptase levels in the upper and lower airways.
The research was funded by Genentech, Inc. Disclosures for study authors can be found in the original publication.
