Abstract Background Portable chest radiographs (CXRs) obtained at presentation of acute respiratory failure (ARF) are interpreted qualitatively to assess airspace disease (ASD) and identify features consistent with acute respiratory distress syndrome (ARDS). The Radiographic Assessment of Lung Edema (RALE) score offers a semiquantitative measure of radiographic ASD, and has demonstrated prognostic value in ARDS, but its ability to quantify radiographic ASD burden across the full spectrum of ARF presentations remains uncertain. Methods We analyzed 4,259 portable CXRs from 814 critically ill adults with expert‑adjudicated ARF subtypes, including ARDS, at‑risk for ARDS, cardiogenic pulmonary edema, acute exacerbation of interstitial lung disease (AE‑ILD), acute‑on‑chronic hypercapnic respiratory failure, and airway‑protection intubations. Trained clinicians, blinded to clinical data, assigned RALE scores. Analyses addressed (1) whether RALE distinguishes CXRs without ASD (airway‑protection intubations and acute-on-chronic hypercapnic respiratory failure) from those with any ASD, and (2) among CXRs with ASD, whether RALE quantifies diffuse bilateral opacification, distinguishing extensive from limited parenchymal involvement. Discrimination was evaluated using receiver operating characteristic curves, with sensitivity analyses assessing the influence of image‑quality features. Results RALE scores increased stepwise from ASD absent to ASD limited to ASD diffuse, discriminated CXRs with any ASD from those without (area under the curve [AUC] 0.81, 95% confidence interval [CI] 0.77–0.85; rule‑out threshold RALE ≥ 7 yielded 96% sensitivity) and quantified diffuse bilateral opacification among ASD-positive CXRs with moderate accuracy (AUC 0.79, 95% CI 0.75–0.82). RALE distributions overlapped substantially across ARDS, cardiogenic pulmonary edema, and AE‑ILD, reflecting shared radiographic appearances rather than etiologic specificity. Suboptimal penetration inflated RALE scores and markedly reduced discrimination (AUC 0.59 vs 0.83 with adequate penetration). Conclusions RALE quantifies radiographic ASD burden across the full spectrum of ARF at intubation — discriminating ASD-absent from ASD-present CXRs and stratifying the extent of parenchymal involvement among those with ASD. However, it did not distinguish between clinical syndromes that share similar diffuse radiographic presentations, highlighting the need to interpret RALE within the broader clinical context and ensure adequate image quality for accurate scoring. These findings reflect RALE’s nature as a radiographic burden metric rather than a diagnostic classifier.

BACKGROUND:Asthma has heterogeneous risk factors, subtypes, and treatments. It is often unclear how to stratify this heterogeneity in scientific studies and clinical care. Genetics could explain root causes of this clinical heterogeneity, called endotypes, but prior studies have used models that are not designed for complex diseases like asthma. OBJECTIVE:We aimed to find genetic effects that partly explain different asthma endotypes. METHODS:We used recent powerful and robust statistical models of context-specific genetic effects in complex traits. We identified genetic subtypes by clustering clinical asthma features in a case-control cohort, GALA II. We replicated the genetic endotypes in the UK Biobank with gene-context interaction tests. RESULTS:Asthma-associated single nucleotide polymorphisms, polygenic scores, and genome-wide heritability revealed subtype-specific genetic endotypes correlated with type 2 inflammation, allergy, and neuroticism. We validated the type 2 associations with molecular data including nasal RNA sequencing. In the UK Biobank, we replicated these endotypes and found they interact with several polygenic scores and drug-relevant genes. CONCLUSION:Our results show how context-specific genetic effects can unravel biomedically meaningful endotypes of complex disease and suggest novel precision treatment strategies.

BACKGROUND:Respiratory diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease, and non-CF bronchiectasis are significant global health burdens. Current treatments aim to improve mucus clearance but do not fully address these diseases, highlighting the need for novel treatments. This study presents the results from phase I and phase IIb trials of GDC-6988, an inhaled, selective, and potent TMEM16A potentiator, in healthy volunteers. OBJECTIVES:To assess the safety and tolerability of orally inhaled GDC-6988 (nebulized and as a dry powder inhaler) in healthy subjects compared with placebo. DESIGN:The phase I trial was a first-in-human, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and repeat doses of nebulized GDC-6988. METHODS:The study consisted of three parts: Part A with six cohorts (doses from 1.5 mg to 150 mg) using a single ascending dose (SAD) design; Part B with three cohorts (22.5 mg BID for 7 days, 75 mg BID for 14 days, and 45 mg BID for 14 days) using a multiple ascending dose (MAD) design; and Part C assessing the effect of salbutamol pretreatment on the highest dose tested in Part B (75 mg). The phase Ib study was a double-blind, randomized, placebo-controlled, single-center, multiple-dose escalation study evaluating the safety and PK of GDC-6988 DPI formulation, with and without salbutamol pretreatment. Three cohorts with doses of 11.2 mg, 28 mg, and 42 mg BID were tested. A bridging cohort compared PK in two capsule strengths of GDC-6988. RESULTS:In the phase I study, 76 healthy subjects received GDC-6988 or placebo; in the phase Ib study, 41 subjects were enrolled (31 in MAD cohorts, 10 in the bridging cohort). GDC-6988 was safe and generally well tolerated, with no serious, severe, or grade ⩾3 adverse events observed at any dose level. Mild-to-moderate dose-dependent FEV1 declines were observed in both studies, but were mitigated by salbutamol pretreatment. In both trials, plasma PK concentrations of GDC-6988 were low, as expected. CONCLUSION:Inhaled GDC-6988 was safe and well tolerated across all dose levels. The plasma PK of GDC-6988 was low and generally dose-proportional with a relatively short half-life. TRIAL REGISTRATION:Phase I: ClinicalTrials.gov Identifier NCT04488705; Phase Ib: ISRCTN30841680.

Background: Cystic fibrosis (CF) is a rare disease characterized by mutations in the Cystic Fibrosis Transmembrane Receptor (CFTR) gene resulting in the missing or malfunctioning CFTR activity and impaired lung clearance. CFTR modulators are the standard of care for CF patients; however, they are not indicated for approximately 10% of CF patients due to their CFTR mutation type. By potentiating the calcium-activated chloride channel TMEM16A, GDC-6988 is expected to compensate for CFTR and restore mucus hydration and mucociliary clearance irrespective of the CFTR mutation in CF patients. Objectives/Methods: In vitro studies showed that GDC-6988 may be a moderate inhibitor and inducer of the CYP3A4 enzyme, indicating co-administration of GDC-6988 with CYP3A4 sensitive substrate concomitant medications (conmeds) may change the conmeds concentration and affect their safety and efficacy. To inform the conmeds exclusion criteria in future GDC-6988 clinical trials in CF patients, physiologically based pharmacokinetic (PBPK) model refined with GDC-6988 Phase 1b study data was used to assess the drug-drug interaction (DDI) risk. IQVIA PharMetrics® Plus claims data between Jan 2020 and March 2021 were used to evaluate the prevalence of conmeds that are considered CYP3A substrates among CF patients with and without CFTR modulator. Detailed medication information that may further influence drug interactions including dose regimen, treatment duration (eg, acute vs. chronic), route of administration, and common diagnosis were also extracted for selected conmeds. Results: PBPK DDI simulations showed minimal to mild (geometric mean exposure change < +/- 15%) impact of GDC-6988 as a perpetrator on midazolam. RWD showed that the majority of the most frequently used sensitive CYP3A4 substrate conmeds in the CF population are considered less sensitive to CYP3A compared to midazolam and do not have a narrow therapeutic window, except for tacrolimus and sirolimus, which are indicated for lung transplant patients who would typically be excluded from clinical studies. Conclusions: Use of RWD allowed the DDI risk assessment to be conducted in a more realistic way by focusing on most frequently used CYP3A sensitive conmeds in the target population. Based on the PBPK modeling and RWD data, CF patients taking CYP3A4 substrates as conmeds will not be excluded from future clinical trials, and instead they will be monitored for adverse events for sensitive CYP3A substrates with narrow therapeutic window.Citations: None

The orally inhaled route of administration for respiratory indications can maximize drug exposure to the site of action (lung) to increase efficacy while minimizing systemic exposure to achieve an improved safety profile. However, due to the difficulty of taking samples from different regions of the human lung, often only systemic pharmacokinetic (PK) samples are taken and assumed to be reflective of the lung PK of the compound, which may not always be the case. In this study, a mechanistic lung physiologically based pharmacokinetic (PBPK) model was built using a middle-out approach (i.e., combining elements of bottom-up prediction and using clinical data to inform some model parameters) to predict plasma and lung PK of an orally inhaled TMEM16A potentiator GDC-6988 in humans. The lung PBPK model accounted for lung deposition, lung and oral absorption, systemic clearance, and tissue distribution. The model was refined using data from a Phase 1b study with dry powder (DP) formulation and was also verified using data from a Phase 1 study with a nebulized (Neb) formulation. The refined model adequately captures the observed GDC-6988 plasma PK profiles in both the DP and Neb studies and allows prediction of the regional lung fluid and tissue concentrations. The sensitivity analyses showed that the systemic Cmax depended on the ratio of airway to alveolar deposition, but this did not impact the AUC. This novel mechanistic lung PBPK modeling framework could be applied to predict plasma and regional lung exposure and inform the early clinical development of inhaled molecules (e.g., dose selection).

Chronic Obstructive Pulmonary Disorder (COPD) is an irreversible and progressive disease which is highly heritable. Clinically, COPD is defined using the summary measures derived from a spirometry test but these are not always adequate. Here we show that using the high-dimensional raw spirogram can provide a richer signal compared to just using the summary measures. We design a transformer-based deep learning technique to process the raw spirogram values along with demographic information and predict clinically-relevant endpoints related to COPD. Our method is able to perform better than prior works while being more computationally efficient. Using the weights learned by the model, we make the framework more interpretable by identifying parts of the spirogram that are important for the model predictions. Pairing up with a board-certified pulmonologist, we also provide clinical insights into the different aspects of the spirogram and show that the explanations obtained from the model align with underlying medical knowledge.

Objectives: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are not indicated for ~10% of people with CF and may not fully restore CFTR function. GDC-6988 is a potent and selective potentiator of TMEM16A and is expected to enhance calcium-induced anion transport, increase airway fluid secretion, and promote mucus hydration and clearance. We previously reported outcomes in healthy volunteers with a nebulized formulation of GDC-6988. Here we present blinded outcomes from an ongoing Phase 1 study of a dry powder (DP) formulation of GDC-6988. Methods: This randomized, double-blind, placebo-controlled study (GB43838) assesses the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses of inhaled DP GDC-6988 with and without albuterol pretreatment in healthy volunteers. Subjects received GDC-6988 or placebo twice daily (BID) for 14 days, with albuterol pretreatment starting on Day 8. Results: Ten subjects received GDC-6988 11.2 mg BID or matching placebo (in an 8:2 ratio). Eight adverse events (AEs) were observed in 3 subjects, all Grade 1 and non-serious. One AE (intermittent chest tightness) was related to GDC-6988, occurred 30 mins after dosing on Days 1–6, and resolved without treatment. No dose-limiting AEs were seen. Decreases in FEV1 of 10–20% from baseline to 30 mins after ≥1 dose were seen in 4 subjects, were asymptomatic except for chest tightness in 1 subject, and were mitigated by albuterol pretreatment in 3 subjects. No PK accumulation was observed, consistent with the short half life of GDC-6988. Mean Cmax and AUC trended slightly higher with albuterol pretreatment. Cmax was ~47% lower and AUC at steady state was ~38% higher than that seen with an equivalent nebulized dose (45 mg BID). Conclusion: GDC-6988 was generally safe and well-tolerated at 11.2 mg BID. Systemic exposure levels of GDC-6988 were low. Additional cohorts at higher doses are ongoing, and a Phase 2 study in patients with CF is planned.

Serious infections are an important concern for patients with autoimmune conditions. We sought to estimate serious infection rates among patients with select autoimmune conditions relative to the general population in Taiwan and the USA. This retrospective cohort study estimated setting-specific standardized serious infection incidence rates and ratios among patients with systemic lupus erythematosus, including extra-renal lupus and lupus nephritis, rheumatoid arthritis and primary membranous nephropathy, compared with the general population using insurance claims for hospitalizations between 2000 and 2013. Multivariable Cox proportional hazard models were used to estimate adjusted hazard ratios for serious infections, adjusting for age, sex, index year, prior serious infection, comorbidities and medications. In Taiwan, serious infection rates were 22.7, 28.7, 70.6, 43.4 and 215.3 per 1000 person-years among the general population and among cohorts of patients with primary membranous nephropathy, rheumatoid arthritis, extra-renal lupus and lupus nephritis, respectively. In the USA, serious infection rates were 2.6, 9.0, 15.6, 21.0 and 63.3 per 1000 person-years among the general population and among cohorts of patients with primary membranous nephropathy, rheumatoid arthritis, extra-renal lupus and lupus nephritis, respectively. Patients had significantly higher serious infection rates than the general population in both settings, largely driven by bacterial, respiratory, urinary tract and opportunistic infections. Patients with lupus nephritis had the highest burden of serious infections relative to the general population, with 7- to 25-fold higher adjusted hazard ratios in Taiwan and the USA, respectively. This study identified a significant excess serious infection burden among patients with targeted autoimmune conditions compared with the general populations in Taiwan and the USA.

OBJECTIVES:Severe cases of COVID-19 pneumonia can lead to acute respiratory distress syndrome (ARDS). Release of interleukin (IL)-33, an epithelial-derived alarmin, and IL-33/ST2 pathway activation are linked with ARDS development in other viral infections. IL-22, a cytokine that modulates innate immunity through multiple regenerative and protective mechanisms in lung epithelial cells, is reduced in patients with ARDS. This study aimed to evaluate safety and efficacy of astegolimab, a human immunoglobulin G2 monoclonal antibody that selectively inhibits the IL-33 receptor, ST2, or efmarodocokin alfa, a human IL-22 fusion protein that activates IL-22 signaling, for treatment of severe COVID-19 pneumonia.DESIGN:Phase 2, double-blind, placebo-controlled study (COVID-astegolimab-IL).SETTING:Hospitals.PATIENTS:Hospitalized adults with severe COVID-19 pneumonia.INTERVENTIONS:Patients were randomized to receive IV astegolimab, efmarodocokin alfa, or placebo, plus standard of care. The primary endpoint was time to recovery, defined as time to a score of 1 or 2 on a 7-category ordinal scale by day 28.MEASUREMENTS AND MAIN RESULTS:The study randomized 396 patients. Median time to recovery was 11 days (hazard ratio [HR], 1.01 d; p = 0.93) and 10 days (HR, 1.15 d; p = 0.38) for astegolimab and efmarodocokin alfa, respectively, versus 10 days for placebo. Key secondary endpoints (improved recovery, mortality, or prevention of worsening) showed no treatment benefits. No new safety signals were observed and adverse events were similar across treatment arms. Biomarkers demonstrated that both drugs were pharmacologically active.CONCLUSIONS:Treatment with astegolimab or efmarodocokin alfa did not improve time to recovery in patients with severe COVID-19 pneumonia.

Background: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations.Aim: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. Methods: This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for > 6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO > 40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. Results: Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was:-6 (-43, 32) at 10 mg QD,-26 (-53, 2) at 30 mg QD,-55 (-78,-32) at 40 mg BID and-52 (-72,-32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. Conclusions: In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns.

logistic regression models adjusted for age, sex, nIVT at baseline, body mass index, homozygote delF508 mutation, diabetes mellitus, chronic pulmonary infection (Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Mycobacterium abscessus, Achromobacter xylosoxidans), and use of a CF transmembrane conductance regulator modulator therapy.Model Akaike information criteria were compared to identify the marker with the best prediction ability.Results are reported as odds ratios with p-values.Results: Of 131 PwCF (43.5% female, mean age 34.0) evaluated, 75 (57.3%)had at least one nIVT during follow-up.In the univariate analysis, having an nIVT during follow-up was significantly associated with higher inflammation scores for all markers examined.In the multivariate analysis, the following markers at baseline were significantly associated with having an nIVT during follow-up: CRP (OR = 7.29, p = 0.01), CRP/albumin (OR = 1.09, p = 0.004), low lymphocyte/monocyte ratio (OR = 0.55, p = 0.03), high neutrophil/lymphocyte ratio (OR = 1.51, p = 0.01), Glasgow prognostic score of 1 vs. 0 (OR = 3.52, p = 0.02), and CF-Able score of 2 to 4.5 vs. less than 2 (OR = 3.82, p = 0.02).Comparison of the regression models showed that CRP/albumin ratio was superior to the other models examined in differentiating patients with and without nIVT during follow-up.Conclusions: Our retrospective study found that several inflammationbased scoring systems or ratios established for other disease entities can identify patients with nIVT in PwCF.Although the CF-Able score was not designed to predict PEx, it includes some variables associated with greater risk for PEx and, correspondingly, nIVT.The easily calculated CRP/albumin ratio is superior to CF-Able score in distinguishing PwCF with nIVT from those without and thus represents an interesting possibility for clinical use.

AbstractObjectiveDual leucine zipper kinase (DLK), which regulates the c‐Jun N‐terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first‐in‐human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC‐0134, a small‐molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC‐0134‐treated ALS patients and DLK conditional knockout (cKO) mice.MethodsThe study included placebo‐controlled, single and multiple ascending‐dose (SAD; MAD) stages, and an open‐label safety expansion (OLE) with adaptive dosing for up to 48 weeks.ResultsForty‐nine patients were enrolled. GDC‐0134 (up to 1200 mg daily) was well tolerated in the SAD and MAD stages, with no serious adverse events (SAEs). In the OLE, three study drug‐related SAEs occurred: thrombocytopenia, dysesthesia (both Grade 3), and optic ischemic neuropathy (Grade 4); Grade ≤2 sensory neurological AEs led to dose reductions/discontinuations. GDC‐0134 exposure was dose‐proportional (median half‐life = 84 h). Patients showed GDC‐0134 exposure‐dependent plasma NFL elevations; DLK cKO mice also exhibited plasma NFL compared to wild‐type littermates.InterpretationThis trial characterized GDC‐0134 safety and PK, but no adequately tolerated dose was identified. NFL elevations in GDC‐0134‐treated patients and DLK cKO mice raised questions about interpretation of biomarkers affected by both disease and on‐target drug effects. The safety profile of GDC‐0134 was considered unacceptable and led to discontinuation of further drug development for ALS. Further work is necessary to understand relationships between neuroprotective and potentially therapeutic effects of DLK knockout/inhibition and NFL changes in patients with ALS.

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m ( 99m Tc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. 99m Tc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma C max similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

AbstractSeveral inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. 99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

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.

Background: The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma. Objective: We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (FENO), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma. Methods: We conducted a double-blind, randomized, placebo controlled, phase 1 proof-of-activity study in adults with mild asthma and FENO higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in FENO from baseline to day 14. Baseline was defined as the average FENO during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed. Results: Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean FENO at baseline across all subjects was 93 +/- 43 ppb. At day 14, placebo-corrected difference in FENO was -23% (95% CI, -37.3 to -9) for 15 mg QD and -42% (95% CI, -57 to -27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater FENO reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition. Conclusions: GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in FENO in mild asthma and was well tolerated without evidence of systemic toxicity.