Daily Respiratory Research Analysis
Three high-impact respiratory studies stood out: an AI-discovered, first-in-class TNIK inhibitor (rentosertib) showed acceptable safety in a randomized phase 2a trial for idiopathic pulmonary fibrosis; a mechanistic study unveiled a host-directed antiviral strategy by preventing virus-induced TFEB degradation via DCAF7 inhibition, achieving efficacy in two SARS-CoV-2 animal models; and a phase 3 immunobridging trial demonstrated that the mRNA-1345 RSV vaccine elicited neutralizing antibodies in
Summary
Three high-impact respiratory studies stood out: an AI-discovered, first-in-class TNIK inhibitor (rentosertib) showed acceptable safety in a randomized phase 2a trial for idiopathic pulmonary fibrosis; a mechanistic study unveiled a host-directed antiviral strategy by preventing virus-induced TFEB degradation via DCAF7 inhibition, achieving efficacy in two SARS-CoV-2 animal models; and a phase 3 immunobridging trial demonstrated that the mRNA-1345 RSV vaccine elicited neutralizing antibodies in at-risk adults aged 18–59 years noninferior to those in older adults.
Research Themes
- AI-designed therapeutics in fibrotic lung disease
- Host-directed antiviral mechanisms via lysosomal/TFEB pathways
- Immunobridging evidence for RSV vaccination in at-risk younger adults
Selected Articles
1. A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial.
This multicenter, double-blind, randomized phase 2a trial tested the AI-generated TNIK inhibitor rentosertib in IPF and found similar treatment-emergent adverse event rates across three dose arms versus placebo over 12 weeks. Safety signals were manageable, supporting further development of a first-in-class, AI-designed antifibrotic.
Impact: This is among the first randomized trials of an AI-designed, first-in-class small molecule in a fatal fibrotic lung disease, demonstrating translational feasibility and acceptable safety.
Clinical Implications: While early-phase and safety-focused, these data support advancing rentosertib into larger efficacy trials in IPF, potentially expanding the therapeutic landscape beyond current antifibrotics.
Key Findings
- Randomized, double-blind, placebo-controlled phase 2a trial in IPF (12 weeks, 4 arms: 30 mg QD, 30 mg BID, 60 mg QD, placebo).
- Treatment-emergent adverse events occurred at similar rates across rentosertib and placebo arms (approximately 70–83%).
- Serious adverse events were infrequent; discontinuations were mainly due to liver toxicity or diarrhea.
- First-in-class TNIK inhibition and AI-generated design represent a novel therapeutic strategy for IPF.
Methodological Strengths
- Multicenter, double-blind, randomized, placebo-controlled design
- Clear pre-specified safety primary endpoint with dose-ranging arms
Limitations
- Small total sample size (~71) and short duration (12 weeks)
- Primary endpoint focused on safety; efficacy outcomes are exploratory
Future Directions: Proceed to larger, longer, efficacy-focused phase 2b/3 trials to assess lung function decline (e.g., FVC), progression-free survival, imaging and biomarker responses, and to refine dose.
2. Inhibition of virally induced TFEB proteasomal degradation as a host-centric therapeutic approach for coronaviral infection.
The study identifies DCAF7- and PAK2-mediated proteasomal degradation of TFEB as a viral strategy to impair lysosomal homeostasis. Novel small molecules blocking DCAF7–TFEB interaction restored TFEB and exhibited broad antiviral activity, attenuating SARS-CoV-2 infection in two animal models.
Impact: Reveals a previously unknown host-pathway hijack by coronaviruses and delivers drug-like inhibitors with in vivo efficacy, defining a new host-directed antiviral class.
Clinical Implications: While preclinical, these findings support development of DCAF7 inhibitors as broad-spectrum antivirals less susceptible to viral escape, complementing direct-acting agents.
Key Findings
- Coronaviruses trigger proteasomal degradation of TFEB, the master regulator of lysosomal homeostasis.
- TFEB stability is co-regulated by DCAF7 (E3 ligase subunit) and PAK2 kinase identified via proteomics and siRNA screening.
- Small molecules disrupting DCAF7–TFEB interaction prevent TFEB degradation and exhibit broad antiviral activity.
- Efficacy demonstrated by attenuation of SARS-CoV-2 infection in two animal models.
Methodological Strengths
- Multi-modal mechanistic approach (mass spectrometry, unbiased RNAi screen, chemical biology)
- In vivo validation in two independent SARS-CoV-2 animal models
Limitations
- Preclinical study; human safety and efficacy are unknown
- Scope limited to coronaviral models; breadth across other respiratory viruses requires testing
Future Directions: Advance lead DCAF7 inhibitors into IND-enabling studies, define PK/PD–biomarker relationships (e.g., TFEB target engagement), and evaluate spectrum against diverse respiratory viruses.
3. Safety, Tolerability, and Immunogenicity of mRNA-1345 in Adults at Increased Risk for RSV Disease Aged 18 to 59 Years.
In at-risk adults aged 18–59 years, a single 50 µg dose of mRNA-1345 was well tolerated and achieved Day 29 neutralizing antibody GMTs against RSV-A and RSV-B that were noninferior to those in ≥60-year-olds from the pivotal trial, with responses persisting through Day 181.
Impact: Provides immunobridging evidence supporting efficacy inference and potential label expansion of an RSV mRNA vaccine to younger at-risk adults.
Clinical Implications: If authorized, immunization of at-risk adults 18–59 could reduce RSV-LRTD burden; data support 50 µg dosing with acceptable tolerability and durable neutralization.
Key Findings
- Randomized, double-blind phase 3 immunogenicity and safety study in at-risk adults aged 18–59 (n=999).
- Day 29 nAb GMTs for 50 µg met noninferiority versus ≥60-year-olds from the pivotal efficacy trial (RSV-A GMR 1.2; RSV-B GMR 1.1).
- Seroresponse noninferiority also achieved; immune responses persisted above baseline to Day 181.
- Solicited adverse reactions were mostly mild–moderate and transient (median 2 days).
Methodological Strengths
- Randomized, double-blind design with dose comparison
- Prespecified immunobridging to pivotal efficacy cohort enabling inference of efficacy
Limitations
- Immunobridging to historical cohort rather than direct clinical efficacy in this age group
- Follow-up limited to Day 181 for persistence; long-term effectiveness and safety beyond this remain to be shown
Future Directions: Conduct effectiveness studies in diverse at-risk subgroups, evaluate clinical endpoints (RSV-LRTD reduction), durability beyond 6 months, and coadministration strategies.