Daily Respiratory Research Analysis
A phase 3 randomized trial shows the long-acting monoclonal antibody pemivibart markedly reduces symptomatic COVID-19 with sustained protection up to 12 months, though anaphylaxis remains a safety concern. Real-world registry data indicate that elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically reduced lung transplant waitlisting and transplantation among people with cystic fibrosis in the US. A cross-species AAV vector (AAV.CPP.16) enables efficient intranasal lung gene delivery in mice an
Summary
A phase 3 randomized trial shows the long-acting monoclonal antibody pemivibart markedly reduces symptomatic COVID-19 with sustained protection up to 12 months, though anaphylaxis remains a safety concern. Real-world registry data indicate that elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically reduced lung transplant waitlisting and transplantation among people with cystic fibrosis in the US. A cross-species AAV vector (AAV.CPP.16) enables efficient intranasal lung gene delivery in mice and non-human primates, supporting therapeutic efficacy in models of pulmonary fibrosis and SARS-CoV-2 infection.
Research Themes
- Respiratory infection prevention with long-acting antibodies
- Transformative CFTR modulator effects on lung transplantation
- Intranasal gene therapy platforms for lung diseases
Selected Articles
1. Safety and Efficacy of Pemivibart, a Long-Acting Monoclonal Antibody, for Prevention of Symptomatic COVID-19: Interim Results From a Phase 3 Randomized Clinical Trial (CANOPY).
In randomized cohort B, pemivibart reduced the composite incidence of symptomatic COVID-19, hospitalization, and all-cause mortality by 84% through 6 months and 74% through 12 months versus placebo, with protection sustained without re-dosing. Infusion reactions were uncommon, but anaphylaxis occurred in 0.6% of pemivibart recipients.
Impact: This is a large, blinded phase 3 RCT showing durable pre-exposure prophylaxis against COVID-19 with a single program of two infusions, directly informing prevention strategies, especially for high-risk groups.
Clinical Implications: Pemivibart could be considered for COVID-19 pre-exposure prophylaxis in adults, including those with immunocompromise, with attention to rare anaphylaxis risk and appropriate monitoring during and after infusion.
Key Findings
- Randomized cohort B: 84.1% standardized relative risk reduction through month 6 and 73.9% through month 12 versus placebo (nominal P < .001).
- Anaphylaxis occurred in 0.6% (4/623) of pemivibart recipients (serious in 2 cases).
- Infusion-related reactions were infrequent (≈2–4%); 12-month protection observed without re-dosing.
Methodological Strengths
- Blinded, randomized phase 3 design with placebo control (cohort B).
- Pre-registered protocol and large multicenter sample with 6- and 12-month endpoints.
Limitations
- Interim analysis; detailed variant-specific efficacy and subgroup analyses are limited.
- Cohort A clinical endpoints were exploratory and non-randomized; anaphylaxis, while rare, is clinically significant.
Future Directions: Define variant-specific neutralization and effectiveness, refine risk mitigation for anaphylaxis, and evaluate broader high-risk populations (e.g., severe immunodeficiency) with pragmatic outcomes.
2. Cross-species tropism of AAV.CPP.16 in the respiratory tract and its gene therapies against pulmonary fibrosis and viral infection.
AAV.CPP.16 enables efficient intranasal transduction of key airway and lung cell types in both mice and non-human primates and surpasses AAV6/9. Single-dose delivery conferred anti-fibrotic effects via a dual VEGF/TGF-β1-neutralizing protein and inhibited SARS-CoV-2 Rdrp transcription using an all-in-one Cas13d system.
Impact: This work introduces a cross-species, intranasal AAV platform optimized for the respiratory tract, demonstrating therapeutic efficacy in pulmonary fibrosis and antiviral applications—key steps toward lung-targeted gene therapies.
Clinical Implications: While preclinical, an intranasal AAV with strong airway tropism could enable noninvasive gene therapies for fibrotic lung disease and rapid antiviral responses in future outbreaks, pending safety, durability, and immunogenicity evaluation.
Key Findings
- AAV.CPP.16 achieved superior respiratory tract transduction versus AAV6 and AAV9 in mice and non-human primates via intranasal delivery.
- A single intranasal dose expressing a dual VEGF/TGF-β1-neutralizing protein protected against idiopathic pulmonary fibrosis in mice.
- An all-in-one CRISPR-Cas13d cassette inhibited SARS-CoV-2 Rdrp transcription in vivo, demonstrating antiviral utility.
Methodological Strengths
- Cross-species validation (mice and non-human primates) with intranasal administration.
- Demonstration of both gene supplementation (anti-fibrotic protein) and gene editing (Cas13d antiviral) in disease-relevant models.
Limitations
- Preclinical study; long-term safety, biodistribution, immunogenicity, and re-dosing feasibility remain to be established.
- Efficacy shown in specific models; translatability to humans requires clinical trials.
Future Directions: Evaluate safety, durability, and re-dosing in large-animal models; optimize dosing and promoters for cell-type specificity; and initiate first-in-human studies in selected lung indications.
3. Impact of availability of a highly effective cystic fibrosis treatment (elexacaftor/tezacaftor/ivacaftor) on lung transplant waitlist and lung transplantation trends in the US.
Using US SRTR data across therapeutic eras, the availability of ETI for cystic fibrosis was associated with a 78% reduction in new lung transplant waitlistings and a 72% decline in lung transplants, alongside an 18-fold increase in waitlist removal due to clinical improvement.
Impact: Demonstrates a real-world, system-level impact of CFTR modulators on transplant demand, reshaping allocation and patient trajectories across the US.
Clinical Implications: ETI may delay or obviate the need for lung transplantation in many CF patients, altering referral timing, transplant evaluation practices, and donor organ availability for non-CF candidates.
Key Findings
- New CF lung transplant waitlistings decreased by 78% in the ETI era versus pre-ETI CFTRm era.
- Waitlist removal due to clinical improvement increased 18-fold among CF patients in the ETI era.
- Lung transplants decreased by 72% for CF in the ETI era, while non-CF transplant rates increased.
Methodological Strengths
- National registry analysis with comparative non-CF cohort and era-based stratification.
- Multiple outcomes assessed: waitlisting, removal, pre-transplant mortality, and transplantation.
Limitations
- Observational, era-based analysis susceptible to confounding (e.g., policy changes, pandemic effects).
- Individual-level ETI exposure and adherence not directly captured.
Future Directions: Link individual ETI exposure to transplant-free survival, model long-term outcomes, and assess equity and access implications across demographic subgroups.