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.
BACKGROUND: We report an interim analysis of safety and efficacy of pemivibart in individuals with (cohort A) or without (cohort B) significant immunocompromise in the phase 3 CANOPY trial. METHODS: Eligible participants (aged ≥18 years; negative for current severe acute respiratory syndrome coronavirus 2 infection) received 2 intravenous 4500-mg pemivibart infusions (cohort A) or were randomized 2:1 to receive blinded pemivibart or placebo infusions (cohort B) 90 days apart. Safety was a primary end point for both cohorts. The primary immunobridging end point for cohort A has been reported elsewhere. Composite incidence of reverse-transcription polymerase chain reaction-confirmed symptomatic coronavirus disease 2019 (COVID-19), COVID-19 hospitalization, and all-cause mortality was an exploratory end point. RESULTS: In September-November 2023, 306 participants received pemivibart (cohort A), and 317 received pemivibart and 162 placebo (cohort B). The most common study drug-related adverse events were infusion-related reactions (cohort A: 11 of 306 [3.6%]; cohort B: 7 of 317 [2.2%] for pemivibart and 0 of 162 for placebo). Four of 623 participants (0.6%) who received pemivibart experienced anaphylactic reactions (serious in 2). In cohort A, the composite COVID-19 incidence through month 6 was 11 of 298 (3.7%; 2 deaths). In cohort B, 6 of 317 pemivibart (1.9%; no deaths) and 19 of 160 placebo (11.9%; no deaths) recipients met the end point through month 6 (84.1% standardized relative risk reduction [95% confidence interval, 60.9-93.5; nominal P < .001]), and 15 of 317 pemivibart (4.7%; 1 death) and 29 of 160 placebo (18.1%; no deaths) recipients met the end point through month 12 (73.9% standardized relative risk reduction [52.8-85.6; nominal P < .001]). Twelve-month protection was conferred with no additional dosing. CONCLUSIONS: Pemivibart provided prophylactic efficacy against COVID-19 and was well tolerated by most participants. Anaphylaxis was an important safety risk. CLINICAL TRIALS REGISTRATION: NCT06039449.
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.
Efficient gene delivery vectors are crucial for respiratory and lung disease therapies. We report that AAV.CPP.16, an engineered adeno-associated virus (AAV) variant derived from AAV9, efficiently transduces airway and lung cells in mice and non-human primates via intranasal administration. AAV.CPP.16 outperforms AAV6 and AAV9, two wild-type AAVs with demonstrated tropism for respiratory tissues, and efficiently targets key respiratory cell types. It supports gene supplementation and editing therapies in two clinically relevant mouse models of respiratory and lung diseases. A single intranasal dose of AAV.CPP.16 expressing a dual-target, vascular endothelial growth factor (VEGF)/transforming growth factor (TGF)-β1-neutralizing protein protected lungs from idiopathic pulmonary fibrosis, while a similar application of AAV.CPP.16 carrying an "all-in-one" CRISPR-Cas13d system inhibited transcription of the SARS-CoV-2-derived RNA-dependent RNA polymerase (Rdrp) gene. Our findings highlight AAV.CPP.16 as a promising vector for respiratory and lung gene therapy.
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.
Cystic fibrosis (CF) is a genetic disease that often leads to progressive lung disease and lung transplantation. CF transmembrane conductance regulator modulators (CFTRm) improve lung function in people with CF. The US Scientific Registry of Transplant Recipients (SRTR) data were used to assess rates of lung transplant waitlisting, waitlist removal, pre-transplant mortality, and lung transplantation in people with CF (CF cohort) compared to those with other respiratory conditions (non-CF cohort) across three time periods: (i) prior to approval of any CFTRm (Pre-CFTRm era); (ii) from approval of ivacaftor to pre-approval of elexacaftor/tezacaftor/ivacaftor (Pre-ETI CFTRm era); and (iii) after approval of ETI (ETI era). Among the CF cohort, new waitlistings decreased by 78 % in ETI era compared to Pre-ETI CFTRm era while rates increased in the non-CF cohort. Among the CF cohort, waitlist removal for improving condition increased 18-fold in ETI era compared to Pre-ETI CFTRm era; rates remained stable among the non-CF cohort. Lung transplants decreased by 72 % in ETI era compared to pre-ETI CFTRm era; rates increased among the non-CF cohort. These results suggest the availability of ETI is associated with reductions in demand for lung transplants for people with CF, increasing availability of donor lungs for non-CF candidates.