Daily Respiratory Research Analysis
An IPD meta-analysis across 23,369 children and adolescents with MDR/RR-TB shows that regimens including two or three WHO Group A drugs (bedaquiline, a fluoroquinolone, linezolid) are associated with higher treatment success. A pivotal single-arm phase 1/2 trial reports a 51% complete response with a novel PRGN-2012 gene therapy in adults with recurrent respiratory papillomatosis. An intranasal Fc-binding nanodisc restores antiviral activity of antibodies and sACE2-Fc against evolving SARS-CoV-2
Summary
An IPD meta-analysis across 23,369 children and adolescents with MDR/RR-TB shows that regimens including two or three WHO Group A drugs (bedaquiline, a fluoroquinolone, linezolid) are associated with higher treatment success. A pivotal single-arm phase 1/2 trial reports a 51% complete response with a novel PRGN-2012 gene therapy in adults with recurrent respiratory papillomatosis. An intranasal Fc-binding nanodisc restores antiviral activity of antibodies and sACE2-Fc against evolving SARS-CoV-2 variants, offering a new prophylactic strategy.
Research Themes
- Pediatric MDR/RR-TB treatment optimization using Group A drugs
- Gene therapy for recurrent respiratory papillomatosis
- Intranasal biologic delivery platforms for respiratory viral prophylaxis
Selected Articles
1. Characteristics of children and adolescents with multidrug-resistant and rifampicin-resistant tuberculosis and their association with treatment outcomes: a systematic review and individual participant data meta-analysis.
This IPD meta-analysis (42 studies; 23,369 participants) found that inclusion of two or three WHO Group A drugs (bedaquiline, a fluoroquinolone, linezolid) was independently associated with higher treatment success in children/adolescents with MDR/RR-TB. Overall pediatric outcomes were better than adults but still below global targets, underscoring the need to expand access and optimize regimens.
Impact: Provides high-quality, large-scale evidence to refine pediatric MDR/RR-TB regimens, directly informing global guideline updates and access priorities.
Clinical Implications: Prioritize inclusion of ≥2 Group A drugs when constructing pediatric MDR/RR-TB regimens and accelerate access to bedaquiline, linezolid, and fluoroquinolones. Strengthen case-finding among younger and clinically diagnosed children who are underrepresented in treated cohorts.
Key Findings
- Across 23,369 pediatric MDR/RR-TB cases, overall treatment success was 72.0%, death 12.2%, failure 3.1%, loss to follow-up 12.7%.
- Use of two Group A drugs increased odds of success (adjusted OR 1.41), and three Group A drugs further increased success (adjusted OR 2.12).
- Younger and clinically diagnosed children were underrepresented among those treated, indicating case-finding gaps.
Methodological Strengths
- Individual participant data meta-analysis with large sample (23,369) across 42 studies
- Multivariable modeling adjusting for key confounders; preregistered (PROSPERO)
Limitations
- Heterogeneity of observational cohorts and regimens across settings
- Loss to follow-up (12.7%) may bias outcome estimates
Future Directions: Prospective pragmatic trials optimizing Group A backbones in pediatric MDR/RR-TB, including safety/PK in younger age groups; implementation studies to expand drug access.
2. PRGN-2012 gene therapy in adults with recurrent respiratory papillomatosis: a pivotal phase 1/2 clinical trial.
In a single-arm phase 1/2 pivotal study (n=38; 35 at RP2D), PRGN-2012 achieved a 51% complete response rate—defined as no interventions required for 12 months—after adjuvant dosing post-surgical debulking, with a favorable safety profile. These results support regulatory submission as the first systemic therapy for adult RRP.
Impact: First-in-class systemic gene therapy demonstrating meaningful, durable clinical benefit in RRP, a rare disease lacking approved systemic treatments.
Clinical Implications: If approved, PRGN-2012 could reduce operative burden and airway morbidity by decreasing repeated surgical interventions in RRP. Centers should prepare for integration of adjuvant dosing schedules post-debulking and monitor long-term durability and safety.
Key Findings
- Single-centre, single-arm phase 1/2 trial enrolled 38 adults with RRP; adjuvant PRGN-2012 dosed on days 1, 15, 43, and 85 post-debulking.
- At the recommended phase 2 dose (n=35), complete response rate (no intervention needed for 12 months) was 51%.
- Safety profile was favorable; results support a planned FDA biologics license application.
Methodological Strengths
- Prospective interventional clinical trial with predefined primary endpoint and dosing schedule
- Clinically meaningful outcome (12-month intervention-free status) and comprehensive safety assessment
Limitations
- Single-arm, single-centre design without randomized comparator
- Short-to-intermediate follow-up; durability beyond 12 months not fully characterized
Future Directions: Randomized or external-controlled studies to confirm efficacy, durability, and safety; exploration of biomarkers predicting response; health-economic evaluations of surgical burden reduction.
3. Fc-binding nanodisc restores antiviral efficacy of antibodies with reduced neutralizing effects against evolving SARS-CoV-2 variants.
An Fc-binding nanodisc co-delivered intranasally with antibodies extended local airway persistence and enhanced neutralization, restoring efficacy of Sotrovimab across Omicron variants and boosting sACE2-Fc activity. In ACE2 transgenic mice, nanodisc complexes reduced lung viral titers by ≥2 logs beyond sACE2-Fc alone.
Impact: Introduces a versatile intranasal platform that can resurrect efficacy of legacy antibodies and receptor decoys against immune-evasive variants, addressing upper-airway delivery and viral escape simultaneously.
Clinical Implications: Supports development of intranasal antibody formulations (including repurposing previously deauthorized mAbs) and sACE2-Fc for pre- or post-exposure prophylaxis in high-risk populations, pending human pharmacokinetic and efficacy data.
Key Findings
- Fc-binding nanodisc extended antibody residence in larynx/trachea and enhanced neutralization in the upper airway.
- Sotrovimab nanodisc complexes restored robust antiviral activity across tested Omicron variants in vitro.
- In ACE2 transgenic mice, nanodisc with sACE2-Fc achieved ≥2 log additional lung viral titer reduction versus sACE2-Fc alone.
Methodological Strengths
- Multi-modal validation: biochemical complexing, in vitro neutralization across variants, and in vivo efficacy in transgenic mice
- Mechanistic design targeting Fc to improve airway half-life and function
Limitations
- Preclinical study; human pharmacokinetics, safety, and efficacy are not yet established
- Long-term mucosal retention and immunogenicity of nanodisc complexes require evaluation
Future Directions: First-in-human studies of intranasal nanodisc–antibody and nanodisc–sACE2-Fc complexes; comparative trials versus parenteral mAbs for pre-exposure prophylaxis; manufacturability and stability assessments.