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.
BACKGROUND: There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population. METHODS: We conducted a systematic review and individual participant data meta-analysis. Databases were searched from Oct 1, 2014, to March 30, 2020. To be eligible, studies must have included more than five children or adolescents (0-19 years of age) treated for microbiologically confirmed or clinically diagnosed MDR or RR tuberculosis within a defined treatment cohort, and reported on regimen composition and treatment outcomes. Abstracts were screened independently by two authors to identify potentially eligible records. Full texts were reviewed by two authors independently to identify studies meeting the eligiblity criteria. For studies meeting eligiblity criteria, anonymised individual patient data was requested and individiual level data included for analysis. The main outcome assessed was treatment outcome defined as treatment success (cure or treatment completed) versus unfavourable outcome (treatment failure or death). Multivariable logistic regression models were used to identify associations between clinical and treatment factors and treatment outcomes. This study is registered with Prospero (CRD42020187230). FINDINGS: 1417 studies were identified through database searching. After removing duplicates and screening for eligibility, the search identified 23 369 individual participants from 42 studies, mostly from India and South Africa. Overall, 16 825 (72·0%) were successfully treated (treatment completed or cured), 2848 died (12·2%), 722 (3·1%) had treatment failure, and 2974 (12·7%) were lost to follow-up. In primary analyses, the median age was 16 (IQR 13-18) years. Of the 17 764 (87·1%) participants with reported HIV status, 2448 (13·8%) were living with HIV. 17 707 (89·6%) had microbiologically confirmed tuberculosis. After adjusting for significant factors associated with treatment outcome, the use of two (adjusted odds ratio [OR] 1·41 [95% CI 1·09-1·82]; p=0·008) or three (2·12 [1·61-2·79]; p<0·0001) WHO-classified group A drugs (bedaquiline, moxifloxacin, levofloxacin, and linezolid) compared with the use of no group A drugs at all was positively associated with treatment success. INTERPRETATION: Younger and clinically diagnosed children are underrepresented among those treated for MDR and RR tuberculosis and should be a focus for case-finding efforts. Overall treatment outcomes in our analysis were better than in adults but lower than the international targets of 90% or more individuals successfully treated. Treatment with more group A drugs was associated with better treatment outcomes in children and adolescents, highlighting the need for more rapid access to these drugs and improved regimens. FUNDING: Unitaid.
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.
BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a rare debilitating condition caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Papillomas develop in the aerodigestive tract, leading to significant voice disturbance and airway obstruction. No systemic treatment currently exists. We aimed to assess the safety and clinical activity of PRGN-2012 in adult patients with RRP treated at the recommended phase 2 dose. METHODS: This was a single-centre, single-arm, phase 1/2 trial. Adult patients aged 18 years or older with RRP who required three or more interventions in the 1 year before treatment received adjuvant PRGN-2012 on day 1 following surgical debulking of disease, and on days 15, 43, and 85. Primary outcome measure was complete response rate, defined as the percentage of patients who did not require an intervention to control RRP in the 12 months after treatment. Safety outcomes included treatment-related adverse events. This study is registered ClinicalTrials.gov (NCT04724980). FINDINGS: From March 16, 2021, to June 1, 2023, 38 patients were enrolled and received the 12-week treatment course. Among the 35 patients treated at the recommended phase 2 dose of 5×10 INTERPRETATION: PRGN-2012 treatment resulted in complete response in 51% of the patients treated and was safe. Based on these positive pivotal study results, a biologics license application to the US Food and Drug Administration (FDA) is planned, positioning PRGN-2012 to be an FDA-approved medical treatment for adult patients with RRP. FUNDING: National Institutes of Health.
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.
Passive antibody therapies, typically administered via parenteral routes, have played a crucial role in the initial response to the COVID-19 pandemic. However, the ongoing evolution of SARS-CoV-2 has revealed significant limitations of this approach, primarily due to mutational escape and the inadequate delivery of antibodies to the upper respiratory tract. To overcome these challenges, we propose a novel prophylactic strategy involving the intranasal delivery of an antibody in combination with an Fc-binding nanodisc. This nanodisc, engineered to specifically bind to the Fc regions of IgG antibodies, served two key functions: extending the antibody's half-life in the larynx and trachea, and enhancing its neutralization efficacy. Notably, Sotrovimab, an FDA-approved monoclonal antibody that has experienced a significant decline in neutralizing potency due to viral evolution, exhibited robust antiviral activity when complexed with the nanodisc against all tested Omicron variants. Furthermore, the Fc-binding nanodisc significantly boosted the antiviral efficacy of the soluble angiotensin-converting enzyme 2 (sACE2) Fc fusion protein, which possesses broad but modest antiviral activity. In ACE2 transgenic mice, the Fc-binding nanodisc protected better than sACE2-Fc alone with two more log reduction in lung viral titer. Therefore, the intranasal Fc-binding nanodisc offers a promising and powerful approach to counteract the diminished antiviral activity of neutralizing antibodies caused by mutational escape, effectively restoring antiviral efficacy against various evolving SARS-CoV-2 variants.