Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia.

Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or ß (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we report interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. As of 31 May 2023, 16 participants were enrolled across 5 dose cohorts. Twelve of the 16 participants completed the dose-optimization study and enrolled in the extension study. A total of 346 intravenous doses of mRNA-3927 were administered over a total of 15.69 person-years of treatment. No dose-limiting toxicities occurred. Treatment-emergent adverse events were reported in 15 out of the 16 (93.8%) participants. Preliminary analysis suggests an increase in the exposure to mRNA-3927 with dose escalation, and a 70% reduction in the risk of metabolic decompensation events among 8 participants who reported them in the 12-month pretreatment period.

Health Care Utilization and Expenditures Following Diagnosis of Nontuberculous Mycobacterial Lung Disease in the United States.

BACKGROUND: Nontuberculous mycobacterial lung disease (NTMLD) is an important public health concern that has been increasing in prevalence. OBJECTIVES: To (a) describe hospitalizations and health care expenditures among patients with newly diagnosed NTMLD and (b) estimate attributable hospitalizations and expenditures to NTMLD in the United States. METHODS: In this matched cohort study, patients and controls were identified from a large U.S. national managed care insurance database containing aggregated health claims of up to 18 million fully covered members annually. NTMLD was defined based on diagnostic claims for NTMLD on ≥ 2 separate occasions ≥ 30 days apart between 2007 and 2016. Thirty-six months of continuous enrollment (12 months before and 24 months after the first diagnostic claim) was required. Health care utilization and standardized health care expenditures were summarized over 12 months before NTMLD diagnosis and for 2 subsequent years. The percentage of patients that were hospitalized in years 1 and 2 was evaluated using a generalized mixed effects model with adjustment for baseline hospitalizations, Charlson Comorbidity Index, and baseline diseases. A general estimating equation model was used to evaluate health care expenditures. RESULTS: There were 1,039 patients in the NTMLD cohort and 2,078 in the control cohort. NTMLD patients had a 55.0% risk of hospitalization in year 1 (95% CI = 45.4-64.3) and a 38.8% risk in year 2 (95% CI = 30.0-48.4). The adjusted risk of hospitalization was significantly higher in the NTMLD group compared with the control group in year 1 (OR = 4.64; 95% CI = 3.74-5.76; P < 0.001) and year 2 (OR = 2.26; 95% CI = 1.78-2.87; P < 0.001). Year 1 adjusted mean health care expenditures for the total NTMLD patient population were $72,475 (95% CI = $58,510-$86,440) and for the matched control population were $28,405 (95% CI = $8,859-$47,950), with a difference of $44,070 (95% CI = $27,132-$61,008; P < 0.001). Year 2 adjusted mean expenditures for the overall NTMLD patient group were $48,114 (95% CI = $31,722-$64,507) and for the matched control group were $28,990 (95% CI = $9,429-$48,552), with a difference of $19,124 (95% CI = $7,865-$30,383; P < 0.001). CONCLUSIONS: Patients with NTMLD have a significantly greater risk of hospitalization and higher total health care expenditures than matched control patients without NTMLD. DISCLOSURES: This study was financially sponsored by Insmed. Marras reports fees from Insmed, Astra Zeneca, RedHill, and Horizon, all outside the current work. Mirsaeidi has nothing to disclose. Eagle, Q. Zhang, Chou, and Leuchars are employees of Insmed. R. Zhang is a contracted consultant at Insmed. The views expressed here are those of the authors and are not to be attributed to their respective affiliations.