Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this ...STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.
STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes vg/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).
From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
The efficacy and safety of intravenous (i.v.) azithromycin followed by the oral form, given in addition to i.v. ampicillin-sulbactam, were evaluated in 151 patients hospitalized due to ...community-acquired pneumonia (CAP). Azithromycin 500 mg i.v. once daily plus ampicillin/sulbactam 3 g i.v. twice daily were administered for 2-5 days, then followed by oral azithromycin 500 mg once daily plus the same i.v. ampicillin/sulbactam regimen for a total of 7-10 days of treatment. The clinical response at day 14 was definedas cure, improvement or failure (with the addition of relapse at follow-up at day 30). The other efficacy measures included microbiological (eradication, presumed eradication, persistence, relapse, superinfection) and radiological (resolution, improvement, failure) findings, and outcome of signs and symptoms. Adverse events, vital signs and routine laboratory tests were the safety variables. The number and rate of patients with a positive clinical outcome at day 14 (cured + improved) in the intention-to-treat (ITT) analysis (n = 138) were 119 (86.2%), while 118 (87.4%) were cured or improved in the per-protocol population (PP) subset (n = 135). The rate of success at day 14 was slightly lower in the treated population (78.8%), which included all patients discontinued due to any cause. Clinical failures in the ITT population were 19 (13.8%) at day 14 and 1 (0.9%) at day 30, while 4 patients (3.6%) relapsed at day 30. Signs and symptoms of CAP improved from baseline to endpoint. The results in patients with a pathogen isolated at baseline in the cultures of respiratory tract secretions showed that 17 patients (77.3%) had eradication and 5 (22.7%) had presumed eradication (i.e. absence of adequate sputum for culture) at day 14, with no cases of persistence or superinfection. In the X-ray exam at day 30, 96 patients (85.0%) had resolution, 11 (9.7%) had improvement and 4 (3.5%) had failure. Treatment-related adverse events were reported in 10 patients (6.6%) and caused study discontinuation in 5 of them (one case of angioedema and one case of anaphylactic reaction were serious). No abnormal changes from baseline were found in laboratory parameters. Azithromycin i.v. followed by oral form given in addition to i.v. ampicillin/sulbactam was effective and well tolerated in patients with CAP who required hospital care.
The authors reexamined 300 autopsies which were carried out from 1965 to 1983, on male subjects affected by pulmonary anthracosilicosis already diagnosed in vita and holders of pensions for ...invalidity allocated to them by the Istituto Nazionale Assicurazione Infortuni sul Lavoro. Their livers were reexamined and the specimens which contained agglomerates of at least 5 macrophages in phagocytic activity with dust particles and birefringent silica crystals were considered positive for a silicotic interstitial type involvement of the organ. Larger accumulations of macrophages in fibroelastic activity, including those with fibrohyaline evolution, were considered as silicotic granulomas. Only the incidence of the hepatic granulomatous types was analyzed and related to the severity of the disease, classified according to four types of increasing gravity: interstitial, nodular, confluent and massive. The statistical analysis of the data demonstrates that there is a close correlation between the gravity of pulmonary anthracosilicosis and hepatic involvement, less in interstitial and more in massive types; thus, it is dependent on the amount of silica. On the other hand, the granulomatous evolution following hepatic involvement is not correlated with the gravity of pulmonary anthracosilicosis; therefore, it is not dependent on the amount of silica but is an individual cellular response.
PDF
