Real-World Safety Data of the Orphan Drug Onasemnogene Abeparvovec (Zolgensma®) for the SMA Rare Disease: A Pharmacovigilance Study Based on the EMA Adverse Event Reporting System.

The recent introduction of the innovative therapy, onasemnogene abeparvovec (Zolgensma®), has revolutionized the spinal muscular atrophy (SMA) therapeutic landscape. Although Zolgensma® therapy has proven to lead to functional improvements in SMA children, some gaps in its safety profile still need to be investigated. To better characterize the Zolgensma® safety profile, we conducted a retrospective observational study, analyzing all the Individual Case Safety Reports (ICSRs) referred to it and collected in the European pharmacovigilance database between 1 January 2019 and 22 September 2023. We found 661 ICSRs related to Zolgensma®, with a growing trend in the annual reporting. The majority of the reports were sent by healthcare professionals and referred to infant females. In more than 90% of the cases, Zolgensma® was the only reported suspected drug. Out of a total of 2744 reported ADRs, increased hepatic enzymes, pyrexia, vomiting, and thrombocytopenia were the most commonly reported adverse reactions. Of these adverse reactions (ADRs), 56.9% were serious, causing or prolonging the patient's hospitalization. A total of 39 ICSRs related to cases with a fatal outcome. Alterations in the heart rhythm, acute hepatic failure, and hepatic cytolysis emerged among the cardiac and hepatic disorders, respectively.

Hyaluronic acid-based fillers in patients with autoimmune inflammatory diseases.

The use of hyaluronic acid (HA)-based aesthetic therapies is growing steadily, and according to the International Society of Aesthetic Plastic Surgery, more than 4.3 million aesthetic procedures using HA were performed in 2019, an increase of 15.7% than 2018. More people are offering these types of services, often without proper training or qualifications. Therefore, there is an increasing number of reports in the literature relating to possible adverse events, with subsequent therapeutic problems and more or less serious consequences for patients. The aim of this research is to carry out a review of the literature in order to evaluate the impact of hyaluronic acid-based fillers in patients with autoimmune inflammatory diseases, in particular scleroderma and Systemic Lupus Erythematosus (SLE). Although HA plays a central role in the inflammatory process, the use of HA-based fillers in patients with autoimmune inflammatory diseases is still controversial. HA, in fact, in inflamed tissues helps to propagate the inflammatory response and, injected in the form of a dermal filler, could potentially promote reactivation of the underlying disease. For this reason, many specialists do not perform HA-based aesthetic treatments in patients with scleroderma or SLE. However, recent scientific evidence suggests that the use of HA-based fillers in patients with scleroderma can lead to improvement of skin lesions, with satisfactory results. In the literature, there are no clinical studies that contraindicate the administration of HA-based dermal fillers in patients with inflammatory disease.

Do peripheral neuropathies differ among immune checkpoint inhibitors? Reports from the European post-marketing surveillance database in the past 10 years.

Although the immunotherapy advent has revolutionized cancer treatment, it, unfortunately, does not spare cancer patients from possible immune-related adverse events (irAEs), which can also involve the peripheral nervous system. Immune checkpoint inhibitors (ICIs), blocking cytotoxic T-lymphocyteassociated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death ligand 1 (PD-L1), can induce an immune imbalance and cause different peripheral neuropathies (PNs). Considering the wide range of PNs and their high impact on the safety and quality of life for cancer patients and the availability of large post-marketing surveillance databases, we chose to analyze the characteristics of ICI-related PNs reported as suspected drug reactions from 2010 to 2020 in the European real-world context. We analyzed data collected in the European pharmacovigilance database, Eudravigilance, and conducted a systematic and disproportionality analysis. In our study, we found 735 reports describing 766 PNs occurred in patients treated with ICIs. These PNs included Guillain-Barré syndrome, Miller-Fisher syndrome, neuritis, and chronic inflammatory demyelinating polyradiculoneuropathy. These ADRs were often serious, resulting in patient disability or hospitalization. Moreover, our disproportionality analysis revealed an increased reporting frequency of PNs with tezolizumab compared to other ICIs. Guillain-Barré syndrome is a notable potential PN related to ICIs, as it is associated with a significant impact on patient safety and has had unfavorable outcomes, including a fatal one. Continued monitoring of the safety profile of ICIs in real-life settings is necessary, especially considering the increased frequency of PNs associated with atezolizumab compared with other ICIs.

Maternal, fetal and neonatal outcomes among pregnant women receiving COVID-19 vaccination: The preg-co-vax study.

Introduction: Although the European Medicines Agency (EMA) encourage coronavirus disease 2019 (COVID-19) vaccination in pregnant women, the scientific evidence supporting the use of COVID-19 vaccines during pregnancy is still limited. Aim: We aimed to investigate adverse events following immunization (AEFI) with COVID-19 vaccines during pregnancy. Methods: We retrieved Individual Case Safety Reports (ICSRs) related to the use of COVID-19 vaccines during pregnancy from the EudraVigilance database for the year 2021. We analyzed AEFI related to the mother and fetus/newborn. The reporting odds ratio (ROR) was computed to compare the reporting probability of spontaneous abortion between COVID-19 vaccines. Results: During the study period, among 1,315,315 ICSRs related to COVID-19 vaccines, we retrieved 3,252 (0.25%) reports related to the use in pregnancy. More than half (58.24%) of ICSRs were submitted by non-healthcare professionals. Although the majority (87.82%) of ICSRs concerned serious AEFI, their outcomes were mostly favorable. In this study, 85.0% of total ICSRs referred to pregnant women (n = 2,764), while 7.9% referred to fetuses/newborns (n = 258). We identified 16,569 AEFI. Moreover, 55.16% were AEFI not related to pregnancy (mostly headache, pyrexia, and fatigue), while 17.92% were pregnancy-, newborn-, or fetus-related AEFI. Among pregnancy-related AEFI, the most reported was spontaneous abortion. Messenger RNA (mRNA) vaccines had a lower reporting probability of spontaneous abortion than viral vector-based vaccines (ROR 0.80, 95% CI 0.69-0.93). Moderna and Oxford-AstraZeneca vaccines had a higher reporting probability of spontaneous abortion (ROR 1.2, 95% CI 1.05-1.38 and ROR 1.26, 95% CI 1.08-1.47, respectively), while a lower reporting probability was found for Pfizer-BioNTech vaccine compared with all other COVID-19 vaccines (ROR 0.73, 95% CI 0.64-0.84). In addition, 5.8% of ICSRs reported a fatal outcome. Conclusions: No strong insight of unknown AEFI associated with COVID-19 vaccination in pregnant women was observed. Considering the high risk associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, our analysis suggests that the benefits of COVID-19 vaccines during pregnancy outweigh the possible risks. However, it is important to continue monitoring the safety profile of COVID-19 vaccines in this subpopulation.

Neurological Manifestations Related to Immune Checkpoint Inhibitors: Reverse Translational Research by Using the European Real-World Safety Data.

Immune checkpoint inhibitors (ICIs) are widely used improving clinical outcomes in many cancer patients. However, they can induce serious consequences, like neurological immune-related adverse drug reactions (NirADRs). Although these are rare complications, they can be serious with important impact on patients' quality of life. Our purpose is to describe these adverse events observed in the European clinical practice context. We carried out a descriptive analysis of individual case safety reports (ICSRs) related to ICIs collected until February 7, 2020, in the European spontaneous reporting database, EudraVigilance, and reported nervous disorders as suspect adverse drug reactions (ADRs). NirADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA). In order to identify a hypothetical different reporting probability of the NirADR types between the ICI classes, we carried out a disproportionality analysis. The reporting odds ratio (ROR) with 95% CI was computed comparing the different ICI classes to each other based on their pharmacological target [the cytotoxic T-lymphocyte antigen-4 (CTLA-4), the programmed death-1 (PD-1) or its ligand (PD-L1)]. Finally, we researched in the literature the hypothesized mechanisms, which could explain the onset of these ICI-related neurological complications. Overall, we found 4,875 cases describing 6,429 ICI-related suspected NirADRs. ICI-related neurotoxicities include a wide range of central and peripheral events. These were mainly related to anti-PD-1 agents and occurred in male patients (59%). Our analysis confirmed a gender difference of NirADRs. Twenty-three percent of the events (comprising myasthenia gravis, neuropathy peripheral, and cerebral infarction) had unfavorable fallouts, including fatal outcome (7%). Majority of the NirADRs were categorized as "Neurological disorders NEC" HLGTs MedDRA (2,076; 32%). In 1,094 cases (22%), more NirADRs overlapped with other neurologic complications. An interesting overlapping of myasthenia gravis with myositis or myocarditis emerged. From our disproportionality analysis, an increased reporting probability of peripheral neuropathies and headaches emerged with ipilimumab when compared to anti-PD-1 and anti-PD-L1 agents. However, neuromuscular disorders were more probably reported with anti-PD-1. Several pathogenic mechanisms, including neuronal damage by T cells and autoantibodies and/or cytokine-mediated inflammation processes, have been hypothesized. However, the pathogenesis of these ICI-related complications is not completely understood. Considering the recent marketing authorizations of ICIs, further studies are strongly needed to monitor their neurologic safety profile.

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database.

BACKGROUND: The introduction of immune checkpoint inhibitors (ICIs) in clinical practice has brought significant benefits for patients. Seven ICIs are available in Europe: nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, and ipilimumab. Despite their proven clinical efficacy, these innovative drugs may cause serious immune-related adverse drugs reactions (irADRs). Given the significance of these ADRs for patients' health, we analyzed individual case safety reports (ICSRs) related to ICIs, focusing on those reporting irADRs, collected in the Italian spontaneous reporting database. METHODS: We analyzed ICI-induced irADRs collected in the Italian Pharmacovigilance database (Rete Nazionale di Farmacovigilanza [RNF]) from January 1, 2002, to February 28, 2019, focusing on those reported in the Campania Region. We retrieved from an open-access Italian pharmacovigilance system, the RAM system (for national safety data), and from the RNF (for Campania safety data) all ICSRs reporting ADRs related to ICIs authorized until the analysis date. Focusing on irADRs, we performed descriptive and disproportionality analyses through the reporting odds ratio (ROR) with 95% confidence interval. RESULTS: National results. Among 2,088 ICI-related ICSRs, 801 reported irADRs. The majority of such ADRs occurred in male patients reporting gastrointestinal and skin toxicities. Nivolumab and pembrolizumab were drugs most commonly reported as suspect drugs. Compared to other ICIs, ROR was statistically significant for pembrolizumab and ipilimumab.Campania Region results. Out of 253 ICI-related ICSRs sent to Regional Pharmacovigilance Center of Campania Region, 121 reported at least one ICI-induced irADR. These were serious in 37.2% of cases and had an unfavorable outcome in 32.2% of cases. Overall, out of 8 ICSRs reported ADR with a fatal outcome, four reported irADRs. From disproportionality analyses on Campania Region ICSRs, statistically significant ROR emerged only for ipilimumab. CONCLUSIONS: Our results showed that during the study period several serious irADRs were reported, some of which had fatal outcome. Given the clinical relevance of irADRs, further investigations in real-life context are necessary for a better characterization of ICIs safety profiles. Oncologists should be trained to early recognize and adequately manage irADRs. Patients should also be educated to immediately report any new symptom or worsening of pre-existed ones during the ICI treatment.