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Background: Although expanded access is an increasingly used pathway for patients to access investigational medicine, little is known on the magnitude and content of published scientific research collected via expanded access. Methods: We performed a review of all peer-reviewed expanded access publications between January 1, 2000 and January 1, 2022. We analyzed the publications for drugs, diseases, disease area, patient numbers, time, geographical location, subject, and research methodology (single center/multicenter, international/national, prospective/retrospective). We additionally analyzed endpoints reported in all COVID-19-related expanded access publications. Results: We screened 3810 articles and included 1231, describing 523 drugs for 354 diseases for 507,481 patients. The number of publications significantly increased over time ( p < 0.001 ). Large geographical disparities existed as Europe and the Americas accounted for 87.4% of all publications, whereas Africa only accounted for 0.6%. Oncology and hematology accounted for 53% of all publications. Twenty-nine percent of all expanded access patients (N = 197,187) reported on in 2020 and 2021 were treated in the context of COVID-19. Conclusions: By summarizing characteristics of patients, diseases, and research methods described in all scientific literature published on expanded access, we provide a unique dataset for future research. We show that published scientific research on expanded access has surged over the past decades, partly due to COVID-19. However, international collaboration and equity in geographic access remain an issue of concern. Lastly, we stress the need for harmonization of research legislation and guidance on the value of expanded access data within real-world data frameworks to improve equity in patient access and streamline future expanded access research. [ABSTRACT FROM AUTHOR]

Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber's Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) is a signal transducer and activator of a protein transcription system that transduces signals from cell surface cytokine and growth factor receptors to the nucleus. Recently developed JAK inhibitors (JAKinibs) inhibit JAKs non-selectively or selectively and down-regulate the effects of corresponding ligands (i.e. cytokines and growth factors). JAKinibs are efficacious against rheumatoid arthritis and other immune-mediated inflammatory diseases and are being increasingly prescribed clinically. Regarding safety, JAKinib use is associated with common or unique changes in laboratory parameters; however, incidence rates of serious adverse drug reactions (ADRs) associated with these changes are low. Opportunistic and other infections, including tuberculosis, are the most critical ADRs of treatment with JAKinibs, and screening and monitoring of patients should be carefully performed. Incidence rates of herpes zoster (HZ) in patients receiving JAKinibs are high in Japan and Korea, and modestly high in other countries. Filgotinib may not be associated with an elevated risk for HZ, but long-term safety data are lacking. Data from clinical development programmes and post-marketing surveillance have indicated no increased risk for malignancy or serious cardiac events; however, long-term observational studies are necessary. Despite the non-elevated risk of gastrointestinal perforations, patients with older age and/or a history of diverticulitis or receiving non-steroidal anti-inflammatory drugs should be carefully evaluated to determine the risk-benefit balance. The incidence rates of venous thromboembolism with all approved doses are similar to that expected in the population, although there are discrepancies in the placebo-controlled portion of the baricitinib clinical development programmes. Regulatory agencies in the USA and Europe suggested a higher risk for thrombotic events in patients receiving JAKinibs. Pharmacokinetic studies demonstrated that dose adjustment should be considered for JAKinib use in patients with moderate-to-severe renal or hepatic dysfunction, depending on the metabolism of each drug. Long-term observational studies enrolling patients with diverse clinical backgrounds are required to strike a risk-benefit balance in clinical settings. [ABSTRACT FROM AUTHOR]

S-1 (Teysuno) is an oral anticancer agent comprising the 5-fluorouracil (5-FU) prodrug tegafur and targeted modulators, gimeracil and oteracil. S-1 in combination with cisplatin is a recommended first-line treatment for gastrointestinal cancers in Japan and has recently been approved in the EU for the treatment of advanced gastric cancer. This article reviews S-1 pharmacology from an EU perspective. In a randomized, open-label trial in 24 non-Asian countries in patients with advanced gastric cancer, there were no significant differences between S-1 plus cisplatin and 5-FU plus cisplatin groups in median overall survival (OS) [primary endpoint], progression-free survival or overall response rate. In a post hoc analysis of OS, S-1 plus cisplatin was noninferior to 5-FU plus cisplatin. There were no significant between-group differences in patient quality of life, according to the Functional Assessment of Cancer Therapy (Gastric) Trial Outcome Index, except that S-1 plus cisplatin recipients had a significantly longer time to worsening in physical well-being than 5-FU plus cisplatin recipients. Overall, S-1 plus cisplatin was better tolerated than 5-FU plus cisplatin, with significantly lower rates of haematological, some gastrointestinal tract and other adverse events, serious adverse events and deaths resulting from toxicity, along with significantly fewer haematological and renal function abnormalities. Compared with 5-FU, S-1 plus cisplatin recipients had significantly higher rates of hand-foot syndrome and hyperbilirubinaemia, although there were no between-group differences in the proportions of patients with increased liver enzymes. S-1 is a useful alternative to 5-FU for patients with advanced gastric cancer. [ABSTRACT FROM AUTHOR]