Search Results (5)

Recently, marketing authorizations were granted by the Federal Drug Administration (FDA) for pegcetacoplan and avacincaptad pegol, which inhibit C3 and C5 complement components, respectively. These two drugs were demonstrated to slow down the growth of atrophic areas in the retina. These authorizations represent a huge breakthrough for patients suffering from geographic atrophy (GA), the late stage of the dry form of Age-related Macular Degeneration (AMD). Until then, no treatment was available to treat this blinding disease. However, these two new compounds inhibiting the complement system are still not available for patients outside of the United States, and they are not devoid of drawbacks, including a poor effect on vision improvement, an increased risk of occurrence of the neovascular form of AMD and the burden of patients receiving recurrent intravitreal injections. Thus, the important medical need posed by GA remains incompletely answered, and new therapeutic options with alternative modes of action are still required. Oxidative stress and inflammation are two major potential targets to limit the progression of atrophic retinal lesions. Dimethyl fumarate, dimethyl itaconate and other activators of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) display antioxidants and immunomodulatory properties that have shown evidence of efficacy in in vitro and in vivo models of dry AMD. Tecfidera^®, whose active principle is dimethyl fumarate, is already commercialized for the treatment of autoimmune diseases such as multiple sclerosis and psoriasis. The aim of this review is to present the rationale and the design of the clinical trial we initiated to test the effectiveness and safety of repurposing Tecfidera^®, which could represent a new therapeutic alternative in patients with the dry form of AMD. Full article

Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated antioxidant responses. Tecfidera is an orally administered FDA-approved drug for the treatment of multiple sclerosis, where the active pharmaceutical ingredient is dimethyl fumarate (DMF), an active Nrf2 activator. However, no studies have evaluated the efficacy of DMF for age-associated persistent lung fibrosis. Here, we demonstrate that in IPF lung fibroblasts, DMF treatment inhibited both TGF-β-mediated pro-fibrotic phenotypes and led to a reversal of established pro-fibrotic phenotypes. We also evaluated the pre-clinical efficacy of lung-targeted (inhaled) vs. systemic (oral) delivery of DMF in an aging murine model of bleomycin-induced persistent lung fibrosis. DMF or vehicle was administered daily to aged mice by oral gavage or intranasal delivery from 3–6 weeks post-injury when mice exhibited non-resolving lung fibrosis. In contrast to systemic (oral) delivery, only lung-targeted (inhaled) delivery of DMF restored lung Nrf2 expression levels, reduced lung oxidative stress, and promoted the resolution of age-dependent established fibrosis. This is the first study to demonstrate the efficacy of lung-targeted DMF delivery to promote the resolution of age-dependent established lung fibrosis. Full article

Dimethyl fumarate is a cytoprotective and immunomodulatory drug used in the treatment of multiple sclerosis. We performed a bibliometric study examining the characteristics and trends of the top 100 cited articles that include dimethyl fumarate in the title. On 21 September 2020 we carried out an electronic search in the Web of Science (WOS), seeking articles that include the following terms within the title: dimethyl fumarate, BG-12, or Tecfidera. To focus our investigation on original research, we refined the search to include only articles, early access, others, case report, and clinical trials. We obtained a total of 1115 items, which were cited 7169 times, had a citation density of 6.43 citations/item, and an h-index of 40. Around 2010, there was a jump in the number of published articles per year, rising from 5 articles/year up to 12 articles/year. We sorted all the items by the number of citations and selected the top 100 most cited (T100). The T100 had 4164 citations, with a density of 37 citations/year and contained 16 classic research articles. They were published between 1961 and 2018; the years 2010–2018 amassed nearly 80% of the T100. We noted 17 research areas with articles in the T100. Of these, the number one ranking went to neurosciences/neurology with 39 articles, and chemistry ranked second on the T100 list with 14 items. We noticed that the percentage of articles belonging to different journals changed depending on the time period. Chemistry held the highest number of papers during 1961–2000, while pharmacology andneurosciences/neurology led the 2001–2018 interval. A total of 478 authors from 145 institutions and 25 countries were included in the T100 ranking. The paper by Gold R et al. was the most successful with 14 articles, 1.823 citations and a density of 140.23 citations/year. The biotechnological company Biogen led the T100 list with 20 articles. With 59 published articles, the USA was the leading country in publications. We concluded that this study analyzed the use of and research on dimethyl fumarate from a different perspective, which will allow the readership (expert or not) to understand the relevance of classic and recent literature on this topic. Full article

Multiple sclerosis (MS) is the most common multifocal inflammatory demyelinating disease of the central nervous system (CNS). Due to the progressive neurodegenerative nature of MS, developing treatments that exhibit direct neuroprotective effects are needed. Tecfidera™ (BG-12) is an oral formulation of the fumaric acid esters (FAE), containing the active metabolite dimethyl fumarate (DMF). Although BG-12 showed remarkable efficacy in lowering relapse rates in clinical trials, its mechanism of action in MS is not yet well understood. In this study, we reported the potential neuroprotective effects of dimethyl fumarate (DMF) on mouse and rat neural stem/progenitor cells (NPCs) and neurons. We found that DMF increased the frequency of the multipotent neurospheres and the survival of NPCs following oxidative stress with hydrogen peroxide (H₂O₂) treatment. In addition, utilizing the reactive oxygen species (ROS) assay, we showed that DMF reduced ROS production induced by H₂O₂. DMF also decreased oxidative stress-induced apoptosis. Using motor neuron survival assay, DMF significantly promoted survival of motor neurons under oxidative stress. We further analyzed the expression of oxidative stress-induced genes in the NPC cultures and showed that DMF increased the expression of transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) at both levels of RNA and protein. Furthermore, we demonstrated the involvement of Nrf2-ERK1/2 MAPK pathway in DMF-mediated neuroprotection. Finally, we utilized SuperArray gene screen technology to identify additional anti-oxidative stress genes (Gstp1, Sod2, Nqo1, Srxn1, Fth1). Our data suggests that analysis of anti-oxidative stress mechanisms may yield further insights into new targets for treatment of multiple sclerosis (MS). Full article

Background: Recently, collaboration between regulators and payers was set up and was mainly focused on evidence generation along product clinical development. However, neither the regulatory path nor the new active substance status (NASs) was considered. Granting NASs will provide the product with 8 years of data protection and 2 years of market exclusivity during which no generic could enter the market. Objective: To review the economic impact (for payers) of NASs granted by the European Medicines Agency (EMA) for dimethyl fumarate (DMF), developed by Biogen and approved for multiple sclerosis (MS) as Tecfidera^® on 3 February 2014. Method: We reviewed the available DMF-containing products and identified their indication and price through relevant databases and official Web sites. The economic impact of Tecfidera^® on payers’ budgets was calculated assuming NASs was or was not granted. The forecast was identified in Datamonitor. Results: Results identified four products already containing DMF as the main or unique active substance. This would have potentially prevented Tecfidera^® from being granted NASs. The EMA Committee for Medicinal Products for Human Use (CHMP) denied Tecfidera^® NASs and, following a company appeal, reversed its position opening as polemic. The impact of that decision has been evaluated at €7 to €10 billion over a 10-year period. Conclusion: NASs is a critical decision because it does have a major budget impact for payers, and it prevents generic competition. Current European Union (EU) regulations on that topic are unclear and open up too many interpretations thus distorting fair trade and affecting payers’ bills. Greater clarity and more stringent rules are required to prevent mistrust of this EMA decision. Full article