The drug development pipeline for glioblastoma—A cross sectional assessment of the FDA Orphan Drug Product designation database

Abstract

Background Glioblastoma (GBM) is the most common malignant brain tumour among adult patients and represents an almost universally fatal disease. Novel therapies for GBM are being developed under the orphan drug legislation and the knowledge on the molecular makeup of this disease has been increasing rapidly. However, the clinical outcomes in GBM patients with currently available therapies are still dismal. An insight into the current drug development pipeline for GBM is therefore of particular interest. Objectives To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat GBM. Methods Quantitative cross-sectional analysis of the U.S. Food and Drug Administration Orphan Drug Product database between 1983 and 2020. STROBE criteria were respected. Results Four orphan drugs out of 161 (2,4%) orphan drug designations were approved for the treatment for GBM by the FDA between 1983 and 2020. Fourteen orphan drug designations were subsequently withdrawn for unknown reasons. The number of orphan drug designations per year shows a growing trend. In the last decade, the therapeutic mechanism of action of designated compounds intended to treat glioblastoma shifted from cytotoxic drugs (median year of designation 2008) to immunotherapeutic approaches and small molecules (median year of designation 2014 and 2015 respectively) suggesting an increased focus on precision in the therapeutic mechanism of action for compounds the development pipeline. Conclusion Despite the fact that current pharmacological treatment options in GBM are sparse, the drug development pipeline is steadily growing. In particular, the surge of designated immunotherapies detected in the last years raises the hope that elaborate combination possibilities between classical therapeutic backbones (radiotherapy and chemotherapy) and novel, currently experimental therapeutics may help to provide better therapies for this deadly disease in the future.

Orphan drug development in alpha-1 antitypsin deficiency

“…Limitations and directions for future research. As pointed out previously, this analysis has some limitations that have to be taken into account for the correct interpretation of the present findings 21,22,27,[35][36][37] . Guided by strategic and patent related considerations manufacturers may choose not to reveal the intent to develop a drug in a publicly visible way at an early stage which may have influenced the timeline to approval in Fig.…”

“…This analysis focusses intentionally on the FDA perspective 40 and did therefore not consider regulatory jurisdictions elsewhere. Because in general drug development for rare diseases is a global endeavour, we regard the findings of the present analysis generalizable within the context of the limitations described 21 . This report serves as a baseline for future progress.…”

“…Therefore, as further explained in the introduction, in 1983, the US Orphan Drug Act passed, in order to provide incentives to pharmaceutical companies to invest into the development of drugs for rare diseases 15 . The output and impact can vary: medicines developed under the US orphan drug act in the very active field of rare cancers were in general very innovative, and had shifted from non-cytotoxic agents to targeted therapies 21,35 . Likewise, in lysosomal storage diseases, orphan drug development was very innovative with "a drug made for a disease" 22,27 .…”

Risk Factors for Prolonged Mechanical Ventilation and Weaning Failure: A Systematic Review

“…Goligher et al [ 25 ] examined respiratory muscle morphology by serial diaphragmatic ultrasound, thereby, both decreasing and increasing thickness was linked to increased PMV risk [ 25 ] The authors suggested that decreasing thickness is associated with abnormally low inspiratory effort and subsequent tissue atrophy, while increasing thickness is associated with excessive effort, possibly related to strain-induced muscle injury [ 25 ]. Relevant risk factors for prolonged weaning were baseline Glasgow Coma Scales (GCS) [ 26 ], elevated PaCO 2 at the beginning of [ 27 ] and during the first SBT [ 28 ], as well as heart rate during the first SBT [ 28 ] Hsieh et al [ 29 ] studied 47 different risk factors for prolonged weaning using an artificial neural network. The 47 input features included subject age, gender, scoring systems, such as Acute Physiology and Chronic Health Evaluation II (APACHE-II), Therapeutic Intervention Scoring System (TISS) and GCS, comorbidities, etiology of intubation and respiratory failure, pre-extubation parameters, weaning methods and parameters, and pre-extubation data.…”

A novel brain penetrant PDGFRα inhibitor HY-008 is effective against glioblastoma

“…After the treatment, GBM always recurs and turns out to be fatal rapidly since the current therapies are generally not very efficient and could hardly increase patients' survival time [4]. In the past four decades, only four drugs were approved by the FDA for GBM clinical treatment while three of them including TMZ are alkylating agents [5], which lack pertinence of oncogene and individual disease specificity. Because of all the above, GBM remains to be one of the most difficult-to-treat cancer types and there is an immense unmet medical need to develop more effective target therapies for this fatal disease.…”