Orphan drugs in glioblastoma multiforme: a review

Lassen, Ulrik; Mau-Sørensen, Morten; Poulsen, Hans Skovgaard

doi:10.2147/odrr.s46018

Cited by 7 publications

(5 citation statements)

References 83 publications

(73 reference statements)

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“…While some of the substances that we highlight here were already discussed and contained in a review by Lassen et al [ 18 ], the surge in immunotherapeutic approaches which we highlight here seems noteworthy. For many of these novel, immunotherapeutic products, no efficacy data in the sense of randomized, placebo-controlled trials have been published.…”

Section: Discussionmentioning

confidence: 92%

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

2021

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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 Fourteen orphan drug designations were subsequently withdrawn for unknown reasons.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.

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Section: Discussionmentioning

confidence: 92%

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

2021

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“…In 2017, the Wick et al RCT concluded that CCNU in combination with bevacizumab did not provide a survival advantage compared to CCNU alone (OS: 9.1 vs. 8.6 months; PFS: 4.2 vs. 1.5 months) [ 39 ]. CCNU is considered the key factor in the PCV regimen (P: procarbazine, C: lomustine, V: vincristine) which has been approved by the FDA as a regimen for HGGs [ 41 ]. In 2010, the Brada et al RCT compared PCV to TMZ in patients with recurrent HGGs; they concluded PCV did not differ significantly in OS (6.7 vs. 7.2 months), PFS (3.6 vs. 4.7 months), quality of life, or adverse events [ 42 ].…”

Section: Fda-approved Therapiesmentioning

confidence: 99%

Current FDA-Approved Therapies for High-Grade Malignant Gliomas

2021

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The standard of care (SOC) for high-grade gliomas (HGG) is maximally safe surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months. Before this SOC was established, glioblastoma (GBM) patients typically lived for less than one year after diagnosis, and no adjuvant chemotherapy had demonstrated significant survival benefits compared with radiation alone. In 2005, the Stupp et al. randomized controlled trial (RCT) on newly diagnosed GBM patients concluded that RT plus TMZ compared to RT alone significantly improved overall survival (OS) (14.6 vs. 12.1 months) and progression-free survival (PFS) at 6 months (PFS6) (53.9% vs. 36.4%). Outside of TMZ, there are four drugs and one device FDA-approved for the treatment of HGGs: lomustine, intravenous carmustine, carmustine wafer implants, bevacizumab (BVZ), and tumor treatment fields (TTFields). These treatments are now mainly used to treat recurrent HGGs and symptoms. TTFields is the only treatment that has been shown to improve OS (20.5 vs. 15.6 months) and PFS6 (56% vs. 37%) in comparison to the current SOC. TTFields is the newest addition to this list of FDA-approved treatments, but has not been universally accepted yet as part of SOC.

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“…1 Lessen et al stated that “the PCV regimen is frequently utilized as a control regimen in randomized phase III studies and has recently received FDA approval for recurrent HGG”. However, the given data only serve as level III evidence, 34 and no evidence could be found to classify it in the FDA-approved regime, and thus PCV is classified as a non-FDA-approved drug and discussed in the following section.…”

Section: Current Drugs For Gbm Treatmentmentioning

confidence: 99%