Chemistry:Asunercept
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Asunercept (INN; development codes APG101 and CAN008)[1] is a soluble CD95-Fc fusion protein which is in clinical development for the treatment of glioblastoma multiforme (GBM) and myelodysplastic syndromes (MDS).[2] Asunercept has been granted orphan drug status for the treatment of GBM and MDS in the EU and the US.[3][4][5] It has also received PRIME designation by the European Medicines Agency (EMA) for the treatment of GBM.[6]
Mechanism of action
Asunercept blocks the CD95–ligand (CD95L) from binding to the CD95-receptor (CD95), which induces apoptosis. In oncology, this blockade is intended to prevent the killing of activated T cells[7] that can be induced by tumor-associated macrophages (TAMs),[8] endothelial cells,[9] or fibroblasts.[10]
In MDS, CD95L-signaling is a negative regulator of erythrocyte production in the bone marrow and its blockade has been shown to rescue erythroid progenitors.[11]
Clinical development
A randomized, double-blind, placebo-controlled phase I study to examine the safety and tolerability of asunercept has shown that it is well tolerated.[12] The efficacy of asunercept was tested in a phase II randomized controlled trial for patients with GBM. A total of 83 patients with first or second relapse of GBM were enrolled in the successful proof-of-concept trial. The primary goal of doubling the number of patients reaching progression-free survival at six months (PFS6) was substantially exceeded.[13]
Asunercept has also been successfully tested in a phase I trial to treat patients with MDS.[14] MDS is a disease in which the bone marrow does not make enough healthy blood cells, which leads to blood cytopenias, especially anemia.[15]
References
- ↑ Wei, Kuo-Chen; Hsu, Peng-Wei; Tsai, Hong-Chieh; Lin, Ya-Jui; Chen, Ko-Ting; Toh, Cheng-Hong; Huang, Hui-Lin; Jung, Shih-Ming et al. (2021-12-15). "Safety and tolerability of asunercept plus standard radiotherapy/temozolomide in Asian patients with newly-diagnosed glioblastoma: a phase I study" (in en). Scientific Reports 11 (1). doi:10.1038/s41598-021-02527-1. ISSN 2045-2322. PMID 34911992.
- ↑ "Protein therapeutics for cancer & inflammatory diseases". Apogenix. http://apogenix.com/en/.
- ↑ "Orphan designation, Europe". Orphanet, the portal for rare diseases and orphan drugs. 2017-10-05. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=82093.
- ↑ "Treatment of glioblastoma multiforme". U.S. Food and Drug Administration (FDA). 2012-07-24. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=293009.
- ↑ "Treatment of Myelodysplastic Syndrome". U.S. Food and Drug Administration (FDA). 2009-10-13. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=371612.
- ↑ "Asunercep, PRIME Designation". European Medicines Agency (EMA). 2017-05-27. https://www.ema.europa.eu/documents/chmp-annex/recommendations-eligibility-prime-scheme-adopted-chmp-meeting-15-18-may-2017_en.pdf.
- ↑ "Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism". Cancer Immunol Immunother 68 (5): 835–847. 2018. doi:10.1038/s41467-017-00784-1. PMID 30406374. Bibcode: 2017NatCo...8.1404Z.
- ↑ "Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes". Nat Commun 8 (1): 1404. 2017. doi:10.1038/s41467-017-00784-1. PMID 29123081. Bibcode: 2017NatCo...8.1404Z.
- ↑ "Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors". Nat Med 20 (6): 607–15. 2014. doi:10.1038/nm.3541. PMID 24793239.
- ↑ "Cancer-associated fibroblasts induce antigen-specific deletion of CD8+ T Cells to protect tumour cells". Nat Commun 9 (1): 948. 2018. doi:10.1038/s41467-018-03347-0. PMID 29507342. Bibcode: 2018NatCo...9..948L.
- ↑ "APG101 efficiently rescues erythropoiesis in lower risk myelodysplastic syndromes with severe impairment of hematopoiesis". Oncotarget 22 (12): 14898–911. 2016. doi:10.18632/oncotarget.7469. PMID 26910909.
- ↑ "Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients". Int Immunopharmacol 13 (1): 93–100. 2012. doi:10.1016/j.intimp.2012.03.004. PMID 22446296.
- ↑ "A phase II, randomized, study of weekly APG101+reirradiation versus reirradiation in progressive glioblastoma". Clin Cancer Res 15 (24): 6304–13. 2014. doi:10.1158/1078-0432.CCR-14-0951-T. PMID 25338498.
- ↑ "Safety and efficacy of the CD95-ligand inhibitor asunercept in transfusion-dependent patients with low and intermediate risk MDS". Leuk Res 68: 62–69. 2018. doi:10.1016/j.leukres.2018.03.007. PMID 29549809.
- ↑ "Myelodysplastic Syndromes Treatment (PDQ®)–Patient Version". National Cancer Institute. 18 February 2005. http://www.cancer.gov/cancertopics/pdq/treatment/myelodysplastic/Patient/page1.
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