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]
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Mechanism of action
editAsunercept 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
editA 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
edit- ^ "Asunercept - Apogenix". AdisInsight. Springer Nature Switzerland AG.
- ^ "Protein therapeutics for cancer & inflammatory diseases". Apogenix.
- ^ "Orphan designation, Europe". Orphanet, the portal for rare diseases and orphan drugs. 2017-10-05.
- ^ "Treatment of glioblastoma multiforme". U.S. Food and Drug Administration (FDA). 2012-07-24.
- ^ "Treatment of Myelodysplastic Syndrome". U.S. Food and Drug Administration (FDA). 2009-10-13.
- ^ "Asunercep, PRIME Designation" (PDF). European Medicines Agency (EMA). 2017-05-27.
- ^ Zhu J, Petit PF, Van den Eynde BJ (2018). "Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism". Cancer Immunol Immunother. 68 (5): 835–847. Bibcode:2017NatCo...8.1404Z. doi:10.1038/s41467-017-00784-1. PMC 5680273. PMID 30406374.
- ^ Zhu J, Powis de Tenbossche CG, Cané S, Colau D, van Baren N, Lurquin C, Schmitt-Verhulst AM, Liljeström P, Uyttenhove C, Van den Eynde BJ (2017). "Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes". Nat Commun. 8 (1): 1404. Bibcode:2017NatCo...8.1404Z. doi:10.1038/s41467-017-00784-1. PMC 5680273. PMID 29123081.
- ^ Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, Coukos G (2014). "Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors". Nat Med. 20 (6): 607–15. doi:10.1038/nm.3541. PMC 4060245. PMID 24793239.
- ^ Lakins MA, Ghorani E, Munir H, Martins CP, Shields JD (2018). "Cancer-associated fibroblasts induce antigen-specific deletion of CD8+ T Cells to protect tumour cells". Nat Commun. 9 (1): 948. Bibcode:2018NatCo...9..948L. doi:10.1038/s41467-018-03347-0. PMC 5838096. PMID 29507342.
- ^ Raimbault A, Pierre-Eugene C, Rouquette A, Deudon C, Willems L, Chapuis N, Mathis S, Kunz C, Fricke H, Kosmider O, Bardet V, Fontenay M, Groupe Francophone des Myélodysplasies (2016). "APG101 efficiently rescues erythropoiesis in lower risk myelodysplastic syndromes with severe impairment of hematopoiesis". Oncotarget. 22 (12): 14898–911. doi:10.18632/oncotarget.7469. PMC 4924760. PMID 26910909.
- ^ Tuettenberg J, Seiz M, Debatin KM, Hollburg W, von Staden M, Thiemann M, Hareng B, Fricke H, Kunz C (2012). "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. doi:10.1016/j.intimp.2012.03.004. PMID 22446296.
- ^ Wick W, Fricke H, Junge K, Kobyakov G, Martens T, Heese O, Wiestler B, Schliesser MG, von Deimling A, Pichler J, Vetlova E, Harting I, Debus J, Hartmann C, Kunz C, Platten M, Bendszus M, Combs SE (2014). "A phase II, randomized, study of weekly APG101+reirradiation versus reirradiation in progressive glioblastoma". Clin Cancer Res. 15 (24): 6304–13. doi:10.1158/1078-0432.CCR-14-0951-T. PMID 25338498.
- ^ Boch T, Luft T, Metzgeroth G, Mossner M, Jann JC, Nowak D, Meir F, Schumann C, Klemmer J, Brendel S, Fricke H, Kunz C, Weiß C, Hofmann WK, Nolte F (2018). "Safety and efficacy of the CD95-ligand inhibitor asunercept in transfusion-dependent patients with low and intermediate risk MDS". Leuk Res. 68: 62–69. doi:10.1016/j.leukres.2018.03.007. PMID 29549809.
- ^ "Myelodysplastic Syndromes Treatment (PDQ®)–Patient Version". National Cancer Institute. 18 February 2005.