Product
APG101 is a fully human fusion protein consisting of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody. A controlled phase II study with APG101 was started in December 2009 in glioblastoma multiforme (GBM, the most aggressive brain tumour). Patient recruitment was completed in September. The primary endpoint of this study has been met in Q1/2012: the study objective of increasing the percentage of patients without a progress at six months after start of treatment by 100 % was substantially exceeded. Additional data on secondary endpoints will become available in the next months.
Preparations for another phase II study with APG101 are currently ongoing in the indication myelodysplastic syndromes (MDS). It is planned to initiate this trial in 2013.
An excellent tolerability of APG101 was shown in a randomized, double-blind, placebo-controlled phase I study in 34 healthy volunteers. Even the highest dose of 20 mg/kg body weight was tolerated very well and no anti-drug antibodies against APG101 were detected. The half-life was approximately 12 days. Preclinical toxicological long-term studies of up to 100 mg/kg bodyweight twice a week underline the excellent safety profile of the drug.
Mode of Action
APG101 binds to the CD95-ligand (CD95L) and therefore inhibits the activation of the CD95 pathway by CD95L. In cancer cells which are mostly resistant to CD95-mediated apoptosis, binding of CD95L to his receptor stimulates the invasive growth of the tumour cells. By binding to CD95L, APG101 is blocking this interaction between receptor and ligand which leads to reduced invasive tumour cell growth.
Similar effects have also been observed in further solid tumours (e.g. liver, ovarian and pancreatic tumours). Various preclinical data underline the therapeutic potential of inhibition of CD95L in these indications. In contrast to tumour cells, binding of CD95L to his receptor leads to apoptosis (programmed cell death) in healthy cells. An excessive stimulation of the CD95 receptor in the bone marrow of MDS patients leads to a massive apoptosis of erythrocyte precursor cells. This results in anemia which is mostly refractory to erythropoiesis-stimulating agents and a transfusion dependency of MDS patients. By blocking the interaction between CD95 ligand and its cognate receptor, APG101 inhibits the apoptotic death of these precursor cells. Preclinical data with bone marrow derived from MDS patients show that APG101 dose-dependently stimulates erythropoiesis. In addition, APG101 prevents the of apoptosis of host cells mediated by transplanted T cells after bone marrow transplantation and therefore opens a route for the treatment of immunological diseases like aGvHD.