Asunercept (APG101) – Overview

Apogenix’ lead drug candidate asunercept (APG101) is a fully human fusion protein that consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG antibody. Asunercept is being developed for the treatment of solid tumors and malignant hematological diseases and has been evaluated in the treatment of glioblastoma and myelodysplastic syndromes (MDS).

The excellent tolerability of asunercept was shown in a double-blind, placebo-controlled phase I trial in healthy volunteers. Even the highest dose of 20 mg/kg body weight was very well tolerated and no anti-drug antibodies against asunercept were detected.

 

 

Asunercept (APG101) as a Therapeutic for Solid Tumors

Asunercept inhibits the CD95 ligand which plays an important role in the progression of solid tumors. Depending on the target cell – immune cell or tumor cell – the interaction between the CD95 ligand and the CD95 receptor induces either apoptotic cell death or invasive growth of cells. Consequently, asunercept has a dual mechanism of action.

 

Mode of Action of Asunercept (APG101)

 

Inhibition of Tumor Immune Escape
(Immune Cells):

The interaction between the CD95 ligand on tumor endothelial cells and on tumor cells and the CD95 receptor on immune cells leads to the death of apoptosis-sensitive immune cells before they can enter the tumor in order to attack it. This process is called tumor immune escape.

 

Asunercept blocks the CD95 ligand on tumor endothelial cells and on tumor cells, thereby preventing its interaction with the CD95 receptor on immune cells. As a result, immune cells remain intact and can enter the tumor in order to attack it.

Inhibition of Invasive Growth
(Tumor Cells):

The second mechanism by which the CD95 system promotes the growth of solid tumors is the binding of the CD95 ligand to the CD95 receptor on tumor cells. This interaction activates an intracellular signaling pathway that stimulates the invasive growth of tumor cells.
 

 

By blocking the CD95 ligand, asunercept prevents the CD95 receptor from binding to its ligand. As a result, the invasive growth of tumor cells is inhibited.
 

 

 

Asunercept (APG101) for the Treatment of Glioblastoma

In a randomized, controlled phase II efficacy trial in recurrent glioblastoma, treatment with asunercept in combination with radiotherapy has shown clinical superiority in all study endpoints compared to treatment with radiotherapy alone. Both progression-free survival at six months, the primary endpoint of the trial, and median progression-free survival were met with statistical significance.

Biomarker Development

Glioblastoma patients having a newly-identified biomarker associated with the CD95 ligand – the target of asunercept – experienced the greatest benefit from treatment with asunercept. The trial showed a significant increase in median overall survival in biomarker-positive patients treated with asunercept.

Apogenix is developing a companion diagnostic based on this biomarker to identify glioblastoma patients who will most likely respond best to treatment with asunercept. The biomarker will be validated in future clinical trials and in additional indications, so asunercept can be developed for use as a targeted therapy.

 

 

Asunercept (APG101) for the Treatment of Myelodysplastic Syndromes (MDS)

In MDS, the CD95 ligand inhibits the differentiation and development of red blood cells. Asunercept blocks the CD95 ligand, thereby enabling the maturation of erythrocyte precursor cells to functional erythrocytes. Preclinical studies with bone marrow from MDS patients show that asunercept dose-dependently stimulates erythropoiesis.

Final results from a phase I trial with asunercept in low and intermediate-1 risk MDS patients demonstrated the tolerability as well as activity of the drug candidate: The substance stimulated erythropoiesis and led to a clear decrease in transfusion frequency in this patient population. Apogenix is currently in preparation of Phase II proof-of-concept trials to further evaluate the efficacy and safety of asunercept in the treatment of MDS patients.