Safety and efficacy of the CD95-ligand inhibitor asunercept in transfusion-dependent patients with low and intermediate risk MDS

Highlights

• Asunercept targets Fas/Fas ligand interaction.

• This is the first trial investigating the compound in patients with low and intermediate risk MDS.

• Given once a week at doses of 100 mg or 400 mg asunercept shows a very good safety profile.

• Asunercept shows biological activity in a subset of patients.

• No promotion of disease progression has been observed in this trial.

Abstract

In low risk MDS, increased apoptosis of erythroid progenitors mediated via CD95 (Fas) activation has been described to result in peripheral cytopenia. Blockade of the CD95 system can improve erythropoiesis in MDS. Asunercept (APG101) is a fusion protein consisting of the extracellular domain of human CD95 and the Fc domain of human IgG1 blocking the interaction between CD95 and its ligand. Here we report on results from a phase I study in 20 transfusion-dependent low and intermediate risk MDS patients treated with intravenous asunercept (EudraCT 2012-003027-37). Primary objectives were safety and tolerability as well as pharmacodynamic effects. Secondary objectives were hematologic improvement, incidence and time to leukemic progression as well as overall survival. Frequency and severity of adverse events were in range of what could be expected in a patient cohort comprising of elderly MDS patients. Two patients experienced a serious adverse event with a suspected relationship to asunercept. The incidence of disease progression was low. In the 20 patients a decrease of the transfusion need from a mean of 10,8 (±5,1) pRBCs during the 12 weeks treatment phase to a mean of 10,0 (±4,2) pRBCs at the end of the study was observed. In conclusion, asunercept was well tolerated and showed efficacy in transfusion-dependent low and intermediate risk MDS patients. Further clinical investigation is warranted, particularly in combination with erythropoiesis stimulating agents (ESAs).

Introduction

Myelodysplastic syndromes (MDS) are a group of heterogeneous oligoclonal stem cell disorders characterized by peripheral cytopenia and a risk of transformation into acute myeloid leukemia (AML). Anemia is the most frequent symptom and reflects the impaired erythroid cell maturation.

The regulation of erythropoiesis partially depends on the CD95 system. CD95 is a member of the death receptor family and among other effects initiates caspase-dependent apoptosis when activated by its ligand (CD95L). Immature CD95-positive erythroblasts undergo apoptotic death when interacting with mature erythroid precursors that express CD95L but also by interaction with erythroblasts at the same stage of differentiation [1,2].

In low risk MDS, a pro-apoptotic milieu with increased activity of apoptosis-promoting factors such as tumor necrosis factor and CD95L has been described [[3], [4], [5]]. The inhibition of CD95 signaling by ectopic expression of a mutated FADD decreased caspase-8 activation and inhibited apoptosis of MDS erythroid precursors [6]. Thus, inadequate activation of the CD95 system may induce excessive apoptosis in MDS erythroid cells and may contribute to impaired erythroid differentiation and anemia. Moreover, recently published results from in vitro studies suggest that overexpression of CD95 on erythroid precursor cells is associated with resistance to treatment with erythropoiesis stimulating agents (ESAs) [7].

ESAs have shown benefit in anemic MDS patients, particularly in those with low transfusion burden and low endogenous levels of erythropoietin [8,9]. Response rates range between only 30% and 60% and median response duration is approximately 2 years, i.e. all patients will eventually become transfusion dependent again [[8], [9], [10]].

In 2016, Raimbault et al. published data from ex vivo studies examining the impact of CD95L inhibition by asunercept on the erythropoiesis in low risk MDS patients. Asunercept rescued erythropoiesis and increased the number of burst-forming unit-erythroid (BFU-E) progenitors. This was exclusively the case in patient samples characterized by an initially low BFU-E forming capacity, i.e. asunercept was able to rescue erythropoiesis particularly in those patients whose hematopoiesis was most severely impaired. Improved BFU-E forming capacity was associated with a decrease in apoptosis of erythroid progenitors [7].

Asunercept is a glycosylated fusion protein consisting of the extracellular domain of the human CD95 receptor and the Fc domain of human IgG1 which effectively binds to CD95L expressed on effector cells as well as to functionally active ligand in solution, blocking the interaction with CD95 and inhibiting CD95 activation.

The aforementioned effects of a CD95 blockade on the erythropoiesis in MDS in an in vitro study provided the scientific rationale for this clinical phase I study [7]. We investigated the safety and tolerability as well as pharmacodynamic effects of asunercept on the erythropoiesis in patients with low and intermediate risk MDS that were either resistant to ESA or had a low chance of response according to the Nordic Score[8].