HEIDELBERG, Germany—Apogenix, a biopharmaceutical company developing next-generation immuno-oncology therapeutics, has announced final results from a Phase 1 trial evaluating APG101 in low to intermediate-1 risk transfusion-dependent patients with myelodysplastic syndromes (MDS). The study showed that APG101 was well tolerated in patients and efficiently stimulates erythropoiesis (the production of red blood cells).
MDS is a bone marrow disorder characterized by ineffective hematopoiesis, and it can lead to severe anemia. In most cases, the anemia is treated with blood transfusions that eventually result in an iron overload, which can damage the liver and other organs. The number of thrombocytes responsible for coagulation and the number of leucocytes that are responsible for immune defense significantly decrease in MDS patients. As a result, MDS patients frequently suffer from sudden bleeding and life-threatening infections, and they can also be at risk of developing acute myeloid leukemia.
The single-arm Phase 1 trial enrolled twenty patients with low to intermediate-1 risk MDS who were transfusion-dependent and refractory to erythropoietin-stimulating agents (ESAs). The patients were treated with APG101 over a period of three months, and followed for an additional six months. An extension of treatment was not intended. The primary objectives of the study were the safety and tolerability of APG101. Secondary objectives included changes in transfusion frequency and changes in parameters involved in erythropoiesis.
According to Dr. Thomas Höger, CEO of Apogenix, APG101 is a fully human Fc fusion protein consisting of the extracellular domain of the CD95 receptor fused to the Fc part of an IgG1 molecule. It acts as a highly specific trap for the CD95 ligand, thus blocking the interaction between CD95 and CD95L and preventing signaling mediated via the CD95 receptor. APG101 is being developed for the treatment of solid tumors and malignant hematological diseases. By blocking the CD95 ligand, which negatively regulates erythrocyte production in MDS patients, APG101 directly addresses the cause of the disorder and could potentially provide a cure for MDS.
“Depending on the cell expressing the CD95 receptor, signaling can, for example, induce programmed cell death (apoptosis). Tumor cells express CD95L and can kill activated tumor specific T cells via CD95 stimulation (tumor counterattack). Blocking the CD95L on tumor cells can therefore prevent the T cells from apoptotic death,” says Höger. “Treatment of patients with APG101 has two effects: APG101 can protect tumor-attacking immune cells by preventing their apoptosis, and APG101 can inhibit the invasive growth of, e.g., glioblastoma cells.” Apogenix has already completed a Phase 2 trial of APG101 for patients with glioblastoma multiforme, as well as this Phase 1 trial for MDS patients.
During the Phase 1 trial, APG101 was given once weekly as a 30-minute intravenous infusion. The amount of drug administered per week varied between 100 mg and 600 mg, according to Dr. Harald Fricke, chief medical officer of Apogenix. The majority of patients treated with APG101 received 400mg/week (as were all patients recruited for the European Phase 2 trial in recurrent glioblastoma). All doses were well tolerated.
According to the Phase 1 study data, treatment with APG101 led to a significant decrease in transfusion frequency for more than six months (end of follow-up period) in 44 percent of the MDS patients. In addition, measurements of parameters involved in erythropoiesis (i.e., number and function of progenitor cells) further supported the activity of APG101 in this patient population. This evidence of in-vivo activity of APG101 confirms in-vitro data recently published in Oncotarget. More details from the final results of the study are being submitted for presentation at a major medical meeting later this year.
“The number of CD34+CD36+ progenitor cells increased up to 500-fold (compared to baseline) during treatment with APG101,” Fricke tells DDNews. “Also, the BFU-E formation was dramatically increased (up to 500-fold compared to baseline), and the percentage of reticulocytes measured in the peripheral blood increased up to 50fold (compared to baseline).”
“The topline data from this Phase 1 trial continue to support the activity of APG101 in MDS patients,” said Fricke. “We were particularly excited to see that APG101 appeared to decrease the number of transfusions required by this very sick patient population. Our next step will be to initiate a Phase 2 trial in MDS to evaluate APG101 in various doses in combination with an erythropoietin-stimulating agent, and we are currently soliciting input from key opinion leaders on the design of that trial.”
According to Fricke, Apogenix is currently setting up the Phase 2 study. Patients will be treated with ESAs over a 12-week run-in phase. Those patients not responding to ESAs will receive additional treatment with APG101. The study will start sometime in the first half of 2017.