Clinical Phase II study ongoing both in France and in the United States
Hybrigenics Pharma launched both in France and the United States a double-blind placebo-controlled clinical Phase II study of inecalcitol in elderly or frail acute myeloid leukemia (AML) patients unfit for standard chemotherapy. All patients receive cycles of intravenous perfusions of decitabine in combination with oral tablet administration of inecalcitol or placebo.
The primary endpoint will be overall survival. The total number of 110 patients to be included in the study is designed to be sufficiently powered to evidence potential efficacy on mortality. Prof. O. Hermine, Chair of the Department of Hematology, Necker Hospital, Paris, is the principal investigator of the study in France and Prof. J. Cortes, Chair of the AML and CML sections, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, is the principal investigator in the United States.
Inecalcitol has been shown to be 3 to 10 times more potent than the active metabolite responsible for the activity of vitamin D to inhibit the growth of human AML cell lines, to stimulate their differentiation into more mature and functional myeloid cell type, or to induce their programmed cell death (apoptosis). In an in vivo model of AML genetically induced in mice, the treatment with inecalcitol resulted in a significant delay in the onset of the disease.
Furthermore, the in vitro combination of inecalcitol and decitabine, a hypo-methylating agent, exerted a more potent effect than the addition of the individual activities of each compound alone. The same synergy has been found in in vivo models of AML in mice treated with both compounds.
The molecular basis of this synergy has been elucidated: decitabine “unmasks” the gene coding for vitamin D receptors (by reducing the methylation of its promoter region). As a consequence, more vitamin D receptors are expressed and available to be activated by inecalcitol.
Watch the video of the mechanism of action of inecalcitol in AML.
Acute myeloid leukemia (AML) has recently become the most frequent form of leukemia and accounts for about 38% of all leukemic patients. Its incidence has recently started to increase due to so-called “secondary” AML cases several years after successful treatment of a previous cancer of a different type. In 2016 in the United States, 19,950 new cases have been diagnosed, a total of at least 40,300 patients were living with the disease and about 10,430 have died from CML; the 5-year survival rate is 26% (LLS Cancer Facts and Figures, 2016). The number of new cases diagnosed each year is estimated at 2,800 in France (Francim, 2013), 18,500 in Europe (RARECARE Working Group, 2012) and 120,000 worldwide (Globocan, 2012). AML has orphan disease regulatory status in Europe, Japan and the United States.
AML is a type of cancer that affects the blood and bone marrow. AML is characterized by a fast-increasing overproduction of immature white blood cells, called myeloblasts. These cells rapidly crowd the bone marrow, soon preventing it from making normal blood cells. They can also spill out into the blood stream and circulate around the body. Due to their immaturity, they are unable to function properly to prevent or fight infection. Inadequate numbers of red cells and platelets being made by the marrow cause anemia, and easy bleeding and/or bruising.
AML can occur at any age but is more common in adults over the age of 50 years. Treatment needs to begin soon after AML is diagnosed, as it progresses very quickly. Chemotherapy is the main form of treatment for AML; occasionally, a stem cell transplant may be used. Despite available treatments, AML shows the lowest 5-year survival rate of all leukemia: 26% in the US and 19% in Europe.