Hybrigenics (ALHYG) has announced the Orphan Drug designation by the American Food and Drug Administration of inecalcitol for the treatment of acute myeloid leukemia (AML) in the United States. Orphan designation qualifies the sponsor of the drug for various development incentives of the Orphan Drug Act, including tax credits for qualified clinical testing.
This favourable decision is based on in vitro and in vivo preclinical evidence showing the synergy between inecalcitol and azacytidine or decitabine, two hypo-methylating anticancer drugs, to inhibit the growth of human AML cell lines in vitro and, in vivo, to prolong the survival of mice in two different experimental models of AML (cf. Hybrigenics’ press releases of March 05 and June 20, 2014).
The molecular basis of their synergy with inecalcitol, a vitamin D receptor agonist, has been elucidated: azacytidine or decitabine “unmask” 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, resulting in an improved efficacy to limit leukemia progression over the hypo-methylating agents alone.
Azacytidine (Vidaza®, Celgene) and decitabine (Dacogen®, Janssen-Cilag) are two hypo-methylating agents already used for AML in older (>65 years old) or frail patients not eligible to standard induction chemotherapy. Inecalcitol alone has already been studied in a Phase II clinical trial in chronic lymphocytic leukemia: an inhibitory effect has been shown in half of the treated patients. Another Phase II clinical study has recently been launched in combination with imatinib (Gleevec®, Novartis) in chronic myeloid leukemia: enrolment is ongoing.
“We are actively preparing an additional clinical Phase II study of inecalcitol in combination with either azacytidine or decitabine in older or frail Acute Myeloid Leukemia patients, in France as well as in the United States,” said Jean-François Dufour-Lamartinie, Hybrigenics’ Head of Clinical R&D. “This Orphan Drug designation by the FDA will make the costs of clinical development of inecalcitol in the United States eligible to the so-called Orphan Drug tax credit. This incentive will substantially support our strategy to undertake a significant part of this Phase II clinical study in the United States, where the frequency of Acute Myeloid Leukemia seems to increase. This leukemia remains the blood cancer with the lowest 5-year survival rate: 25 per cent at best,” added Remi Delansorne, Hybrigenics’ CEO.