Acute Myeloid Leukemia +

Clinical Phase II study both in France and in the United States

Hybrigenics 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.

The objective of the study is to focus on the elderly or frail AML patients who can only receive monthly cycles of intravenous perfusions of decitabine (Dacogen®, Johnson & Johnson). In addition to this treatment, they will receive oral 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.

Preclinical results

In vitro, inecalcitol has been shown to be 1,000 fold more potent than 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 a model of AML genetically induced in mice, in vivo treatment by inecalcitol resulted in a delay in the onset of the disease.

Furthermore, inecalcitol has been shown to synergize with decitabine (Dacogen®, Johnson & Johnson), a hypo-methylating agent. The in vitro combination of the two compounds 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.

Disease description

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. Annual estimates of newly diagnosed AML cases amount to 20,830 in the United States (Cancer Facts and Figures 2015), 18,500 in Europe (RARECARE Working Group, 2012) and 120,000 worldwide (Globocan, 2012). AML is designated as an orphan disease in the United States, Europe and Japan.

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 is sometimes called acute myelocytic, myelogenous or granulocytic leukemia.

AML can occur at any age but is more common in adults over the age of 60 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 leukemias: 25% in the US and 19% in Europe.

Chronic Myeloid Leukemia +

Clinical Phase II study ongoing in France

Hybrigenics is currently performing an open-label clinical Phase II study of oral inecalcitol in chronic myeloid leukemia (CML) patients already under treatment by oral imatinib (Gleevec®, Novartis) for more than two years, but who still present a residual disease as measured in the blood by the specific CML biomarker called BCR-ABL. The primary endpoint is to further reduce the BCR-ABL biomarker to 10 times lower or even undetectable levels, which could be the sign of a possible cure. The objective is to enroll 54 CML patients who will be treated with the oral combination of inecalcitol and imatinib for one year. The principal investigator is Prof. H.-A. Johnson-Ansah from Caen University Hospital.

Preclinical results

Inecalcitol has been shown to preferentially inhibit the proliferation of CML progenitors and stem cells isolated from CML patients at diagnosis and cultured in vitro, as compared to normal myeloid progenitors and stem cells isolated from healthy volunteers. Furthermore, this activity was synergistic with the inhibition exerted in vitro by imatinib (Gleevec®), the reference first generation treatment of CML. By contrast, the combination of inecalcitol and imatinib had no effect on normal myeloid progenitors. The same kind of synergy has been demonstrated between inecalcitol and dasatinib (Sprycel®, BMS) or nilotinib (Tasigna®, Novartis), two other inhibitors of the Bcr-Abl tyrosine-kinase of a more recent generation than imatinib, to inhibit the in vitro growth of progenitors and stem cell isolated from CML patients.
Inecalcitol has been tested on in vitro cultures of CML stem cells isolated from a total of 18 different patients and shown to exert growth inhibition by itself, without any Bcr-Abl inhibitor, on CML stem cells from 15 out of these 18 patients. In addition, under the in vitro effect of inecalcitol alone, a panel of genes characteristic of differentiation of CML stem cells into macrophages has been identified, which could potentially be used as biomarkers predictive of clinical response to inecalcitol.

Disease description

Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is a type of cancer that starts in the bone marrow, invades the blood and then other parts of the body such as the spleen. CML evolves slowly at the beginning and, without treatment, ends by deteriorating into acute (“blast”) phases, causing deadly anemia, coagulation impairment or lack of defense against infections.

CML is an orphan adult leukemia. In the United States, 6,000 new cases are diagnosed every year and a total of 34,000 patients are presently living with the disease; the 5-year survival rate is 60% and about 800 patients die from CML every year (LLS Facts and Figures, 2015). In Europe, the incidence is 1.02 patient per year per 100,000 inhabitants (EuTOS, 2014). CML has orphan disease regulatory status in Europe, Japan and the United States.

CML is characterized by the over-production of all types of white blood cells (except lymphocytes) originating from a single stem cell, which starts escaping proper regulations. In all CML patients, the loss of cell control results from the same accidental “exchange” of “bits” of chromosomes (translocation between chromosomes number 9 and 22), which gives rise to the abnormal fusion gene called BCR-ABL. The product of this gene, the Bcr-Abl protein is hyper-functional and continuously stimulates cell proliferation. The inhibitors of the Bcr-Abl protein are used to treat CML patients and the BCR-ABL gene transcripts are well-established biomarkers of the blood concentration of residual CML cells.

Chronic Lymphocytic Leukemia +

Clinical results

The beneficial effect of vitamin D on the progression of chronic lymphocytic leukemia (CLL) was established very recently. Epidemiological studies have revealed the CLL patients suffering from vitamin D deficiency were twice as likely to die within 3 years of diagnosis compared to patients with normal vitamin D levels. Another study also showed that oral administration of vitamin D by a CLL patient could strongly decrease their blood leukemia lymphocyte count of a CLL patient.

In this context, a pilot open-label Phase II clinical study of inecalcitol has been performed in 21 CLL patients not yet eligible for immuno-chemotherapy but at high risk of progression. One patient experienced complete normalization of its blood lymphocyte count, the disease has been stablized for at least 5 months in 10 patients and no effect was seen in the 10 other patients.

Disease description

CLL is the second most frequent form of leukemia (cancerous proliferative disease of circulating blood cells) and accounts for about 30% of all newly diagnosed leukemia cases. Annual estimates amount to close to 15,000 in the United States (American Cancer Facts & Figures 2015), 4,500 in France (Francim 2013) and 105,000 worldwide (Globocan 2012).

CLL patients make too many lymphocytes (mononuclear white blood cells) of one single abnormal “family” (monoclonal) which are not fully developed (immature). Over time, these circulating lymphocytes build up in the lymphatic system and cause large, swollen lymph nodes. They may also fill the bone marrow, reducing the number of normal white cells, red cells and platelets that can be made, thereby lowering their blood counts. CLL cannot usually be cured, therapy is used to slow its progression and manage symptoms. CLL is designated as an orphan disease in the United States, Europe and Japan.


Useful links

Prostate cancer +

Clinical results

A Phase IIa study of inecalcitol, in 54 castrate-resistant prostate cancer (CRPC) patients, was run in five centers in France and led by the medical oncology department at the Georges Pompidou Hospital in Paris. The study was designed to determine the maximum tolerated dose (MTD) of inecalcitol in combination with the standard of care, Taxotere® (docetaxel).

While demonstrating excellent safety, inecalcitol, administrated in addition to Taxotere®, also showed a highly promising efficacy signals with 85% of the patients showing a PSA (Prostate Specific Antigen – a marker of disease likelihood, also used as a marker of response to therapy) decline of at least 30% during the first 3 months of therapy. This compares very favorably to Taxotere® alone as the main registration trial for Taxotere® demonstrated a greater than 30% reduction in PSA scores over the same timeframe in 67% of patients tested. Moreover, this observed response rate was also greater than published rates for other drugs in development with Taxotere®for CRPC.

Disease description

Prostate cancer is a slow-growing cancer which can be treated surgically if identified early enough. Unfortunately, it can quickly spread beyond the prostate gland before it is properly diagnosed, then requiring lengthy therapy following surgery. With 520,000 new prostate cancer cases diagnosed in 2011 in the United States, France, Germany, Italy, Spain, United Kingdom and Japan, prostate cancer is the most common cancer in men and is the second cause of death from cancer after lung cancer. The treatment modality usually includes hormonal therapy which is effective in 80% of cases however, it does not cure the cancer, it just stops it from spreading. In 20% of the cases, the cancer will grow again despite the hormonal therapy, it is then designated as “castrate-resistant prostate cancer” and will require chemotherapy-based treatment.

Useful links

Mechanism of action +

Identified for its major role in regulating calcium absorption from the gut, storage in mineral form in the bones, and excretion by the kidneys, vitamin D can influence the regulation of a very broad range of biological functions linked with cell proliferation, cell differentiation, cell death, inflammation or immune reactions. Therefore, vitamin D's role has been investigated in multiple diseases.

As shown in the figure below, calcitriol (1,25(OH)2D3- the active form of vitamin D) circulates in the body bound to the vitamin D binding protein which protects it from degradation. When it dissociates from the vitamin D binding protein and enters into the cell, calcitriol binds to the vitamin D receptor (VDR) which then links to the retinoid X receptor (RXR). This calcitriol/VDR/RXR complex then binds to specific DNA sequences called vitamin D response elements (VDRE) to induce or repress expression of target genes. VDRE-regulated genes are involved in a wide variety of biological functions (calcium homeostasis, cell proliferation or apoptosis, cell differentiation, inflammation and immunomodulation…).

Reproduit de Davis and Milner: J Nutrigenet Nutrigenomics 2011;4:1–11

Inecalcitol also acts by binding to the vitamin D receptor but some of its properties differ from calcitriol's. Inecalcitol does not bind to the vitamin D binding protein which means that it readily penetrates into cells without accumulating in the bloodstream, allowing it to have a more manageable half-life. Inecalcitol's binding to VDR is performed in a different conformation to that of calcitriol, which leads to an inecalcitol/VDR/RXR complex that not bind to the same VDREs or binds with different affinities than those of calcitriol's complex. The genes up- or down-regulated following inecalcitol binding are therefore different. For example, inecalcitol has been shown to repress cyclin D1 and cyclin C gene expression and to induce p21 and p27 gene expression more efficiently than calcitriol ; all four genes are involved in cell cycle progression.

 Literature references +


This section focuses on papers describing inecalcitol, also known as TX522.

  • Ma Y, Yu WD, Hidalgo AA, Luo W, Delansorne R, Johnson CS, Trump DL. Inecalcitol, an analog of 1,25D₃, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system. Cell Cycle. 2013 March 1. PMID: 23388458
  • Okamoto R, Delansorne R, Wakimoto N, Doan NB, Akagi T, Shen M, Ho QH, Said JW, Phillip Koeffler H. Inecalcitol, an analog of 1α,25(OH)(2) D(3) , induces growth arrest of androgen-dependent prostate cancer cells. Int J Cancer. 2011 Jul 5. PMID:21732345
  • Eelen G, Verlinden L, Rochel N, Claessens F, De Clercq P, Vandewalle M, Tocchini-Valentini G, Moras D, Bouillon R, Verstuyf A. Superagonistic action of 14-epi-analogs of 1,25-dihydroxyvitamin D explained by vitamin D receptor-coactivator interaction. Mol Pharmacol. 2005 May;67(5):1566-73. Epub 2005 Feb 22. PMID:15728261
  • Verlinden L, Verstuyf A, Quack M, Van Camp M, Van Etten E, De Clercq P, Vandewalle M, Carlberg C, Bouillon R. Interaction of two novel 14-epivitamin D3 analogs with vitamin D3 receptor-retinoid X receptor heterodimers on vitamin D3 responsive elements. J Bone Miner Res. 2001 Apr;16(4):625-38. PMID: 11315990
  • Verlinden L, Verstuyf A, Van Camp M, Marcelis S, Sabbe K, Zhao XY, De Clercq P, Vandewalle M, Bouillon R. Two novel 14-Epi-analogues of 1,25-dihydroxyvitamin D3 inhibit the growth of human breast cancer cells in vitro and in vivo. Cancer Res. 2000 May 15;60(10):2673-9. PMID:10825140

Vitamin D

This section highlights a selection of recent papers describing vitamin D and its role in cancer or other diseases.

  • Shanafelt TD, Drake MT, Maurer MJ, Allmer C, Rabe KG, Slager SL, Weiner GJ, Call TG, Link BK, Zent CS, Kay NE, Hanson CA, Witzig TE, Cerhan JR. Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia. Blood. 2011 Feb 3;117(5):1492-8. Epub 2010 Nov 3.PMID:21048153
  • Davis CD, Milner JA. Nutrigenomics, vitamin D and cancer prevention. J Nutrigenet Nutrigenomics. 2011;4(1):1-11. Epub 2011 Mar 23. PMID:21430387.
  • Plum LA, DeLuca HF. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov. 2010 Dec;9(12):941-55. Review. PMID:21119732
  • Gocek E, Studzinski GP. Vitamin D and differentiation in cancer. Crit Rev Clin Lab Sci. 2009;46(4):190-209. Review. PMID:19650715