Analogous to CTIC, SUPG has a "hidden" drug that might eventually prove much more significant than its high profile lead drug. IN SUPG's case it is decitabine which I predict will eventually become a fairly widely used adjunct to much chemotherapy. (It has some tox issues, though, so it's not a wonder drug). Its mode of action is quite unique - it's a demethylating agent. Excess methylation silences tumor suppressor genes in many cancers. (It potentially also is synergistic partner for HDAC drugs - see the recent review of this topic in the NEJM).
(NASDAQ:SUPG) SuperGen, Inc.
Published Clinical Data Suggests that Dacogen(TM), Administered
Subcutaneously, is Active as a Treatment for Sickle Cell Anemia
- Dec 4, 2003 09:15 AM (PR Newswire)
- finance.lycos.com
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Data appearing in current issue of Blood to be presented at symposium
preceding Annual Meeting of the American Society of Hematology
DUBLIN, Calif., Dec. 4 /PRNewswire-FirstCall/-- SuperGen, Inc.
(Nasdaq: SUPG) announced today that results of a clinical study, published in the current issue of the journal Blood (vol. 102, no. 12, pp. 3855-56), suggest that the investigational anticancer compound Dacogen(TM) (decitabine for injection) is active in treating sickle cell anemia. Updated data from the clinical study will be presented Friday, December 5th at a SuperGen-sponsored symposium preceding the 45th Annual Meeting of the American Society of Hematology (ASH) in San Diego.
Principal Investigator Yogen Saunthararajah, M.D., at the University of Illinois at Chicago led the Phase I/II clinical study. The primary objective of the study was to test whether subcutaneously administered Dacogen could safely reactivate fetal hemoglobin. Eight patients diagnosed with sickle cell anemia and resistant or intolerant to hydroxyurea (the current standard of
care) were enrolled. Each patient received Dacogen administered subcutaneously, one to three times per week, in two cycles of six-week duration. Each patient treated with Dacogen had increases in levels of fetal hemoglobin. Fetal hemoglobin interacts with sickle hemoglobin to reduce the complications of sickle cell disease. Some debilitating complications of sickle cell disease include severe pain, pneumonia, stroke, and renal failure.
Surrogate (laboratory) indicators of sickle cell disease also improved in Dacogen treated patients. In addition, levels of total hemoglobin increased an average of 26 percent.
Researchers reported that the subcutaneous regimen was well tolerated, with the only significant toxicity and most frequent event being neutropenia.
Standard NCI criteria for toxicity were used. No local toxicity was noted at the subcutaneous injection site and no nausea, vomiting, diarrhea, constipation or loss of appetite was reported.
"The preclinical and clinical data continue to be very encouraging and help to validate our belief that Dacogen could become an important agent in the treatment of sickle cell disease," said Dr. Saunthararajah, Assistant Professor of Medicine and Director of the Adult Sickle Cell Clinic at the University of Illinois at Chicago. Dr. Saunthararajah was the lead author of the paper that was published in Blood and will present updated results at the symposium.
"The publication of these encouraging clinical results in the peer- reviewed medical journal Blood is a further indication that Dacogen may be useful as a treatment for sickle cell disease," said Craig Rosenfeld, M.D., Senior Vice President and Chief Scientific Officer of SuperGen.
The primary mechanism of action for Dacogen in sickle cell disease is thought to be reduction of DNA methylation at the gamma globin gene promoter.
In the publication, Dr. Saunthararajah directly demonstrates reduction in gamma globin gene promoter methylation by two molecular techniques.
Dacogen previously received orphan-drug designation from the Food and Drug Administration (FDA) for the treatment of sickle cell anemia, which may provide seven years of market exclusivity if, among other conditions, the drug is approved for this indication.
Sickle cell anemia is an inherited disorder of the red blood cells. Red blood cells carry oxygen to all parts of the body using a protein called hemoglobin. Normal red blood cells contain mostly Hemoglobin A and are shaped like discs. Normal red cells are very flexible and move easily through small blood vessels. However, in sickle cell anemia, the red blood cells contain sickle hemoglobin, which causes them to change to a curved shape (sickle
shape) and become less flexible after oxygen is released. 'Sickled' cells therefore may become stuck and form blockages in small blood vessels. Because these vessel blockages can occur in all parts of the body, damage can occur in any part of the body. Elevations in fetal hemoglobin are associated with reduced complication from sickle cell anemia.
Sickle cell anemia is most common among people whose ancestors come from Africa, the Middle East, the Mediterranean basin, and India. In the United States, it affects primarily African Americans, more than 50,000 of whom have the disease, according to the Center for Disease Control and Prevention. One in 12 African-Americans carries the sickle cell trait. The median age at death of patients with sickle cell anemia is reduced by 25-30 years, compared to African-Americans in general.
Here is an ASH abstract on a combo with a Histone Deacetylase Inhibitor:
2295] Preclinical Studies of the Combination of the Hypomethylating Agent 5-aza-2-Deoxycytidine (Decitabine) and the Histone Deacetylase Inhibitor (HDI) Valproic Acid (VPA) in Leukemic Cell Systems. Session Type: Poster Session 466-II
Hui Yang, Koyu Hoshino, Andreia A. Canalli, Blanca Sanchez-Gonzalez, Hagop Kantarjian, Jean-Pierre Issa, Guillermo Garcia-Manero Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA
DNA methylation and the biochemical modification of nucleosome associated histone tails are two epigenetic mechanisms that have a role in gene expression control. In oncogenesis, aberrant DNA methylation of promoter associated CpG islands results in gene repression, a phenomenon functionally equivalent to deletion or inactivating mutations. DNA methylation is frequently associated with histone deacetylation, and both molecular mechanisms have been reported to be tightly regulated. Several agents with hypomethylating and histone deacetylase inhibitory activity are currently being developed. Because of the close relationship between DNA methylation and histone deacetylation, we hypothesized that the combination of a hypomethylating agent and a HDI will have synergistic antineoplastic activity. To test this hypothesis and to develop future clinical studies, we have studied the effect of the combination of decitabine, a potent antileukemia agent with hypomethylating activity, with VPA. VPA is currently used as an antiepileptic agent and has been recently shown to have potent HDI activity. We treated the leukemic cell lines MOLT4 and HL60 with VPA and decitabine alone and in combination at increased concentrations and time exposures. Both agents were able to reinduce the expression of the cyclin dependent kinase inhibitors p57KIP2 (that is methylated and silenced in both cell lines) and p21CIP1 (that is not methylated but silenced also in both cell lines). As expected, the induction of p57KIP2 by VPA was not mediated by hypomethylation of its promoter CpG island, but it was associated with histone hyperacetylation as measured by western blot. Decitabine induced the demethylation of p57KIP2 in MOLT4 but not in HL60, despite its positive effect on p57KIP2 gene rexpression in that cell line. Using trypan blue and MTT assays, both decitabine and VPA had cytostatic effects in both cell lines with a 1 to 3 log reduction in cell growth after a 3 day exposure to decitabine at doses ranging from 1 to 10 M, and 5 days of VPA at doses of 0.1 to 10 mM. We then combined decitabine with VPA using the following schema: decitabine for 4 days at a concentration of 0.5 M and VPA for 3 days at a concetration of 1 mM starting 24 hours after decitabine. By the four day of this combination no viable HL60 or MOLT4 cell could be detected. This is in contrast with the untreated cell line control that continue to grow at an exponential rate at that endpoint. These results suggest that the combination of a hypomethylating agent and a HDI, in this case VPA, is more potent than each agent alone and may have significant in vivo antileukemia activity at dose levels achievable in humans.
Abstract #2295 appears in Blood, Volume 102, issue 11, November 16, 2003
Keywords: 5-aza-2-deoxycytidine|valproic acid|leukemia
Sunday, December 7, 2003 5:45 PM
Poster Session: Acute Leukemia: New Agents II (5:45 PM-7:15 PM) |
