The FDA approved Dacogen (decitabine), an orphan drug for myelodysplastic syndromes (MDS) from MGI Pharma Inc. and SuperGen Inc.
"It truly addresses the MDS," said Jennifer Davis, MGI's senior manager of investor relations, "rather than just the symptoms of the disease."
MDS refers to a group of bone marrow diseases characterized by the production of poorly functioning and immature blood cells. MGI plans a launch at the end of this month for Dacogen, a hypomethylating agent believed to work by incorporating into DNA and inhibiting an enzyme called DNA methyltransferase. That means the drug works at "the true core of this disease," Davis told BioWorld Today, "at the bone marrow and genetic level."
The Minneapolis company has worldwide rights to the intravenous product through a partnership with Dublin, Calif.-based SuperGen, its initial developer. Upon launch, SuperGen stands to receive a $20 million milestone payment and is due royalties equal to 20 percent of annual U.S. sales up to the first $50 million. Those royalties move up 2.5 percent for each additional $50 million in annual U.S. sales and peak at 30 percent.
The approval was based largely on positive Phase III data that demonstrated an overall response rate of 21 percent in Dacogen-treated patients considered evaluable for response, defined as those with pathologically confirmed MDS at baseline who received at least two cycles of treatment, compared to 0 percent in the supportive care arm. The study randomized 170 MDS patients almost evenly into the two arms, and all those who responded to Dacogen became or remained transfusion independent during the time of the response.
Among all who received Dacogen, the overall response rate was 17 percent (p<0.001), made up of a 9 percent complete response rate and a partial response rate of 8 percent. There was a median response duration of 288 days. In addition, 13 percent of patients in the Dacogen arm had hematologic improvement, compared to 7 percent of patients who received supportive care, which consisted of blood and blood product transfusions, prophylactic antibiotics and hematopoietic growth factors.
The study's co-primary endpoints were overall response rate and time to acute myeloid leukemia or death, and secondary endpoints included hematologic improvement, duration of response, cytogenetic response rate, transfusion requirements, quality of life, survival and safety.
Additional support came from two single-arm, open-label studies that generated overall response rates of 26 percent and 24 percent. Dacogen is indicated for MDS patients including previously treated and untreated, de novo, and secondary MDS of all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation and chronic myelomonocytic leukemia), and Intermediate-1, Intermediate-2 and High-Risk International Prognostic Scoring System (IPSS) groups.
MGI publicized that up to 30,000 new MDS cases are diagnosed annually in the U.S., though the FDA estimated less than half that figure, and most diagnoses are in people older than 60. Their life expectancies typically range between six months and five years, depending on the disease's severity at the time of diagnosis. About 20,000 are treated monthly, and of the more than a dozen treatments used in that space, most are used to treat MDS symptoms, according to several patient advocacy groups. But two drugs represent more direct competition as they also treat the underlying disease: Revlimid (lenalidomide, from Celgene Corp.) and Vidaza (azacitidine, from Pharmion Corp.).
Since Revlimid's label is indicated for just a subset of MDS patients, whereas Vidaza's label is indicated for a wider group like Dacogen, the latter is seen as a more direct competitor. Davis noted that Dacogen's potency differentiates the two, although she said efficacy comparisons would be difficult given that there have not been any head-to-head studies.
MGI's projections put Dacogen sales at $25 million this year and eventually peaking at $250 million in the U.S. The company's sales staff, which numbers more than 150, will target about 6,000 oncologists who treat MDS stateside.
The FDA said the newly approved treatment could help patients avoid blood transfusions. Dacogen-induced hypomethylation in neoplastic cells is thought to restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the drug's cytotoxicity also might be attributed to the formation of covalent adducts between DNA methyltransferase and its active ingredient incorporated into DNA.
MGI, which already has a footprint in oncology with Aloxi (palonosetron hydrochloride) and the Gliadel Wafer (polifeprosan 20 with carmustine implant) in its portfolio, is eyeing a wider label for Dacogen. The company is conducting a Phase III trial to evaluate its use in AML patients, and additional Phase II studies also are under way to test alternative dosing regimens for MDS, AML and chronic myelogenous leukemia. In addition, there is a non-company sponsored Phase III study of Dacogen in European MDS patients.
The most common adverse reactions associated with Dacogen include neutropenia, thrombocytopenia, anemia, pyrexia, fatigue, nausea, cough, petechiae, constipation and diarrhea. Also, Dacogen could cause fetal harm when administered to pregnant women. It is recommended that patients be treated for a minimum of four cycles, and treatment may continue as long as the patient continues to benefit.
MGI, which has manufacturing responsibility, plans to seek a partner for Europe, and expects to file for approval there after signing a deal. Staged behind Dacogen is Saforis, an oral formulation of glutamine to treat oral mucositis for which the company recently submitted a new drug application, as well as Aquavan (fospropofol disodium), a short-acting anesthetic projected to complete Phase III enrollment by the end of this year. MGI is planning to file for its approval in the first half of next year, the same time frame in which it plans to seek a supplemental approval for Aloxi in patients with postoperative nausea and vomiting. (See BioWorld Today, March 22, 2006, and April 14, 2006.)
For SuperGen, Dacogen's approval represents a third drug from which it will earn revenue. Its portfolio already includes two chemotherapy agents, Nipent (pentostatin) for hairy-cell leukemia and Mitomycin, a generic version of Mutamycin. Its pipeline of investigational products includes Orathecin (rubitecan) for pancreatic cancer and a number of preclinical drugs being developed as inhibitors of aurora-A tyrosine kinase and DNA methyltransferase.
Wednesday, shares in MGI (NASDAQ:MOGN) were up 89 cents to $19.28, and SuperGen's stock (NASDAQ:SUPG) lost 16 cents to close at $5.22.