With approval of Dacogen (decitabine), the injectable drug for myelodysplastic syndromes from MGI Pharma Inc. and SuperGen Inc. expected May 15, analysts continue to weigh the compound’s chances against Vidaza (azacitidine), Pharmion Inc.’s pyrimidine nucleoside analogue.
Both drugs target higher-risk, further-advanced cases, and a physician poll by Robert Baird & Co. last summer found for those patients not given erythropoietin, Vidaza held the front position. Almost 80 percent of doctors said they had used the drug alone or in combination with Celgene Corp.’s Thalomid or Trisenox (arsenic trioxide), Cell Therapeutics Inc.’s leukemia compound that was sold last year to Cephalon Inc. in a deal worth up to $170 million. (See BioWorld Financial Watch, Aug. 29, 2005.)
In lower-risk patients, about one-third of physicians said they prescribed Vidaza, which was approved in the U.S. in May 2004, and another third prescribed Thalomid, with 10 percent prescribing the two in combination.
The survey reported that Vidaza’s overall penetration still was only 20 percent. Revlimid (lenalidomide, a derivative of Thalomid), which gained approval at the start of this year for severe anemia associated with MDS, was called in the Baird report "clearly top of mind" among doctors questioned. (See BioWorld Financial Watch, Jan. 2, 2006.)
Cleared specifically for patients with low to intermediate-1 risk MDS associated with a deletion 5q cytogenetic abnormality, Revlimid also gained acceptance in October of its review for the same indication by the European Medicines Agency.
Add another opinion to the stack. Vinny Jindal, newly appointed co-head of ThinkEquity Partners LLC’s health care research group, published a report as he initiated coverage of SuperGen this month, predicting that "superior data, more favorable reimbursement, and the marketing muscle [of MGI] will make Dacogen the drug of choice in the high-risk MDS market."
Dacogen works two ways. It’s a nucleoside analogue, replacing cytosine in the cancer cell’s DNA and halting cell division, and it’s a hypomethylating agent, blocking the activity of DNA methyltransferase enzymes, an action that allows for proper expression of cells that regulate how cells divide.
"Hematologists view [Dacogen and Vidaza] as undifferentiated from each other," Jindal told BioWorld Financial Watch, but urged them, and investors, to "look a little more closely at the data."
Dacogen’s Phase III trial proved the drug "basically the same" as Vidaza, he said, except that Dacogen helped sicker patients with lesser amounts - two cycles of therapy, as opposed to nine cycles of Vidaza. Also, with Dacogen, one-fourth the amount of drug was used per cycle. Because Dacogen is less toxic, it’s likely to prevail in all subtypes of MDS, except those patients with the 5q abnormality who respond well to Revlimid, Vindal said.
Could the FDA, which last fall called Dacogen "approvable" but asked for more material (provided by MGI and SuperGen), ultimately give the drug a thumbs-down? It’s possible but not likely, since the drug met its co-primary endpoint of response rate, which was enough to win clearance for Vidaza. But the latter still gets only a 16 percent overall response rate (Dacogen gets 17 percent), which leaves a high unmet need and more incentive for the FDA to give its nod.
Dacogen also may have an advantage in its three-day, inpatient administration cycle. Vidaza’s cycle lasts for seven days, but patients often do not comply. Many attend only for five days.
"Most patients don’t like going into the hospital on the weekend," Jindal said.
Pharmion has experimented with Vidaza given for five days, with two days off, followed by five more days, or with the drug given for five days, with two days off, followed by only two more days. Another schedule tested was five days on drug with no therapy after.
"There was no difference in response rates with all three trials," he said. "Vidaza has done all it can do."
Dacogen may have more potential. Though the intravenous drug requires a three-hour infusion, thrice daily for three days, and thus requires two overnights in a hospital, patients may prefer this to seven consecutive days of travel to the clinic for subcutaneous Vidaza, he said.
New dosing regimens are being tried with Dacogen, too. First results from a Phase II trial at M.D. Anderson Cancer Center were reported at last year’s American Society of Hematology meeting. In that study, patients with intermediate-1, intermediate-2 and high-risk MDS were randomized to get one of three Dacogen regimens every four weeks: a 20 mg/m2 intravenous one-hour infusion once per day for five days, a 10 mg/m2 one hour infusion once per day for 10 days or a 10 mg/m2 subcutaneous injection twice per day for five days.
For 96 evaluable patients, the overall response rate was 47 percent, including a 42 percent complete response and a 5 percent partial response. In the 65 patients treated in the first regimen, the complete response rate was 49 percent, with the most frequently observed adverse events showing up mainly as a result of myelosuppression. They included fever (4 percent) and infection (9 percent).
"Because it’s a single-center trial, hematologists are taking it with a grain of salt," Jindal allowed. "But if [the response rate] is even half that in a multicenter trial, and you’re in the 22 percent or 23 percent range, that’s significantly better" than what’s been achieved so far, he noted.
At any rate, "there appears to be some plasticity" and advantage to changed dosing with Dacogen, unlike its main competitor, he said. MGI expects to complete enrollment in an ongoing multicenter Phase II trial evaluating the one-hour infusion daily for five days, which investigators determined to be the optimal of the three alternates in the M.D. Anderson studies.
Chemotherapy, radiation, viral infection or a genetic flaw can cause MDS, which includes five diseases regarded as precursors to leukemia. The symptoms are anemia, with weakness, fatigue, frequent infections, easy bruising, bleeding, fever, weight loss and a sense of feeling full. Officially classed as a disease in 1976, MDS arises in 7,000 to 12,000 new patients annually, mainly in people older than 60.
Also taking their place in the MDS market, of course, are erythropoietin-stimulating proteins such as Epogen (epoetin alfa) and Aranesp, the second generation of Epogen, from Amgen Inc., front-line therapies for anemia, which typically crops up as a complication of MDS.
Since Dacogen is a nucleoside analogue, MGI is trying Dacogen against acute myeloid leukemia (with eight trials ongoing), chronic myelogenous leukemia, and various solid tumors.
Meanwhile, Jindal expects the drug to launch for MDS in the third quarter of this year, and by the end of the year, "there will be a clear signal" that Dacogen is better, he said.
"The clinical experience of Dacogen will prove to be superior, but the major driver in changing the view of hematologists will be the publication of more data," he said.