San Diego, CA—Data presented at the American Society of Hematology
suggest that the antibody conjugate drug, gemtuzumab ozogamicin (Mylotarg; Pfizer)—once approved for use in acute myeloid leukemia (AML) in 2000, and then voluntarily pulled from the market in 2010 due to post-marketing evidence of lack of efficacy, as well as unacceptable toxicity—may have a shot at a second coming.
Sylvie Castaigne, MD, of the Hôpital de Versailles in France, and lead investigator from the Acute Leukemia French Association (ALFA) study, detailed how she and her colleagues use a fractionated dosing regimen for Mylotarg—one that would limit toxicity, thereby allowing for its use in combination with standard chemotherapy which would boost overall efficacy.
Dr. Castaigne was able to perform the study because Mylotarg is still available in France under the limitations of compassionate use. “But using the standard dose of 9mg/m2, the drug could not be combined with chemo,” she said. By dosing the drug in three increments of 3mg/m2 over a week’s time, a combination with chemotherapy was enabled.
The trial included 278 AML patients, ages 50-70 years, who were randomized to one of two treatment arms of standard chemotherapy (60 mg/m2 of daunorubicin for three days and 200 mg/m2 of cytarabine for seven days) with or without fractionated Mylotarg. Patients were followed for three years.
Results showed that the median event-free survival time was 19.6 months in the Mylotarg arm vs 11.9 months in the chemotherapy alone arm. Overall survival was also improved significantly in the Mylotarg arm, with a median overall survival of 34 months vs 19.2 months in the chemotherapy alone arm. Adverse events were substantially lower than those historically observed with the 9mg/m2, single dose infusion of Mylotarg.
All this puts Pfizer in an awkward position. “I’ve been aware of Dr. Castaigne’s work for quite some time,” said Mark Shapiro, MD, head of Global Medical Affairs for hematology programs at Pfizer Oncology. “It’s extremely exciting. I’ve been working on this compound for several years and not just these, but other data presented at the conference are quite impressive.”
Two other unrelated studies using the fractionated dosing regimen in AML were presented with both reporting data in support of this new approach.
Where do we go from here?
The way forward, however, is not so clear. Only one other drug has plied these regulatory waters. Many healthcare stakeholders had clamored for Iressa to be pulled from the market for poor efficacy, and side effects, but in the end the FDA chose to make it available on a highly restricted basis. Like Mylotarg, Iressa had been the beneficiary of an accelerated approval.
Is there any other precedent for bringing a dead drug back to life? “I don’t know,” said Dr. Shapiro. “First we need to assess the quality of the data and determine if the results are truly robust; then we’ll sit down and have a conversation with the regulatory authorities to see if there is a path forward. “
Suffice it to say that for now, there’s an elephant in the room, as noted by, Susan O’Brien, MD, Professor, Department of Leukemia, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX. "There are actually three presentations with Mylotarg here – the (ALPHA study) was in the plenary session because the data was the most impressive. It clearly showed a dramatic improvement – not in CR rate, which is consistent across all the trials – but for event-free survival (EFS). The arm with Mylotag had a 2 year EFS of 45% vs. 15% without it."
Assuming this clinical success can be validated, Dr. O’Brien wonders about the business angle. "It’s a rather small market for Pfizer (perhaps $100 million or so). Would they sell it? Or would someone else come in that might be interested?”
And as far as a regulatory precedent… “There are drugs that have been approved and then pulled, Avastin of course, but I’m unaware of any drug that was pulled and then later re-introduced. I have no idea what the mechanism of going about that would be,“ said Dr. O’Brien, “But it’s very hard to ignore these data."
by Neil Canavan
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