Ten years after Pfizer Inc. voluntarily yanked it from the market due to toxicity issues, acute myeloid leukemia (AML) drug Mylotarg (gemtuzumab ozogamicin) is returning to the market, following FDA approval Friday for use in adults with newly diagnosed disease whose tumors express the CD33 antigen.
The agency also approved use of the antibody-drug conjugate (ADC) in patients, ages 2 and older, with CD33-positive AML refractory to treatment. New York-based Pfizer noted that made it the only AML drug with a pediatric indication.
Mylotarg originally won FDA accelerated approval back in 2000 for treating older patients with CD33-positive AML following relapse, at the time marking a big win for the AML space, which hadn’t seen a new therapy in decades. But after confirmatory trials fell short in terms of clinical benefit – no improvement was seen in complete response, disease-free survival or overall survival – while highlighting safety issues, including a number of early deaths, and fatal hepatotoxicity and veno-occlusive disease (VOD) added to the label during the postmarketing period, Pfizer opted to pull it from shelves. (See BioWorld Today, May 22, 2000, and Oct. 15, 2010.)
But the unmet need prompted additional work and, on the second regulatory pass, a reduced dosage ameliorated much of the safety concern. The FDA’s Oncologic Drugs Advisory Committee voted 6-1 in July that the ALFA-0701 trial demonstrated a favorable risk-benefit for Mylotarg to once again be used to treat AML. (See BioWorld, July 12, 2017.)
“Mylotarg’s history underscores the importance of examining alternative dosing, scheduling and administration of therapies for patients with cancer, especially in those who may be most vulnerable to the side effects of treatment,” noted Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
Friday’s approval also signals that the agency is willing to consider event-free survival (EFS) as a valid endpoint, which could be good news for other leukemia drugs making their way through the clinic, such as Immunogen Inc.’s ADC, IMGN-779, which reported promising first-in-human data at the Congress of the European Hematology Association meeting in Madrid in June.
IMGN-779, which also targets CD33, is the first ADC in Immunogen’s pipeline to use the firm’s new DNA-alkylating agent, IGN DGN462.
A CD33-targeting ADC from Seattle Genetics Inc. was one of the stars of last year’s American Society of Hematology meeting before toxicity issues resulted in an FDA clinical hold on phase I and phase I/II AML trials in December. In June, the Bothell, Wash.-based firm discontinued the phase III CASCADE trial testing the drug, designated vadastuximab talirine (formerly SG N-CD33A), as a front-line treatment for older patients with AML after reviewing unblinded data indicating a higher rate of deaths in the vadastuximab talirine-containing arm vs. the control arm. (See BioWorld Today, Dec. 28, 2016.)
Whether the FDA’s Mylotarg decision will have any bearing on Seattle Genetics’ program is anyone’s guess. But in a research note just ahead of Mylotarg’s July adcom, H.C. Wainwright analysts wrote they “believe a possible approval of Mylotarg based on EFS could in fact resurrect SGEN’s 33A in the near future.”
Analysts said a Mylotarg approval could also give a “boost” to Actinium Pharmaceuticals Inc.’s Actimab-A, an alpha particle immunotherapy also targeting CD33, currently undergoing a phase II study in newly diagnosed AML patients, ages 60 and older.
AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of white blood cells in the bloodstream. CD33 is estimated to be expressed in up to 90 percent of AML patients.
In its approval, the FDA’s label includes a boxed warning for hepatotoxicity, including severe or fatal hepatic VOD.