Pfizer's withdrawal of the myeloid leukemia therapy Mylotarg (gemtuzumab ozogamicin) from the market is not the end for the product, the company maintained.

After the confirmatory trial intended to convert the drug's approval from accelerated to full was halted early after the death rate appeared higher among patients receiving Mylotarg, Pfizer and FDA announced the voluntary withdrawal June 21.

The NDA for the conjugate therapy, a legacy Wyeth drug, will be withdrawn as of Oct. 15. Although Pfizer is recommending that no new patients be prescribed Mylotarg, patients who are currently taking the product and who have been prescribed the drug will be able to continue their course of therapy - typically two injections 14 days apart - in consultation with their physicians.

Pfizer Isn't Giving Up

Pfizer remains convinced a population can be identified that will benefit from Mylotarg.

"We need to better identify in an effective manner the people the doctors are saying benefit" from Mylotarg, Craig Eagle, vice president of Pfizer's global oncology business unit, said in an interview. "We know from hearing from specialists that there are patients who benefit from this therapy."

For that reason FDA and Pfizer have agreed that the company will make the drug available to individual specialists who want to treat new patients in the U.S. through an individual Investigational New Drug application. The one-off INDs will allow patients to access the drug and allow FDA and Pfizer to keep a closer eye on the information the IND produces and on the patients themselves, Eagle said.

Editor's note: Pfizer subsequently emphasized that it is not relying on those INDs to resurrect the drug. Neither is Pfizer recruiting patients or the physicians who treat them.

As far as the ongoing Mylotarg clinical program goes, Pfizer plans to talk with the head investigator on each trial, and ask, given this new information, how they want to manage the trial going forward, Eagle said. "We'll discuss whether the trial is still relevant, whether it's capturing the right information and so forth, revisit all that and go through the appropriate steps to affirm patients are being continually taken care of," he said.

Setbacks In The Confirmatory Trial And Post-market Reporting

"Mylotarg was granted accelerated approval to allow patients access to what was believed to be a promising new treatment for a devastating form of cancer," Richard Padzur, director of FDA's Office of Oncology Drug products, said in a statement. "However a confirmatory trial and years of postmarketing experience ... have not shown evidence of clinical benefit in patients with AML."

Padzur also pointed to the rate of veno-occlusive disease, a serious liver condition, that was a concern at the time of the 2000 approval and has increased in post-market reporting.

Post-market reporting doesn't offer the opportunity for comparisons that a trial does, argues Eagle. "The drug is being used in people who are dying of leukemia, so it becomes very difficult to ascertain whether it was infections or other things, including the disease, that cause their deaths. ... It is a challenge to interpret that data."

Clinical trials are the best way to get safety data because they offer a comparison, rather than post-market, "where you just get numbers," he said.

Mylotarg was approved to treat patients over age 60 with recurrent AML who are not considered candidates for other therapy. Approval was based on the surrogate endpoint of response rate, observed in 142 patients with AML across three trials (Health News Daily, May 19, 2000).

Wyeth, now Pfizer, launched the required confirmatory, post-approval trial in 2004. The study (SWOG S0106) compared Mylotarg added to chemotherapy (daunorubicin and cytosine arabinoside) with chemo alone in first-line patients under age 61 to determine whether the combination demonstrated an improvement in survival time.

Altogether, 627 patients were enrolled in SWOG S0106, which failed to confirm a benefit for the combination. In addition, among all patients evaluable for early toxicity, the fatal induction toxicity rate from all-cause death was significantly higher in the combination arm (16/283, or 5.7 percent versus 4/281 or 1.4 percent, P=0.01).

AML is relatively uncommon, with about 13,000 new patients annually in the U.S. Fewer than 2,500 patients receive Mylotarg each year in the U.S.

Alternative therapies include chemo, both off label and on, and bone marrow transplant regimens.

-Shirley Haley (s.haley@elsevier.com)

Mylotarg Pulled Off Market, But Pfizer Continues Search For Appropriate Population

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