Pfizer Withdraws Mylotarg Drug After Deaths, No Proven Benefit

Pfizer Inc. will withdraw its blood cancer drug Mylotarg after 10 years on the U.S. market because studies didn’t prove it works and the treatment was linked to deaths from liver and lung complications.

Mylotarg, for relapsed acute myeloid leukemia, is the first medicine to be pulled off the market that was cleared through the Food and Drug Administration’s accelerated approval program, the agency said today in a statement. Pfizer volunteered to halt sales after trial results raised safety concerns “and the drug failed to demonstrate clinical benefit,” the FDA said.

Mylotarg was approved in 2000 based on preliminary data showing improved remission rates, with a requirement for more complete trials to prove it extended survival. Wyeth, which sold Mylotarg before being purchased by Pfizer in October, didn’t start mandated follow-up research until 2004 and didn’t provide results until this year.

“Accelerated approval still has a place in the approval process but it’s also more important that we learn over the years that the whole development plan be set up well in advance,” said Robert Kane, acting deputy director for safety in the FDA’s Division of Hematology Products, in a phone interview today. “The trials should be planned and if possible under way when the sponsor submits the application.”

Photographer: Michele Tantussi/Bloomberg

A Pfizer Inc. employee walks through the company's German headquarters in Berlin, Germany. Close

A Pfizer Inc. employee walks through the company's German headquarters in Berlin, Germany.

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Photographer: Michele Tantussi/Bloomberg

A Pfizer Inc. employee walks through the company's German headquarters in Berlin, Germany.

Wyeth began a required study designed to confirm Mylotarg’s benefits in 2004, four years after it won the conditional marketing clearance. The test was stopped early when patients didn’t show any benefit on treatment and four times as many deaths were possibly attributed to the drug.

‘Disappointed’ in Results

“We are disappointed that the study did not confirm the clinical benefit of Mylotarg,” said Mace Rothenberg, Pfizer’s head of oncology development.

Pfizer will withdraw the drug from the U.S. market Oct. 15 to allow time to assess current studies and planned individual treatments, he said. Patients and researchers who want to continue using it after that time must file an investigational new drug application with the FDA. Sales of Mylotarg were $8.8 million in the first quarter, the company said.

“We have to label the drug for investigational purposes,” Rothenberg said today in a phone interview. “There’s a lot of processes to work back from saying we need this much time.”

Pfizer fell 11 cents, or less than 1 percent, to $15.10 at 4 p.m. in New York Stock Exchange composite trading. The stock dropped 17 percent this year, compared with an 8.8 percent decline in the 11-member Standard & Poor’s 500 Pharmaceuticals Index.

First Drug Approved

Mylotarg was cleared in May 2000 for patients 60 years and older who were on their first relapse of acute myeloid leukemia and weren’t considered candidates for cytotoxic chemotherapy. It was the first drug approved for this specific condition, and is used by about 2,500 patients a year, Pfizer said. The medicine is given in two infusions about 14 days apart.

“This is the first accelerated approval drug that has ever been pulled from the market,” said Ira Loss, an analyst at Washington Analysis who has followed the FDA for more than three decades. “That makes it a big deal. I don’t think it’s a big deal for Pfizer.”

The accelerated approval was based on three studies of 142 patients showing a 26 percent overall remission rate and a 5.9- month median duration of overall survival. Almost all study participants experienced declines in blood cells used in clotting and fighting infections, and half had anemia.

Risk Increased

At the time the drug was cleared, about 1 percent of patients had experienced veno-occlusive disease, a potentially deadly liver complication. The FDA revised the prescribing information to show a 10 percent risk in 2006, according to Kane. The agency hasn’t tracked a precise number of deaths caused by Mylotarg because it’s difficult to determine if a fatality was the result of the treatment or the disease, he said.

“I’m very mixed about this decision,” Mikkael Sekeres, director of the Cleveland Clinic’s leukemia program and a member of the FDA’s Oncologic Drugs Advisory Committee, said in an interview after the recall was announced. “On the one hand, it limits my arsenal of therapies. On the other hand, kudos to the FDA for saying that a drug that hasn’t shown a survival advantage, and that hasn’t resulted in improvements in patient reported outcomes, maybe shouldn’t be an option.”

European Rejection

European regulators recommended against approval of Mylotarg in 2007, citing three studies that showed “only a small proportion” of patients achieving complete remission while on the drug and a lack of comparisons with other treatments.

The five-year Mylotarg study released in December didn’t show benefit in response rate, disease free survival or overall survival in 627 previously untreated patients ages 18 to 60. Deaths possibly related to treatment were reported in 1.4 percent of patients taking standard therapy and 5.7 percent of patients with Mylotarg added to therapy, according to an analysis by the Southwest Oncology Group, one of the largest clinical trials cooperative groups supported by the National Cancer Institute.

Acute myeloid leukemia causes abnormal cells to grow inside bone marrow and replace healthy blood cells, increasing the risk of infection and bleeding. The disease most often occurs around age 65, according to the National Cancer Institute. About 13,000 patients are diagnosed a year in the U.S., according to Pfizer.

Common Form

A more common form of the condition, called chronic myelogenous leukemia, occurs in youth or middle-age and is usually caused by a chromosome abnormality. Treatments include Gleevec and Tasigna, from Basel, Switzerland-based Novartis AG, and Sprycel from New York-based Bristol-Myers Squibb Co.

Accelerated approval was authorized in 1992 to help spur development of medicines for HIV. The first accelerated cancer drug came in 1995, and many subsequent grants have been given because tumor shrinkage or other physical signs that cancer is being defeated can be measured more quickly than prolonged survival.

Of 53 new uses for cancer drugs approved from July 2005 to December 2007, nine got accelerated approval, according to a study provided by the FDA. The agency said it doesn’t have complete historical data on these decisions.

Pfizer’s recall of the drug is “very bad news” for leukemia patients who haven’t responded to other treatments, said Peter Marks, director of leukemia services at Yale-New Haven Hospital.

Keeping Patients Alive

“There are some people who I can honestly say would not be on this earth were it not for this drug,” Marks said today in an interview. While some of Marks’s patients suffered “serious liver complications” after taking the drug at the FDA-approved dose, he said he administers the medicine in smaller doses over a longer period of time.

“Since we’ve changed over to this method of using it in divided doses, we’ve really not seen any of those same complications,” Marks said. “It just doesn’t happen. The question is, with larger studies, will that be shown to have the kind of efficacy that will be needed to convince FDA that this is a valuable drug.”

To contact the reporter on this story: Catherine Larkin in Washington at clarkin4@bloomberg.net.

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