FDA: Pfizer Voluntarily Withdraws Cancer Treatment Mylotarg from U.S. Market

Pfizer Inc. today announced the voluntary withdrawal from the U.S. market of the drug Mylotarg (gemtuzumab ozogamicin) for patients with acute myeloid leukemia (AML), a bone marrow cancer. The company took the action at the request of the U.S. Food and Drug Administration after results from a recent clinical trial raised new concerns about the product’s safety and the drug failed to demonstrate clinical benefit to patients enrolled in trials.

Mylotarg was approved in May 2000 under the FDA’s accelerated approval program. This program allows the agency to approve a drug to treat serious diseases with an unmet medical need based on a surrogate endpoint – a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that directly measures how a patient feels, functions, or survives.

Under accelerated approval, the company is required to conduct additional clinical trials after approval to confirm the drug’s benefit. If those trials fail to confirm clinical benefit to patients, or if the company does not pursue the required confirmatory trials with due diligence, the FDA can withdraw the drug from the market using expedited procedures.

Mylotarg was approved to treat patients ages 60 years and older with recurrent AML who were not considered candidates for other chemotherapy. The initial approval was based on the surrogate endpoint of response rate (i.e., the percentage of patients whose leukemia decreased or disappeared in laboratory tests), observed in 142 patients with AML across three clinical trials.

A confirmatory, post approval clinical trial was begun by Wyeth (now Pfizer) in 2004. The trial was designed to determine whether adding Mylotarg to standard chemotherapy demonstrated an improvement in clinical benefit (survival time) to AML patients. The trial was stopped early when no improvement in clinical benefit was observed, and after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone.

At initial approval, Mylotarg was associated with a serious liver condition called veno-occlusive disease, which can be fatal. This rate has increased in the postmarket setting.

“Mylotarg was granted an accelerated approval to allow patient access to what was believed to be a promising new treatment for a devastating form of cancer,” said Richard Pazdur, M.D., director, Office of Oncology Drug Products, part of FDA’s Center for Drug Evaluation and Research. “However, a confirmatory clinical trial and years of postmarketing experience with the product have not shown evidence of clinical benefit in patients with AML.”

As a result of the withdrawal, Mylotarg will not be commercially available to new patients. Patients who are currently receiving the drug may complete their therapy following consultation with their health care professional. Health care professionals should inform all patients receiving Mylotarg of the product’s potential safety risks.

Following the withdrawal, any future use of Mylotarg in the United States will require submission of an investigational new drug application to FDA.

Mylotarg is manufactured by New York City-based Pfizer.

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FDA Approves New Indication for Tasigna

The U.S. Food and Drug Administration on June 17 approved a new indication for Tasigna (nilotinib) for the treatment of a rare blood cancer when it is first diagnosed. The cancer, called Philadelphia chromosome positive chronic phase chronic myeloid leukemia (Ph+ CP-CML), is a slowly progressing blood and bone marrow disease linked to a genetic abnormality.

Tasigna is believed to work by blocking a signal that leads to leukemic cell development. The new indication expands the use of Tasigna to adult patients in earlier stages of the disease. The FDA originally approved Tasigna in October 2007 for the treatment of Ph+CP-CML in adult patients whose disease had progressed or who could not tolerate other therapies, including Gleevec (imatinib).

When Tasigna was originally approved in October 2007, the FDA identified that the therapy placed patients at risk of an abnormal heart rhythm called QT prolongation. In March 2010, the FDA approved a Risk Evaluation and Mitigation Strategy (REMS) for Tasigna to help patients and health care professionals to better understand this risk. The REMS includes an updated Medication Guide and a communication plan to help reduce medication errors involving drug-food interactions and incorrect dosing intervals.

“It’s important for companies to continue developing oncology drugs for earlier stages of the disease once they have demonstrated clinical effectiveness in resistant forms of cancer,” said Richard Pazdur, M.D., director of the Office of Oncology Drug Products, part of the FDA’s Center for Drug Evaluation and Research. “This approach has the potential to increase the availability of an effective treatment to more patients.”

In CML, too many blood stem cells develop into a type of white blood cell called granulocytes. These granulocytes are abnormal and do not become healthy white blood cells. These cells can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. When this happens, infection, anemia, or unexpected bleeding may occur.

The FDA granted Tasigna a priority review for Ph+ CP-CML. The agency completed the review in six months. The new indication for Tasigna was approved under the FDA’s accelerated approval program, which allows FDA to approve a drug to treat serious diseases with an unmet medical need based on an endpoint thought to reasonably predict clinical benefit. The company is required to collect additional long term efficacy and safety information data confirming the drug’s benefit. The accelerated approval program provides earlier patient access to promising new drugs while the confirmatory clinical trials are being conducted.

The safety and effectiveness of Tasigna were evaluated in a single clinical trial enrolling 846 patients with newly diagnosed Ph+ CP-CML. Patients received either Tasigna or Gleevec until the disease worsened, or until unacceptable side effects developed. The study was designed to measure a significant reduction in the surrogate endpoint of the number of CML cancer cells in the blood stream (i.e., major molecular response) at 12 months. About 44 percent of patients who received Tasigna experienced a major molecular response, compared with 22 percent of patients receiving Gleevec.

In patients with newly diagnosed CP-CML, the most commonly reported non-blood-related adverse drug reactions were rash, itching (pruritus), headache, nausea, fatigue, and muscle pain (myalgia). Serious blood-related drug reactions included decrease in bone marrow activity (myelosuppression), low level of platelets in the blood (thrombocytopenia), decrease in infection-fighting white blood cells (neutropenia), and anemia.

Other FDA-approved drugs to treat CML include Gleevec in May 2001 and Sprycel (dasatinib) in June 2006. Tasigna and Gleevec are marketed by East Hanover, N.J.-based Novartis Pharmaceuticals. Sprycel is marketed by New York City-based Bristol-Myers Squibb.

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