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FDA Approves Pfizer's Chronic Philadelphia Chromosome-Positive CML Drug Bosulif

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The US Food and Drug Administration has approved Pfizer's Bosulif (bosutinib) as a treatment for chronic, accelerated, or blast-phase Philadelphia chromosome-positive chronic myelogenous leukemia for patients who are resistant or intolerant to other treatments, such as Novartis' Gleevec (imatinib).

Approximately 5,000 patients in the US will be diagnosed with Ph-positive CML this year. The disease is caused by a genetic mutation — the Philadelphia chromosome — that produces the defective BCR-ABL kinase, which produces too many abnormal white blood cells. Bosulif inhibits the BCR-ABL kinase as well as Src-family kinases.

In approving Bosulif, the FDA gave the drug Orphan Drug status, which means it is a treatment for a rare condition. As part of its marketing application, Pfizer submitted data from a single study involving 546 patients with chronic, accelerated, or blast-phase CML, who had progressed despite treatment with Gleevec, Novartis' Tasigna (nilotinib), or Bristol-Myers Squibb's Sprycel (dasatinib), or could not tolerate the side effects of these other treatments. All patients in the study received Bosulif.

In the study, Pfizer researchers gauged efficacy in terms of the number of patients who experienced a major cytogenetic response within the first 24 weeks of treatment. Among those who had previously been treated with Gleevec, 34 percent achieved MCyR after six months. "Of the patients who achieved MCyR at any time, 52.8 percent had their response last at least 18 months," FDA reported in a statement announcing the drug's approval. Among patients who were treated with Gleevec followed by Tasigna or Sprycel, around 27 percent experienced MCyR within the first six months, and for those who achieved MCyR at any time, 51.4 percent experienced MCyR for at least nine months.

"In patients with accelerated CML previously treated with at least imatinib, 33 percent had their blood counts return to normal range (complete hematologic response) and 55 percent achieved normal blood counts with no evidence of leukemia (overall hematologic response) within the first 48 weeks of treatment," the agency reported. "Meanwhile, 15 percent and 28 percent of patients with blast phase CML achieved complete hematologic response and overall hematologic response, respectively."

Common side effects seen in Bosulif-treated patients were diarrhea, nausea, low platelet count, vomiting, stomach pain, rash, anemia, fever, and fatigue.

Bosulif is the fourth drug the agency has approved for Ph-positive CML in the last 11 years. The FDA approved approved Gleevec in 2001, Sprycel in 2006, and Tasigna in 2007.

Pfizer told PGx Reporter that the average monthly cost for Bosulif is less than $8,200, which is similar to the price of other approved agents for patients who have progressed on Gleevec treatment.

Clinical guidelines recommend that doctors periodically monitor Ph-positive CML patients' response to tyrosine kinase inhibitors such as Bosulif and Gleevec by tracking BCR-ABL transcript levels. If, during treatment, BCR-ABL transcript levels rise, that is a signal that the patient may not be achieving a major cytogenic response and that a different treatment strategy may be necessary.

There are a number of companies marketing tests to monitor BCR-ABL transcripts. Cepheid and Novartis are collaborating on the development of a test for monitoring BCR-ABL gene transcripts to help doctors more reliably manage Ph-positive CML patients treated with Gleevec and other tyrosine kinase inhibitors (PGx Reporter 10/13/2010).

Cepheid recently launched an updated version of its Xpert BCR-ABL Monitor test that incorporates lot-specific standardization using the World Health Organization's BCR-ABL standards. The test has CE-IVD marking in Europe. Cepheid and Novartis plan to file for regulatory approval for the test in the US.

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