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FDA Approves Ariad's Iclusig for Molecularly Defined, TKI-Resistant Leukemias


Originally published Dec. 17.

The US Food and Drug Administration this week granted accelerated approval for Ariad Pharmaceuticals' Iclusig as a treatment for two types of rare, genetically characterized leukemias.

Iclusig (ponatinib) is a treatment for patients with chronic, accelerated phase, or blast phase chronic myeloid leukemia or Philadelphia-chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to tyrosine kinase inhibitors. The drug targets the Philadelphia chromosome gene mutation T315I, which is found in most CML patients and confers resistance to marketed TKIs. Translocations in the Philadelphia chromosome resulting in BCR-ABL fusions also occur in ALL in up to 30 percent of adult patients and between 2 percent and 10 percent of pediatric cases.

In September, MolecularMD, a diagnostics firm that was developing a companion test to personalize treatment with Ariad for Iclusig, announced that it had voluntarily withdrawn its premarket approval application for the test. The agency informed the companies at the time that MolecularMD's BCR-ABL T315I Mutation Test was "no longer considered to be a companion diagnostic test for ponatinib" (PGx Reporter 9/19/2012).

According to publicly available statements from Ariad, the company designed Iclusig to bind to the BCR-ABL tyrosine kinase and inhibit the "entire spectrum of mutants conferring resistance against other TKIs, including the T315I" mutation, which makes patients resistant to all current therapies for these diseases. Ariad estimates that between 15 percent and 30 percent of resistance-causing BCR-ABL mutations are T315I mutations.

"The drug is effective in all settings: with no mutations, with T315I, or with other mutations, making the companion test less impactful," Jorge Cortes of the University of Texas MD Anderson Cancer Center, who led the clinical trial for the drug, previously explained to PGx Reporter.

According to Cortes, looking at drug response based on T315I mutation carriers and non-carriers in clinical trials was a learning experience about the underlying disease biology, but the data indicated that a companion test was not necessary for Iclusig. Mutation testing with a companion test "would be more relevant for dasatinib [Bristol-Myers Squibb's Sprycel], nilotinib [Novartis's Tasigna], or bosutinib [Pfizer's Bosulif] than for ponatinib," he noted, "because they do not work if there is [a] T315I [mutation]."

The FDA said that it reviewed the marketing application for Iclusig under a six-month priority review clock, but granted approval for the drug more than three months ahead of its user fee date of March 27, 2013.

In order to garner approval for Iclusig, Ariad submitted data from a single trial involving approximately 450 patients with various phases of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. In CML patients, researchers looked at how well Iclusig reduced the percentage of cells expressing the T3151 mutation. In the trial, 54 percent of all patients, and 70 percent of those with the T3151 mutation, achieved major cytogenetic response.

In patients who had accelerated or blast phase CML and Ph-positive ALL, researchers looked at whether the drug caused a major hematologic response — in other words, whether Iclusig treatment normalized white cell counts and all evidence of leukemia disappeared. The data showed that 52 percent of accelerated phase CML patients experienced a major hematologic response for a median of 9.5 months; 31 percent with blast phase CML saw a major hematologic response for a median of 4.7 months; and 41 percent of Ph-positive ALL patients had a major hematologic response for a median of 3.2 months.

FDA has also granted orphan designation to Iclusig, since CML and Ph-positive ALL are rare blood and bone marrow diseases. “The approval of Iclusig is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T315I mutation who have had few therapeutic options,” Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, said in a statement.

This year brought the availability of a number of new treatment options for leukemia patients. The FDA in September approved Pfizer's Bosulif for patients with chronic, accelerated or blast phase Philadelphia chromosome positive CML who are resistant to or who cannot tolerate other therapies; and in October approved Teva Pharmaceuticals' Synribo (omacetaxine mepesuccinate) to treat various phases of CML for those progressing despite treatment with TKIs. In August, the agency approved Talon Therapeutics' Marqibo (vincristine sulfate liposome) for Ph-negative ALL, a rare type of the disease causing BCR-ABL fusions, as well as other cytogenetic abnormalities.

Like Iclusig, none of these other drugs — Bosulif, Marqio, or Synribio — were approved with a companion test to identify best responders.

However, there is data suggesting that patients with certain BCR-ABL mutations have resistance to Bosulif, Gleevec, Sprycel, and Tasigna. For example, a study conducted by researchers from Wyeth and the University of Milano-Bicocca tested the activity of these drugs against a panel of 18 BCR-ABL mutations associated with Gleevec resistance in CML and Ph-positive ALL. The researchers, led by Sara Redaelli of the University of Milano-Bicocca, identified eight mutations conferring moderate resistance to Bosulif, 10 mutations conferring moderate resistance to Sprycel, and 13 mutations showing moderate resistance to Tasigna and Gleevec. In addition to T315I, the V299L mutation showed high resistance for Bosulif and E255V for Gleevec and Tasigna. T315I represented the only highly resistant mutation for Sprycel.

Although no FDA-approved BCR-ABL mutation test is currently available, according to MolecularMD's website, the company offers a lab-developed Sanger sequencing-based test that gauges a number of mutations in the BCR-ABL fusion gene, including T315I.

Additionally, Novartis and Cepheid are working to launch a standardized BCR-ABL transcript monitoring test to gauge therapeutic response in CML patients. As previously reported by PGx Reporter sister publication PCR Insider, the partners plan to gain clearance for this test through the FDA (PCR Insider 9/20/2012).

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