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EMA Reviewing Ariad's Iclusig; Firm Presents Additional Data at ASH Meeting

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The European Medicines Agency announced it would launch an in-depth review of the benefits and risks of the leukemia medicine Iclusig (ponatinib).

“In November 2013, the EMA reviewed updated clinical trial data with Iclusig indicating that cases of blood clots and blockages in the arteries and veins were occurring at a higher rate than was observed at the time of the medicine's initial authorization,” the EMA said in an announcement, noting that at the time the agency recommended several measures to minimize these risks, such as including a warning for those with cardiovascular risks.

Iclusig received marketing authorization from EU regulators in July as an orphan drug. The US Food and Drug Administration approved the drug last year, but in November asked Ariad to suspend marketing of the drug while the agency evaluated higher rates of life-threatening blood clots and narrowing of the blood vessels in clinical studies involving the drug.

The FDA-approved label for Iclusig includes a boxed warning for thrombosis risk and liver toxicities. However, the rate of serious blood clots was a lot lower in studies before the drug's approval, around 8 percent, compared to 20 percent in more recently available study results.

The EMA is taking a similarly cautious strategy given these observations. “A number of issues require further investigation, including a better understanding of the nature, frequency, and severity of events obstructing the arteries or veins, the potential mechanism through which the medicine leads to these side effects, and whether there is a need to revise the dosing recommendation of Iclusig,” the EMA said. “The agency will now carry out this review to assess the need for further changes to how the medicine is used.”

The EMA's Pharmacovigilence Risk Assessment Committee will conduct the review and make recommendations to the Committee for Medicinal Products for Human Use, which then will adopt a final opinion on the drug.

Iclusig, an inhibitor of the BCR-ABL tyrosine kinase, is indicated as a treatment of leukemia patients who cannot receive other drugs in this class, such as Gleevec (imatinib), and don't respond or can't tolerate other drugs such as Sprycel (dasatinib) or Tasigna (nilotinib). Ariad's drug is also for those who have the genetic mutation T315I, which makes leukemia patients resistant to these other agents, but the drug is not restricted to patients with this mutation.

Ariad was initially contemplating developing it with a companion test that gauges T315I mutations. However, the available evidence on Iclusig showed its ability to target all mutations conferring resistance to TKIs, and the FDA informed Ariad and test developer MolecularMD that a companion diagnostic to gauge the T315I mutation was not needed for the safe and effective use of the drug.

At the American Society of Hematology's annual meeting last week, researchers led by Javier Pinilla-Ibarz of Lee Moffitt Cancer Center presented data showing that leukemia patients can still benefit from Iclusig if they need to have their doses adjusted. “Although optimal responses were seen with average ponatinib dose intensity greater than 42 mg/day, patients can be effectively managed with dose reduction or interruption if clinically indicated,” researchers concluded.

Also at the ASH meeting, researchers led by Michael Deininger from the University of Utah looked at how single, low-level, and compound mutations at baseline impacted patients' responses to Iclusig in the Phase II PACE trial. Usingnext-generation sequencing, researchers identified20 unique single mutations in more than one patient at baseline. However,“responses to ponatinib were observed regardless of baseline mutation status,” they reported in an abstract presented at the meeting.

Notably, responses “tended to be lower” in those without mutations, Deininger and colleagues said, which may signal that BCR-ABL independent mechanisms are important for treatment response. “No single mutation conferring resistance to ponatinib in CP-CML has been observed to date,” the researchers reported. “In general, ponatinib activity was not adversely affected by the presence of compound mutations at base line.”

Additionally, in this study, compound mutations were rare at the end of treatment, which investigators believe may be because early treatment with Iclusig may suppress the emergence single BCR-ABL mutations, which in turn hinder development of compound mutations.

At the same meeting, researchers led by Cristina Papayannidis of the University of Bologna presented data from a study involving 17 leukemia patients (14 Ph+ ALL and 3 blast-phase CML), which confirmed the activity of Iclusig in advanced Ph+ leukemias, “mainly in T315I mutated patients.” The researchers noted, however, that further research is needed to better understand the molecular mechanisms associated with resistance or lack of response to the drug.

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