UPDATED: Ariad hammered on toxicity concerns for leukemia drug Iclusig

Lingering safety concerns about Ariad Pharmaceuticals' ($ARIA) blockbuster leukemia drug Iclusig (ponatinib) erupted into a crisis today as the biotech slammed the brakes on new trial enrollment and rolled out a lower dosing schedule for patients in a slate of ongoing studies after investigators tracked a rising rate of blood clots among patients taking the treatment.

Ariad shares were down 76% by midmorning, wiping out $2.5 billion of the $3.2 billion market cap the Cambridge, MA-based company had at yesterday's close.

Investigators tracked serious arterial thrombosis--blood clots--in 11.8% of Iclusig-treated patients after 24 months of therapy, up from the 8% rate seen after a year, prompting the FDA to clamp a partial hold on enrollment as the company changes the dose for currently enrolled patients from 45 mg to 30 mg daily unless they have achieved a "major molecular response." Patients at that stage will see their dose drop to 15 mg. And in the future investigators will exclude patients who have "experienced prior arterial thrombosis resulting in heart attack or stroke."

Ariad added that the label will also be changed on Iclusig. 

Iclusig was given an accelerated approval for resistant or intolerant chronic myeloid leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia patients last December on Phase II data, which arrived just 5 years after clinical trials began for the drug. And the biotech had ambitiously pursued a slate of studies aimed at broadening its use among leukemia patients as it began marketing the drug at a cost of $115,000 a year.

According to Ariad's website there are currently 8 different trials underway for ponatinib, including the pivotal PACE study for newly diagnosed patients with chronic myeloid leukemia. Investors will likely question now whether the drug's toxicity issues will severely crimp sales.

In addition to the rate of arterial thrombosis, researchers tracked a 6.2% rate of cardiovascular events, a 4% rate of cerebrovascular events and 3.6% peripheral vascular events, with some patients having more than one type of event.

Iclusig targets CML cells that have a particular mutation, known as T315I, that makes these cells resistant to currently approved tyrosine kinase inhibitors. Ponatinib generated impressive results in a pivotal study, which showed that more than half of patients with chronic myeloid leukemia who failed prior treatment had a major cytogenetic response on the experimental BCR-ABL inhibitor. This is important because patients with the disease build resistance to current therapies such as Novartis' ($NVS) blockbuster Gleevec, and patients with resistant disease eventually run low on treatment options. 

"We believe that the actions we are taking will help us ensure the most appropriate and safe use of Iclusig. With two years of follow up, we have learned a great deal about both the efficacy and safety of Iclusig in patients with Philadelphia-positive leukemias," said Ariad CEO Harvey Berger. "We are focused first and foremost on the needs of cancer patients--to have new medicines that provide both safe and effective treatment of their malignancies. Our unwavering commitment to patients has led us to promptly take the steps we have outlined."

- here's the press release

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