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Ariad Suspends Iclusig Sales; Shares Take Another Tumble

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By Catherine Shaffer
Staff Writer

Ariad Pharmaceuticals Inc. suspended sales of its leukemia drug Iclusig (ponatinib) due to potential blood clot issues upon request from the FDA. The discouraging news follows termination of Ariad’s Phase III EPIC trial in first-line chronic myelogenous leukemia (CML), and a clinical hold due to those same safety issues.

While Ariad is negotiating with the FDA and said it would like to continue marketing the drug, investors are fleeing in droves. Ariad’s stock (NASDAQ:ARIA) fell $1.76, or 44.4 percent, to close Thursday at $2.20.

“We continue to work with the FDA to negotiate updates to prescribing information for Iclusig,” said Ariad CEO Harvey J. Berger during a conference call Thursday morning. “We believe there are patients for whom there’s a positive risk-benefit profile.”

The Cambridge, Mass.-based biotech’s troubles kicked into high gear early in October, when follow-up safety data showed increased incidents of arterial blood clots in patients treated with Iclusig, prompting the FDA to issue a partial clinical hold. Ariad immediately lost three-quarters of its stock value, as nervous investors waited to learn how the news would affect the drug’s status as a potential blockbuster. It was approved in late 2012 for use in patients with chronic, accelerated and blast phases of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia whose disease is resistant or intolerant to tyrosine kinase inhibitors (TKIs). (See BioWorld Today, Oct. 10, 2013.)

The approval came with a black-box warning for potential risks of arterial thrombosis and liver toxicity, which raised concerns from analysts. (See BioWorld Today, Dec. 17, 2012.)

Updated data from the pivotal PACE study seemed to confirm those concerns. At a median follow-up of 24 months, serious arterial thrombosis occurred in 11.8 percent of patients treated with Iclusig, compared to a rate of 8 percent at 11 months, the data used in the current prescribing label for the drug.

Serious venous occlusion occurred in 2.9 percent of Iclusig-treated patients, compared to a figure of 2.2 percent reported in the prescribing information. The total nonserious and serious arterial and venous adverse event rate was 20 percent of treated patients.

According to Ariad, there was no new information or safety data revealed since Oct. 9 that led to the FDA’s request to suspend U.S. sales of the product.

In an update to its previous communication regarding increased reports of serious blood clots connected with use of Iclusig, the FDA issued a new safety announcement for Iclusig on Oct. 31 . In that update, the agency said approximately 24 percent of patients in the Phase II trial and approximately 48 percent of patients in the Phase I trial have experienced serious adverse events, including heart attack, stroke, loss of blood flow to the extremities resulting in tissue death and severe narrowing of blood vessels requiring surgical intervention.

Those trials did not include control groups, so the relationship to treatment with Iclusig is unclear. “However, the increasing rate and pattern of the events strongly suggests that many are drug-related,” the agency said. “At this time, FDA cannot identify a dose level or exposure duration that is safe.”

That wording was especially troubling for Cowen and Co. analyst Phil Nadeau. “We found two pieces of new information in the FDA’s communication concerning,” he wrote in a research note. In addition to being unable to identify a safe dose level, “the FDA highlights an analysis of adverse events that is even more worrisome than the one released a couple of weeks ago.”

The FDA also said that in the Phase II trial, adverse events affecting the blood vessels that supply the heart, brain and extremities were observed in 12 percent, 6 percent and 8 percent of patients, respectively, and that those events were observed even in patients in their 20s without cardiovascular risk factors, as well as in patients with risk factors. Other observed serious adverse events included blindness and blurred vision, high blood pressure and heart failure.

During the conference call, Berger said the FDA’s analysis was consistent with the company’s analysis.

The FDA’s instructions for patients and doctors were that patients currently taking the drug and not responding should immediately discontinue it. Those who are responding to the drug and whose physicians believe that the benefits outweigh the risks should be treated under a single-patient Investigational new drug application or expanded access registry program while the agency is conducting its safety investigation. It said doctors should not begin treating new patients with Iclusig unless no other treatment options are available and all other available therapies have failed.

Iclusig’s uncertain status gives breathing space to two other CML drugs that were recently approved. Pfizer Inc.’s Bosulif (bosutinib) was approved in September 2012 based on data showing a 27 percent major cytogenetic response. And the agency approved Teva Pharmaceuticals Industries Ltd.’s Synribo (omacetaxine mepesuccinate) in October 2012.

Ariad executives expressed confidence that Iclusig eventually would return to the market under a narrower label than what was previously approved. Berger said Ariad has shared information with other regulatory bodies around the world. “We’ve been completely transparent with each of them over the past several weeks with available information about the safety of Iclusig,” Berger said. “It’s too early to know exactly how the EMA and European countries will react to our decision to suspend marketing in the U.S. We are not suspending marketing anywhere other than the U.S.”

The company said it did not yet have any information on whether further studies would be necessary, or what the path forward would be. “There hasn’t been guidance given to us,” Berger said. “We are definitely going to enroll patients in trials of one type or another at lower doses. More than that, I can’t make any comment. We haven’t reached any decisions.”

Analyst opinion, however, was largely negative. “If negotiations around an updated label were going to be resolved quickly, then it’s probably unlikely the suspension would have been implemented in the first place,” wrote JP Morgan analyst Cory Kasimov.

Outside of Iclusig, Ariad is developing AP26113 for ALK-positive non-small-cell lung cacer, and that drug has shown activity, with a 65 percent overall response rate. But much of the company’s value is perceived to reside in Iclusig.