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Ariad's Iclusig to Relaunch in Advanced T315I-Mutated Leukemia or Third-Line Patients

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Originally published Jan. 10.

Ariad Pharmaceuticals is planning to resume marketing its leukemia drug Iclusig (ponatinib) in mid-January, with a narrower indication for a genetically-defined population and for those with unmet medical needs.

According to an Ariad spokesperson, doctors will use a lab-developed test to gauge which patients have T315I mutations.

Two months ago, upon the request of the US Food and Drug Administration, Ariad temporarily stopped selling Iclusig after the treatment was found in studies to cause life-threatening blood clots and narrowing of the blood vessels. After further reviewing the available data on the drug, the agency informed Ariad in mid-December that it could sell Iclusig as an option for a more limited subpopulation of leukemia patients and required the company to develop a risk mitigation plan under which it would inform healthcare providers of the revised indication.

The FDA initially approved Iclusig in December of 2012 as a treatment for advance chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblasic leukemia patients who are resistant or intolerant to prior treatment with other tyrosine kinase inhibitors. Following its safety review late last year, the agency altered the indication of the drug so that it now can be given only to T315I-positive, advanced CML, or Ph-positive ALL patients. Additionally, Ariad can also market the drug for advanced CML or Ph-positive ALL patients "for whom no other TKI is indicated," the FDA approved label states.

This essentially means that second-line leukemia patients must be T315I-positive to receive Iclusig. For newly diagnosed patients, there is Novartis's Gleevec (imatinib) and Tasigna (nilotinib). In later stages of disease, patients have a number of options, including Pfizer's Bosulif (bosutinib), Bristol-Myer's Squibb's Sprycel (dasatinib), and Tasigna. If patients don't respond to these TKIs, then they can receive Iclusig.

Ariad officials told investors last month that upon market reintroduction of Iclusig, the company plans to price the drug at a "modest premium" to second-generation TKIs on the market, such as Bosulif and Tasigna.

For the first three quarters, Iclusig brought in less than $40 million in sales. According to Ariad, the drug appeared to be the top choice for prescribers for patients who had failed two prior TKIs. Ariad took a financial hit in the third quarter of 2013, however, due to the temporary marketing restriction on Iclusig.

For the three months ended Sept. 30, the company had to defer nearly $5 million in revenue due to inventory at distributors that hadn't been shipped to customers. Net loss for Ariad during the third quarter was $66.3 million, compared to a net loss of $53.2 million in the year-ago period. The company also had to reduce its US staff by 40 percent (160 positions) and alter R&D plans for certain clinical trials in order to reduce or defray expenses.

Notably, for the investigational lung cancer agent AP26113, Ariad will now study the drug in a Phase I/II trial only in ALK-positive, treatment-naive and resistant patients who are resistant to Pfizer's Xalkori (crizotinib), and those with central nervous system activity. "We will no longer enroll EGFR, T790M, ROS1 or other patients in the ongoing Phase I/II trial," said Timothy Clackson, Ariad's chief scientific officer, in a call with investors in December. He added that a single-arm, open-label pivotal registration study of AP26113 in 150 patients will start in early 2014.

Despite these cuts and adjustments, in order to market Iclusig again in the US, company officials have said that they are planning to put together a dedicated sales team. The starting dose for the drug is 45 mg/daily as before, but the company will provide guidance on dose reductions for doctors who feel they need to lower Iclusig's dose to mitigate the risk of adverse events in their patients.

The FDA has asked the company to conduct a number of post-marketing studies to better understand the safety issues seen with Iclusig and to investigate the safety and efficacy of the treatment when patients are given other doses of the drug. Under the risk mitigation plan, Ariad will continue to educate doctors and professional societies about the safety risk associated with Iclusig for three years.

According to an Ariad spokesperson, "the FDA chose to limit the indication [for Iclusig] based on its analysis of updated safety data from the ongoing PACE trial." In the Phase II PACE trial, approximately 24 percent of patients treated for a median of 1.3 years on Iclusig and 48 percent in the Phase I trial treated for a median of 2.7 years experienced serious vascular events. However, there is also data from the Phase II study suggesting that leukemia patients benefit from Iclusig regardless of the resistance mutations they carry.

At the American Society of Hematology's annual meeting late last year, 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. Using next-generation sequencing, researchers identified 20 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.

Despite this evidence, FDA clearly restricted the drug's indication to advanced, T315I-mutated CML and Ph-positive ALL patients and for those who have failed to respond to two or more TKIs, in order to limit how many people are exposed to drug-related adverse events.

When developing Iclusig, Ariad had initially contemplated using a companion test to gauge the common resistance mutation T315I and identify best responders. However, in studies the drug appeared 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.

In revising Iclusig's indication, the FDA still did not require a companion test to identify leukemia patients with T315I mutations. "Physicians will use their own labs or outside labs and the T315I tests that are already available to them," the Ariad spokesperson told PGx Reporter.

In the US, around 5,000 patients are diagnosed with CML each year. Of these patients, Ariad can hope to market its drug to 1,300 patients who have T315I mutations, or require third-line or later lines of treatment. "We believe the revised indication provides physicians with the latitude to determine whether Iclusig is appropriate for patients in any phase of disease, and for whom no other TKIs are indicated," Martin Duvall, Ariad's executive VP and chief commercial officer, told investors on the December call.

During the temporary sales halt for Iclusig, the FDA had to approve an investigational new drug application for each patient taking Iclusig, responding, and whose physician recommended continuation with the treatment. At the end of October, when Ariad stopped marketing Iclusig, 640 patients were on the drug. From November to mid-December, the agency approved 350 INDs for patients.

Of these, 55 percent of patients were in chronic phase disease and 33 percent had T315I mutations. The majority of patients receiving the drug in the second-line did not have such mutations, however.

In addition to clearing Iclusig for marketing, the FDA also lifted the hold on at least one clinical trial involving the drug in medullary thyroid cancer. Ariad officials anticipate that the agency will lift its hold on other Iclusig trials in the near term. The company, however, has discontinued its Phase III EPIC study, in which it had hoped to investigate Iclusig in newly diagnosed CML patients.

"We will certainly explore additional indications in CML that will include patients who are earlier in the treatment of their disease and for other cancers such as GIST, AML, and specific forms of non-small cell lung cancer," the Ariad spokesperson said. "Several of these clinical trials are being conducted by clinical investigators working with Ariad."

Ariad officials had previously said that the FDA might convene a meeting of its Oncologic Drugs Advisory Committee this year to look into Iclusig's safety issues. But no such meeting has been scheduled, according to more recent comments from Ariad officials.

In November, the European Medicines Agency's Committee for Medicinal Products for Human Use recommended that Iclusig be marketed for advanced CML patients who are resistant or intolerant to Sprycel and Tasigna, who can't receive Gleevec, or who have a T315I mutation. Ph-positive ALL patients who are resistant or intolerant to Sprycel, who can't be on Gleevec, or those with T315I mutations can also receive Iclusig, CHMP recommended. However, the EMA is conducting a more in-depth review of Iclusig risk/benefit profile and may make additional recommendations.

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