Ariad Pharmaceuticals Inc. got an unexpected holiday gift from the FDA, with the agency granting approval to its much-lauded pan BCR-ABL inhibitor, ponatinib, more than three months ahead of the drug's March 27, 2013, PDUFA date, and only two months after the Cambridge, Mass.-based firm completed a rolling new drug submission.

Ponatinib, which has been branded Iclusig, already had been slated for a priority six-month review and accelerated approval had been widely expected by analysts.

It also came as little surprise to Ariad, which had moved the drug rapidly through clinical testing, having only enrolled the first patient in a Phase I study about 4.5 years ago, noted CEO Harvey Berger.

"I can't think of a better way to end the year," he said on a conference call, adding that, despite the earlier-than-expected nod, Ariad's commercial team is "fully trained and ready to launch," with sales reps expected to hit the field late next week and drug availability anticipated within two weeks.

Iclusig's price has been set at $9,500 per month, or about $115,000 per year.

The FDA's quick turnaround on Iclusig also could mark a promising trend. Guggenheim Partners analyst Bret Holley noted that Iclusig's nod "is further evidence of the FDA's current motivation to approve highly efficacious cancer therapies."

And few can doubt the drug's efficacy to date. Designed to block certain proteins that promote the development of cancerous cells, Iclusig is indicated for once-daily dosing in patients with chronic, accelerated and blast phases of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) whose disease is resistant or intolerant to tyrosine kinase inhibitors (TKIs) such as Gleevec (imatinib, Novartis AG).

A full readout from the PACE study was presented at the American Society of Clinical Oncology meeting in June, with data showing that 54 percent of chronic-phase CML patients, besting what had been reported previously in top-line results. And Ariad execs attending the American Society of Hematology (ASH) meeting in Atlanta earlier this week said 12-month follow-up data bumped up that response rate to 56 percent. (See BioWorld Today, June 5, 2012.)

As a comparison, Pfizer Inc.'s Bosulif (bosutinib) gained approval in September based on data showing a 27 percent major cytogenetic response.

Ponatinib also produced a 70 percent rate in patients testing positive for T3151, a mutation that has been attributed to TKI resistance.

Even better, Berger said, was the fact that the label for Iclusig goes beyond patient eligibility in the PACE study, allowing any CML or Ph+ALL patient "who has failed or been intolerant to any prior tyrosine kinase inhibitor" to be eligible for treatment. There will be no need for a companion diagnostic to screen patients specifically for the T3151 mutation, he added.

Still, all the good news was not enough to keep Ariad's stock from plummeting Friday, thanks to another unexpected gift from the FDA: a black-box warning on Iclusig's label. The company's stock (NASDAQ:ARIA) lost $4.95, or 20.7 percent, to close at $18.93.

'Efficacy Really is the Driver'

In fact, most of the analyst discussion on the conference call focused on the black-box warning, which lists the potential risks of arterial thrombosis and liver toxicity. In clinical testing, serious arterial thrombosis occurred in 8 percent of patients treated with Iclusig, while two cases of liver failure in patients with advanced disease were reported.

More than one analyst admitted to being caught off guard by the warning, clearly concerned that those potential risks could affect the company's plans to eventually expand the drug's use in first-line settings. The initial approval would open Iclusig to the roughly 2,500 patients each year who become resistant or intolerant to TKI therapy, whereas about 5,000 patients are newly diagnosed with CML in the U.S. each year.

Ariad currently is enrolling newly diagnosed patients in a Phase III trial, dubbed EPIC, which is designed to compare Iclusig to Gleevec, with a primary endpoint of major molecular response at 12 months. Full enrollment is expected by the end of 2013, and company execs said they do not expect the black-box warning to affect recruitment in that study or to affect the drug's uptake in the market.

Many TKIs have black-box warnings, including CML drug Tasigna (nilotinib, Novartis AG), Berger pointed out, adding that the Iclusig warning is "not an impediment."

Chief Medical Officer Frank Haluska agreed, noting that patients in the PACE trial all had advanced disease and that patients with earlier-stage disease had lower event rates and could tolerate higher doses of the drug. He also pointed again to the Iclusig's response rate in clinical trials, which he said will be the primary data physicians will consider when prescribing the drug. "Efficacy really is the driver," he said.

With the approval of Iclusig, the CML space has gained a total of three new drugs just in the latter half of 2012. Along with Bosulif, the FDA granted clearance in October to Synribo (omacetaxine mepesuccinate) from Teva Pharmaceuticals Industries Ltd. (See BioWorld Today, Oct. 31 , 2012.)

Iclusig has orphan drug status. It also is being reviewed in Europe for use in both CML and Ph+ALL.

Ariad Prepping for Transformation

The launching of Iclusig on the market will mark Ariad's long-awaited transformation into a commercial-stage biotech.

Initial hopes had been pinned on Taltorvic (ridaforolimus), an mTOR inhibitor partnered with Merck & Co. Inc. for use as a maintenance therapy for metastatic sarcoma. But the FDA rejected Taltorvic earlier this year, following a thumbs-down from the Oncology Drugs Advisory Committee, though by then Ariad had handed sole responsibility for the drug's development and commercialization to Whitehouse Station, N.J.-based Merck, in favor of focusing on Iclusig. (See BioWorld Today, March 21, 2012, and June 7, 2012.)

Ariad has retained global rights to Iclusig, with plans to launch the drug on its own in the U.S., as well as in Europe. The firm said European approval remains on track, and a sales team will be on the ground, ready to launch by July 1, 2013.

As of Sept. 30, Ariad had about $207 million on its balance sheet, and Berger said the company had no plans to raise additional money at present. In fact, the early FDA decision means Ariad will start seeing revenues a quarter ahead of schedule, he added.

Beyond Iclusig, which also is being studied in acute myeloid leukemia and in solid tumors, Ariad is working on AP26113, a dual inhibitor of EGFR and ALK, in Phase I/II testing in non-small-lung cancer (NSCLC) patients. Pivotal trials are in the works in the works for next year in ALK-positive NSCLC patients and possibly in patients with EGFR-mutant lung cancer who have failed prior EGFR inhibitor therapy.