The future for Ariad Pharmaceuticals Inc.’s cancer drug Iclusig (ponatinib) got murkier Friday after the company said it decided to terminate the Phase III EPIC study testing the pan-Bcr-Abl inhibitor in first-line chronic myelogenous leukemia, a week after disclosing a partial clinical hold due to troubling safety data.

It was an about-face from company management, who had reported during the Oct. 9 conference call that it was counting on the data from EPIC to provide convincing enough risk-benefit data in favor of Iclusig to preserve the drug’s market potential in the wake of increasing reports of arterial thrombotic events associated with treatment. News of EPIC’s halt sent shares (NASDAQ:ARIA) sliding 40.7 percent, or $1.83, to a new 52-week low of $2.67.

The stock has lost more than 80 percent of its value since follow-up safety data from the PACE trial – which served as the basis for Iclusig’s accelerated approval late last year – emerged showing a serious arterial thrombosis event rate in 11.8 percent of patients treated with Iclusig at 24 months, with the highest percentage in cardiovascular events. While Ariad executives maintained that the adverse effects rate had remained constant with the increase due to longer duration of treatment, the safety data justified earlier concerns raised by the unexpected black-box warning at the time of approval, and Friday’s news only piled on the doubt surrounding Iclusig. (See BioWorld Today, Oct. 10, 2013.)

“After last week’s safety update/implosion, and now this, we can’t in good faith continue to tell people to buy this name and are stepping to the sidelines until we can get more clarity on the future of this drug,” J.P. Morgan analyst Cory Kasimov wrote in a research report.

Some clarity is expected during Ariad’s earnings call, scheduled in early November. The company said it is working to address issues to lift the partial hold on other Iclusig studies and determine a development plan for Iclusig and other pipeline programs. It also will be “working on a substantially revised financial plan that will extend out our cash runway substantially beyond where we are today,” CEO Harvey Berger told investors on Friday morning’s conference call.

Cambridge, Mass.-based Ariad ended the second quarter with about $351 .9 million in cash.

By the time of the earnings call, the company also anticipates having finalized with the FDA an updated label including the latest safety data for Iclusig, currently approved for use in patients with chronic, accelerated and blast phases of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia whose disease is resistant or intolerant to tyrosine kinase inhibitors (TKIs). While the firm expects a narrower label going forward, executives declined to provide specifics. “The time to talk will be when the label is defined and public,” said Timothy Clackson, president of R&D and chief scientific officer.

But, he assured investors on the call, an outright withdrawal is unlikely. “I do not believe that is the direction this is going,” he said.

Clackson further stressed that data from the EPIC trial had been requested for postmarketing purposes in terms of dose-response and pharmacokinetic follow-up results. But the primary requirement for converting Iclusig’s accelerated approval to full approval is the 24-month data from the PACE trial, expected to be presented at the American Society of Hematology meeting in December.

A meeting of the FDA’s Oncologic Drugs Advisory Committee also likely will be convened sometime next year to review the drug’s risk-benefit profile in different settings, he said.

‘Timing Impossible to Say’

The recently halted EPIC study had been designed to move the drug into first-line CML. The study, which had enrolled about 50 percent of the expected 500 patients as of early September, was designed to compare Iclusig with Gleevec (imatinib) in newly diagnosed CML in the chronic phase, with Ariad’s drug administered at 45 mg once daily.

Following reports earlier this month of the increased thrombotic incidents, Ariad said it would start reducing the doses in EPIC, to 30 mg once daily, at which efficacy appears to be similar. The firm also has said that maintenance response with Iclusig appears efficacious at 15 mg.

After further consideration, however, the company said it made sense to stop the trial altogether. Clackson said thrombotic events had been reported from the EPIC study, though the firm did not provide a specific event rate. “I think it almost doesn’t really matter how many events we’ve seen,” he said. “I think it’s now that we have a high concern about those events” given the new regulatory situation.

Moreover, Berger explained that once it became clear that the 45-mg dose was not appropriate, EPIC was unlikely to provide data necessary to gain approval in first-line CML, “no matter how we tweaked or added things.” Changes to the trial midstream would only “muddy the waters” in any future efforts to move Iclusig beyond the refractory setting, he added.

It’s not clear yet whether the firm will initiate a new first-line study, or move into a revised/extended EPIC trial. “Timing is impossible to say today,” Berger said.

Moving into first-line is critical for Iclusig to reach blockbuster status, as analysts had predicted when the drug gained its earlier-than-expected approval last year with an original label going patient eligibility in the PACE study, allowing any CML or Ph+ALL patient who had failed or had been intolerant to any prior TKI to receive treatment, regardless of whether they tested positive for T3151, a mutation that has been attributed to TKI resistance. (See BioWorld Today, Dec. 17, 2012.)

With the new safety concerns, “we think future use will likely be relegated to T3151/salvage patients,” said J.P Morgan’s Kasimov.

Analysts on the call echoed that thought, asking Ariad whether it will change its commercialization strategy to seek partners and licensing deals rather than taking on worldwide marketing on its own.

While calling it “too early to get into various options,” Berger acknowledged that Ariad is “not precluding any decisions,” and that its best opportunities “maybe different today than they were a month ago.”

Next Steps

As it moves forward, Ariad said its priorities will include focusing on Iclusig in the refractory CML populations, re-evaluating dosing and re-evaluating ways to mitigate the thrombotic events seen in chronic use of the drug. And as it works to address issues for lifting the partial hold, it will continue considering other possible indications for the drug.

Iclusig has potential to treat “refractory disease for a variety of liquid and solid tumors,” said Frank Haluska, chief medical officer. Among those include gastrointestinal stromal tumors (GIST), particularly patients with refractory GIST who often can’t tolerate treatment with TKIs such as Sutent (sunitinib, Pfizer Inc.).

Ariad also plans to continue development of another pipeline program, AP26113, a small-molecule TKI that has shown activity against anaplastic lymphoma kinase (ALK), epidermal growth factor receptor and c-ros oncogene 1. Data presented last month from a Phase I/II study in non-small-cell lung cancer (NSCLC) showed antitumor activity in patients with TKI-naïve and Xalkori (crizotinib, Pfizer)-resistant ALK-positive disease, including in patients with brain metastases after treatment with Xalkori.

A registrational study is slated to start shortly testing that drug in ALK-positive NSCLC patients who are resistant to Xalkori.