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Ariad Stops Iclusig Sales Due to Serious AEs; Would a CDx Have Changed Risk/Benefit Profile?

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This article has been updated with a statement from the FDA and to clarify that MolecularMD withdrew its PMA for the T315I companion test after the FDA deemed it not necessary to support Iclusig's administration. Originally published Nov. 1.

Due to serious safety concerns, Ariad Pharmaceuticals has decided to temporarily stop selling its leukemia drug Iclusig (ponatinib) upon the request of the US Food and Drug Administration.

The FDA announced yesterday that Iclusig has shown to cause life-threatening blood clots and narrowing of the blood vessels in clinical studies. The agency said it will continue to evaluate the drug to better understand its risk-benefit profile. “Patients currently receiving Iclusig should discuss with their healthcare professionals the risks and benefits of continuing treatment with the drug,” the agency advised in a statement.

The drug was approved last year for advanced leukemia patients who have developed resistance to available tyrosine kinase inhibitors, and Ariad was initially contemplating developing it with a companion test that gauges the common resistance mutation T315I. However, the available evidence on Iclusig showed its ability 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.

The FDA-approved label for Iclusig includes a boxed warning for thrombosis risk and liver toxicities. However, the rate of serious blood clots was a lot lower in studies before the drug's approval, around 8 percent, compared to 20 percent in more recently available study results.

Now, having halted sales for Iclusig due to serious cardiovascular and thrombotic adverse events, Ariad may face the prospect of relaunching the drug for a more narrowly defined patient subset, based on discussions with the agency. Ultimately, the adverse events seen with the drug in a clinical trial involving first-line, untreated leukemia patients may not have been avoidable with a more personalized strategy. However, if the drug had been developed and launched on the market with a companion test from the start, the risk and exposure to patients would have certainly been minimized.

Ariad did not respond to questions ahead of press time.

An FDA spokesperson said in a statement to PGx Reporter that at the time it approved Iclusig, "data suggested [the drug] could be used to treat patients whose disease had the specific T315I mutation and those whose disease did not have it. As such, we granted the drug accelerated approval for an indication not limited to patients with the T315I mutation." The agency representative further noted that patients with and without the mutation experienced serious adverse events.

Even if at the time of Iclusig's approval the sponsors and the agency were convinced that a predictive marker was not needed, such a marker, if it exists, may help to relaunch the drug on the market. Pharmacogenetic considerations are increasingly becoming a critical part of the discussion on the risk/benefit profile of cancer drugs, particularly those brought to market on an accelerated time frame.

For example, a predictive marker may have changed the risk/benefit profile for Avastin as a breast cancer treatment. However, during the FDA's review of the available efficacy and safety data on Avastin, Genentech couldn't convince the agency that it had a viable predictive marker with which to identify super-responders to the treatment.

Subsequently, the FDA revoked Avastin's accelerated approval in metastatic breast cancer. Agency officials noted during a public hearing that while some patients may be benefiting from Avastin, many had succumbed to the drug's serious toxic effects (PGx Reporter 1/26/2011).

The FDA spokesperson said that Iclusig's "marketing is currently suspended while we work with Ariad to further understand the risks of the drug and identify the potential patient populations where the benefits of the drug may outweigh the risks."

Halting sales

Less than a year ago, the FDA approved Iclusig as a new option for patients with chronic-, accelerated-, or blast-phase chronic myeloid leukemia, or Philadelphia-chromosome-positive acute lymphoblastic leukemia who have become resistant or intolerant to tyrosine kinase inhibitors, such as Gleevec (imatinib). The drug, approved under FDA's priority review program, targets the Philadelphia chromosome gene mutation T315I, which is found in most CML patients and confers resistance to marketed TKIs. Translocations in the Philadelphia chromosome resulting in BCR-ABL fusions also occur in ALL in up to 30 percent of adult patients and between 2 percent and 10 percent of pediatric cases (PGx Reporter 12/19/2012).

The FDA reviewed the marketing application for Iclusig under a six-month priority review clock, but granted approval for the drug in December, more than three months ahead of its user fee date of March 27, 2013. Because the agency approved the drug on an accelerated time frame, Ariad was required to do additional studies to ensure the safety and efficacy of Iclusig. After reports of an increased number of blood clots in the Phase III EPIC trial, the agency put a partial hold on recruiting new patients into the study on Oct. 9. The trial was halted on Oct. 18, with 50 percent of the study participants enrolled.

In mid-October, Ariad held a call with investors to announce that it was discontinuing the EPIC trial, in which the company was studying Iclusig in newly diagnosed, previously untreated CML patients. “Arterial thrombotic events have occurred in the Iclusig arm of the EPIC trial over time,” Timothy Clackson, Ariad's CSO, told investors last month. After discussing the trial with the FDA and the EPIC data monitoring committee, Ariad decided to halt the study and put other trials involving Iclusig on partial hold.

At the time, however, Clackson had told investors that he didn't expect the company would need to pull the drug from the market as an option for those with advanced forms of leukemia or who are resistant to other TK inhibitors. He said then that the company might shift development focus for Iclusig from the front-line CML setting to studying the drug in refractory patients. “As we contemplate a narrower US label, we will use” the refractory CML population “as a platform to explore Iclusig use in additional indications both within and beyond CML,” Clackson said to investors during the call in October.

However, upon FDA's review of data from studies involving Iclusig, Ariad this week decided to temporarily pull the drug from the market while the agency performs further risk/benefit analysis. Given this, the agency advised patients currently taking Iclusig but not responding to the drug to discontinue taking it and discuss alternative options with their doctors. For those who are taking Iclusig and responding to the drug, doctors should determine if the benefits of the drug outweigh the risks for that patient. If so, then these patients will need to be treated in the context of an investigational new drug application or through an expanded registry program while the FDA investigates the drug's safety.

The “FDA will work with the manufacturer on a plan to quickly transition these patients to a program that will allow access under an IND or expanded access registry program,” the agency said in a statement. The FDA further advised doctors to not start new patients on Iclusig “unless no other treatment options are available and all other available therapies have failed.”

Upon FDA's review of data from ongoing clinical trials, the agency found that in a Phase II study, 24 percent of patients treated with Iclusig for a median of more than one year, and 48 percent of participants in a Phase I study treated with the drug for a median of more than two-and-a-half years, experienced serious adverse events. The adverse events included fatal and life-threatening heart attacks, strokes, and loss of blood flow causing tissue death.

The drug also caused some patients' blood vessels in their extremities, heart, and brain to narrow to the point where they needed urgent surgery to restore blood flow. In the Phase II trial, adverse reactions negatively impacting the blood flow to the heart, brain, and extremities were seen in 12 percent, 6 percent, and 8 percent of patients, respectively. Around 67 percent of Iclusig treated patients had high blood pressure in the clinical trials, and 8 percent experienced heart failure, as well as fatalities.

“Patients with and without cardiovascular risk factors, including patients in their 20s, have experienced these events,” according to the FDA. “Serious adverse reactions involving the eyes, which led to blindness or blurred vision, occurred in Iclusig-treated patients.”

These adverse events in some patients occurred very soon after they started treatment with Iclusig, as early as within two weeks. Because the Phase I and II studies reviewed by the FDA did not include a control arm, “it is not possible to determine the relationship of these adverse events to Iclusig, however the increasing rate and pattern of the events strongly suggests that many are drug-related,” the agency stated. Based on its current review of the information, the agency said it could not recommend a safe Iclusig dose for patients.

In need of a CDx strategy?

According to previous statements made by Ariad, it's clear that the company did not anticipate having to withdraw its drug from the market. “The benefit of the drug extends beyond [those with] T315I” resistance mutations, Clackson told investors back in October. “With the new information we have, we do anticipate a narrower label,” he said, adding that such an approach is “not supported by our current view of the risk-benefit” for Iclusig.

The company is currently in discussions with the FDA about potentially relaunching the drug with a narrower indication. Neither the FDA nor Ariad has a timeline for when such a determination might be issued.

Although Ariad had a partnership with MolecularMD to develop a companion test for Iclusig to identify leukemia patients with the T315I mutation, the test developer voluntarily withdrew its pre-market approval application for its BCR-ABL T315I Mutation Test, and the FDA informed the parties that the test was "no longer considered to be a companion diagnostic test for ponatinib" (PGx Reporter 9/19/2012).

However, after temporarily halting sales of the drug, if the agency narrows Iclusig's indication for a specific patient subset, a companion test that identifies best responders may help reestablish market confidence in the drug. Of course, short of an FDA-approved companion test, healthcare providers can also make use of lab-developed tests to inform therapeutic strategies with the drug. In CML, LDT are commonly used to track disease progression.

In describing the mechanism of Iclusig, Ariad has previously highlighted that the agent binds to the BCR-ABL tyrosine kinase and inhibits the "entire spectrum of mutants conferring resistance against other TKIs, including the T315I" mutation, which makes patients resistant to all current therapies for these diseases. Ariad estimates that between 15 percent and 30 percent of resistance-causing BCR-ABL mutations are T315I mutations.

"The drug is effective in all settings: with no mutations, with T315I, or with other mutations, making the companion test less impactful," Jorge Cortes of the University of Texas MD Anderson Cancer Center, who led the clinical trial that led to the approval for the drug, has explained to PGx Reporter in earlier interviews. Mutation testing with a companion test "would be more relevant for dasatinib [Bristol-Myers Squibb's Sprycel], nilotinib [Novartis's Tasigna], or bosutinib [Pfizer's Bosulif] than for ponatinib," according to Cortes, "because they do not work if there is [a] T315I [mutation]."

Of course, had Ariad pursued a CDx strategy for Iclusig and indicated the drug for patients with certain resistance mutations, the company could have minimized the exposure of the marketed drug to patients, which would have had changed Iclusig's benefit-risk profile. Ariad anticipates that the FDA will likely hold a meeting of its Oncologic Drugs Advisory Committee next year to get a better understanding of Iclusig's safety.

Ariad officials said during the call with investors in October that the company is committed to figuring out the underlying mechanism for Iclusig that might be causing the cardiovascular and thrombotic events in CML patients.

Some market observers had predicted that Iclusig had blockbuster potential when it first launched. Investors are now contemplating the extent to which the observed adverse events will reduce its market potential. Ariad executives told investors that the market depends on how FDA revises the label for the drug and whether the company can continue to pursue the agent in the front-line setting.

“We need to decide what is necessary to create value from Iclusig,” Ariad CEO Harvey Berger told investors in October. “It is by far the most potent, broadly active TKI in CML. We have to understand and put the vascular events in an appropriate context from a safety perspective. That's got to be our priority, no matter how we are going to go forward.”

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