Taking The Temperature Of Accelerated Approval: An Interview With Ariad's President Of R&D Tim Clackson (Part 1 Of 2)

R&D head talks about the company's lead candidate ponatinib's developmental plan under accelerated approval.

Flush from a recent $25 million milestone as partner Merck & Co. files for European approval of ridaforolimus, cancer specialty firm Ariad is pressing ahead with the accelerated approval program for its BCR-ABL inhibitor ponatinib against drug-resistant chronic myelogenous leukemia and Philadelphia-positive acute lymphoblastic leukemia (Also see "Ariad Comes Of Age With Oncology Drugs, Readies For Commercial Leap" - Pink Sheet, 27 Jun, 2011.).

Timothy Clackson, Chief Science Officer and President of R&D at Ariad, has taken the lead in crafting the developmental plan for ponatinib and an earlier asset, the ALK/EGFR inhibitor AP26113 against non-small cell lung cancer. He spoke with "The Pink Sheet" DAILY recently about the accelerated approval process for ponatinib in the wake of recent FDA guidelines (Also see "FDA Will Make Advisory Committee Review Of Accelerated Approvals An Annual Event" - Pink Sheet, 14 Feb, 2011.).

"The Pink Sheet" DAILY: Why did Ariad choose an accelerated approval path for ponatinib rather than full approval?

Clackson: We believed that AA was appropriate for the indications we were pursuing, and the unmet need that we were attempting to address. We are currently evaluating ponatinib in its pivotal PACE trial in patients who are resistant or intolerant to the established approved therapies, dasatinib (Bristol-Myers Squibb Co.) and nilotinib (Novartis AG). Moreover, we are testing it in patients with the T3151 mutation who are resistant to all approved tyrosine kinase inhibitors (TKIs) in CML.

So, the patient population was one for which there are no approved therapies, and for T3151, there's absolutely no agent known to have any activity in that setting. I should add that in the area of CML, of course, we have the prior TKIs dasatinib and nilotinib being approved in a second-line setting after failure of imatinib, both of them approved via AA, and in a trial similar to our PACE trial.

"The Pink Sheet" DAILY: The Phase II PACE trial is a single-arm study. Why do you think FDA allowed a single-arm pivotal trial in light of what is appearing to be its stated preference for randomized trials in AA?

Clackson: In view of the landscape for CML that I described, I think that FDA felt that a well-conducted, well-constructed single-arm trial was going to be an effective way to assess the efficacy of the drug and the risk/benefit ratio in this population, given that the population has essentially no approved therapies against which a hypothetical, randomized trial could be controlled.

"The Pink Sheet" DAILY: Will Ariad pursue an accelerated path for AP26113?

Clackson: I would say that, from our point of view, unless the regulatory landscape were to change, we see the kind of path that we're taking with ponatinib to be appropriate for the kind of agent that ponatinib is and that we hope '113 will turn out to be once we evaluate it in its first trial in the clinic.

As a reminder, '113 is an inhibitor of both ALK and activated EGFR, which are present in different, non-overlapping subsets of NSCLC, as well as other tumor types. So, it's possible that we would be structuring pivotal trials in both of those settings. But it's certainly very early days for the molecule at this stage; we'll not be initiating the clinical trial until later this quarter.

"The Pink Sheet" DAILY: I heard in your recent earnings call that the goal for the confirmatory trial which you plan to run for a first-line CML indication would be a trial similar to the one that Novartis ran of nilotinib compared to imatinib. This way you would have a comparable dataset to compare against the standard of care, which would be imatinib for the foreseeable future. Is it fair to say that, although imatinib is the comparator in that confirmatory trial, nilotinib is your real target?

Clackson: I think what you're recounting from the call was an indication of where we're currently leaning and what we're currently evaluating as a potential trial. Yes, the trial with which nilotinib was approved for the front-line use was a randomized trial against imatinib, with major molecular response as the primary endpoint.

I think that trial fulfills the requirement; we certainly hope that the agency is in agreement that, like nilotinib, such a trial would represent a test of the drug against imatinib, the dominant agent of use in the front line. Imatinib is the only agent that is fully approved for use in newly diagnosed cases of CML. Dasatinib and nilotinib are also approved, but they only have accelerated approval that will not be converted to full approval until the agency sees five-year follow-up data.

So, we've discussed publicly, and heard advice and seen various publications, that a comparative trial should be run with a comparator that is fully approved, as opposed to an one that is only subject to accelerated approval, not least because one could run a randomized trial against an agent that is subsequently deemed not to be effective for the clinical indication.

-Michael Goodman ([email protected])