Pazdur’s Tale Of Two Targeted Therapies

FDA’s oncology office director suggests Ariad’s ponatinib and ChemGenex’s Omapro represent the best and worst of times, respectively, in the quality of development programs for personalized medicines.

Offering his own version of Charles Dickens’ “A Tale of Two Cities,” FDA Office of Hematology and Oncology Products Director Richard Pazdur highlighted two real-world examples representing the best and worst of times in the quality of development programs for personalized cancer medicines.

Both therapies cited by Pazdur at a Sept. 14 conference on drug/diagnostic co-development are targeted at patients with chronic myelogenous leukemia who have the acquired BCR-ABL T315I mutation, which can create resistance to tyrosine kinase inhibitors approved for CML. However, the two drugs were worlds apart in strength of the efficacy data and reliability of diagnostic testing in pivotal trials.

Pazdur started out with the “worst of times” example, ChemGenex Pharmaceuticals Ltd.’s Omapro (omacetaxine) for patients who have failed treatment with Novartis AG’s Gleevec (imatinib).

In March 2010, FDA’s Oncologic Drugs Advisory Committee voted 7-1 that omacetaxine should not be approved without a well-characterized in vitro diagnostic for identifying the small subset of CML patients with the T315I mutation.

FDA and ODAC members were critical of the clinical development program, with agency review staff asserting that ChemGenex failed to develop an adequate assay for differentiating which patients carried the mutation even though it was pursuing an indication that would make omacetaxine, a highly toxic injectable chemotherapy agent, second-line therapy ahead of other available TKIs, specifically Bristol-Myers Squibb Co.’s Sprycel (dasatinib) and Novartis’ Tasigna (nilotinib).

Physicians treating patients in the company's 66-person clinical trial used multiple techniques for determining the presence of the mutation. Many samples were sent to commercial labs in the communities where the patients were treated, and more than one-third of patients never had their T315I mutation diagnosis confirmed by the central labs before being included in the trial. The two central labs used different testing methods for the mutation and different cut-off points for determining when a patient was considered resistant to TKIs (Also see "Personalized Medicine At A Crossroads: Omapro Stumble At Advisory Committee Underscores Need For Better Genetic Testing Standards" - Pink Sheet, 29 Mar, 2010.).

The review ended with a “complete response” letter that required the company to validate its existing tissue samples against an assay that FDA considers to be valid, ChemGenex said (Also see "No Additional Omapro Trials Needed, FDA Tells ChemGenex In Complete Response Letter" - Pink Sheet, 12 Apr, 2010.). The company was subsequently acquired by Cephalon Inc., which became part of Teva Pharmaceutical Industries Ltd. last year.

Pazdur said omacetaxine had relatively modest activity. “It was very important to have a really well-defined in vitro diagnostic to identify patients with this disease because if you misdiagnosed the patients as having this mutation, you were denying them potentially a very effective drug” in the existing TKIs, he said. “If this drug really went on the market without a really well-defined in vitro diagnostic, one could do more harm than good.”

The oncology office director then moved on to his “best of times” example. Although Pazdur declined to identify the drug since it is currently under FDA review, it’s evident from his remarks that the compound is Ariad Pharmaceuticals Inc.’s BCR-ABL inhibitor ponatinib, which was submitted as part of a rolling NDA in July for treatment of patients with resistant or intolerant CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Also see "Ariad Prepares For Early Launch Of CML Drug Ponatinib" - Pink Sheet, 6 Aug, 2012.). Simultaneous with the NDA submission, Ariad’s diagnostic development partner, MolecularMD Corp., submitted a premarket approval application for a companion test for the BCR-ABL T315l mutation.

“The basic science behind this drug is, I would call, relatively exquisite. It was very well done,” Pazdur said. “This drug has very, very good activity in patients that have this acquired genetic mutation, but it also has very impressive activity in patients that do not have the mutation, that have had disease that [is] refractory to imatinib, in other words that would be candidates for dasatinib and nilotinib. One could question whether one needs an in vitro diagnostic here because the activity of this drug is so impressive … in patients that have the mutation as well as those that do not have it.”

On Sept. 18, four days after Pazdur’s remarks, Ariad and MolecularMD announced that the companion diagnostic PMA was voluntarily withdrawn.

The companies said MolecularMD was recently informed by FDA’s Center for Devices and Radiological Health that the test is no longer considered to be a companion diagnostic because such a designation requires that it provide information essential to the safe and effective use of the drug.