Ariad’s Leukemia Drug Iclusig Sails Through FDA In Less Than 3 Months

Ponatinib received accelerated approval for use in chronic myeloid leukemia and acute lymphoblastic leukemia patients who are resistant or intolerant to prior therapy with tyrosine kinase inhibitors.

The three-month early approval of Ariad Pharmaceuticals Inc.’s leukemia drug Iclusig (ponatinib) is yet another demonstration of the speed at which FDA has cleared novel cancer medicines in recent years, even before the advent of new provisions in the FDA Safety and Innovation Act aimed at expediting the development and approval of “breakthrough” and other innovative therapies.

The agency granted accelerated approval to ponatinib on Dec. 14, more than three months ahead of the drug’s March 27, 2013 priority review user fee date.

The indication is for treatment of adults with chronic phase, accelerated phase or blast phase chronic myeloid leukemia that is resistant or intolerant to prior tyrosine kinase inhibitor therapy, and Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant or intolerant to prior TKI therapy.

Ponatinib will cost $9,580 per month, or about $115,000 per year.

The sub-three month review period places ponatinib among the fastest times from submission to approval for a new oncologic (Also see "Evolution, Not Revolution, Marks Progress In Targeted Oncology Therapy – AACR" - Pink Sheet, 1 Oct, 2012.). It also represents the speediest cancer drug approval to date in 2012, taking that title away from Genentech Inc.’s basal cell carcinoma treatment Erivedge (vismodegib) which was approved in January following a 4.7-month review.

Ponatinib’s speedy approval also reflects the advantages of a rolling submission. Ariad submitted the NDA in late July and provided the agency with the remaining chemistry, manufacturing and controls data in late September, at which point the six-month review clock was triggered.

Ponatinib becomes the fourth new leukemia therapy approved this calendar year. Pfizer Inc.’s Bosulif (bosutinib) and Teva Pharmaceutical Industries Ltd.’s Synribo (omacetaxine) were approved in September and October, respectively, to treat various phases of chronic myeloid leukemia (Also see "Teva’s Synribo Clears FDA For Third-Line Chronic Myeloid Leukemia" - Pink Sheet, 26 Oct, 2012.). Talon Therapeutics Inc. ’s Marqibo, a liposomal form of vincristine, was approved in August for acute lymphoblastic leukemia (Also see "Marqibo Clears FDA Despite Advisory Committee Concerns About Confirmatory Trial" - Pink Sheet, 9 Aug, 2012.).

“Iclusig is the third drug approved to treat CML and the second drug approved to treat ALL this year, demonstrating FDA’s commitment to approving safe and effective drugs for patients with rare diseases,” FDA Office of Hematology and Oncology Products Director Richard Pazdur said in a press release.

The drug will carry a wholesale acquisition cost of $9,580 per month, or approximately $115,000 a year. The product is expected to be available to patients within the next two weeks.

A Broad Label …

Ponatinib’s indication provides for use in all TKI-resistant patients regardless of line of therapy and is broader than the patient eligibility criteria for the Phase II, single-arm, open label PACE study upon which approval was based, Ariad Chairman and CEO Harvey Berger said during a Dec. 14 conference call.

Only patients who were resistant or intolerant to Bristol-Myers Squibb Co.’s Sprycel (dasatinib) or Novartis AG’s Tasigna (nilotinib) or who had the BCR-ABL T315I genetic mutation were eligible for enrollment. “With the approved indication, any CML or Philadelphia-positive ALL patient who has failed or become intolerant to any prior tyrosine kinase inhibitor therapy is eligible on label for treatment,” Berger said.

The company estimates there are 2,500 U.S. patients who will switch their TKI therapy due to failure in 2013, thereby making them eligible for on-label use of Iclusig.

… With No Companion Diagnostic

Notably, the indication is not restricted based upon T315I mutation status; this mutation is associated with resistance to currently approved TKIs

Simultaneous with the NDA submission in July, Ariad’s diagnostic development partner, MolecularMD Corp., submitted a pre-market approval application for a companion test for the T315I mutation.

FDA’s Pazdur made a veiled reference to the filings during a conference on drug/diagnostic co-development in September. Pazdur noted that the drug, which he did not identify by name, had good activity in patients who had the T315I 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.”

The level of activity seen in those patients who lacked the targeted mutation raises questions as to whether a companion diagnostic is actually needed, he said (Also see "Pazdur’s Tale Of Two Targeted Therapies" - Pink Sheet, 24 Sep, 2012.).

Several days after Pazdur’s remarks, Ariad and MolecularMD announced that the companion diagnostic PMA was voluntarily withdrawn because the Center for Devices and Radiologic Health had determined that the test was not essential to the safe and effective use of the drug.

“The agency accepted that there’s nothing biologically unique about the T315I mutation of BCR-ABL and therefore a companion diagnostic test is not needed to establish patient eligibility for therapy with Iclusig,” Berger said.

Ponatinib labeling reflects the efficacy in 267 patients with chronic phase CML, of which 203 were resistant or intolerant to prior TKI therapy and 64 had the T315I mutation. Fifty-four percent of all chronic phase patients had a major cytogenetic response. The response was 70% in the cohort of patients with the T315I mutation and 49% in the resistant/intolerant group.

“The approval of Iclusig is important because it provides a treatment option to patients with CML who are not responding to other drugs, particularly those with the T315I mutation who have had few therapeutic options,” Pazdur said in the agency’s press release.

Safety Labeling Worries Analysts

During the company’s hour-long conference call, most of the analyst questions focused on potential safety concerns identified in ponatinib’s labeling, which includes a boxed warning on arterial thrombosis and hepatotoxicity.

Company representatives attributed the strong warning language to the conservative approach FDA takes to labeling about serious adverse events, particularly when clinical trials lack a comparator arm. They stressed that the patient population studied was heavily pretreated, older and had other underlying risk factors, such as arterial disease, which may have contributed to the events seen in the PACE trial.

The company also downplayed any concerns that the safety issues would impact commercial uptake, maintaining that the drug’s efficacy will drive its use.