Ariad Pharmaceuticals will advance its investigational pan-BCR-ABL tyrosine kinase inhibitor ponatinib into a pivotal trial with the help of a companion diagnostic developed by MolecularMD that gauges T315I mutations in the BCR-ABL gene.
Ponatinib is being developed as a treatment for patients with resistant or intolerant chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, or those with T315I mutations. Studies have shown that leukemia patients with the single-point mutation T315I in the BCR-ABL fusion transcript are resistant to Novartis' Gleevec, another BCR-ABL inhibitor.
The trial, called PACE, will determine the efficacy of ponatinib in patients with CML in chronic phase, accelerated phase, or blast phase, or with Ph-positive acute lymphoblastic leukemia, who either are resistant or intolerant to either dasatinib (Bristol-Myers Squibb's Sprycel) or nilotinib (Novartis's Tasigna), or have the T315I mutation.
"The MolecularMD companion diagnostic test is being developed to identify CML and Ph+ ALL patients who have the T315I mutation," Ariad said in a statement. The company added, however, that a companion diagnostic test "is not necessary to support the broader potential use of ponatinib in patients who are resistant or intolerant to the current second-generation BCR-ABL inhibitors, as being studied in the PACE trial" because "many mutations in addition to T315I account for resistance to currently marketed BCR-ABL inhibitors."
In early studies, ponatinib has shown activity against several other BCR-ABL mutations, such as F317L and G250E mutations, as well as in other targets, such as FLT3, FGF, VEGF and PDGF, and c-KIT, that could potentially contribute to patients' resistance to BCR-ABL TK inhibitors. However, the most marked response to ponatinib in a Phase I study reported at the American Society of Hematology's annual meeting last year was seen in patients with T315I mutations.
In that study, 9 evaluable patients in chronic-phase CML with T3151 mutations, all achieved a complete hematologic response and a major cytogenetic response, and eight patients had a complete cytogenetic response. Meanwhile, in patients with blast-phase CML, and in those with Ph+ ALL with T3151 mutations, 20 percent saw a major hematologic response and 20 percent achieved a major cytogenetic response. No patient experienced a complete responses.
The clinical utility of T315I testing in cancer pharmacogenetics is currently not settled. At a Centers for Medicare and Medicaid Services meeting last year where the CMS Medicare Coverage and Evidence Development Advisory Committee considered whether a handful of cancer PGx tests improved outcomes, a review team identified "consistent evidence" from studies that T315I mutations predicted which patients would not respond to treatment with certain tyrosine kinase inhibitors.
However due to limited data on whether such testing contributed to an improvement in patient survival and how such mutations were impacted by other genetic anomalies in the BCR-ABL pathway, MEDCAC imparted low confidence that BCR-ABL testing using point mutations was clinically useful, and deemed such technology premature (PGx Reporter 02/03/2010).
However, the clinical utility consideration may change for T315I mutation testing in the underserved leukemia patient population who have an aggressive or resistant form of the disease.
The test that will be developed for ponatinib by MolecularMD will apply its ABL kinase domain sequencing technology. According to a statement from the codevelopment partners, MolecularMD will file a premarket approval application with the US Food and Drug Administration for the test next year, as Ariad simultaneously files a new drug application for ponatinib. MolecularMD will also file for CE Marking in Europe for the companion test.
This diagnostic codevelopment deal is an extension of an existing partnership between Ariad and MolecularMD, since the diagnostics firm performed BCR-ABL mutation testing for Ariad's Phase I trial of ponatinib.
Under the terms of the extended deal, Ariad will reimburse MolecularMD for "predefined expenses for the development of the T315I diagnostic test." Additionally, MolecularMD will also receive milestones for advancing the test in clinical trials and regulatory approval from the FDA. The diagnostic company will be responsible for commercializing the test.
According to MolecularMD's website, the assay detects mutations between amino acids 30 and 510, including the domains SH3, SH2, as well as regions 3’ to the ABL kinase domain. The test analyzes patients' peripheral blood or bone marrow, and has a sensitivity of between 20 percent and 30 percent in the population of wild type.
Last November, MolecularMD notified customers that it had discontinued its T31FI FRET assay, since the company was developing a new, allele-specific T315I direct sequencing assay, "with an expected implementation date for the fourth quarter of this year." In the interim, the company offered clients its BCR-ABL kinase domain sequencing assay.
Portland, Ore.-based MolecularMD was founded by Brian Druker, director of the Knight Cancer Center at Oregon Health & Science University, and Sheridan Snyder, founder of Genzyme and Upstate Biotechnology. Its BCR-ABL mutation testing assay was developed with the help of Druker's research and intellectual property. Druker has also collaborated with Ariad in the development of ponatinib.