ARIAD takes ponatinib into pivotal preclinical trial
CAMBRIDGE, Mass.óARIAD Pharmaceuticals Inc. is advancing its investigational, pan-BCR-ABL inhibitor, ponatinib, by partnering with MolecularMD in a pivotal PACE trial of patients with resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL), or those with the T315I mutation.
Ponatinib has been shown in preclinical studies to have activity against Flt-3, the tyrosine kinase associated with approximately 30 percent of cases of acute myeloid leukemia (AML). In addition to AML, ponatinib has demonstrated preclinical inhibition of all FGF receptors, VEGR receptors and Tie-2, which are promising targets for treatment of certain solid tumors, the company notes. T315I represents about 15 to 20 percent of all clinically observed BCR-ABL mutations and is completely resistant to all currently approved pharmaceutical therapies. The observed prevalence of the T315I mutant is likely to increase as use of the current second-generation BCR-ABL inhibitors expands. Therefore, development of a T315I inhibitor represents a significant unmet medical need, ARIAD states.
ARIAD and MolecularMD have a longstanding working relationship, and MolecularMD has performed BCR-ABL mutation testing with its standardized and validated sequencing test in patients enrolled in ARIAD's earlier Phase I trial of ponatinib. MolecularMD is now conducting similar testing prior to patient treatment in the PACE trial.
Under the terms of the agreement between the two companies, MolecularMD will develop and commercialize a companion diagnostic test to identify CML and Ph+ ALL patients who have the T315I mutation. 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. Many mutations in addition to T315I account for resistance to currently marketed BCR-ABL inhibitors.
ARIAD will reimburse MolecularMD for predefined expenses for the development of the T315I diagnostic test. ARIAD will also pay MolecularMD milestones for achievement of key development and regulatory activities.
As part of the agreement, MolecularMD will further optimize its currently available sequencing test and will file a premarket approval application (PMA) with the U.S. Food and Drug Administration (FDA) to support commercialization of the diagnostic test. The companies expect MolecularMD to submit the PMA at approximately the same time ARIAD files its new drug application for ponatinib in 2012. MolecularMD will also seek a CE Mark for a companion diagnostic test kit in Europe. Once approved, MolecularMD will have responsibility for commercializing the T315I diagnostic test.
MolecularMD was a 2008 start-up, and its expertise in BCR-ABL mutation testing stems in part from the research and intellectual property of its scientific founder, Dr. Brian Druker, director of the Oregon Health & Science University (OHSU) Knight Cancer Institute, Howard Hughes Medical Institute Investigator and JELD-WEN chair of leukemia research at OHSU. Druker has also been a longstanding scientific and medical collaborator of ARIAD in the development of ponatinib.
The company's chief scientific officer, Dr. Stephane Wong, draws an analogy between the work being done at MolecularMD and HIV treatment. In the case of BCR-ABL and the T315I mutation, a relapse is indicated when detected in blood above the major molecular response (MMR) level, indicating a need for treatment by a third-generation drug such as ponatinib. MolecularMD now offers tests in its CLEA lab for melanoma, NSCLC, glioma and colon cancer.
Wong notes that a panel of markers is required for solid tumors, while blood-based disorders may look at only one or two genes. In the future, he says, the diminishing effectiveness of drug therapies may be tracked by sensitive and specific tests at the molecular level.
"MolecularMD was founded with the goal of offering clinically relevant molecular testing in the age of targeted cancer therapies," says Wong. "We have been working with ARIAD throughout ponatinib's clinical development and share in the excitement over the drug's activity in resistant and intolerant CML patients and those with the T315I mutation for whom current therapies are ineffective. We are pleased to be advancing our partnership with ARIAD, and we look forward to commercializing our T315I test as a companion diagnostic to ponatinib."
"We believe that MolecularMD has more experience with T315I mutation assays than any other laboratory in the world," states Dr. Timothy P. Clackson, president of research and development and chief scientific officer at ARIAD. "We are pleased to extend our highly productive collaboration with MolecularMD and look forward to working together on the development of a commercial test for the detection of the T315I mutation."
ARIAD's earlier anti-cancer product candidate, ridaforolimus, is an investigational mTOR inhibitor being developed by Merck that has successfully completed a Phase III clinical trial in patients with soft-tissue and bone sarcomas and is being studied in multiple cancer indications.