ARIAD takes ponatinib into pivotal preclinical trial

CAMBRIDGE, Mass.—ARIAD Pharmaceuticals Inc. is advancing itsinvestigational, pan-BCR-ABL inhibitor, ponatinib, by partnering withMolecularMD in a pivotal PACE trial of patients with resistant or intolerantchronic myeloid leukemia (CML) and Philadelphia positive acute lymphoblasticleukemia (Ph+ ALL), or those with the T315I mutation.

Ponatinib has been shown in preclinical studies to haveactivity against Flt-3, the tyrosine kinase associated with approximately 30percent of cases of acute myeloid leukemia (AML). In addition to AML, ponatinibhas demonstrated preclinical inhibition of all FGF receptors, VEGR receptors andTie-2, which are promising targets for treatment of certain solid tumors, thecompany notes. T315I represents about 15 to 20 percent of all clinicallyobserved BCR-ABL mutations and is completely resistant to all currentlyapproved pharmaceutical therapies. The observed prevalence of the T315I mutantis likely to increase as use of the current second-generation BCR-ABLinhibitors expands. Therefore,development of a T315I inhibitor represents a significant unmet medical need,ARIAD states.

ARIAD and MolecularMD have a longstanding workingrelationship, and MolecularMD has performed BCR-ABL mutation testing with itsstandardized and validated sequencing test in patients enrolled in ARIAD'searlier Phase I trial of ponatinib. MolecularMD is now conducting similartesting 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 toidentify CML and Ph+ ALL patients who have the T315I mutation. A companiondiagnostic test is not necessary to support the broader potential use ofponatinib in patients who are resistant or intolerant to the currentsecond-generation BCR-ABL inhibitors, as being studied in the PACE trial. Manymutations in addition to T315I account for resistance to currently marketedBCR-ABL inhibitors.

ARIAD will reimburse MolecularMD for predefined expenses forthe development of the T315I diagnostic test. ARIAD will also pay MolecularMDmilestones for achievement of key development and regulatory activities.

As part of the agreement, MolecularMD will further optimizeits currently available sequencing test and will file a premarket approvalapplication (PMA) with the U.S. Food and Drug Administration (FDA) to supportcommercialization of the diagnostic test. The companies expect MolecularMD tosubmit the PMA at approximately the same time ARIAD files its new drugapplication for ponatinib in 2012. MolecularMD will also seek a CE Mark for acompanion diagnostic test kit in Europe. Once approved, MolecularMD will haveresponsibility for commercializing the T315I diagnostic test.

MolecularMD was a 2008 start-up, and its expertise inBCR-ABL mutation testing stems in part from the research and intellectualproperty of its scientific founder, Dr. Brian Druker, director of the OregonHealth & Science University (OHSU) Knight Cancer Institute, Howard HughesMedical Institute Investigator and JELD-WEN chair of leukemia research at OHSU.Druker has also been a longstanding scientific and medical collaborator ofARIAD 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 whendetected in blood above the major molecular response (MMR) level, indicating aneed for treatment by a third-generation drug such as ponatinib. MolecularMDnow offers tests in its CLEA lab for melanoma, NSCLC, glioma and colon cancer.

Wong notes that a panel of markers is required for solidtumors, while blood-based disorders may look at only one or two genes. In thefuture, he says, the diminishing effectiveness of drug therapies may be trackedby sensitive and specific tests at the molecular level.

"MolecularMD was founded with the goal of offeringclinically relevant molecular testing in the age of targeted cancer therapies,"says Wong. "We have been working with ARIAD throughout ponatinib's clinicaldevelopment and share in the excitement over the drug's activity in resistantand intolerant CML patients and those with the T315I mutation for whom currenttherapies are ineffective. We are pleased to be advancing our partnership withARIAD, and we look forward to commercializing our T315I test as a companiondiagnostic to ponatinib."

"We believe that MolecularMD has more experience with T315Imutation assays than any other laboratory in the world," states Dr. Timothy P.Clackson, president of research and development and chief scientific officer atARIAD. "We are pleased to extend our highly productive collaboration withMolecularMD and look forward to working together on the development of acommercial test for the detection of the T315I mutation."

ARIAD's earlier anti-cancer product candidate,ridaforolimus, is an investigational mTOR inhibitor being developed by Merckthat has successfully completed a Phase III clinical trial in patients withsoft-tissue and bone sarcomas and is being studied in multiple cancerindications.