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MDx/CDx Focus: EC Approves Kalydeco; Cabozantinib in PGx-Targeted NSCLC; Ponatinib, CDx FDA Filing


European Commission Approves Vertex's Personalized CF Drug Kalydeco

The European Commission has approved Vertex Pharmaceuticals' cystic fibrosis drug Kalydeco, which is indicated for patients who have one copy of the G551D mutation in the cystic fibrosis transmembrane conductance regulator gene.

Mutations in the CFTR gene result in defective or missing proteins that cause cystic fibrosis, a disease that is characterized by a buildup of sticky mucus that becomes infected and hinders breathing. Kalydeco helps normalize CFTR protein function in people harboring the G551D mutation. Vertex estimates just over 1,000 people in Europe have this mutation.

The EC approval for Kalydeco follows a positive opinion for the drug from the European Committee for Medicinal Products for Human Use. The EC approved the drug after reviewing data from two Phase III trials in which Kalydeco significantly improved breathing, weight gain, and other measures in cystic fibrosis patients with the G551D mutation compared to placebo. Those who received Kalydeco in the studies were 55 percent less likely that those who were on the placebo arm to experience pulmonary difficulties and deteriorating health symptoms that required treatment with antibiotics or hospital visits.

Most of the adverse events due to Kalydeco were "mild to moderate," Vertex reported, and fewer people treated with Kalydeco stopped participating in the clinical trial due to the ill effects of the treatment. Common adverse reactions due to Kalydeco included headache; upper respiratory tract infection, including sore throat and nasal congestion; rash; diarrhea; and stomach aches. Two Kalydeco-treated patients reported serious abdominal pain.

The CF gene was discovered in 1989. Kalydeco is considered a major advancement in the personalized treatment of the disease. Vertex developed Kalydeco in collaboration with the non-profit Cystic Fibrosis Foundation Therapeutics, the drug discovery affiliate of the Cystic Fibrosis Foundation. The US Food and Drug Administration approved Kalydeco in January (PGx Reporter 2/1/2012).

Exelixis Launches Cabozantinib Study in NSCLC Patients with RET Fusion Genes

Exelixis this week launched a clinical trial investigating cabozantinib in non-small cell lung cancer patients who harbor gene fusions that activate the RET kinase.

Cabozantinib, an inhibitor of MET, VEGFR2, and RET kinases, acts against angiogenesis and hinders cancer metastasis. The Phase II NSCLC trial will be led by Naiyer Rizvi, a lung cancer specialist at Memorial Sloan Kettering Cancer Center. Patients in the study will be tested for KIF5B/RET fusion genes.

According to, the primary outcome of this study is response rate while on cabozantinib at 12 weeks. Researchers will also track progression-free survival, overall survival, and safety. Study investigators are planning to enroll 25 NSCLC patients with KIF5B/RET fusion genes.

"Investigators will also seek to determine the frequency of KIF5B/RET and related variant RET fusions in patients whose tumors are negative for previously identified oncogenic activating mutations or translocations (including those involving EGFR, KRAS, and ALK)," Exelixis said in a statement.

Separately, Exelixis is also studying cabozantinib in relapse or refractory multiple myeloma patients. At this point, the company has not elucidated a pharmacogenomic strategy to investigate whether this drug works particularly well in a molecularly defined patient subset.

The drug is also being studied as a treatment for medullary thyroid cancer, prostate cancer, and several solid tumors.

Ariad, MolecularMD Seek Marketing Approval of Ponatinib, Companion Test in CML, Ph-positive ALL

Ariad Pharmaceuticals has submitted to the US Food and Drug Administration a new drug application for its investigational BCR-ABL inhibitor ponatinib.

Ariad is developing ponatinib as a treatment for patients with chronic myeloid leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia who have become resistant or intolerant to earlier tyrosine kinase inhibitor therapy and who harbor a T315I mutation in the BCR-ABL kinase. According to a statement from Ariad, "Ponatinib targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment with existing tyrosine kinase inhibitors, including the T315I mutation for which no effective therapy currently exists."

Simultaneously, Ariad's diagnostic partner, MolecularMD, has also submitted a premarket approval application with the agency for a companion test to identify CML and Ph-positive ALL patients who have a T315I mutation in BCR-ABL. The BCR-ABL T315I Mutation Test uses Sanger sequencing to assess BCR-ABL RNA transcripts in blood.

Ariad is seeking accelerated approval for the drug. It said it was ahead of schedule in filing a rolling NDA application and will complete all portions of the submission by the third quarter. Ariad expects to commercially launch the drug and the companion test in the first quarter of next year. The company is also planning to garner regulatory approval for ponatinib with the European Medicines Agency this quarter.

Studies have shown that leukemia patients with the single-point T315I mutation in the BCR-ABL fusion transcript are resistant to Novartis' Gleevec (imatinib), another BCR-ABL inhibitor.

At the American Society of Clinical Oncology's annual meeting this year, researchers from MD Anderson Cancer Center, Ariad, and elsewhere found that 54 percent of chronic-phase CML patients in the trial who were resistant or intolerant to tyrosine kinase inhibitor therapy, including 70 percent of patients who have a T315I mutation, achieved a major cytogenetic response with ponatinib treatment. Thirty percent of these patients also achieved a major molecular response with treatment.

"Ponatinib has substantial activity in heavily pretreated [patients] and those with refractory T315I. Response rates continue to improve with longer follow-up," the researchers concluded based on interim results from January. In this study, researchers identified T315I mutations in 29 percent of nearly 450 enrolled patients, as well as other gene mutations that could contribute to TKI resistance, including F317L in 8 percent, E255K in 4 percent, F359V in 4 percent, and G250E in 3 percent of patients.

Ariad is currently conducting a Phase II study, called EPIC, comparing ponatinib to imatinib in newly diagnosed chronic-phase CML patients. The researchers will compare 500 patients' major molecular response rate at 12 months of treatments, MMR at five years, molecular response at three months defined as a reduction in the level of BCR-ABL transcripts to 10 percent or less, complete cytogenetic response rate at one year, as well as overall survival and progression-free survival.

USPTO Grants Genelex Patent on PGx Decision Support Tools and Payments

Genelex, a Seattle-based developer of genetic tests and decision support tools, this week announced that the US Patent and Trademark Office had granted it Patent No. 8,099,298, titled "Genetic Data Analysis and Database Tools."

The patent, which Genelex filed in 2008, covers tools for conducting genetic analysis and interpretation, prescribing treatments, processing electronic medical records, and facilitating online reimbursement. The patent describes "a computerized tool and method for delivery of pharmacogenetic and pharmacological information."

The analysis tools covered by the patent include, among other things, "mechanisms for ‘pass through’ third party and insurance reimbursement for interpretive reports, insurance reimbursement for online access to pharmacogenetic information at the point of care, tools for market segmentation, … a conversion tool for capturing new subscribers," as well as "tools and predictive algorithms for preventing drug-drug and drug-gene adverse drug reactions."

With the software tools described in this patent, Genelex is hoping to enable efficient point-of-care adoption, delivery, and reimbursement of personalized treatments.

The '298 patent is awarded to inventors Howard Coleman, Jessica Oesterheld, and Robert Patterson. Coleman is CEO and Oesterheld is medical director of Genelex. Patterson is founder of Mental Health Connections, a company that developers medical management software.

Genelex noted in a statement that in addition to its '298 patent, the company has pending patents in the area of pharmacogenetics and personalized medicine business models. The company developed and markets GeneMedRx, a software program that incorporates patients' genetic tests results with treatment and medical information to assess their potential for experiencing adverse drug reactions.