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MDx/CDx Focus: FDA Accepts Pfizer's Bosutinib NDA; Kalydeco Approval; AssureRx Credit Line; and more


FDA Grants Standard Review for Pfizer's NDA for Bosutinib in Ph-Positive CML

The US Food and Drug Administration has accepted Pfizer's new drug application for bosutinib, an investigational drug for previously treated Philadelphia chromosome-positive chronic myeloid leukemia patients.

Pfizer said this week that the agency will conduct a standard review of the NDA, which places it on a 10-month review cycle from the date of its receipt.

According to Pfizer, the NDA submission for bosutinib included efficacy and safety data from Study 200, a single-arm trial involving 500 patients who were given bosutinib after they became resistant or intolerant to Novartis's Gleevec or had limited response to Bristol-Myers Squibb's Sprycel (dasatinib) or Novartis's Tasignia (nilotinib).

If bosutinib gains regulatory approval, it would serve an unmet need for Ph+ CML patients. Currently, there are no approved therapies for CML patients after they've been treated in the second-line setting with dasatinib or nilotinib.

Pfizer submitted a regulatory filing for bosutinib to the European Medicines Agency last August. That application seeks regulatory approval for bosutinib as a treatment for patients with newly diagnosed Ph+ CML in the chronic phase.

Ph+ CML patients harbor a DNA mutation that causes the Bcr-Abl tyrosine kinase to spur leukemia cells to grow and reproduce. However, patients may become resistant to Bcr-Abl inhibitors. "Inhibition of both Src and Abl tyrosine kinases may help overcome this resistance, as overexpression of the Src family of tyrosine kinases has been implicated in resistance and CML progression," Pfizer said in a statement.

Bosutinib is a dual inhibitor of Src and Abl kinases; the once daily, oral agent also has some inhibitory effect on c-kit and PDGFR. "It is believed that, by dual inhibition of the Src and Abl tyrosine kinases, bosutinib may inhibit signaling in CML cells that allows the cells to grow, survive and reproduce," the company stated.

Pfizer told PGx Reporter that the company "is not currently developing any Bcr-Abl diagnostic tests at this time."

Pfizer "is dedicated to further understanding and developing agents to better match specific patients with treatments and increase benefit from selected therapies," a company spokesperson said. "We are currently evaluating possible characteristics of patients that have had varying responses to bosutinib, but it is too soon to comment on specific scientific means that will be developed through which to identify specific groups of responders."

Specifically, in the hematological cancer space, Pfizer said it is exploring molecular subtypes and gene over-expression, as well as investigating mechanisms of resistance to treatments.

Novartis, meanwhile, is collaborating with Cepheid to develop a test for monitoring Bcr-Abl gene transcripts, which the companies hope will help doctors better manage Ph+ CML patients on Gleevec. It is necessary for doctors to molecularly monitor Bcr-Abl transcript levels in patients to confirm they have the disease and to ensure patients aren't relapsing or having a refractory response to treatment (PGx Reporter 10/13/2010).

FDA Approves Vertex's Personalized Rx for Cystic Fibrosis

The US Food and Drug Administration has approved Vertex Pharmaceutical's Kalydeco (ivacaftor) for the treatment of cystic fibrosis in patients who have a G551D mutation in the cystic fibrosis transmembrane regulator gene.

"Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup," FDA Commissioner Margaret Hamburg said in a statement announcing the drug's approval. "The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development."

Vertex developed Kalydeco with an approximately $75 million investment from the Cystic Fibrosis Foundation.

CF is a genetic disorder that debilitates the lungs and other organs, leading those who have this disease to die early. There are 30,000 people in the US with CF, and it is considered the most common fatal genetic disease in the Caucasian population.

The disorder occurs in those who have mutations in a gene that encodes for the CFTR protein, which regulates how water and ions are transported in the body. When mutations in CFTR hinder regular transport of ions, such as chloride, and water, an overabundance of mucus builds up on the lungs, digestive organs, and other body parts leading to respiratory and digestive complications, as well as infections and diabetes.

More than 1,800 mutations in the CFTR gene have been identified to date, the most common being F508. The FDA estimated that approximately 4 percent of CF patients harbor the G551D mutation, making it a rare form of the disease.

To gain approval for the drug in patients six years or older with the G551D mutation, Vertex submitted safety and efficacy data from two 48-week, placebo-controlled studies involving 213 patients. One trial enrolled patients 12 years and older and the second trial enrolled patients 6 years to 11 years old. In these trials, the most common side effects experienced by patients given Kalydeco were upper respiratory tract infection, headache, stomach ache, rash, diarrhea, and dizziness.

The agency highlighted in a statement that Kalydeco is effective only in patients with CF who have the G551D mutation. "It is not effective in CF patients with two copies of the F508 mutation in the CFTR gene," the FDA emphasized.

Furthermore, the agency also informed doctors that in order to gauge whether patients have the G551D mutation, they should use an FDA-cleared CF mutation test. In 2010, the FDA approved Luminex's xTAG Cystic Fibrosis 60 Kit v2, a test that can simultaneously screen for up to 60 CF-causing gene mutations, including G551D. TM Bioscience's Tag-It Cystic Fibrosis Kit also has FDA approval.

Under its priority review program, the agency reviewed and approved Kalydeco in approximately three months, well before its prescription user fee date of April 18. The drug has orphan designation.

Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, called Kalydeco a "breakthrough" therapy.

"Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis," Woodcock said in a statement. "[C]urrent therapies only treat the symptoms of this genetic disease."

Kalydeco is being investigated in combination with VX-809, another potential CF therapy, in patients who have the F508 mutation.

AssureRx Secures Additional Credit from Silicon Valley Bank

AssureRx Health has secured $8 million from Silicon Valley Bank to fund further adoption of its lead pharmacogenomic test GeneSightRx and to finance commercialization of several new products slated for launch this year.

"The new line of credit, combined with $11 million in Series B financing in 2011, will help AssureRx Health continue building the leading personalized medicine company in behavioral health," the Mason, Ohio-based firm said in a statement.

The Series B financing in March 2011 was led by Claremont Creek Ventures and Sequoia Capital to support the commercial launch of GeneSightRx and begin development of new products.

Last week, AssureRx announced its laboratory had been certified by the New York State Department of Health (PGx Reporter 1/25/2012). Following this, the company's lab is certified to analyze DNA samples for pharmacogenomic testing in all 50 US states, the company said. AssureRx is also planning to increase the size of its sales force this year to help drive adoption of GeneSightRx and its new product in the neuropsychiatric space.

BioTheranostics Launches New Oncology Genomic Testing Service

BioMérieux subsidiary BioTheranostics this week launched a new testing service called Precis Precision Medicine, which gauges biomarkers associated with oncology drug response, resistance, and cancer pathways.

"Precision medicine, a new paradigm in cancer management, partners accurate diagnosis of primary tumor site and predictive biomarkers to drive targeted therapy," BioTheranostics said in a statement. "The Precis tests help oncologists predict potential response and evaluate underlying disease pathways as they consider targeted therapies."

The tests in the Precis product line gauge markers associated with non-small cell lung cancer and colorectal cancer, such as EGFR, ALK rearrangement, KRAS, BRAF, c-MET, PIK3CA, and 10q23 deletion.

According to Richard Ding, CEO of BioTheranostics, the company will continue to expand the biomarkers included in the Precis suite of tests as clinical utility is established for those markers. BioTheranostics said it will provide Precis test results to healthcare providers within 7 to 10 days.

- TR