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FDA Grants Orphan Drug Designation to BGB324 for AML

Andrew J. Roth
Published: Monday, Nov 24, 2014

Cancer Cell The FDA has granted an orphan drug designation to the novel AXL inhibitor BGB324 (R428) for the treatment of patients with acute myeloid leukemia (AML), according to BerGenBio AS, the company developing the drug.

The designation comes following the initiation of a phase Ib trial aimed at evaluating the safety and tolerability of BGB324 as a single agent and in combination with cytarabine in patients with AML. Secondary endpoints of the study focus on evidence of clinical response and the assessment of novel biomarkers. The first patient has been dosed and trial data will be available in 2015.

The FDA orphan designation is part of the Orphan Drug Act, which was a law passed to facilitate the development of new drugs for rare diseases. The designation qualifies the sponsor, BerGenBio, for several incentives, including tax credits.

“The FDA’s decision to grant BerGenBio orphan drug status for BGB324 is a significant milestone for the company and recognizes the need for innovative new ways to treat AML,” Richard Godfrey, CEO, BerGenBio, said in a statement. “The designation will give BerGenBio access to various development incentives from the agency, including tax credits for qualified clinical testing.”

BGB324 is an orally bio-available small molecule inhibitor of AXL, a receptor tyrosine kinase overexpressed in many solid tumors. AXL overexpression has been linked with the epithelial-mesenchymal transition (EMT) and treatment resistance. In preclinical models, AXL inhibition alone was shown to reverse drug resistance, while AXL inhibition plus cytotoxic therapy was shown to have a synergistic affect.

Positive results from a phase Ia dose escalation study of BGB324 were presented at the 2014 AACR Annual Meeting. The study of 32 healthy volunteers showed that the agent was safe and tolerable in doses up to 1.5 g daily with a predictable pharmacokinetic profile. The observed long plasma half-life of BGB324 signified the possibility of a range of dosing options.

In doses up to 1 g, reported adverse events were only grade 1 and were fully reversible. Gastrointestinal adverse events were most commonly reported and occurred more frequently at doses greater than 1 g.

The poster presented at AACR also showed that in preclinical in vivo studies, BGB324 in combination with chemotherapeutic agents delayed or blocked drug resistance in animal models of triple negative breast cancer (TNBC), pancreatic cancer and non-small cell lung cancer (NSCLC). Further, the agent blocked the ability of TNBC cells to initiate tumor formation.

In a statement following the AACR meeting in April 2014, Godfrey said that these phase Ia results supported the idea that inhibiting AXL looks promising for drug-resistant cancers.

“BGB324 is the only selective AXL inhibitor in clinical development and has the potential to significantly enhance the efficiency of targeted and chemotherapeutic agents,” Godfrey said.

In addition to AML, BGB324 is being evaluated in several other tumor types. BGB324 is being looked at in NSCLC in combination with erlotinib (currently in phase Ib), NSCLC in combination with docetaxel (phase Ib), liver fibrosis (phase IIa), and chronic myeloid leukemia (phase IIa).


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