BERGEN, Norway--(EON: Enhanced Online News)--Leading oncology biopharmaceutical company BerGenBio AS, today presented clinical and biological data from a Phase I trial of its potent, highly selective, first-in-class Axl inhibitor BGB324 in acute myeloid leukaemia in an oral session at the 58th ASH Annual Meeting & Exposition in San Diego. The company regards the results as an important indicator of the clinical utility of BGB324 in AML and the possibility of selecting patients who may benefit from treatment in advance of therapy.
“BGB324 is active and well tolerated in AML patients, furthermore, BGB324 promotes diversification of the TCR repertoire in AML patients and therefore holds potential as an immune-activating drug.”
The oral presentation was entitled BGB324, an orally available selective Axl inhibitor exerts anti-leukaemic activity in the First-in-Patient trial BGBC003 and induces unique changes in biomarker profiles (Paper 0592, Session: Acute Myeloid Leukemia: Clinical Studies: New Drugs for Older AML). It reported clinical and biological data demonstrating the impact of BGB324 on the Axl signalling pathway in leukemic blast cells. Furthermore, an analysis of patients T-cell lymphocyte diversification illustrated that BGB324 amplified the immune response in a proportion of patients. Twenty-five patients (twenty-two with relapsed/refractory AML and three with high risk MDS) were treated in a classical 3+3 dose escalation design. Three dose levels were explored: 400/100 mg, 600/200 mg and 900/300 mg. Treatment was generally well-tolerated and steady-state levels of BGB324 were reached between three and six days after initiation of treatment. One AML patient achieved a CRi and two achieved a PR. Four additional AML patients (25%) experienced disease stabilisation for more than four months. One MDS patient experienced a PR. Treatment with BGB324 also led to an increase in the levels of soluble Axl receptor (sAXL) which was directly correlated to compound exposure (n=13; r=0.86), indicating that Axl could be used as a biomarker of target engagement.
Professor Sonja Loges (MD, PhD), Principle Investigator for the Clinical Study commented: “BGB324 is active and well tolerated in AML patients, furthermore, BGB324 promotes diversification of the TCR repertoire in AML patients and therefore holds potential as an immune-activating drug.”
Also presented was a poster that showed single cell signaling pharmacodynamics in a Phase 1 trial of BGB324 in acute myeloid leukemia (Paper 3995, Session: Acute Myeloid Leukemia: Clinical Studies: Poster III). The effect of BGB324 on intracellular signaling and the immune profile of leukaemic blasts in patients treated in the clinical study was investigated using phospho-flow cytometry. Leukemic blasts were identified using surface markers and treatment-related changes in direct and indirect downstream targets of Axl were explored. Analyses of blood samples from six patients showed rapid changes in signalling pathways downstream of Axl. In most patients, the CD117+/CD34- blast population appeared more responsive to treatment, and this cell population decreased during treatment with BGB324, suggesting that Axl inhibition may push leukemic blasts towards differentiation. The clinical trial is ongoing, and the signaling profile of leukaemic blasts in blood and bone marrow of treated patients will continue to be examined by conventional phospho-flow and mass cytometry.
Richard Godfrey, Chief Executive Officer of BerGenBio, commented: “The two presentations show BGB324 is well tolerated in AML patients and exhibits anti-leukaemic activity. Furthermore, BGB324 can induce a diversification of the T-cell repertoire in AML patients and holds potential as an immune-activating drug. These studies suggest a patient enrichment strategy could be adopted to achieve a personalised medicine approach to BGB324 therapy.”
BGB324 is a first-in-class, highly selective small molecule inhibitor of the Axl receptor tyrosine kinase. It blocks the epithelial-mesenchymal transition (EMT), which is a key driver in immune evasion, drug-resistance and metastasis. Phase Ib clinical trials are underway as single agent and in combination with standard of care drugs in acute myeloid leukaemia (AML) and erlotinib as well as docetaxel in non-small cell lung cancer (NSCLC).
BGBC003 (NCT02488408) is a phase I/II multicenter open-label study of BGB324 as a single agent and in combination with cytarabine in patients with AML and high-risk MDS. The study consists of a dose-escalation phase of BGB324 and a single agent as well as combination with cytarabine arm at the recommended phase 2 dose. Primary endpoints of the trial are the evaluation of safety as well objective response rate and progression free survival. The study is run at centres in Norway, Germany and the US. For more information see: www.bergenbio.com/what-we-do/ongoing-clinical-trials/