Azd1152-Hqpa Accurins: Nanoparticle Formulations Showing Extended Release And The Potential For Improved Therapeutic Index

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The prodrug, Barasertib (AZD1152) is a potent selective inhibitor of the Aurora B kinase which plays a pivotal role in chromosomal segregation during the cell cycle. In a Phase 2 randomised study in elderly AML patients unfit for intensive therapy, Barasertib showed a statistically significant improvement in Overall Complete Response Rate and a trend for improved Overall Survival as a continuous infusion over 7 days (Kantarjian et al, Cancer 2013;119:2611-2619) . The Dose Limiting Toxicities were neutropenia and stomatitis. AccurinTM nanoparticle formulations of the active metabolite, AZD1152-hQPA, have been developed utilizing medicinal nanoengineering to optimize critical nanoparticle properties such that a short infusion has the potential for extended target cover and an improved therapeutic index from increased biodistribution to the tumour site. In nude rats bearing SW620 tumours, AZD1152-hQPA Accurins gave extended target cover leading to sustained pharmacodynamic (PD) inhibition of phospho-histone H3 in the tumour relative to Barasertib at the same dose. Interestingly the Accurins gave a differentiated PD profile with maximal PD seen at later time points. This profile led to improved anti-tumour effects when AZD1152-hQPA Accurins were dosed intravenously at 25mg/kg on day 1 and 3, compared to Barasertib dosed at 25mg/kg on days 1, 2, 3, 4. Significantly, one of the AZD1152-hQPA Accurins had minimal impact on bone marrow pathology, demonstrating the potential for increased efficacy and lower toxicity at half the dose intensity of Barasertib in this preclinical model. The impact on efficacy of different dose intensities and schedules with this AZD1152-hQPA Accurin has also been explored in the equivalent nude mouse SW620 model. Together these studies demonstrate that by careful selection of formulation parameters, AZD1152-hQPA can be formulated with an extended release profile able to deliver improved efficacy and tolerability in pre-clinical models. AZD1152-hQPA Accurins offer the potential to overcome the therapeutic index challenges which previously limited the clinical development of agents in the class. Citation Format: Simon T. Barry, Elaine Cadogan, Rajesh Odedra, Susan Ashton, John Foster, Young Ho Song, Susan Low, Paula Taylor, Rebecca Ellston, Urszula Polanska, Joanne Wilson, Colin Howes, Dawn Trueman, Mike Walker, David De Witt, Marianne Ashford, Jeff Hrkach, Phil Jewsbury. AZD1152-hQPA Accurins: Nanoparticle formulations showing extended release and the potential for improved therapeutic index. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5409. doi:10.1158/1538-7445.AM2014-5409