(T-128) Application of PKPD Principles to Drive the Discovery and Development of Novel BCR-ABL Tyrosine Kinase Inhibitors

Stefan Gross, PhD – VP, Enliven Therapeutics; Helen Collins, MD – Chief Medical Officer, Enliven Therapeutics; Joseph Lyssikatos, PhD – Chief Scientific Officer, Enliven Therapeutics; Samuel Kintz, MBA – Chief Executive Officer, Enliven Therapeutics

Although six tyrosine kinase inhibitors (TKIs) targeting BCR-ABL fusion proteins have been approved in the USA, namely, imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and asciminib, resistance and intolerance negatively impact life expectancy and quality of life. Therefore, there is a need for new TKIs targeting existing and emerging resistance mutations with better tolerability. The objective of this abstract is to determine keys drivers for anti-CML activity and to drive the discovery and development of novel TKIs for CML, using ELVN-001 as an example.

The in vitro IC50 values of phosphorylated CRKL (pCRKL) for all approved TKIs and ELVN-001, except asciminib, were determined by using a K562 cell model in the presence or absence of 100% human serum. In addition, the inhibition (IC50 and IC90) of phosphorylation of STAT5 (pSTAT5), a downstream effector of ABL, was also measured.
Steady-state human plasma exposure parameters (Cmax, AUC, and Cmin) and variability to all approved TKIs were obtained from the literature or NDA review documents [3,4,5,6, & 11]. Plasma protein binding (PPB) values were obtained from the literature for the approved TKIs or determined using an equilibrium dialysis method for Enliven compounds. The proportion of patients with newly diagnosed CML that achieved different levels of molecular response (MR, BCR-ABL transcript level in plasma on an international scale, %) was obtained from the literature. [8,9,&10]

Exposures response analyses were conducted for MR2 (≤1%), MR3 (≤0.1%), and MR4 (≤0.01%) at 12, 24, and 60 months versus steady-state Cavg (AUCtau/tau), Cmin, and Cmax using linear correlations or other relationships for TKIs with data in patients with newly diagnosed CML, with consideration of PPB and potency. PFS or OS were not included for ER analyses due to that CML patients have similar life span as normal subjects.

Results:
The analysis of MR3 and Cavg/Cmin with PPB adjusted in vitro potency showed that the cumulative MR3 rate at 12 months correlated linearly with Cavg values better than other PK parameters. The relationship of MR3 at 60 months with Cavg/Cmin and PPB adjusted potency is hyperbolic.

In conclusion, PK and variability, PPB, and potency on BCR-ABL drive TKI’s efficacy in CML patients. This model didn't need to factor kinases inhibitions other than BCR-ABL pathway into efficacy estimation. Using this PKPD relationship as guidance, ELVN-001 [1], which is highly active in vitro and less plasma protein-bound, was discovered by Enliven Therapeutics and is currently under clinical development [2].

Citations: 1. Gross SD, Eide CA, et al. Blood (2022) 140 (Supplement 1): 3095-96;
2. Lang F., Branford S., et al. Hemasphere (2023) 7 (Suppl) :e32603d4
3. Peng B., Hayes M. et al. J. Clin Oncol. (2004) 22 (5): 935-42
4. Tian X., Zhang H. et al. J. Clin Pharmacol. (2018), 58 (12): 1533-40
5. Amita A. Abumiya M. et al. Exp Hematol. Oncol. (2018) 7:9
6. Wang X., Hochhaus A. et al. J. Clin Oncol. (2008) 26 15_Suppl 3590
7. Hanley MJ., Diderichsen PM., et al. J. Clin Pharmacol. (2022), 62 (4): 555-67
8. Hochhaus A. Sagli G., et al. Leukemia (2016) 30, 1044-54
9. Brummendorf TH, Cortes JE et al. Leukemia. (2022) 36: 1825-33
10. Cortes JE., Saligo G., et al. J Clin Oncol. (2016) 34: 2333-40
11. FDA review asciminib, NDA 215358