374P - NX-019, a brain penetrant, mutation selective EGFR inhibitor with broad mutant EGFR activity

Background

NX-019 is a potent, orally bioavailable and CNS penetrant EGFR inhibitor selectively targeting a broad range of EGFR mutations including common mutations (e.g., exon 19 deletions and exon 21 L858R), T790M, exon 20 insertions and other rare mutations. Therefore, NX-019 has the potential to treat patients with mutant EGFR tumors not adequately addressed by current therapies.

Methods

NX-019 was optimized for enhanced CNS penetration and potency against a broad range of EGFR mutations. Preclinical studies in multiple mutant EGFR disease models characterized the properties of NX-019 both in vitro and in vivo. These experiments included assessments of potency, efficacy, pharmacodynamic, pharmacokinetic and toxicity parameters.

Results

Preclinical in vitro and in vivo studies reveal that NX-019 has high potency across a broad range of mutant EGFR models indicating the potential of NX-019 to treat patients not currently covered or resistant to current EGFR TKI therapies. NX-019 is selective for mutant EGFR over wild-type EGFR and exhibits greater potency (7.3-200+ fold) in cell lines in cells with classic, exon20 insertion, and other rare mutations compared to cells expressing wildtype EGFR. This improved mutant selectivity should facilitate improved tolerability at higher dose levels and greater systemic exposures. Studies in preclinical animal models (mouse, rat, dog) did not show classical EGFR dermatological findings, in agreement with the improved selectivity profile of NX-019. Studies to measure the CNS efficacy of NX-019 in xenograft brain models (such as PC9 brain orthotopic model) show tumor regressions and prolonged PD effects (e.g., inhibition of phospho-EGFR). CNS exposure studies in multiple preclinical species shows a Kp,uu of approximately 1 indicating excellent CNS exposure.

Conclusions

Based on the preclinical profile of broad potency and mutant selectivity for EGFR mutations with excellent CNS exposure, NX-019 is entering a Phase I dose escalation and dose expansion trial in mutant EGFR selected patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Nalo Therapeutics.

Funding

Nalo Therapeutics.

Disclosure

K. Wilson: Financial Interests, Personal, Full or part-time Employment: Nalo Therapeutics; Financial Interests, Personal, Member of the Board of Directors: Nalo Therapeutics; Financial Interests, Personal, Stocks/Shares: Nalo Therapeutics; Financial Interests, Personal, Leadership Role: Nalo Therapeutics. R. Dusek: Financial Interests, Personal, Full or part-time Employment: Nalo Therapeutics; Financial Interests, Personal, Stocks/Shares: Nalo Therapeutics. G. Gammon: Financial Interests, Personal, Full or part-time Employment: Nalo Therapeutics.