Mechanism of action: MEK 1/2 inhibitor
RDEA119 (refametinib) is an orally available, non-ATP-competitive inhibitor of the mitogen-activated protein kinases 1 and 2 (MEK 1/2). It selectively binds to an allosteric pocket and inhibits the MEK1 and MEK2 enzymes with IC50 values of 17 nM and 43 nM respectively. RDEA119 effectively inhibited the growth of a variety of human tumor cell lines that have RAS-RAF-MEK-ERK pathway activation, at sub-micromolar concentration. It inhibits tumor growth in orthotopic, syngeneic, and patient-derived xenograft mouse models, including those of melanoma, breast cancer, CRC, NSCLC, HCC, and pancreatic cancer. In addition, RDEA119 has also shown anti-inflammatory activity in rodent models of arthritis, colitis, IBD and psoriasis.
Safety and tolerability
Dose escalation study in cancer patients has established the maximum-tolerated dose (MTD) as 100 mg P.O. daily, administered as either a qd dose or divided as bid in 28-day courses. Common adverse events associated with single-agent treatment include fatigue, lymphoedema, nausea, vomiting, diarrhea, and dermatitis acneiform.
In the single ascending dose segment of a Phase 1 healthy volunteer study, RDEA119 showed inhibition of induced pERK in PBMCs starting at a dose of 6 mg qd, and achieved a maximum effect at 25 mg qd. Inhibition of cytokine induction was seen across the entire pro-inflammatory panel at 12 mg, 25 mg, and 40 mg doses.
Suitable for and exclusions
The reproductive toxicology package indicates a risk of fetal toxicity. The inclusion of women of child-bearing potential would need to be assessed for any proposal based on the risk benefit and the use of appropriate highly effective contraception. Due to the substantial increase in exposure, co-administration of RDEA119 and strong CYP3A4 inhibitors is prohibited.
AstraZeneca is not keen on pursuing RDEA119 for additional preclinical or clinical oncology indication research at this time.