Thursday, April 2, 2015

Drugs in Clinical Pipeline: ARRY-614

ARRY-614  [1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(5-fluoro-2-((1-(2-hydroxyethyl)-1H-indazol-5-yl)oxy)benzyl)urea] is an orally bioavailable small molecule inhibitor of MAPK14 (also known as p38) and Tie-2 kinases with potential antineoplastic, anti-inflammatory and antiangiogenic activities. Data suggest that activity of p38 and Tie-2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies.

ARRY-614 is being developed by Array BioPharma. It has been quoted by the name Pexmetinib, which though doesn't appear on the company site (retrieved on 02/04/2015).

Common Name: ARRY-614
Synonyms: ARRY 614; Pexmetinib (net-searches)
IUPAC Name: 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(5-fluoro-2-((1-(2-hydroxyethyl)-1H-indazol-5-yl)oxy)benzyl)urea
CAS Number: 945614-12-0 
Mechanism of Action: Kinase Inhibitior; MAPK14 Inhibitor; Tie-2 Inhibitor
Indication: Myelodysplastic Syndromes
Development Stage: Phase I
Company: Array BioPharma

Phase I Study:

A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria. Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts.

The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1-2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. 

ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. Authors recommend 1,200 mg once daily as the optimal dose for further study [1].

1. Garcia-Manero, G.; et. al. A Phase I Study of Oral ARRY-614, a p38 MAPK/Tie2 Dual Inhibitor, in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes. Clin Cancer Res 2015, 21(5), 985-994.