Hele interessante data van BrystelMyerSquib gisteren, zie hieronder analyse van Kempen.
BMS LPA1 antagonist gives credence to GLPG1690 target and data GLPG NA
11 September 2018, 08:46
BMS published the results for its terminated phase II trials with LPA1 receptor antagonist (Palmer, 2018), demonstrating a stat sig slowdown in FVC decline in IPF patients, supported by the numerically higher proportion of patients with no decline in FVC. In our view, the results not only provide validation of targeting the ATX-LPA pathway in fibrosis, but also give credence to the observed stabilization of FVC in the phase II FLORA trial with Galapagos' GLPG1690. Meanwhile, the observed safety issues with LPA1 receptor antagonist that led to the termination of the program, were identified as off-target toxicities related to the specific drug profile with no read-through to GLPG1690. We believe if GLPG1690 maintains the magnitude of disease stabilization shown in the FLORA trial, it would be positioned to take the leading market share among second-generation therapies.
Efficacy validates LPA as a target in IPF. The phase II study with BMS' LPA1 receptor antagonist BMS-986020 in IPF demonstrated significantly slower rates of FVC decline at 600mg BID dose -42ml vs. -134ml placebo after 26 weeks. The finding was further supported by a numerically higher percentage of patients not experiencing a decline in FVC: 38% vs. 18% The authors concluded that demonstrated results are suggestive of a clinical benefit with LPA1 inhibition in IPF. In our view, the results also provide validation for Galapagos' GLPG1690, an inhibitor of autotaxin - a key enzyme in the production of LPA, and observed stabilization of FVC (+8ml vs. -87ml at w12) in its phase IIa FLORA study, suggesting a biological drug effect rather than random fluctuations of spirometry results.
Safety issues are off target, drug-specific. Although the treatment was well tolerated in most patients, the study was terminated prematurely on the evidence of hepatobiliary toxicity as manifested by dose-related elevations in hepatic transaminases and ALP and 3 cases treatment-related cholecystitis. Based on preclinical research, the authors concluded that the liver toxicity was off-target, drug-specific effects related to inhibition of hepatobiliary transporters and bile composition and not related to LPA1 antagonism (Rosen, 2017). The phase II FLORA trial with GLPG1690 and the phase I trial in healthy volunteers did not identify any significant safety and tolerability issues in 17 IPF patients treated with GLPG1690 for 12 weeks: mainly headaches and no signs of hepatotoxicity