Abstract
Purpose :
The inhibitory activities of VVN539 on ROCK were assessed in multiple in vitro studies, demonstrating that both molecules inhibit both ROCK 1 and ROCK2. Additionally, the potency of VVN539 as a NO donator were verified in vitro studies. The objectives of this study were to evaluate the ocular hypotensive activity and tolerability of 0.02% VVN539 ophthalmic solution compared to Netarsudil (coded as VIP-5001) in the same vehicle in normotensive Dutch Belted (DB) rabbits.
Methods :
VVN539 was tested in vivo and vitro for its ability to release functionally active NO through analyzing the levels of intracellular cGMP by which many biological actions of NO are mediated. 0.02% VVN539 and 0.02% VIP-5001 formulations were administered topically to one eye of each animal once daily (AM) for 10 consecutive days and the other eye was untreated as control. Intraocular pressure (IOP) was measured daily for both eyes in the conscious animals at pre-dose, 4, 8, 12 and 24 hours after dosing from Day 1 to Day 10. Hyperemia was scored on a scale of 0 to 3 (none to severe) with 0.5 increment by a masked ophthalmologist under slit lamp at 2 hours post dosing on Day 1 to Day 3 and on Day 10.
Results :
VVN539 increased intracellular cGMP formation. Peak IOP-lowering effect of 0.02% VVN539 and VIP-5001 formulations in the normotensive rabbits was -5.28±0.40 mmHg and -3.36±0.42 mmHg, respectively. VVN539 produced a about 50% greater peak IOP lowering activity than VIP-5001 at the same concentration on the last dosing day (Day 10). The maximum reduction in IOP was achieved at 4 hours after each dose once per day. The ROCK kinase inhibition combined with another validated IOP lowering mechanism of NO releasing resulted better efficacy vs. the Rho kinase inhibitor, VIP-5001 in ocular normotensive Dutch Belted rabbits.
Conclusions :
Topical ocular VVN539 was well tolerated and lowered IOP in normotensive rabbits, demonstrating increased efficacy with only minimal conjunctival hyperemia when compared with topical ocular VIP-5001. Our study indicates that the VVN539, a highly selective Rho-Kinase Inhibitor with dual MOA are superior to VIP-5001 (Netarsudil) in lowering IOP in normotensive rabbit model.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.