Topical drug delivery via mucus-penetrating particles blocks VEGF signaling

Take-home message: A topical receptor tyrosine kinase inhibitor may be a potential noninvasive inhibitor of vascular endothelial growth factor signaling.

By Lynda Charters; Reviewed by Lisa Schopf, PhD

Waltham, MA-A topical receptor tyrosine kinase inhibitor candidate (K106, Kala Pharmaceuticals) is designed to potently and selectively block vascular endothelial growth factor (VEGF) signaling.

When applied topically as mucus-penetrating particles (MPPs) in animals, the drug reaches the back of the eye-implying potential relevance in retinal disease therapy, according to Lisa Schopf, PhD.

Mucus is an innate defense mechanism comprising a heterogeneous mesh of mucin that defends against pathogens and other particles by excluding particles larger than its pore sizes. In this situation, glycosylated macromolecules bind to foreign particles to facilitate clearance.

MPPs should be able to overcome both steric exclusion and binding to allow for more efficient delivery of drugs in mucus-protected tissues.

“The MPPs rapidly and uniformly coat and penetrate mucosal barriers, and have the potential to increase drug exposure to underlying tissues and improve topical ocular drug delivery,” Dr. Schopf said.

Research goals

The goals of Dr. Schopf and colleagues in this research were to design a small molecular inhibitor of the VEGF signaling pathway that was highly potent against VEGF receptors and against the platelet-derived growth factor receptor with good selectivity against particular growth factor, cell cycle, and other detrimental receptors. The K106 affinity for KDR over the other targets-i.e., EGFR, FGFR1 and RET-were 680, 188, and 28-fold, respectively.

Ocular and systemic pharmacokinetics of K106-MPP were evaluated after topical instillation in rabbits and mini-pigs.

After one topical 0.5% dose to rabbits, the drug concentrations-which were expressed as the area under the curve calculated over 0 to 12 hours-were 4,270 in the choroid, 474 in the retina, and 9 nM*hr in the plasma.

Multiple doses given twice daily for 5 days were also studied in rabbits and compared with single doses. The multidose drug levels in the choroid were 8-fold higher and in the retina 2-fold higher compared with the single dose, Dr. Schopf noted.

Little or no change was seen in the plasma levels. The MPP delivered concentrations to the back of the eye that were well above the IC50 level.

In the rabbit model of vascular leakage, K106-MPP gave significantly decreased vascular leakage compared with the vehicle control, which suggested that topical instillation delivered biologically active concentrations of this novel drug formulation to the back of the eye, according to Dr. Schopf.

In the larger mini-pigs, the results confirmed the drug levels at the back of the eye with choroidal and retinal tissue levels were well about the IC50 levels.

“We demonstrated that K106 is a potent and selective VEGF signaling inhibitor,” Dr. Schopf summarized. “When applied topically as a MPP, the drug reaches the back of the eye in rabbits and mini-pigs. The ability to reach the back of the eye may be a major breakthrough in providing a noninvasive means to treat retinal disease.”

Lisa Schopf, PhD

E: Lisa.Schopf@kalarx.com

This article was adapted from a poster presentation at the 2015 meeting of the Association for Research in Vision and Ophthalmology. Dr. Schopf is an employee of Kala Pharmaceuticals.