Summary: systemic and aqueous humor exposure in DAVIO 2

In the phase 2 DAVIO 2 trial, a single vorolanib insert dose (2,060 µg or 3,090 µg) was given at week 8. Mean plasma vorolanib concentrations were 0.000 pg/mL at week 8 (the visit at which the insert was administered), 23.206 pg/mL (2,060 µg; 46 participants) and 27.121 pg/mL (3,090 µg; 47 participants) at week 20, and 7.733 pg/mL (45 participants) and 10.392 pg/mL (50 participants) at week 56. Mean aqueous humor concentrations at week 20 were 17.426 ng/mL (43 participants) and 25.066 ng/mL (49 participants). Plasma concentrations were reported in picograms per milliliter and aqueous humor concentrations in nanograms per milliliter. Mean plasma concentrations of the main metabolite did not exceed 2.46 pg/mL at any sampled visit.

Release duration by design

“Each EYP-1901 insert has been designed to deliver vorolanib into the vitreous humor for at least 9 months.” (opens the source at this quote in a new tab)

“Consistent daily dosing with target inhibition for ≥6 months” (opens the source at this quote in a new tab)
“Full elution of vorolanib before matrix bioerosion; no free-floating drug particles” (opens the source at this quote in a new tab)

Preclinical release kinetics in rabbits

“In rabbit studies, the EYP-1901 insert showed a burst in drug release that rapidly resulted in steady-state levels in ocular tissues with an average zero-order drug-release rate of approximately 8% of the total dose per month through 8 months; this was followed by a rapid decrease through 10 months.” (opens the source at this quote in a new tab)

Preclinical ocular and plasma concentrations in rabbits

“Findings showed that EYP-1901 was able to reach steady state quickly in all locations and this was maintained until depletion of the drug around 240–270 days after insert. The main targets of retina and choroid maintained a VEGFR2 IC50 of above 23 ng/ml through day 240 while plasma and aqueous humor levels were consistently below 23 ng/ml” (opens the source at this quote in a new tab)
“Based on the insert measurements, the 643 μg insert showed a release rate of 1.73 μg per day while the 2 inserts of 900 μg showed a release rate of 2.33 μg per day” (opens the source at this quote in a new tab)

DAVIO 2: plasma vorolanib concentrations (pg/mL) after a single insert dose at week 8

Visit	2,060 µg mean	2,060 µg SD	3,090 µg mean	3,090 µg SD
Week 8	“0.000”	“0.0000”	“0.000”	“0.0000”
Week 20	“23.206”	“8.8871”	“27.121”	“10.0821”
Week 32	“14.333”	“6.1098”	“19.335”	“7.3783”
Week 44	“10.292”	“5.2086”	“14.180”	“4.9819”
Week 56	“7.733”	“4.9684”	“10.392”	“5.2315”

DAVIO 2: aqueous humor vorolanib concentrations (ng/mL) after a single insert dose at week 8

Visit	2,060 µg mean	2,060 µg SD	3,090 µg mean	3,090 µg SD
Week 8	“0.000”	“0.0000”	“0.000”	“0.0000”
Week 20	“17.426”	“13.7143”	“25.066”	“18.8594”
Week 32	“11.890”	“10.8436”	“19.813”	“15.0833”

DAVIO: plasma exposure after 6 months

“In both patients, these SAEs occurred >6 months after receiving EYP-1901 at a time point when the study drug was undetectable in plasma.” (opens the source at this quote in a new tab)

Pharmacokinetics after repeat dosing every 6 months

No evidence found.

Vitreous clearance of tyrosine kinase inhibitors and the rationale for sustained release

“Rapid vitreous clearance of existing VEGF inhibitors limits durability to 1-4 months.” (opens the source at this quote in a new tab)
“TKIs are small molecules and rapidly cleared from the vitreous.” (opens the source at this quote in a new tab)
“Combining TKIs with sustained release platforms, such as hydrogel or polyvinyl alcohol, allow for the sustained release of the molecules and the potential for extended durability.” (opens the source at this quote in a new tab)
“The implant is designed to release vorolanib at near zero order kinetics for 9 months and to be completely bioerodible.” (opens the source at this quote in a new tab)