Summary: safety in LUGANO through week 56

Through week 56 of LUGANO, the ocular adverse events in the study eye with the largest absolute differences between vorolanib intravitreal insert 2.7 mg (211 participants) and aflibercept 2 mg (221 participants) were conjunctival haemorrhage (11.4% and 5.0%), vitreous floaters (9.0% and 3.6%), and neovascular age-related macular degeneration (7.1% and 1.4%). Intraocular inflammation (0.5% in each arm) and retinal detachment (0.5% in each arm) were infrequent, and the sponsor reported no cases of insert migration into the anterior chamber, retinal vasculitis, or severe intraocular inflammation. Nine participants (4%) in the vorolanib insert arm lost 15 or more letters from causes attributed by the sponsor to geographic atrophy (6), glaucoma (2), or retinal detachment (1); no participant in the aflibercept arm had such a loss. These data are preliminary and pending final analysis.

FDA-approved prescribing information, contraindications, boxed warnings, and REMS

Not applicable.

LUGANO: ocular adverse events in the study eye (≥2%) through week 56

Adverse event	DURAVYU 2.7 mg (n=211)	Aflibercept 2 mg (n=221)
Conjunctival haemorrhage	“11.4%”	“5.0%”
Vitreous floaters	“9.0%”	“3.6%”
Neovascular age-related macular degeneration	“7.1%”	“1.4%”
Retinal haemorrhage	“4.7%”	“1.8%”
Vitreous detachment	“4.7%”	“4.1%”
Cataract	“4.3%”	“5.4%”
Dry eye	“4.3%”	“6.3%”
Posterior capsule opacification	“4.3%”	“2.3%”
Intraocular pressure increased	“3.8%”	“3.2%”
Visual acuity reduced	“3.8%”	“5.4%”
Retinal oedema	“2.8%”	“0.9%”
Visual impairment	“2.4%”	“0.0%”
Dry age-related macular degeneration	“2.4%”	“3.2%”
Eye pain	“2.4%”	“0.9%”
Subretinal fluid	“2.4%”	“1.4%”

LUGANO: selected ocular adverse events in the study eye

Adverse event	DURAVYU 2.7 mg (N=211)	Aflibercept 2 mg (N=221)
Intraocular inflammation (IOI)	“0.5%”	“0.5%”
Retinal detachment	“0.5%”	“0.5%”
Geographic atrophy	“2.4%”	“2.7%”

LUGANO: adverse events of particular interest and discontinuations

“AEs of particular interest – all <1% in both arms” (opens the source at this quote in a new tab)
“All cases of floaters were mild or moderate with no required treatment or impact on vision” (opens the source at this quote in a new tab)
“Low patient discontinuation rate of 6% through Week 56 in each arm” (opens the source at this quote in a new tab)
“No study or treatment discontinuations were related to DURAVYU” (opens the source at this quote in a new tab)

“No difference in cataracts, elevated intraocular pressure, or intraocular inflammation between study and control group” (opens the source at this quote in a new tab)
“No observed occurrences of insert migration, anterior chamber opacities, free-floating drug particles, retinal vasculitis, or severe intraocular inflammation (IOI)” (opens the source at this quote in a new tab)

LUGANO: vision loss of 15 or more letters not attributed to wet AMD

“9 patients (of 211) lost ≥ 15 letters from non-wet AMD etiologies in DURAVYU arm, driving the endpoint result” (opens the source at this quote in a new tab)
“Zero patients (of 216) in aflibercept control arm lost ≥15 letters from non-wet AMD etiologies” (opens the source at this quote in a new tab)
“Geographic atrophy (n=6)” (opens the source at this quote in a new tab)
“Glaucoma (n=2)” (opens the source at this quote in a new tab)
“Retinal detachment (n=1)” (opens the source at this quote in a new tab)

LUGANO: baseline ocular history of dry AMD and glaucoma in the study eye

Medical history in study eye	DURAVYU 2.7 mg (n=211)	Aflibercept 2 mg q8W (n=216)
Dry AMD	“24.6%”	“21.7%”
Glaucoma	“11.4%”	“5.9%”

Phase 2 DAVIO 2: selected ocular adverse events in the study eye through week 56

Adverse event	Aflibercept 2 mg (54 participants)	EYP-1901 2,060 µg (50 participants)	EYP-1901 3,090 µg (52 participants)
Endophthalmitis	“2”	“0”	“3”
Intraocular pressure increased	“2”	“3”	“2”
Vitreous floaters	“1”	“2”	“6”
Visual acuity reduced	“3”	“1”	“8”
Retinal haemorrhage	“1”	“2”	“6”

Phase 1 DAVIO: ocular events not observed after a single dose

“There were no vitreous floaters, endophthalmitis, retinal detachment, insert migration into the anterior chamber, retinal vasculitis, posterior or anterior segment inflammation, vascular occlusive events, or ischemic optic neuropathy observed throughout the study.” (opens the source at this quote in a new tab)

Oral vorolanib: systemic adverse events in the APEX trial

“The APEX Trial was stopped prematurely due to gastrointestinal and hepatobiliary AEs associated with oral vorolanib use such as elevated liver enzymes, and due to the fulfillment of the primary endpoint (noninferiority to placebo).” (opens the source at this quote in a new tab)

Hypersensitivity

“Vorolanib and the inactive ingredients of EYP-1901 are not known to cause hypersensitivity reactions.” (opens the source at this quote in a new tab)

Class labeling for intravitreal VEGF inhibitors (aflibercept 8 mg)

“Endophthalmitis, retinal detachments, and retinal vasculitis with or without occlusion may occur following intravitreal injections.” (opens the source at this quote in a new tab)
“Increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection.” (opens the source at this quote in a new tab)
“There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors.” (opens the source at this quote in a new tab)

Oral vorolanib: timing and reversibility of liver enzyme elevations

“Most of the elevations occurred within 8–10 weeks of randomisation.” (opens the source at this quote in a new tab)
“Most commonly, liver enzymes returned to normal within a few weeks after discontinuation of X-82, although some patients required several months to return to baseline.” (opens the source at this quote in a new tab)
“Importantly, all elevations returned to baseline and there were no accompanying elevations of bilirubin or alkaline phosphatase.” (opens the source at this quote in a new tab)

Oral vorolanib: transaminase elevation on rechallenge and liver function monitoring

“An asymptomatic 71-year-old woman receiving 100-mg daily had an ALT level 3.1 times the ULN and an AST level 2.7 times the ULN at month 3. X-82 was withheld, and both normalized within 3 weeks. After rechallenging with 100 mg daily, the ALT level rose to 1.6 times the ULN, and the AST level to 1.5 times the ULN. X-82 was discontinued and transaminases normalized.” (opens the source at this quote in a new tab)
“The transaminase elevations did not appear to be dose related, and thus, it is important to monitor liver function in all patients receiving X-82 regardless of dose.” (opens the source at this quote in a new tab)

Duravyu (vorolanib intravitreal insert)

Contraindications/Warnings/Precautions/Adverse effects

Warnings and precautions