DME Data

PHOTON Pivotal Trial: Efficacy and Safety Results in Patients With Diabetic Macular Edema (DME)

In the 48-week results of the PHOTON phase 2/3 trial in patients with DME (N=658), the EYLEA HD Q12W and Q16W treatment arms demonstrated noninferiority in mean change in BCVA from baseline compared with EYLEA^® (aflibercept) Injection 2 mg Q8W with fewer injections and a comparable safety profile.^1,2

EYLEA HD Was Studied in a Phase 2/3 Pivotal Clinical Trial of 658 Patients With DME¹

PHOTON study design

Multicenter, randomized, double-masked study in patients with DME. Patients had DME with central involvement and were treatment-naïve (56%) or previously treated (44%) with a mean age of 62.3 years (range: 24-90) and a mean visual acuity of 63 ETDRS letters at baseline (range: 24-79).²

Primary endpoint

Mean change in BCVA (ETDRS letters) [noninferiority] from baseline at week 48

Key secondary endpoint

Proportion of patients with ≥2-step improvement in DRSS Score from baseline at week 48

Study Dosing Parameters for EYLEA HD Q12W and Q16W and EYLEA^® (aflibercept) Injection Q8W¹

	Note: Figure does not reflect all dosing options once a patient is shortened.
	At week 36, patients on EYLEA HD Q16W who were previously shortened to Q12W could have been shortened to Q8W.

	Note: Figure does not reflect all dosing options once a patient is shortened.
	At week 36, patients on EYLEA HD Q16W who were previously shortened to Q12W could have been shortened to Q8W.

Note: EYLEA 2 mg Q8W arm received 5 monthly injections compared with the EYLEA HD arms, which both received 3 initial monthly injections

EYLEA HD Met Its Primary Endpoint for Mean Change in BCVA From Baseline for Both Treatment Arms at Week 48^1,2

EYLEA HD Q12W and Q16W treatment arms demonstrated comparable ETDRS letter gains in patients with DME with fewer injections than EYLEA 2 mg Q8W¹*

	LS mean difference at week 48 (95% CI): EYLEA HD Q12W vs EYLEA 2 mg Q8W, -0.6 (-2.3, 1.1) letters; EYLEA HD Q16W vs EYLEA 2 mg Q8W, -1.4 (-3.3, 0.4) letters. NI margin was 4 letters.
	FAS: EYLEA HD Q12W n=328; EYLEA HD Q16W n=163; EYLEA 2 mg Q8W n=167 (at baseline). FAS, observed values (censoring data post ICE) at week 48: EYLEA HD Q12W (n=277); EYLEA HD Q16W (n=149); EYLEA 2 mg Q8W (n=150).
*	After 3 initial monthly injections for patients in the EYLEA HD Q12W and Q16W treatment arms. Patients in the EYLEA 2 mg Q8W arm received 5 initial monthly injections.
^†	Patients completing week 48: EYLEA HD Q12W, n=298; EYLEA HD Q16W, n=155; EYLEA Q8W, n=156.

Reductions in Central Retinal Thickness From Baseline in EYLEA HD Q12W and Q16W Treatment Arms With Fewer Injections vs EYLEA 2 mg Q8W at Week 48¹*

Mean change in CRT from baseline through week 48 (additional secondary endpoint)¹

*	After 3 initial monthly injections for patients in the EYLEA HD Q12W and Q16W treatment arms. Patients in the EYLEA 2 mg Q8W arm received 5 initial monthly injections. Reductions in CRT were determined by a central reading center on OCT.
^†	Patients who completed Week 48: EYLEA HD Q12W (n=298), EYLEA HD Q16W (n=155), EYLEA 2 mg Q8W (n=156).
^‡	FAS at baseline. FAS; observed values (censoring data post ICE) at week 48: EYLEA HD Q12W (n=276), EYLEA HD Q16W (n=149), EYLEA 2 mg Q8W (n=148).

EYLEA HD Dosing Frequency Results: 93% of Patients With DME in the Combined EYLEA HD Group Maintained Dosing Intervals ≥Q12W Through Week 48¹*

Proportion of patients maintaining Q12W and Q16W dosing intervals through week 48

*	Following 3 initial monthly doses.
^†	Patients completing 48 weeks of treatment.
^‡	Patients who met DRM criteria for interval shortening.
^§	Patients completing week 48: EYLEA HD Q12W, n=298; EYLEA HD Q16W, n=155; EYLEA 2 mg Q8W, n=156.

EYLEA HD Delivered ≥2-Step Improvements in DRSS Score With Fewer Injections vs EYLEA 2 mg at 48 Weeks^1-3

^∥	The EYLEA HD Q16W group did not meet the noninferiority criteria for the proportion of patients with a ≥2-step improvement on ETDRS-DRSS and is not considered clinically equivalent to EYLEA 2 mg administered Q8W for this endpoint. EYLEA HD Q16W is not an approved dosing regimen in DR.²
*	After 3 initial monthly doses for patients in the EYLEA HD Q12W and Q16W treatment arms. Patients in the EYLEA 2 mg Q8W arm received 5 initial monthly injections.
^†	Baseline values for EYLEA HD Q12W do not total 100% due to rounding.
^‡	Full analysis set. Last observation carried forward (censoring data post ICE).
^§	EYLEA HD Q12W vs EYLEA 2 mg difference (95% CI): 2% (-6.6, 10.6); noninferiority established (margin of 10%).

Recommended dosing in DR²

The recommended dose for EYLEA HD is 8 mg (0.07 mL of 114.3 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 days +/- 7 days) for the first 3 doses, followed by 8 mg (0.07 mL of 114.3 mg/mL solution) via intravitreal injection once every 8 to 12 weeks, +/- 1 week.

Safety Profile of EYLEA HD Was Consistent With the Established Profile of EYLEA 2 mg Through Week 48^2,4

*	After 3 initial monthly injections in patients in the EYLEA HD Q12W and Q16W treatment arms. Patients in the EYLEA 2 mg Q8W arm received 5 initial monthly injections.
^†	Represents grouping of related terms.
	Adverse drug reactions (ADRs) reported in <1% of participants treated with EYLEA HD were ocular hyperemia (includes adverse events of conjunctival hyperemia, conjunctival irritation, ocular hyperemia), lacrimation increased, eyelid edema, hypersensitivity (includes adverse events of rash, urticaria, pruritus), retinal tear, and injection site hemorrhage.²
	No cases of endophthalmitis or occlusive retinal vasculitis were reported through week 48.¹
	SELECT IMPORTANT SAFETY INFORMATION FOR EYLEA HD AND EYLEA (aflibercept) Injection 2 mg
	WARNINGS AND PRECAUTIONS
	Endophthalmitis, Retinal Detachments, and Retinal Vasculitis With or Without Occlusion: Intravitreal injections, including those with aflibercept, have been associated with endophthalmitis and retinal detachments and, more rarely, retinal vasculitis with or without occlusion. Proper aseptic injection technique must always be used when administering EYLEA HD or EYLEA. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately.

IMPORTANT SAFETY INFORMATION FOR EYLEA HD AND EYLEA (aflibercept) Injection 2 mg

CONTRAINDICATIONS

EYLEA HD and EYLEA are contraindicated in patients with ocular or periocular infections, active intraocular inflammation, or known hypersensitivity to aflibercept or to any of the excipients in EYLEA HD or EYLEA.

WARNINGS AND PRECAUTIONS

Intravitreal injections, including those with aflibercept, have been associated with endophthalmitis and retinal detachments and, more rarely, retinal vasculitis with or without occlusion. Proper aseptic injection technique must always be used when administering EYLEA HD or EYLEA. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis, retinal detachment, or retinal vasculitis without delay and should be managed appropriately.
Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with EYLEA HD and EYLEA. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with VEGF inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately.
There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including EYLEA HD and EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause).
- EYLEA HD: The incidence of reported thromboembolic events in the wet AMD study (PULSAR) from baseline through week 48 was 0.4% (3 out of 673) in the combined group of patients treated with EYLEA HD compared with 1.5% (5 out of 336) in patients treated with EYLEA 2 mg. The incidence in the DME study (PHOTON) from baseline to week 48 was 3.1% (15 out of 491) in the combined group of patients treated with EYLEA HD compared with 3.6% (6 out of 167) in patients treated with EYLEA 2 mg.
- EYLEA: The incidence of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with EYLEA compared with 1.5% (9 out of 595) in patients treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 out of 1824) in the EYLEA group compared with 3.2% (19 out of 595) in the ranibizumab group. The incidence in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with EYLEA compared with 2.8% (8 out of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with EYLEA compared with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with EYLEA in the first six months of the RVO studies.

ADVERSE REACTIONS

EYLEA HD:
- The most common adverse reactions (≥3%) reported in patients receiving EYLEA HD were cataract, conjunctival hemorrhage, intraocular pressure increased, ocular discomfort/eye pain/eye irritation, vision blurred, vitreous floaters, vitreous detachment, corneal epithelium defect, and retinal hemorrhage.
EYLEA:
- Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis and retinal detachment.
- The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased.
Patients may experience temporary visual disturbances after an intravitreal injection with EYLEA HD or EYLEA and the associated eye examinations. Advise patients not to drive or use machinery until visual function has recovered sufficiently.

INDICATIONS

EYLEA^® HD (aflibercept) Injection 8 mg is indicated for the treatment of patients with Neovascular (Wet) Age-Related Macular Degeneration (AMD), Diabetic Macular Edema (DME), and Diabetic Retinopathy (DR).

EYLEA^® (aflibercept) Injection 2 mg is indicated for the treatment of patients with Neovascular (Wet) Age-Related Macular Degeneration (AMD), Macular Edema following Retinal Vein Occlusion (RVO), Diabetic Macular Edema (DME), and Diabetic Retinopathy (DR).

Please see full Prescribing Information for EYLEA HD and EYLEA.

BCVA = best corrected visual acuity; CRT = central retinal thickness; DME = diabetic macular edema; DR = diabetic retinopathy; DRSS = diabetic retinopathy severity score; ETDRS = Early Treatment Diabetic Retinopathy Study; FAS = full analysis set; ICE = intercurrent events; LS = least squares; NI = noninferiority; OCT = optical coherence tomography; Q8W = every 8 weeks; Q12W = every 12 weeks; Q16W = every 16 weeks.

References: 1. Boyer D; PHOTON Study Investigators. Intravitreal aflibercept injection 8mg for DME: 48-week results from the phase 2/3 PHOTON trial. Presented at: Angiogenesis, Exudation, and Degeneration 2023; February 10-11, 2023. 2. EYLEA HD full U.S. Prescribing Information. Regeneron Pharmaceuticals, Inc. December 2023. 3. Brown DM; PHOTON Study Investigators. Intravitreal aflibercept injection 8 mg for DME: 48-week results from the Phase 2/3 PHOTON Trial. Presented at: Retina Society 2022; November 2-5, 2022. 4. EYLEA full U.S. Prescribing Information. Regeneron Pharmaceuticals, Inc. December 2023.

01/2024
US.EHD.23.12.0054

DME Data

PHOTON Pivotal Trial: Efficacy and Safety Results in Patients With Diabetic Macular Edema (DME)

EYLEA HD Was Studied in a Phase 2/3 Pivotal Clinical Trial of 658 Patients With DME1

Primary endpoint

Key secondary endpoint

Study Dosing Parameters for EYLEA HD Q12W and Q16W and EYLEA® (aflibercept) Injection Q8W1

Note: EYLEA 2 mg Q8W arm received 5 monthly injections compared with the EYLEA HD arms, which both received 3 initial monthly injections

EYLEA HD Met Its Primary Endpoint for Mean Change in BCVA From Baseline for Both Treatment Arms at Week 481,2

EYLEA HD Q12W and Q16W treatment arms demonstrated comparable ETDRS letter gains in patients with DME with fewer injections than EYLEA 2 mg Q8W1*

Reductions in Central Retinal Thickness From Baseline in EYLEA HD Q12W and Q16W Treatment Arms With Fewer Injections vs EYLEA 2 mg Q8W at Week 481*

Mean change in CRT from baseline through week 48 (additional secondary endpoint)1

EYLEA HD Dosing Frequency Results: 93% of Patients With DME in the Combined EYLEA HD Group Maintained Dosing Intervals ≥Q12W Through Week 481*

Proportion of patients maintaining Q12W and Q16W dosing intervals through week 48

EYLEA HD Delivered ≥2-Step Improvements in DRSS Score With Fewer Injections vs EYLEA 2 mg at 48 Weeks1-3

Recommended dosing in DR2

Safety Profile of EYLEA HD Was Consistent With the Established Profile of EYLEA 2 mg Through Week 482,4

No cases of endophthalmitis or occlusive retinal vasculitis were reported through week 48.1

SELECT IMPORTANT SAFETY INFORMATION FOR EYLEA HD AND EYLEA (aflibercept) Injection 2 mg

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