Two-year Results for Aflibercept 8 mg from Pivotal PHOTON Trial Demonstrate Durable Vision Gains at Extended Dosing Intervals in Diabetic Macular Edema

89% of all aflibercept 8 mg patients maintained ≥12-week dosing intervals through two years

Of those assigned to a 16-week dosing regimen at baseline, 83% maintained ≥16-week dosing intervals through two years

Many patients met the extension criteria for even longer dosing intervals, including 43% for ≥20-week intervals and 27% for 24-week intervals

Visual gains and safety of aflibercept 8 mg remained consistent with the established profile of EYLEA^® (aflibercept) 2 mg Injection

TARRYTOWN, NY, June 27, 2023 (GLOBE NEWSWIRE) -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced top-line, two-year (96 weeks) data for aflibercept 8 mg from the pivotal PHOTON trial in patients with diabetic macular edema (DME). During the trial, aflibercept 8 mg patients were initially randomized to either 12- or 16-week dosing intervals (after three initial monthly doses) and were able to shorten or extend dosing intervals if pre-specified criteria were met. The longer-term data among aflibercept 8 mg patients who completed the trial demonstrated that the vast majority of patients were able to maintain or further extend these dosing intervals through two years with:

• 89% maintaining ≥12-week dosing intervals through two years, compared to 93% through one year (48 weeks)
• 83% maintaining ≥16-week dosing intervals through two years, compared to 89% maintaining a 16-week dosing interval through one year
• 43% meeting the criteria for ≥20-week dosing intervals by week 96, including 16% and 27% who were eligible for 20- and 24-week dosing intervals, respectively
  

“The two-year PHOTON results for aflibercept 8 mg in patients with diabetic macular edema are extremely compelling,” said Jeffrey Heier, M.D., Director of the Retina Service and Retina Research at Ophthalmic Consultants of Boston and a trial investigator. “To be able to rapidly achieve extended dosing intervals without any sacrifice of vision gains over two years is a tremendous benefit in the treatment of diabetic macular edema.”

“The two-year PHOTON results certainly exceeded my expectations and indicate that the majority of patients may eventually be able to control their diabetic macular edema with as few as two or three aflibercept 8 mg injections per year, if approved by regulatory authorities, with similar excellent visual gains and a safety profile consistent with EYLEA given every 8 weeks,” said David M. Brown, M.D., FACS, Director of Research at Retina Consultants of Texas and a trial investigator. “Reducing the treatment burden in patients with diabetic macular edema is a critical unmet need, and the two-year PHOTON results reinforce the potential of aflibercept 8 mg to become the standard of care for the treatment of diabetic macular edema.”

PHOTON (N=658) is a double-masked, active-controlled pivotal trial evaluating non-inferiority of aflibercept 8 mg 12-week (n=328) and 16-week (n=163) dosing regimens after three initial monthly doses compared to an 8-week dosing regimen for EYLEA (aflibercept) Injection (n=167) after five initial monthly doses. In addition to the vast majority of trial patients maintaining extended dosing intervals through two years, visual gains for aflibercept 8 mg remained consistent with the first year of the trial.

	Through 48 weeks (one year)							Through 96 weeks (two years)
	EYLEA 8-week regimen		aflibercept 8 mg 12-week regimen		aflibercept 8 mg 16-week regimen			EYLEA 8-week regimen		aflibercept 8 mg 12-week regimen		aflibercept 8 mg 16-week regimen
Mean number of injections^	7.9		6.0		5.0			13.8		9.5		7.8
Mean observed BCVA improvement, letters	9.2		8.8		7.9			8.4		8.8		7.5
LS mean (SE) change from baseline, letters	8.7 (0.7)		8.1 (0.6)		7.2 (0.7)			7.7 (0.9)		8.2 (0.6)		6.6 (0.8)
Difference in LS mean (95% CI), letters			-0.6* (-2.3, 1.1)		-1.4† (-3.3, 0.4)					+0.5‡ (-1.6, 2.5)		-1.1§ (-3.3, 1.1)
Proportion of patients losing ≥15 letters, per LOCF	1.2%		2.1%		0.6%			3.6%		3.4%		1.2%

BCVA: best corrected visual acuity; LS: least squares; SE: standard error; LOCF: last observation carried forward
^Based on patients completing week 48 or 96 in the trial
*Non-inferiority p-value: p<0.0001
^†Non-inferiority p-value: p=0.0031
^‡Nominal non-inferiority p-value: p<0.0001
^§Nominal non-inferiority p-value: p=0.0044

In PHOTON, the safety of aflibercept 8 mg also continued to be similar to EYLEA through two years and remained consistent with the known safety profile of EYLEA from previous clinical trials for DME. Ocular treatment emergent adverse events (TEAE) occurring in ≥5% of patients in any treatment group, in decreasing frequency, were cataract, vitreous floaters, and conjunctival hemorrhage. There were no cases of retinal vasculitis, occlusive retinitis or endophthalmitis. The rate of intraocular inflammation was 1.2% for both the EYLEA and aflibercept 8 mg groups. Anti-platelet trialists' collaboration-defined arterial thromboembolic TEAEs occurred in 7.2% of patients treated with EYLEA and 6.5% of patients treated with aflibercept 8 mg.

“The aflibercept 8 mg clinical trial program is the first to demonstrate that patients with diabetic macular edema can immediately be treated with every 12- or 16-week dosing after their initial monthly doses and experience lasting vision control,” said George D. Yancopoulos, M.D., Ph.D., Board Co-Chair, President and Chief Scientific Officer at Regeneron, and a principal inventor of EYLEA. “With these two-year results, Regeneron continues to raise the bar in clinical advancements for retinal treatments and remains committed to pursuing groundbreaking innovations in ophthalmology.”

The two-year data from the pivotal PULSAR trial for aflibercept 8 mg in wet age-related macular degeneration are expected in the third quarter of 2023, and the two-year data from both PHOTON and PULSAR are planned for presentation at an upcoming medical meeting.

Aflibercept 8 mg is investigational, and its safety and efficacy have not been fully evaluated by any regulatory authority. Aflibercept 8 mg is being jointly developed by Regeneron and Bayer AG, with Regeneron sponsoring the PHOTON trial. In the U.S., Regeneron maintains exclusive rights to EYLEA and aflibercept 8 mg. Bayer has licensed the exclusive marketing rights outside of the U.S., where the companies share equally the profits from sales of EYLEA and aflibercept 8 mg following any regulatory approvals.

About the Aflibercept 8 mg Clinical Trial Program
PULSAR in wAMD and PHOTON in DME are double-masked, active-controlled pivotal trials that are being conducted in multiple centers globally. In both trials, patients were randomized into 3 treatment groups to receive either: aflibercept 8 mg every 12 weeks, aflibercept 8 mg every 16 weeks, or EYLEA every 8 weeks. The lead sponsors of the trials were Bayer for PULSAR and Regeneron for PHOTON.

Patients treated with aflibercept 8 mg in both trials had 3 initial monthly doses, and patients treated with EYLEA received 3 initial doses in PULSAR and 5 in PHOTON. In the first year, patients in the aflibercept 8 mg groups could have their dosing intervals shortened down to an every 8-week interval if protocol-defined criteria for disease progression were observed. Intervals could not be extended until the second year of the study. Patients in all EYLEA groups maintained a fixed 8-week dosing regimen throughout their participation in the trials.

About DME
DME is a common complication in eyes of people living with diabetes. DME occurs when high levels of blood sugar lead to damaged blood vessels in the eye that leak fluid into the macula. This can lead to vision loss and, in some cases, blindness. Of the nearly 28 million American adults living with diabetes, an estimated 1.2 million have DME.

About Ophthalmology at Regeneron
At Regeneron, we relentlessly pursue groundbreaking innovations in eye care science to help maintain the eye health of the millions of Americans impacted by vision-threatening conditions. Over a decade ago, our breakthrough scientific research resulted in the development of EYLEA, a vascular endothelial growth factor (VEGF) inhibitor designed to block the growth of new blood vessels and decrease the ability of fluid to pass through blood vessels in the eye. EYLEA has since brought fundamental change to the retinal disease treatment landscape and is supported by a robust body of research that includes eight pivotal Phase 3 trials, 11 years of real-world experience, and more than 60 million EYLEA injections globally.

Regeneron continues to advance our anti-angiogenesis expertise with new solutions with the aim of offering optimal flexibility for a broad group of patients and eye care professionals. This includes aflibercept 8 mg, which has been developed with the aim of extending the time between injections, while maintaining the vision gains, anatomic benefits and safety previously observed with EYLEA.

IMPORTANT EYLEA SAFETY INFORMATION AND INDICATIONS

INDICATIONS
EYLEA (aflibercept) Injection 2 mg (0.05 mL) 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), Diabetic Retinopathy (DR) and Retinopathy of Prematurity (ROP) (0.4 mg [0.01 mL]).

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

• Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique must always be used when administering EYLEA. Patients and/or caregivers should be instructed to report any signs and/or symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately. Intraocular inflammation has been reported with the use of EYLEA.
• Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with 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.
• In infants with ROP, reactivation of abnormal angiogenesis and tortuosity may occur following treatment with EYLEA. Infants should be monitored closely after injection with EYLEA until retinal vascularization has completed or until the examiner is assured that reactivation of ROP will not occur. Treatment with EYLEA will necessitate extended periods of ROP monitoring and additional EYLEA injections and/or laser treatments may be necessary.
• There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). 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

• 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.
• In pre-term infants with ROP receiving EYLEA the most common adverse reactions (≥4%) reported were retinal detachment, conjunctival hemorrhage, and intraocular pressure increased. Adverse reactions established for adult indications are considered applicable to pre-term infants with ROP, though not all were observed in the clinical studies.
• Patients may experience temporary visual disturbances after an intravitreal injection with EYLEA and the associated eye examinations. Advise patients not to drive or use machinery until visual function has recovered sufficiently.

For more information, please see full Prescribing Information.

About Regeneron
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led for 35 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to 9 FDA-approved treatments and numerous product candidates in development, almost all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, pain, hematologic conditions, infectious diseases and rare diseases.

Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite^® technologies, such as VelocImmune^®, which uses unique genetically humanized mice to produce optimized fully human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center^®, which is conducting one of the largest genetics sequencing efforts in the world.

For more information, please visit www.Regeneron.com or follow @Regeneron on Twitter.

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