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Clinical Trial
. 2024 Mar 23;403(10432):1141-1152.
doi: 10.1016/S0140-6736(24)00063-1. Epub 2024 Mar 7.

Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial

Paolo Lanzetta  1 , Jean-François Korobelnik  2 , Jeffrey S Heier  3 , Sergio Leal  4 , Frank G Holz  5 , W Lloyd Clark  6 , David Eichenbaum  7 , Tomohiro Iida  8 , Sun Xiaodong  9 , Alyson J Berliner  10 , Andrea Schulze  11 , Thomas Schmelter  11 , Ursula Schmidt-Ott  11 , Xin Zhang  4 , Robert Vitti  10 , Karen W Chu  10 , Kimberly Reed  10 , Rohini Rao  10 , Rafia Bhore  10 , Yenchieh Cheng  10 , Wei Sun  10 , Boaz Hirshberg  10 , George D Yancopoulos  10 , Tien Y Wong  12 ; PULSAR Investigators
Affiliations
Clinical Trial

Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial

Paolo Lanzetta et al. Lancet. .

Abstract

Background: Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg.

Methods: PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing.

Findings: Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]).

Interpretation: Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD.

Funding: Bayer AG and Regeneron Pharmaceuticals.

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Conflict of interest statement

Declaration of interests PL is a consultant for Aerie, Allergan, Apellis, Bausch + Lomb, Bayer, Biogen, Boehringer Ingelheim, I-Care, Genentech, Novartis, Ocular Therapeutix, Outlook Therapeutics, and Roche. J-FK receives consulting fees from AbbVie, Apellis, Bayer, Janssen, Nano Retina, Roche, Théa Pharmaceuticals, and Carl Zeiss Meditec; and is a member of data and safety monitoring boards or advisory boards for Alexion, Novo Nordisk, and Oxular. JSH receives consulting fees for 4D Molecular Therapeutics, Abpro, Adverum, AffaMed Therapeutics, Applied Genetics Technologies Corporation, Akouos, Allegro, Annexon, Apellis, AsclepiX Therapeutics, Bausch + Lomb, Biovisics, Clearside, Curacle, DTx Pharma, Exegenesis, Roche and Genentech, Glaukos, Gyroscope Therapeutics, ImmunoGen, Iveric Bio, Janssen R&D, jCyte, Kriya, Nanoscope, NGM Bio, Notal Vision, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, OliX, ONL Therapeutics, Outlook Therapeutics, Palatin Technologies, Perceive Biotherapeutics, Ray Therapeutics, Regeneron Pharmaceuticals, REGENXBIO, RetinAI, RevOpsis Therapeutics, Stealth BioTherapeutics, Théa Pharmaceuticals, and Vanotech; receives grants or contracts for 4D Molecular Technologies, Annexon, Apellis, AsclepiX Therapeutics, Ashvattha, Bayer, Cognition Therapeutics, Curacle, Roche and Genentech, Gyroscope Therapeutics, Iveric Bio, Janssen R&D, Kodiak, NGM, Notal Vision, Novartis, OcuTerra, Perceive Bio, Regeneron Pharmaceuticals, and REGENXBIO; has equity in Adverum, Aldeyra Therapeutics, Allegro, Aviceda, DTx Pharma, jCyte, Ocuphire, Ocular Therapeutix, RevOpsis Therapeutics, Vinci Pharmaceuticals, and Vitranu; and is on the Board of Directors for Ocular Therapeutix. FGH has served as a consultant for Acucela, Apellis, Bayer, Boehringer Ingelheim, Bioeq/Formycon, Roche and Genentech, Graybug Vision, IvericBio, Lin BioScience, Novartis, and Stealth BioTherapeutics; has received research support from Acucela, Apellis, Bayer, Bioeq/Formycon, and Roche and Genentech; has received honoraria from Bayer, Ellex, Roche and Genentech, Graybug Vision, Lin BioScience, Novartis, Oxurion, and Stealth BioTherapeutics; has received support for attending meetings or travel from Bayer, Roche and Genentech, Heidelberg Engineering, Lin BioScience, Novartis, and Stealth BioTherapeutics; has been a member of EURETINA and the German Ophthalmology Society (DOG); has other financial or non-financial interests in Acucela, Allergan, Apellis, Bayer, Bioeq/Formycon, CenterVue, Ellex, Roche and Genentech, Geuder, Heidelberg Engineering, IvericBio, Chengdu Kanghong Pharmaceuticals, NightStarX, Novartis, Optos, Pixium Vision, and Zeiss. WLC serves as a consultant for Genentech and Regeneron Pharmaceuticals; has received research support from Genentech; is a lecturer for Bayer, Genentech, and Regeneron Pharmaceuticals; and has received travel support from Bayer, Genentech, and Regeneron Pharmaceuticals. TYW receives consulting fees from Aldropika Therapeutics, Bayer, Boehringer Ingelheim, Genetech, Iveric Bio, Novartis, Oxurion, Plano, Roche, Sanofi, and Shanghai Henlius; and holds patents and is the co-founder of EyRiS and Visre. DE is a speaker for Allergan, Apellis, Bausch + Lomb, Bayer, the Dutch Ophthalmic Research Center, EyePoint, Genentech, and Novartis; is a consultant for Alimera Sciences, Allergan, Apellis, Bausch + Lomb, Coherus, Crinetics, DORC, EyePoint, Genentech, Gyroscope Therapeutics, Iveric Bio, KKR, Kodiak, Novartis, Ocular Therapeutix, Opthea, Outlook Therapeutics, RecensMedical, Regeneron Pharmaceuticals, REGENXBIO, Revive Pharmaceuticals, USRetina, and Vial; is an investigator for 4D Molecular Therapeutics, Alexion, Alkahest, Allgenesis, Annexon, AsclepiX Therapeutics, Bayer, Chengdu Kanghong Biotech (PANDA Trial stopped April, 2021), EyePoint, Gemini Therapeutics, Genentech, Gyroscope Therapeutics, Ionis, Iveric Bio, Kodiak, Mylan, NGM Bio, Novartis, Ocular Therapeutix, Opthea, RecensMedical, Regeneron Pharmaceuticals, REGENXBIO, and UNITY Biotechnology; is a stockholder for or has equity in Boston Image Reading Center, Clearside Biomedical, Hemera Biosciences, Network Eye, Revive Pharmaceuticals, and USRetina; and is a founder of Network Eye. TI has received financial support from NIDEK, Topcon Healthcare, Santen Pharmaceutical, Novartis, Senju Pharmaceutical, Alcon Japan, HOYA Vision Care, and AMO Pharma; has received consultancy fees from Bayer Yakuhin, Chugai Pharmaceutical, Nippon Boehringer Ingelheim, Janssen Pharmaceutical, Novartis Pharma, Senju Pharmaceutical, and Kyowa Kirin; has received lecture fees from Bayer Yakuhin, Novartis, Alcon Japan, Santen Pharmaceuticals, Senju Pharmaceutical, Topcon Healthcare, Chugai Pharmaceutical, Canon, NIDEK, Otsuka Pharmaceutical, and Nikon; has a patent with Topcon; and has received rewards from Kyowa Kirin. SX has received consulting fees from Alcon, Allergan, Bayer, Innovent Biologics, Chengdu Kanghong Biotech, Novartis, Roche, and Carl Zeiss Meditec. US-O and TS are employees and stockholders of Bayer. SL, AS, and XZ are employees of Bayer. AJB, RV, KWC, KR, RR, YC, WS, RB, and BH are employees and stockholders of Regeneron Pharmaceuticals. GDY is the Founding Scientist, President, and Chief Scientific Officer of Regeneron Pharmaceuticals.

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