Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial.
Journal
Lancet (London, England)
ISSN: 1474-547X
Titre abrégé: Lancet
Pays: England
ID NLM: 2985213R
Informations de publication
Date de publication:
07 Mar 2024
07 Mar 2024
Historique:
received:
26
09
2023
revised:
08
11
2023
accepted:
16
11
2023
medline:
11
3
2024
pubmed:
11
3
2024
entrez:
10
3
2024
Statut:
aheadofprint
Résumé
A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO. PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503). Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]). Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO. Regeneron Pharmaceuticals and Bayer.
Sections du résumé
BACKGROUND
BACKGROUND
A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO.
METHODS
METHODS
PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503).
FINDINGS
RESULTS
Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]).
INTERPRETATION
CONCLUSIONS
Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO.
FUNDING
BACKGROUND
Regeneron Pharmaceuticals and Bayer.
Identifiants
pubmed: 38461843
pii: S0140-6736(23)02577-1
doi: 10.1016/S0140-6736(23)02577-1
pii:
doi:
Banques de données
ClinicalTrials.gov
['NCT04429503']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Investigateurs
Prema Abraham
(P)
Christopher Aderman
(C)
Kunihiko Akiyama
(K)
Daniel V Alfaro
(DV)
Fareed A Ali
(FA)
Payam Amini
(P)
Andres Emanuelli Anzalotta
(AE)
György Bátor
(G)
Ivan Batlle
(I)
Adam Berger
(A)
Ramanath Bhandari
(R)
William Bridges
(W)
Christian Brinkmann
(C)
Jamin Brown
(J)
Stuart Burgess
(S)
Jorge Calzada
(J)
Antonio Capone
(A)
Dana Cervena
(D)
Steven Charles
(S)
Nauman Chaudhry
(N)
David Chow
(D)
W Lloyd Clark
(WL)
Paul Conrad Iii
(P)
Matthew Cunningham
(M)
Hajir Dadgostar
(H)
Amr Dessouki
(A)
Dana Deupree
(D)
Christopher Devine
(C)
David Eichenbaum
(D)
Jan Ernest
(J)
Nicolas Feltgen
(N)
Moss Fenberg
(M)
Philip Ferrone
(P)
Ronald Frenkel
(R)
Scott Friedman
(S)
Julie Gasperini
(J)
Adam Gerstenblith
(A)
Ghassan Ghorayeb
(G)
Michel Giunta
(M)
Mitchell Goff
(M)
Liliya Golas
(L)
Joseph M Googe
(JM)
Jordana Goren Fein
(J)
Curtis Hagedorn
(C)
Akira Hagiwara
(A)
Paul Hahn
(P)
Richard Hairston
(R)
Jason Handza
(J)
Vivienne Hau
(V)
Ken Hayashi
(K)
Jeffrey Heier
(J)
Vrinda Hershberger
(V)
Patrick Higgins
(P)
Yoshio Hirano
(Y)
Shigeru Honda
(S)
Yasuko Ikegami
(Y)
Yuichiro Ishida
(Y)
Isao Ishikawa
(I)
Kiyoshi Ishii
(K)
Eric P Jablon
(EP)
Atul Jain
(A)
Yuichi Kaji
(Y)
Kapil Kapoor
(K)
Ágnes Kerényi
(Á)
Kazuhiro Kimura
(K)
Genichiro Kishino
(G)
Katalin Kiss
(K)
Takashi Kitaoka
(T)
James M Klancnik
(JM)
Namie Kobayashi
(N)
Jiro Kogo
(J)
Vladimir Korda
(V)
Erik Kruger
(E)
Sentaro Kusuhara
(S)
Wilfredo Lara
(W)
Ketan Laud
(K)
Seong Lee
(S)
James Luu
(J)
Dennis Marcus
(D)
Calvin Mein
(C)
Annal Meleth
(A)
Tibor Milibák
(T)
Yoshinori Mitamura
(Y)
Toshinori Murata
(T)
Sumiyo Noge
(S)
Hajime Onoe
(H)
James Osher
(J)
András Papp
(A)
Justin Parschauer
(J)
Sugat Patel
(S)
Sunil Patel
(S)
Matthew Pezda
(M)
Ashkan Pirouz
(A)
Pradeep Prasad
(P)
Omar Punjabi
(O)
Llewelyn Rao
(L)
Richard Roe
(R)
Ramin Schadlu
(R)
Eric Schneider
(E)
Ankur Shah
(A)
Milan Shah
(M)
Sandeep Shah
(S)
Sumit Shah
(S)
Ashish Sharma
(A)
Veeral Sheth
(V)
Masahiko Shimura
(M)
Lawrence Singerman
(L)
Georg Spital
(G)
Robert Stoltz
(R)
Eric Suan
(E)
Kiyoshi Suzuma
(K)
Hidenori Takahashi
(H)
Yoshihiro Takamura
(Y)
Masaru Takeuchi
(M)
Jeffrey Tan
(J)
Benjamin Thomas
(B)
Edit Tóth-Molnár
(E)
Tetsuo Ueda
(T)
Hiroaki Ushida
(H)
Attila Vajas
(A)
Deepali Varma
(D)
Balázs Varsányi
(B)
Miroslav Veith
(M)
Pamela Weber
(P)
Raymond Wee
(R)
Geoff Williams
(G)
Haruhiko Yamada
(H)
Yoshihiro Yonekawa
(Y)
Shigeo Yoshida
(S)
Informations de copyright
Copyright © 2024 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests DMB serves as a scientific adviser for Regeneron/Bayer and Genentech/Roche and as a member of the Regeneron Combination Products Steering Committee. DSB has served as a consultant for Adverum, Allergan, Bayer, Genentech, Graybug, Novartis, Regeneron Pharmaceuticals, REGENXBIO, and Roche. DVD is a consultant to Allergan, AsclepiX, Boehringer Ingelheim, Clearside, Genentech, Kodiak Sciences, and Regeneron Pharmaceuticals and has received research funding from AsclepiX, Boehringer Ingelheim, Genentech, and Regeneron Pharmaceuticals. CCW is a consultant for 4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Annexon, Apellis, Arrowhead, Bausch + Lomb, Boehringer Ingelheim, Cholgene, Clearside, Curacle, EyePoint, Genentech, Gyroscope, IACTA, Iveric Bio, Janssen, Kato, Kiora, Kodiak Sciences, Kriya, Merck, Nanoscope, NGM, Novartis, Ocular Therapeutix, OcuTerra, ONL, Opthea, Oxular, Palatin, PerceiveBio, Perfuse, Ray, RecensMedical, Regeneron Pharmaceuticals, REGENXBIO, Roche, and Stealth and has received research support from 4DMT, Adverum, AffaMed, Alexion, Alimera, Alkahest, Allgenesis, Amgen, Annexin, Annexon, Apellis, AsclepiX, Bayer, Boehringer Ingelheim, Clearside, Curacle, EyePoint, Gemini, Genentech, GlaxoSmithKline, Gyroscope, IONIS, iRENIX, Iveric Bio, Kodiak Sciences, LMRI, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, Opthea, Ophthotech, Oxurion, Oxular, Oyster Point, PerceiveBio, Regeneron Pharmaceuticals, REGENXBIO, Roche, and UNITY. TSa is a consultant for Bayer, Boehringer Ingelheim, Chugai/Roche, Novartis, and Senju. ASe is a consultant for Syneos Health and Novartis; has served as an adviser for Roche; and has contributed to the industry-sponsored international multicentre studies for Allergan, Amgen, Bayer, Formycon, Hexal, Iveric Bio, Kodiak Sciences, Oculis, Opthea, Novartis, Qilu Pharma, Regeneron Pharmaceuticals, Roche, and Sam Chun Dang Pharma. AJB, RV, KWC, KR, RR, YC, WS, DV, RB, and BH are employees and stockholders of Regeneron Pharmaceuticals. SL, US-O, TSc, ASc, and XZ are employees of Bayer. GDY is the founding scientist, President, and Chief Scientific Officer of Regeneron Pharmaceuticals. SS is an adviser and contributes to the industry-sponsored international multicentre studies for AbbVie, Bayer, Boehringer Ingelheim, Novartis, Optos, and Roche and has received consultancy fees from Allergan, Apellis, Bayer, Biogen, Boehringer Ingelheim, Eyebiotech, Novartis Pharma, Optos, and Roche. All other authors declare no competing interests.