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APEX: a phase II randomised clinical trial evaluating the safety and preliminary efficacy of oral X-82 to treat exudative age-related macular degeneration
  1. Michael N. Cohen1,2,
  2. Denis O’Shaughnessy3,
  3. Kate Fisher4,
  4. Jennifer Cerami3,
  5. Carl C Awh5,
  6. Daniel E Salazar3,
  7. Philip Rosenfeld6,
  8. Jeffrey S Heier1
  1. 1 The Retina Service, Ophthalmic Consultants of Boston, Boston, Massachusetts, USA
  2. 2 New England Eye Center, Tufts University School of Medicine, Boston, Massachusetts, USA
  3. 3 Tyrogenex, Inc., Rockville, Maryland, USA
  4. 4 IDDI, Inc., Raleigh, USA
  5. 5 Tennessee Retina, Nashville, Tennessee, USA
  6. 6 Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
  1. Correspondence to Michael N Cohen, Ophthalmic Consultants of Boston, 50, Staniford Street, Suite 600, Boston, MA 02114, USA; mcohen{at}midatlanticretina.com

Abstract

Purpose The safety and efficacy of X-82, an orally administered inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor, was investigated for treatment of wet age-related macular degeneration (AMD) in a phase II clinical trial.

Methods This phase II, randomised, double-masked, placebo-controlled trial enrolled subjects with a prior diagnosis of exudative AMD having received at least two intravitreal injections of anti-VEGF therapy. Subjects were randomised equally into four groups that received either daily 50mg, 100mg or 200mg dosages of X-82 or a placebo tablet. At each 4-week interval visit for 52 weeks, subjects were to be assessed to determine if rescue treatment was needed with anti-VEGF therapy.

Results 157 patients were enrolled. Due to gastrointestinal and hepatobiliary adverse events and the fulfilment of the primary endpoint, the trial was stopped prematurely after a second interim analysis. The primary endpoint of non-inferiority of visual acuity compared with placebo was demonstrated in all groups receiving X-82 (p<0.001). There was a dose-dependent trend in the number of injections over a 52-week period, with the 50 mg (n=40), 100 mg (n=39), 200 mg (n=39) and placebo (n=39) group requiring 6.7, 6.0, 4.7 and 8.1 injections, respectively.

Conclusions X-82 oral therapy in combination with pro re nata anti-VEGF injections showed non-inferiority in visual acuity outcomes while achieving a dose-dependent decrease in the number of anti-VEGF injections compared with placebo. Given the limited tolerability and safety issues observed, X-82 does not have a sufficient benefit to risk profile in treatment of patients with AMD.

  • Vitreous
  • Retina
  • Macula
  • Angiogenesis
  • Choroid
  • randomized controlled trial
  • Macular Degeneration
  • oral
  • exudative macular degeneration
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Footnotes

  • Twitter MichaelNCohenMD.

  • Contributors Data collection: DOS, JC, CCA, DES, PJR, JSH. Article composition: MNC. Statistical analysis: KF, DOS, DES, JC. Draft review and critical revision: MNC, DOS, KF, JC, CCA, DES, PJR, JSH.

  • Funding MNC— Allergan: Consultant/Advisory Board. DO—Tyrogenex Inc.: Employee. KFNone. JC – Tyrogenex Inc.: Consultant. CCAAllergan: Advisory Board, Honoraium; Apellis Pharma: Investigator, Research Grant; ArcticDX: Consultant, Stockholder; Bausch+Lomb: Consultant, Honoraium; Genentech: Consultant, Investigator, Research Grant, Honoraium; GlaxoSmithKline: Investigator, Research Grant; Hoffman-LaRoche: Investigator, Research Grant; Katalyst Surgical: Consultant, Stockholder, Royalties; Merck Pharma: Investigator, Research Grant; Ophthotec: Investigator, Research Grant; PanOptica: Investigator, Research Grant; Regeneron: Investigator, Research Grant; Volk: Consultant, Honoraria. DESTyrogenex Inc: Consultant; Brace Pharma Capital (investor in Tyrogenex Inc.): Consultant PJRApellis: Consultant/Advisor, Equity Owner; Boehringer-Ingelheim: Grant Support, Consultant/Advisor; Carl Zeiss Meditec: Grant Support, Consultant/Advisor; Chengdu Kanghong Biotech: Consultant/Advisor; Healios K.K.: Consultant/Advisor; Hemera Biosciences: Consultant/Advisor; Isarna Pharmaceuticals: Consultant/Advisor; Lin Bioscience: Consultant/Advisor; MacRegen: Consultant/Advisor; Ocudyne: Consultant/Advisor, Equity Owner; Ocunexus: Consultant/Advisor; Stealth Biotherapeutics: Grant Support; Tyrogenex Inc.: Grant Support, Consultant/Advisor; Unity Biotechnology: Consultant/Advisor; Verana Health: Equity Owner. JSH4D Molecular Technologies: Consultant/Advisor; Adverum: Consultant/Advisor, Equity Owner; Aerie: Consultant/Advisor, Grant Support; Aerpio: Consultant/Advisor, Grant Support; Aldeyra: Consultant/Advisor, Equity Owner; Alkahest: Consultant/Advisor; Allegro: Consultant/Advisor, Equity Owner; Allergan: Consultant/Advisor; Annexon: Consultant/Advisor; Apellis: Consultant/Advisor, Grant Support; Array: Consultant/Advisor; Asclepix: Consultant/Advisor; Clearside: Grant Support; Daiichi Sankyo: Grant Support; Eloxx: Consultant/Advisor; Galimedix: Consultant/Advisor; Genentech/Roche: Consultant/Advisor, Grant Support; Generation Bio: Consultant/Advisor; Graybug: Grant Support; Gyroscope: Grant Support; Interface: Consultant/Advisor; iRenix: Consultant/Advisor; Hemera: Grant Support; Janssen R&D: Consultant/Advisor, Grant Support; jCyte: Consultant/Advisor, Equity Owner; Kala: Consultant/Advisor; KalVista: Grant Support; Kanghong: Consultant/Advisor; Kodiak: Consultant/Advisor; NGM Biopharmaceuticals: Consultant/Advisor; Notal Vision: Consultant/Advisor; Novartis: Consultant/Advisor, Grant Support; Ocugenix: Consultant/Advisor; Ocular Therapeutix: Consultant/Advisor, Equity Owner; Board of Directors Member; Omeicos: Consultant/Advisor; Ophthotech: Grant Support; Optos: Grant Support; Optovue: Grant Support; Orbit/Gyroscope: Consultant/Advisor; Regeneron: Consultant/Advisor, Grant Support; Regenxbio: Consultant/Advisor, Grant Support; Retrotope: Consultant/Advisor; Santen: Consultant/Advisor; Scifluor: Consultant/Advisor; Shire: Consultant/Advisor; Stealth Biotherapeutics: Consultant/Advisor, Grant Support; Takeda: Consultant/Advisor; Thrombogenics: Grant Support; Tyrogenex Inc.: Grant Support; Voyant: Consultant/Advisor.

  • Competing interests None declared.

  • Data sharing statement Data are available upon reasonable request.

  • Ethics statement Each study site received institutional review board approval and adhered to the principles outlined in the Declaration of Helsinki. All patients provided his/her written informed consent prior to enrolling.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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