July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
EXN407, a novel topical therapeutic candidate with high retinal bioavailability for the treatment of diabetic macular oedema, inhibits ocular neovascularisation
Author Affiliations & Notes
  • Jennifer Batson
    Exonate Ltd, Nottingham, ENGLAND, United Kingdom
  • Hamish Toop
    University of New South Wales, New South Wales, Australia
  • Susan Liddell
    Exonate Ltd, Nottingham, ENGLAND, United Kingdom
  • James Daubney
    Exonate Ltd, Nottingham, ENGLAND, United Kingdom
  • Elizabeth Anne Stewart
    Exonate Ltd, Nottingham, ENGLAND, United Kingdom
  • Anthony Habgood
    Exonate Ltd, Nottingham, ENGLAND, United Kingdom
  • Amy Murphy
    Exonate Ltd, Nottingham, ENGLAND, United Kingdom
  • Ken McKechnie
    Exonate Ltd, Nottingham, ENGLAND, United Kingdom
  • Jonathan Morris
    University of New South Wales, New South Wales, Australia
  • David O Bates
    Exonate Ltd, Nottingham, ENGLAND, United Kingdom
  • Footnotes
    Commercial Relationships   Jennifer Batson, Exonate (E), Exonate (P); Hamish Toop, None; Susan Liddell, Exonate (E); James Daubney, Exonate (E); Elizabeth Stewart, Exonate (E); Anthony Habgood, Exonate (E); Amy Murphy, Exonate (E); Ken McKechnie, Exonate (E); Jonathan Morris, Exonate (C), Exonate (P); David Bates, Exonate (I), Exonate (C), Exonate (P), Exonate (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 26. doi:
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      Jennifer Batson, Hamish Toop, Susan Liddell, James Daubney, Elizabeth Anne Stewart, Anthony Habgood, Amy Murphy, Ken McKechnie, Jonathan Morris, David O Bates; EXN407, a novel topical therapeutic candidate with high retinal bioavailability for the treatment of diabetic macular oedema, inhibits ocular neovascularisation. Invest. Ophthalmol. Vis. Sci. 2019;60(9):26.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Retinal vascular diseases are treated by intra-ocular injection of anti-VEGFs. SRPK1 inhibitors reduce angiogenic VEGF-A isoforms and choroidal neovascularisation (CNV) in vivo. To address the challenge posed by injections, we developed topical SRPK1 inhibitors with high retinal exposure and low systemic availability. Here we present EXN407, fully profiled preclinically through to in vivo efficacy, pharmacokinetics (PK) and safety/toxicology in large eyes.

Methods : SRPK1 inhibition and selectivity were shown by radiometric assays. VEGF-A isoform expression was analysed by ELISA. Ex vivo trans-scleral permeability was assessed in porcine eye tissue using mass spectrometry. Efficacy was evaluated in vivo after bi-daily administration of 0.05% EXN407 in (i) laser-induced CNV in C57/Bl6 mice at 7 days, and (ii) STZ-induced diabetic retinopathy in rats over 28 days. Ocular and systemic pharmacokinetic profiles for EXN407 were determined in (i) Hy79b rabbits administered a single eye drop for successive timepoints or dosed b.i.d for 6 days, (ii) Non-human primate (NHP) after 21 days b.i.d of dosing, up to 0.15%. Ocular toxicity and safety was assessed over 10 days t.i.d in rabbits or 21 days b.i.d in NHP administered EXN407.

Results : EXN407 is a potent, specific SRPK1 inhibitor (IC50 4nM), reduces pro-angiogenic VEGF-A (IC50 211nM) and shows exceptional ocular permeability, (>10x pazopanib and regorafenib) resulting in superior efficacy in vivo. EXN407 inhibits CNV after 0.2µg/ml bid eye drops (p<0.05 n=25, comparable to anti-VEGF injection) and diabetes-induced VEGF-A and vascular permeability after 0.05% bid eye drops. In rabbit and NHP, EXN407 reached retinal exposure levels at concentrations >10x that required for in vivo efficacy. It displays low systemic exposure and no toxicity.

Conclusions : EXN407 has superior retinal permeability ex vivo, correlating with high retina levels and low systemic exposure in rabbits and NHP. EXN407 potently reduces choroidal neovascularisation and permeability in vivo by blocking SRPK1 splicing of VEGF-A. EXN407 is an exemplar compound showing how improved retinal permeability can be identified through methodical rational drug design. The compound has the attributes to move into clinical development as a topical therapeutic to reduce intravitreal injections of anti-VEGF antibodies.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

 

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