June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
In-vitro and In-vivo pharmacology of SAF312 as a TRPV1 inhibitor for ocular surface pain
Author Affiliations & Notes
  • Quint Medley
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • JUNZHENG YANG
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • John T Demirs
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Julien Papillon
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Yan Gao
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • YongYao Xu
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • James Chastain
    Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
  • Sameena Haque
    Novartis Pharma AG, Basel, Basel-Stadt, Switzerland
  • Michela Montecchi Palmer
    Novartis AG, Fort Worth, Texas, United States
  • Aileen Wrynn
    Novartis Pharma AG, Basel, Basel-Stadt, Switzerland
  • Footnotes
    Commercial Relationships   Quint Medley, Novartis Institutes for Biomedical Research (E); JUNZHENG YANG, Novartis Institutes for Biomedical Research (E); John Demirs, Novartis Institutes for Biomedical Research (E); Julien Papillon, Novartis Institutes for Biomedical Research (E); Yan Gao, Novartis Institutes for Biomedical Research (E); YongYao Xu, Novartis Institutes for Biomedical Research (E); James Chastain, Novartis Institutes for Biomedical Research (E); Sameena Haque, Novartis Pharma AG (E); Michela Montecchi Palmer, Novartis Pharmaceuticals Inc (E); Aileen Wrynn, Novartis Pharma AG (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 722. doi:
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      Quint Medley, JUNZHENG YANG, John T Demirs, Julien Papillon, Yan Gao, YongYao Xu, James Chastain, Sameena Haque, Michela Montecchi Palmer, Aileen Wrynn; In-vitro and In-vivo pharmacology of SAF312 as a TRPV1 inhibitor for ocular surface pain. Invest. Ophthalmol. Vis. Sci. 2021;62(8):722.

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

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Abstract

Purpose : The transient receptor potential cation channel subfamily V member 1 (TRPV1) plays a key role in ocular surface pain. The use of SAF312, a potent non-competitive antagonist of TRPV1, is a novel steroid sparing approach for treatment of ocular surface pain. The study evaluated the in-vitro and in-vivo pharmacology of SAF312.

Methods : Expression of TRPV1 was evaluated in donor human cornea by immunostaining of TRPV1, along with b-iii–tubulin, a marker for corneal neurons. The selective action of SAF312 on TRPV1-mediated Ca2+-flux was assessed by the fluorescent FLIPR assay. The inhibitory action of SAF312 was evaluated in CHO cells expressing human TRPV1 using fluorescent Ca2+-sensitive indicator dyes. The ocular tissue and plasma pharmacokinetic (PK) parameters (Cmax, AUC, and Tmax) of SAF312 were described in New Zealand white rabbits following a single dose of bilateral ocular administration (0.5, 1.0, 1.5, and 2.5%; 0.175, 0.350, 0.525, and 0.875 mg/eye/35 μL, respectively).

Results : TRPV1 was expressed in superficial nerves, nerves in the mid-stroma, and deep stroma indicating a potential role for TRPV1 in nociception within the cornea (Fig 1). TRPV1 is also expressed at a high level in the corneal epithelium. SAF312 was >150-fold selective for TRPV1 when tested against a panel of 18 TRP channels. SAF312 inhibited capsaicin, low pH 2-(n-morpholino)ethanesulfonic acid (MES, pH 5.5), anandamide (AEA), and N-arachidonoyl dopamine (NADA) stimulated human TRPV1 with IC50 values of 12, 16, 7.3 and 36 nM, respectively in a selective, non-competitive, and reversible manner. PK analysis of SAF312 in the rabbit ocular tissues and plasma showed the highest exposure in cornea and conjunctiva, followed by aqueous humor, lens, retina, plasma and vitreous humor. The exposure for SAF312 in cornea 12 h after single bilateral 0.5% administration was at least 69-fold and 23-fold higher than the IC50 assessed in the cellular assays for capsaicin (12nM) and NADA (36nM), respectively.

Conclusions : SAF312 has been shown to be a selective and potent inhibitor of TRPV1, a key mediator of ocular pain process which is expressed in the corneal neurons, and has potential for further investigation in clinical trials.

This is a 2021 ARVO Annual Meeting abstract.

 

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