PMID- 36394843
OWN - NLM
STAT- MEDLINE
DCOM- 20221121
LR  - 20221201
IS  - 2164-2591 (Electronic)
IS  - 2164-2591 (Linking)
VI  - 11
IP  - 11
DP  - 2022 Nov 1
TI  - Topical Ocular TRPV1 Antagonist SAF312 (Libvatrep) Demonstrates Safety, Low 
      Systemic Exposure, and No Anesthetic Effect in Healthy Participants.
PG  - 15
LID - 10.1167/tvst.11.11.15 [doi]
LID - 15
AB  - PURPOSE: This first-in-human (FIH) study evaluated the safety, tolerability, 
      pharmacokinetics, and effect on corneal sensitivity of topical ocular SAF312 in 
      healthy participants. METHODS: This double-masked, randomized study comprised 
      single-ascending dose (SAD), multiple-ascending dose (MAD), and esthesiometry 
      parts. In SAD and MAD, 8 participants in each dose cohort were randomized 3:1 to 
      receive SAF312 or vehicle, 1 drop once (SAD), or 1 drop 4 or 8 times daily for 7 
      days (MAD). Safety and pharmacokinetics were the primary and secondary 
      objectives. Blink rate, tear production, tear film break-up time (TFBUT), and 
      corneal sensitivity were also explored. RESULTS: SAF312 was tolerated in single 
      and multiple doses, including the maximum concentration of 2.5% dosed up to 1 
      drop 8 times daily for 7 days. Most adverse events (AEs) were mild and similar 
      between SAF312 and vehicle-treated groups. No serious AEs were reported. SAF312 
      was rapidly absorbed, and had low systemic exposure. After supratherapeutic 
      dosing for 7 days, mean steady-state exposures of SAF312 were low and afforded 
      safety margins of >70-fold compared with no-observed-AE levels following oral 
      dosing in preclinical studies. No clinically relevant changes were observed in 
      blink rate, tear production, and TFBUT. SAF312 showed no undesired anesthetic 
      effect on the cornea. CONCLUSIONS: SAF312 was well tolerated, with no ocular or 
      systemic safety concerns; had no anesthetic effect, and demonstrated rapid 
      topical absorption with low systemic exposure. TRANSLATIONAL RELEVANCE: This work 
      bridges the gap between basic research and clinical care by providing FIH data of 
      SAF312, supporting the further investigation as a potential treatment for ocular 
      surface pain.
FAU - Stasi, Kalliopi
AU  - Stasi K
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Alshare, Qusai
AU  - Alshare Q
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Jain, Monish
AU  - Jain M
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Wald, Michael
AU  - Wald M
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
FAU - Li, Yifang
AU  - Li Y
AD  - Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Transl Vis Sci Technol
JT  - Translational vision science & technology
JID - 101595919
RN  - 0 (TRPV1 protein, human)
RN  - 0 (TRPV Cation Channels)
SB  - IM
MH  - Humans
MH  - Healthy Volunteers
MH  - Double-Blind Method
MH  - *Cornea
MH  - *TRPV Cation Channels
PMC - PMC9684620
COIS- Disclosure: K. Stasi, Novartis Institutes for BioMedical Research, Cambridge, MA, 
      USA at the time of study conduct (E), Tenpoint Therapeutics (E); Q. Alshare, 
      Novartis Institutes for BioMedical Research, Cambridge, MA, USA at the time of 
      study conduct (E), Jordan University of Science and Technology (E); M. Jain, 
      Novartis Institutes for BioMedical Research, Cambridge, MA, USA at the time of 
      study conduct (E); M. Wald, Novartis Institutes for BioMedical Research, 
      Cambridge, MA, USA at the time of study conduct (E), Biogen (E); Y. Li, Novartis 
      Institutes for BioMedical Research, Cambridge, MA, USA at the time of study 
      conduct (E)
EDAT- 2022/11/18 06:00
MHDA- 2022/11/22 06:00
PMCR- 2022/11/17
CRDT- 2022/11/17 14:02
PHST- 2022/11/17 14:02 [entrez]
PHST- 2022/11/18 06:00 [pubmed]
PHST- 2022/11/22 06:00 [medline]
PHST- 2022/11/17 00:00 [pmc-release]
AID - 2783868 [pii]
AID - TVST-22-4614 [pii]
AID - 10.1167/tvst.11.11.15 [doi]
PST - ppublish
SO  - Transl Vis Sci Technol. 2022 Nov 1;11(11):15. doi: 10.1167/tvst.11.11.15.