PMID- 29190672
OWN - NLM
STAT- MEDLINE
DCOM- 20180101
LR  - 20220409
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 11
DP  - 2017
TI  - First-in-human phase I study of ISTH0036, an antisense oligonucleotide 
      selectively targeting transforming growth factor beta 2 (TGF-beta2), in subjects 
      with open-angle glaucoma undergoing glaucoma filtration surgery.
PG  - e0188899
LID - 10.1371/journal.pone.0188899 [doi]
LID - e0188899
AB  - PURPOSE: To evaluate the safety and tolerability of intravitreal ISTH0036, an 
      antisense oligonucleotide selectively targeting transforming growth factor beta 2 
      (TGF-beta2), in patients with primary open angle glaucoma (POAG) undergoing 
      trabeculectomy (TE; glaucoma filtration surgery). METHODS: In this prospective 
      phase I trial glaucoma patients scheduled for TE with mitomycin C (MMC) received 
      a single intravitreal injection of ISTH0036 at the end of surgery in escalating 
      total doses of 6.75 mug, 22.5 mug, 67.5 mug or 225 mug, resulting in calculated 
      intraocular ISTH0036 concentrations in the vitreous humor of approximately 0.3 
      muM, 1 muM, 3 muM or 10 muM after injection, respectively. Outcomes assessed 
      included: type and frequency of adverse events (AEs), intraocular pressure (IOP), 
      numbers of interventions post trabeculectomy, bleb survival, visual acuity, 
      visual field, electroretinogram (ERG), slit lamp biomicroscopy and optic disc 
      assessment. RESULTS: In total, 12 patients were treated in the 4 dose groups. 
      Main ocular AEs observed were corneal erosion, corneal epithelium defect, or too 
      high or too low IOP, among others. No AE was reported to be related to ISTH0036. 
      All other safety-related analyses did not reveal any toxicities of concern, 
      either. The mean medicated preoperative IOP at decision time-point for surgery 
      was 27.3 mmHg +/- 12.6 mmHg (SD). Mean IOP (+/-SD) for dose levels 1, 2, 3, and 4 
      were at Day 43 9.8 mmHg +/- 1.0 mmHg, 11.3 mmHg +/- 6.7 mmHg, 5.5 mmHg +/- 3.0 mmHg and 
      7.5 mmHg +/- 2.3 mmHg SD; and at Day 85 9.7 mmHg +/- 3.3 mmHg, 14.2 mmHg +/- 6.5 mmHg, 
      5.8 mmHg +/- 1.8 mmHg and 7.8 mmHg +/- 0.6 mmHg, respectively. In contrast to IOP 
      values for dose levels 1 and 2, IOP values for dose levels 3 and 4 persistently 
      remained below 10 mmHg throughout the observation period. CONCLUSION: This 
      first-in-human trial demonstrates that intravitreal injection of ISTH0036 at the 
      end of TE is safe. Regarding IOP control, single-dose ISTH0036 administration of 
      67.5 mug or 225 mug at the time of TE resulted in IOP values persistently < 10 mmHg 
      over the three month postoperative observation period.
FAU - Pfeiffer, Norbert
AU  - Pfeiffer N
AUID- ORCID: 0000-0002-5766-2617
AD  - Dpt. of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
FAU - Voykov, Bogomil
AU  - Voykov B
AD  - Dpt. of Ophthalmology, University Hospital Tuebingen, Tuebingen, Germany.
FAU - Renieri, Giulia
AU  - Renieri G
AD  - Dpt. of Ophthalmology, Otto-von-Guericke-University, Magdeburg, Germany.
FAU - Bell, Katharina
AU  - Bell K
AD  - Dpt. of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
FAU - Richter, Paul
AU  - Richter P
AD  - Dpt. of Ophthalmology, University Hospital Tuebingen, Tuebingen, Germany.
FAU - Weigel, Melanie
AU  - Weigel M
AD  - Dpt. of Ophthalmology, Otto-von-Guericke-University, Magdeburg, Germany.
FAU - Thieme, Hagen
AU  - Thieme H
AD  - Dpt. of Ophthalmology, Otto-von-Guericke-University, Magdeburg, Germany.
FAU - Wilhelm, Barbara
AU  - Wilhelm B
AD  - STZ Eyetrial, University Hospital Tuebingen, Tuebingen, Germany.
FAU - Lorenz, Katrin
AU  - Lorenz K
AD  - Dpt. of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
AD  - SynteractHCR Deutschland GmbH, Munich, Germany.
FAU - Feindor, Martin
AU  - Feindor M
AD  - SynteractHCR Deutschland GmbH, Munich, Germany.
FAU - Wosikowski, Katja
AU  - Wosikowski K
AD  - Isarna Therapeutics GmbH, Munich, Germany.
FAU - Janicot, Michel
AU  - Janicot M
AD  - Isarna Therapeutics GmbH, Munich, Germany.
FAU - Packert, Daniela
AU  - Packert D
AD  - Isarna Therapeutics GmbH, Munich, Germany.
FAU - Rommich, Regina
AU  - Rommich R
AD  - Isarna Therapeutics GmbH, Munich, Germany.
FAU - Mala, Carola
AU  - Mala C
AD  - Isarna Therapeutics GmbH, Munich, Germany.
FAU - Fettes, Petra
AU  - Fettes P
AD  - Isarna Therapeutics GmbH, Munich, Germany.
FAU - Leo, Eugen
AU  - Leo E
AD  - Isarna Therapeutics GmbH, Munich, Germany.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20171130
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (ISTH0036)
RN  - 0 (Oligonucleotides)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 76057-06-2 (Transforming Growth Factors)
SB  - IM
MH  - Aged
MH  - Female
MH  - *Glaucoma Drainage Implants
MH  - Glaucoma, Open-Angle/*drug therapy/surgery
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Oligonucleotides/adverse effects/pharmacology/*therapeutic use
MH  - Oligonucleotides, Antisense/adverse effects/pharmacology/*therapeutic use
MH  - Prospective Studies
MH  - Transforming Growth Factors
PMC - PMC5708654
COIS- Competing Interests: This study was fully sponsored by Isarna Therapeutics GmbH. 
      Norbert Pfeiffer is Coordinating Investigator of the study and a paid member of 
      the scientific advisory board to Isarna Therapeutics GmbH. Bogomil Voykov is an 
      Investigator and received a travel grant from Isarna Therapeutics GmbH. Giulia 
      Renieri, Katharina Bell, Paul Richter, Melanie Weigel, Hagen Thieme and Barbara 
      Wilhelm are Investigators and have no further financial relationship to the 
      sponsor. Katrin Lorenz is an employee of the Dpt. of Ophthalmology, University 
      Medical Center Mainz and a consultant to SynteractHCR. Martin Feindor is an 
      employee of SynteractHCR. SynteractHCR is a Contract Research Organization paid 
      for by Isarna Therapeutics GmbH. Katja Wosikowski, Daniela Packert, Regina 
      Rommich, Carola Mala and Petra Fettes are employees of Isarna Therapeutics GmbH. 
      Michel Janicot and Eugen Leo are consultants to Isarna Therapeutics GmbH. Isarna 
      Therapeutics GmbH holds four patent families based on WO 2014/154835, WO 
      2014/154836 and WO 2014/154843 comprising members in Brazil, Canada, China, South 
      Korea, Japan, Hong Kong, USA and members before the Eurasian and the European 
      Patent Offices as well as European Patent application no. 16198445. This does not 
      alter our adherence to all the PLOS ONE policies on sharing data and materials.
EDAT- 2017/12/01 06:00
MHDA- 2018/01/02 06:00
PMCR- 2017/11/30
CRDT- 2017/12/01 06:00
PHST- 2017/01/04 00:00 [received]
PHST- 2017/11/10 00:00 [accepted]
PHST- 2017/12/01 06:00 [entrez]
PHST- 2017/12/01 06:00 [pubmed]
PHST- 2018/01/02 06:00 [medline]
PHST- 2017/11/30 00:00 [pmc-release]
AID - PONE-D-16-50032 [pii]
AID - 10.1371/journal.pone.0188899 [doi]
PST - epublish
SO  - PLoS One. 2017 Nov 30;12(11):e0188899. doi: 10.1371/journal.pone.0188899. 
      eCollection 2017.