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Three-year results of phase I retinal gene therapy trial for CNGA3-mutated achromatopsia: results of a non randomised controlled trial
  1. Felix Friedrich Reichel1,2,
  2. Stylianos Michalakis3,
  3. Barbara Wilhelm1,
  4. Ditta Zobor2,
  5. Regine Muehlfriedel2,
  6. Susanne Kohl4,
  7. Nicole Weisschuh4,
  8. Vithiyanjali Sothilingam2,
  9. Laura Kuehlewein1,
  10. Nadine Kahle5,
  11. Immanuel Seitz1,2,
  12. Francois Paquet-Durand2,
  13. Stephen H Tsang6,
  14. Peter Martus5,
  15. Tobias Peters5,
  16. Mathias Seeliger2,
  17. Karl Ulrich Bartz-Schmidt1,
  18. Marius Ueffing2,
  19. Eberhard Zrenner1,2,
  20. Martin Biel7,
  21. Bernd Wissinger4,
  22. Dominik Fischer1,8
  1. 1Department of Ophthalmology, University Eye Hospital Tübingen, Tübingen, Germany, Tübingen, Germany
  2. 2Institute for Ophthalmic Research, University of Tübingen, Tübingen, Baden-Württemberg, Germany
  3. 3Department of Ophthalmology, University Hospital, LMU Munich, Munich, Bayern, Germany
  4. 4Molecular Genetics Laboratory, Institute for Ophthalmic Research, University of Tübingen, Tubingen, Baden-Württemberg, Germany
  5. 5University of Tübingen, Tübingen, Germany
  6. 6Columbia University, New York City, new York, USA
  7. 7Ludwig-Maximilians-Universität München, Munich, Germany
  8. 8Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
  1. Correspondence to Dominik Fischer, Universitätsklinikum Tübingen Universitäts-Augenklinik, Tubingen, Baden-Württemberg, Germany; dominik.fischer{at}uni-tuebingen.de

Abstract

Aims To determine long-term safety and efficacy outcomes of a subretinal gene therapy for CNGA3-associated achromatopsia. We present data from an open-label, nonrandomised controlled trial (NCT02610582).

Methods Details of the study design have been previously described. Briefly, nine patients were treated in three escalating dose groups with subretinal AAV8.CNGA3 gene therapy between November 2015 and October 2016. After the first year, patients were seen on a yearly basis. Safety assessment constituted the primary endpoint. On a secondary level, multiple functional tests were carried out to determine efficacy of the therapy.

Results No adverse or serious adverse events deemed related to the study drug occurred after year 1. Safety of the therapy, as the primary endpoint of this trial, can, therefore, be confirmed. The functional benefits that were noted in the treated eye at year 1 were persistent throughout the following visits at years 2 and 3. While functional improvement in the treated eye reached statistical significance for some secondary endpoints, for most endpoints, this was not the case when the treated eye was compared with the untreated fellow eye.

Conclusion The results demonstrate a very good safety profile of the therapy even at the highest dose administered. The small sample size limits the statistical power of efficacy analyses. However, trial results inform on the most promising design and endpoints for future clinical trials. Such trials have to determine whether treatment of younger patients results in greater functional gains by avoiding amblyopia as a potential limiting factor.

  • retina
  • clinical trial
  • treatment surgery
  • degeneration

Data availability statement

The authors confirm that the most relevant data supporting the findings of this study are available within the article and its supplementary materials. Additional data supporting the findings of this study are available from the corresponding author, [M.D. Fischer], upon reasonable request.

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Data availability statement

The authors confirm that the most relevant data supporting the findings of this study are available within the article and its supplementary materials. Additional data supporting the findings of this study are available from the corresponding author, [M.D. Fischer], upon reasonable request.

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Footnotes

  • Correction notice This paper has been corrected since it was published online. Figure 1 and 2 legends were transposed and they have now been updated.

  • Contributors FRR and DF were responsible for the design and draft of the article. All authors were involved in the acquisition, analysis or interpretation of data for the article, and all authors discussed the results and contributed to the final manuscript.

  • Funding The Tistou und Charlotte Kerstan Foundation provided the sole funding of this study as part of the RD-CURE project (Bringing Gene Supplementation Therapy for Inherited PDE6A- and CNGA3-associated Retinopathies into Clinical Practice: A joint Tübingen-München Project). Funds were granted to Drs Wissinger, Biel and Michalakis on behalf of the RD-CURE Consortium. Dr Michalakis reports grants from Tistou und Charlotte Kerstan Foundation, during the conduct of the study; other from ViGeneron GmbH, co-Founder and shareholder, outside the submitted work; In addition, Dr Michalakis has a patent EP3419673B1: Gene therapy for the treatment of a disease of retinal cone cells issued to EyeServ GmbH. Dr Wilhelm reports grants from Tistou and Charlotte Kerstan Foundation. Dr. Kohl reports grants from Charlotte and Tistou Kerstan Foundation, during the conduct of the study; personal fees from Novartis, outside the submitted work. Dr Kuehlewein reports grants from Tistou and Charlotte Kerstan Foundation, during the conduct of the study; grants from Novartis, outside the submitted work. Dr Paquet-Durand reports other from Mireca Medicines GmbH, outside the submitted work; In addition, Dr. Paquet-Durand has a patent WO 2016/146669 A1 issued, and a patent WO 2018/010965 A1 pending. Dr Seeliger reports grants from Tistou and Charlotte Kerstan Foundation, grants from German Research Council DFG SE837/12-1, during the conduct of the study; in addition, Dr Seeliger has a patent EP3419673B1: Gene therapy for the treatment of a disease of retinal cone cells issued to EyeServ GmbH. Dr Zrenner reports grants from Tistou and Charlotte Kerstan Foundation, during the conduct of the study; personal fees from EyeServ GmbH, personal fees from Janssen Research Development LLC, personal fees from ProQR Therapeutics IV B.V., personal fees from Biogen, personal fees from Gyroscope Therapeutics LTD, personal fees from ORA Inc., personal fees from Astellas Pharma, outside the submitted work. Dr Biel reports grants from Tistou und Charlotte Kerstan Foundation, during the conduct of the study. In addition, Dr Biel has a patent EP3419673B1: Gene therapy for the treatment of a disease of retinal cone cells issued to EyeServ GmbH. Professor Fischer is on the advisory board of and/or consulting and/or receiving honoraria/grant money/travel support from following companies: Adelphi Values, Advent France Biotechnology, Alphasights, Arctos Medical, Atheneum, Axiom Healthcare Strategies, Biogen, Cambridge Consultants, Decision Resources, Dialectica, Frontera Therapeutics, Janssen Research & Development, Navigant, Novartis, Roche, RegenxBio, Sirion, System Analytic, and STZeyetrial. He is the director of Fischer Consulting Limited and holds a patent (50%) on a gene therapy product for X-linked Retinitis Pigmentosa.

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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