Corneal Transplantation: a reovlution in evolution

Transcription

1 Corneal Transplantation: a reovlution in evolution Dr. Mor M. Dickman 1,2 and Prof. Dr. Rudy M.M.A. Nuijts 1 1. University Eye Clinic Maastricht, Center for Cornea and Refractive Surgery 2. MERLN Institute for Technology-Inspired Regenerative Medicine

2 Revolution in Evolution 2

3 The human cornea 3

4 The first solid tissue transplantation 4

5 Penetrating keratoplasty 5

6 Lamellar corneal transplantation 6

7 DMEK: Descemet Membrane Endothelial Keratoplasty 7

8 Endothelial keratoplasty No sutures and related complications Faster and better recovery of visual acuity Improved long-term survival? EMA press release, 19 December

9 Therapy for corneal endothelial disease Stocker 1953: Application of hot air for reducing corneal edema 2018: Descemet Membrane Endothelial Keratoplasty (DMEK) 9

10 Global perspective CT performed in 2012 in 116 countries Gain et al. JAMA Ophthalmology

11 Global perspective Type of keratoplasty Lamellar 29.7% Lamellar>50% 7 countries Did not perform lamellar 33% Leading indication in 98 countries Keratoconus 40 countries (41%) Secondary BK 29 countries (30%) Infections 24 countries (24%) Fuchs dystrophy 5 countries (5%) Actual global CT performed Fuchs dystrophy (39% ) Keratoconus (27%) Infectious keratitis (20%) Secondary BK (15%) 11

12 Practice patterns in the Netherlands Endothelial keratoplasty Penetrating keratoplasty Dickman et al. AJO

13 Corneal transplants: how good are we? PK only as good as renal Tx High risk PK worse then liver Tx 13

14 Practice patterns in the Netherlands Dickman et al. AJO

15 Practice patterns in the Netherlands Dickman et al. AJO

16 Therapy for limbal stem cell deficiency 16

17 Limbal epithelial stem cells Cornea Limbus Palisades of Vogt 17

18 Limbal stem cell deficiency 18

19 Holoclar First stem cell therapy approved in Europe First therapy approved for Limbal Stem Cell Deficiency (LSCD) LSCD is a rare eye condition that can result in blindness EMA press release, 19 December

20 What is Holoclar? Holoclar is a transparent circular sheet of autologous human corneal epithelial cells including 3.5% limbal stem cells and stem cell-derived transient amplifying and terminally differentiated cells. These cells are expanded ex vivo from an autologous biopsy obtained from an undamaged portion of the eye (if bilateral injury) or the other healthy eye. 20 Holoclar SmPC

21 Holoclar: production and delivery Ophthalmic Centre 1-2 mm 2 limbal biopsy Ophthalmic Centre Implantation Production facility Manufacturing Production facility Holoclar 21

22 The Holoclar manufacturing process 22

23 Holoclar indication Holoclar is indicated for the treatment of unilateral or bilateral moderate to severe limbal stem cell deficiency due to physical or chemical ocular burns The patient must be at least 18 years old with a minimum of 1-2 mm 2 of undamaged limbus for biopsy A moderate to severe deficit is defined as the presence of superficial corneal neovascularisation in at least two corneal quadrants, with central corneal involvement, and severely impaired visual acuity Holoclar SmPC 24

24 Long-Term Efficacy of Autologous Cultivated Limbal Stem Cell Transplantation (1/2) 112 patients treated with ACLSCT 25 Rama et al, NEJM, 2010

25 Long-Term Efficacy of Autologous Cultivated Limbal Stem Cell Transplantation (2/2) Rama et al, NEJM,

26 Restoration of Functional Corneal Epithelium and Restoration of Visual Acuity 27 Rama et al, NEJM, 2010

27 Stem cell markers correlate with clinical success 28 Rama et al, NEJM, 2010

28 Regulatory path of Holoclar 7 Nov 2008: Orphan Medicinal Product Designation 6 Mar 2013: Marketing Authorization Application at the EMA 18 Dec 2014: Positive opinion from CAT/CHMP 20 Feb 2015: Conditional Marketing Authorization by the EC 20 Feb 2015: Approval by CBG-MEB 01 Aug 2017: Add-on request approved by NZA 29

29 Safety profile Body system / Adverse event HLSTM01 N=113 HLSTM02 N=29 Overall N=142 Treatments with at least one AE Treatments with at least one ADR Treatments with at least one SAE 73 (64.6%) 19 (65.5%) 92 (64.8%) 19 (16.8%) 10 (34.5%) 29 (20.4%) 6 (5.3%) 3 (10.3%) 9 (6.3%) Number of serious ADRs Treatments with at least one serious ADR Common ( 1/100 to <1/10 treatments) Conjunctival haemorrhage, eye haemorrhage, blepharitis, corneal epithelium defect, eye pain, glaucoma, ulcerative keratitis 0 (0.0%) 2 (6.9%) 2 (1.4%) Uncommon ( 1/1,000 to <1/100) Conjunctival adhesion, conjunctival hyperaemia, corneal oedema, corneal perforation, eye irritation, photophobia, corneal infection, haemorrhage subcutaneous, eye metaplasia, suture rupture Holoclar EPAR 30 Syncope vasovagal

30 Holoclar: clinical development plan & post-approval commitments HLSTM01 N=104 Pivotalstudy Success 72,1% Registry Holoclar safety and efficacy in standard clinical practice HOLOSIGHT N=100 HLSTM02 N=29 Favourable SafetyProfile Prospective Multicenter International Interventional Study HOLOCORE N=65 HLSTM04 N=15 HLSTM02 N=29 Good clinicalresultsusing to-be-marketed product Holoclar EPAR 31

31 Holoclar in Nederland Behandeling met Holoclar in Nederland Tot nu toe alleen in Maastricht 32

32 Vision: imaging corneal regeneration OCT MRI IVCM Stem cell labeled with nanoprobes Dickman, van Rijt, LaPointe, Ferrari, Nuijts and van Blitterswijk

33 European Cornea and Cell Transplantation Registry Co-funding 60% Co-funding 40% 34

34 European Cornea and Cell Transplantation Registry 35

35 European Cornea and Cell Transplantation Registry 36

36 European Cornea and Cell Transplantation Registry Donor information Recipient information Follow-up data Graft failure and rejection Patient-reported outcome measures (PROMs) EMA press release, 19 December

37 European Cornea and Cell Transplantation Registry 38

38 Thanks for your attention Mor Dickman Rudy Nuijts 39