Real Life Data on Efficacy and Safety of Topical NGF Eye Drops (Cenegermin)

Abstract

Background Topical NGF eye drops (Cenegermin) were approved in 2015 as an orphan drug for the treatment of neurotrophic keratopathy (NK). The active substance Cenegermin is a recombinant form of human NGF (nerve growth factor).

Objectives Presentation of efficacy and safety of Cenegermin for use in patients in an university real-life setting.

Material and Methods Retrospective study at the Köln University Eye Hospital from 2017 to 2019 with n = 11 eyes. Average follow-up was 13.5 ± 7.1 months. Reasons for treatment were neurotrophic keratopathy stage II and III, clinically mostly in combination with corneal neovascularization.

Results Seven eyes with a NK II and 4 eyes with a NK III with a median observation period of 13.6 months (range 1.2 – 20.3 months) from a total of 11 patients were included. The median patient age was 42.8 ± 23.6 years (range 18 – 75 years). Before the start of therapy, the median erosion area measured 3.1 ± 1.4 × 1.9 ± 1.1 mm and the median ulcer area had a size of 2.3 ± 1.1 × 2.1 ± 0.8 mm. After the start of therapy with Cenegermin (application 6×/day), the epithelial defect closed in all 11 study eyes (100%) within 4 – 12 weeks (mean: 49 d ± 9 d). In 9 out of 10 patients (90%) pre-existing corneal neovascularization regressed significantly (p < 0.001). Before the start of therapy, a value in the Luneau test of 2.9 ± 1.9 (minimum 1/6, maximum 4/6) was found and rose to a median value of 4.2 ± 1.7 (minimum 2/6, maximum 6/6) after 18 months (p = 0.015). Therapy with Cenegermin had no long-term effect on intraocular pressure: the pressure ranged between 13.2 ± 4.1 mmHg (minimum 8 mmHg, maximum 21 mmHg). Under therapy with NGF eye drops, 67% of the patients, after an initial decrease, showed a long-term improvement in visual acuity (BSCVA) from 0.72 ± 0.31 to 0.46 ± 0.29 logMAR after 18 months (p = 0.005). Relapses in form of a corneal erosion in the long-term follow-up were observed in only one eye. One patient had to stop therapy because of local pain, no other local and systemic side effects were observed.

Conclusion This real-life series on the use of Cenegermin in a university context shows a good effectiveness of the substance for epithelial closure in various underlying diseases (100% within 12 weeks). There is a long-term improvement in vision and corneal sensitivity. Larger real-life cohorts with various underlying diseases should follow.

Key words

neurotrophic keratopathy - cornea - orphan drugs - Cenegermin - Oxervate

• References/Literatur

• 1 Dompé Farmaceutici S.p.A. Oxervate prescribing information. Accessed August 1, 2018 at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm618047.htm
• 2 Dompé Farmaceutici S.p.A. Evaluation of safety and efficacy of rhNGF in patients with stage 2 and 3 neurotrophic keratitis (REPARO) [NCT01756456]. Accessed July 29, 2019 at: https://clinicaltrials.gov/ct2/show/NCT01756456
• 3 Bucher F, Hos D, Matthaei M. et al. Corneal nerve alterations after Descemet membrane endothelial keratoplasty: an in vivo confocal microscopy study. Cornea 2014; 33: 1134-1139 doi:10.1097/ICO.0000000000000250
• 4 Bremond-Gignac D, Daruich A, Robert MP. et al. Recent innovations with drugs in clinical trials for neutrotrophic keratitis and refractory corneal ulcers. Expert Opin Investig Drugs 2019; 28: 1013-1020 doi:10.1080/13543784.2019.1677605
• 5 Sheha H, Tighe S, Hashem O. et al. Update on Cenegermin eye drops in the treatment of neurotrophic keratitis. Clin Ophthalmol 2019; 13: 1973-1980 doi:10.2147/OPTH.S185184
• 6 Adler J, Mertsch S, Menzel-Severing J. et al. Aktuelle und experimentelle Therapieansätze bei neutrotropher Keratopathie. Ophthalmologe 2019; 116: 127-137 doi:10.1007/s00347-018-0843-5
• 7 Cursiefen C, Seitz B, Kruse FE. Neurotrophic keratitis. Ophthalmologe 2005; 102: 7-14 doi:10.1007/s00347-004-1140-z
• 8 Dua HS, Said DG, Messmer EM. et al. Neurotrophic keratopathy. Prog Retin Eye Res 2018; 66: 107-131 doi:10.1016/j.preteyeres.2018.04.003
• 9 Seitz B, Grüterich M, Cursiefen C. et al. [Conservative and surgical treatment of neurotrophic keratopathy]. Ophthalmologe 2005; 102: 15-26 doi:10.1007/s00347-004-1161-7
• 10 European Medicine Agency. EMA/330858/2017 EMEA/H/C/004209. Oxervate. Accessed November 10, 2020 at: https://www.ema.europa.eu/en/documents/overview/oxervate-epar-summary-public_de.pdf
• 11 Pflugfelder SC, Massaro-Giordano M, Perez VL. et al. Topical recombinant human nerve growth factor (Cenegermin) for neutrotrophic keratopathy. Ophthalmology 2020; 127: 14-26 doi:10.1016/j.ophtha.2019.08.020
• 12 Fleeman N, Mahon J, Nevitt S. et al. Cenegermin for treating neutrophic keratitis: An evidence review group perspective of a NICE single technology appraisal. Pharmacoecon Open 2019; 3: 453-461 doi:10.1007/s41669-019-0138-z
• 13 Cursiefen C, Bock F, Horn FK. et al. GS-101 antisense oligonucleotide eye drops inhibit corneal neovascularization. Ophthalmology 2009; 116: 1630-1637 doi:10.1016/j.ophtha.2009.04.016
• 14 Dietrich T, Weisbach V, Seitz B. et al. [Manufacture of autologous serum eye drops for out-patient therapy: cooperation between ophthalmic clinic and transfusion medicine department]. Ophthalmologe 2008; 105: 1036-1038 1040–1042 doi:10.1007/s00347-008-1692-4
• 15 Tahmaz V, Gehlsen U, Sauerbier L. et al. Treatment of severe chronic ocular graft-versus-host disease using 100 % autologous serum eye drops from a sealed manufacturing system: a retrospective cohort study. Br J Ophthalmol 2017; 101: 322-326 doi:10.1136/bjophthalmol-2015-307666
• 16 Bonini S, Lambiase A, Rama P. et al. Phase I trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology 2018; 125: 1468-1471 doi:10.1016/j.ophtha.2018.03.004
• 17 Bonini S, Lambiase A, Rama P. et al. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology 2018; 125: 1332-1343 doi:10.1016/j.ophtha.2018.02.022
• 18 Deecks ED, Lamb YN. Cenegermin: a review in neutrotrophic keratitis. Drugs 2020; 80: 489-494 doi:10.1007/s40265-020-01289-w
• 19 Weinlander E, Ling J, Reddy A. et al. Epithelial plaque formation secondary to recombinant human nerve growth factor. Cornea 2020; 39: 1174-1176 doi:10.1097/ICO.0000000000002300