Efficacy of Recombinant Human Nerve Growth Factor in Stage 1 Neurotrophic Keratopathy

Abstract

Neurotrophic keratopathy (NK) is a vision-threatening condition that results from injury or dysfunction of corneal nerves and subsequent decrease or loss of corneal sensation.1Lambiase A. Rama P. Aloe L. Bonini S. Management of neurotrophic keratopathy.Curr Opin Ophthalmol. 1999; 10: 270-276Crossref PubMed Scopus (101) Google Scholar Impaired corneal sensory function affects epithelial homeostasis, resulting in epithelial breakdown, as well as impairing corneal healing, potentially resulting in stromal melting.2Mackie I.A.F. Roy F.H. Meyer S.M. Neuroparalytic Keratitis. Current Ocular Therapy. Philadelphia.WB Saunders. 1995; : 452-454Google Scholar Clinically, NK is classified into 3 stages based on changes in corneal sensation, corneal epithelium, and stroma.2Mackie I.A.F. Roy F.H. Meyer S.M. Neuroparalytic Keratitis. Current Ocular Therapy. Philadelphia.WB Saunders. 1995; : 452-454Google Scholar Nerve growth factor plays an important role in neuronal regeneration and survival.3Bonini S. Rama P. Olzi D. Lambiase A. Neurotrophic keratitis.Eye (Lond). 2003; 17: 989-995Crossref PubMed Scopus (259) Google Scholar Recombinant human nerve growth factor (rhNGF; 0.002% [20 mcg/ml] cenegermin) was approved by the Food and Drug Administration in 2018 for all stages of NK. However, to date, clinical trials have included only patients with stages 2 and 3 NK.4Pflugfelder S.C. Massaro-Giordano M. Perez V.L. et al.Topical recombinant human nerve growth factor (cenegermin) for neurotrophic keratopathy: a multicenter randomized vehicle-controlled pivotal trial.Ophthalmology. 2020; 127: 14-26Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar,5Mastropasqua L. Manuela L. Dua H.S. et al.In vivo evaluation of corneal nerves and epithelial healing after treatment with recombinant nerve growth factor for neurotrophic keratopathy.Am J Ophthalmol. 2020; 217: 278-286Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar However, treatment of stage 1 NK is important to prevent progression to more advanced disease states, which may result in significant vision loss resulting from subepithelial scarring, corneal melting, and corneal perforation. This retrospective study included 17 patients with a diagnosis of stage 1 NK2Mackie I.A.F. Roy F.H. Meyer S.M. Neuroparalytic Keratitis. Current Ocular Therapy. Philadelphia.WB Saunders. 1995; : 452-454Google Scholar from 3 sites (Tufts Medical Center, University of Pennsylvania, and Scripps Green Hospital) and were treated with rhNGF for exactly 8 weeks between December 2018 and March 2020. Inclusion criteria included diffuse punctate epitheliopathy by corneal fluorescein staining (CFS), which had to include a central corneal grade of 2 or more on the Oxford scale, decreased corneal sensation by Cochet Bonnet esthesiometry or cotton swab, and unresponsiveness to conventional medical therapy. Patients with epithelial defects, active ocular infections, or ocular surgery in the prior 3 months were excluded. Central corneal in vivo confocal microscopy (IVCM) and image analysis were performed as previously described.6Cruzat A. Witkin D. Baniasadi N. et al.Inflammation and the nervous system: the connection in the cornea in patients with infectious keratitis.Invest Ophthalmol Vis Sci. 2011; 52: 5136-5143Crossref PubMed Scopus (164) Google Scholar Nerve density of patients for whom IVCM was available before and after treatment (n = 5) were compared with age- and sex-matched healthy reference controls (n = 13). The study was approved by the institutional board review of Tufts Medical Center/Tufts University Health Sciences. The study complied with the Health Insurance Portability and Accountability Act and adhered to the tenets of the Declaration of Helsinki. Informed consent was not obtained because this was a retrospective chart review and was exempt from informed consent requirements. Statistical analysis was carried out using SPSS software version 21.00 (SPSS, Inc., IBM), and P < 0.05 considered statistically significant. The mean ± standard deviation age of patients with stage 1 NK was 67.5 ± 12.4 years, and most patients were women (94.1%; Table S1, available at www.aaojournal.org). The underlying causes of NK in these patients included long-standing dry eye disease (DED; 64.7%), a history of ocular surgery (35.2%), and herpes simplex keratitis (11.7%); and 82.4% of NK cases were multifactorial (Table S2, available at www.aaojournal.org). The most common prior conventional therapies were artificial tears (88.2%), autologous serum tears (47.0%), lifitegrast ophthalmic solution (47.0%), and tobramycin dexamethasone (47.0%; Table S2). At baseline, before rhNGF treatment, mean ± standard deviation CFS score was 4.0 ± 1.0, which improved significantly to 1.06 ± 0.77 after 8 weeks of rhNGF therapy (P < 0.001; Fig 1A). The mean best-corrected visual acuity (BCVA) of patients at baseline before rhNGF treatment was 20/40 (range, 20/20–20/400), which improved to 20/30 (range, 20/20–20/200; P = 0.0013; Fig 1B). None of the patients experienced vision reduction with topical rhNGF therapy. Ten patients (58.8%) reported mild to moderate discomfort while receiving rhNGF therapy, which did not result in interruption or discontinuation of therapy. After 8 weeks of rhNGF therapy, the mean total nerve density, main trunk nerve density, and the branch nerve density increased (P = 0.006, P = 0.013, P = 0.004, respectively; Fig 1C–D) compared with baseline. The average speed of nerve regeneration was calculated as 1.87 mm/mm2 per month. This case series demonstrated that topical rhNGF treatment for stage 1 NK increased corneal nerve density in a subset of patients after rhNGF therapy who initially demonstrated severe nerve loss. Moreover, we showed that as a result of rhNGF treatment, BCVA and CFS scores improved significantly. Furthermore, rhNGF was well tolerated with minimal adverse events in these patients. To date, 2 randomized clinical trials have evaluated the efficacy and tolerability of rhNGF in moderate and severe forms of NK (stages 2 and 3).4Pflugfelder S.C. Massaro-Giordano M. Perez V.L. et al.Topical recombinant human nerve growth factor (cenegermin) for neurotrophic keratopathy: a multicenter randomized vehicle-controlled pivotal trial.Ophthalmology. 2020; 127: 14-26Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar,7Bonini 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: 1332-1343Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar The current study is novel in that it evaluates the use of topical rhNGF treatment in patients with stage 1 NK. Efficacy was assessed by CFS and BCVA. The NGF0212/REPARO and NGF0214 studies did not demonstrate a statistically significant difference between rhNGF and the control group regarding BCVA parameters.4Pflugfelder S.C. Massaro-Giordano M. Perez V.L. et al.Topical recombinant human nerve growth factor (cenegermin) for neurotrophic keratopathy: a multicenter randomized vehicle-controlled pivotal trial.Ophthalmology. 2020; 127: 14-26Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar,7Bonini 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: 1332-1343Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar In contrast, BCVA improved significantly in this series of patients with stage 1 NK after rhNGF treatment as compared with baseline. We believe that in later stages of NK (stages 2 and 3), BCVA may not improve significantly because of corneal thinning, subepithelial scarring, or both. For this reason, early treatment of NK (during stage 1) is important to retain BCVA and prevent permanent loss of vision. Topical rhNGF therapy generally is well tolerated with mild ocular symptoms. Eye pain was the most common adverse event in patients who received rhNGF therapy, reported in 0% to 7.7% of patients in the NGF0212/REPARO study and by 13.0% of rhNGF-treated patients in the NGF0214 study. In the current series of patients with stage 1 NK, 10 patients (58.8 %) reported mild ocular pain that did not result in discontinuation of therapy. None of the study patients demonstrated any reduction in visual acuity or worsening of corneal deposits during the 8-week follow-up period. Corneal nerves can be visualized directly and analyzed quantitatively by IVCM, which can be helpful to assess the in vivo effects of ocular treatment, and the corneal recovery process after ocular surgeries. Recently, Mastropasqua et al5Mastropasqua L. Manuela L. Dua H.S. et al.In vivo evaluation of corneal nerves and epithelial healing after treatment with recombinant nerve growth factor for neurotrophic keratopathy.Am J Ophthalmol. 2020; 217: 278-286Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar demonstrated increased corneal nerve density by IVCM and corneal sensitivity after 20 mcg/ml rhNGF therapy in patients with stage 2 and 3 NK. Because only patients with stage 1 NK were included in the current case series, the baseline total corneal nerve density was markedly higher compared with their study. In our study, total nerve density also was increased significantly after 8 weeks of rhNGF therapy. Our study has several limitations. First, it was retrospective and had a relatively small sample size, although NK is not a common condition. Second, given the retrospective nature, corneal sensation data after rhNGF therapy are lacking. Third, the study had no vehicle control group. Fourth, corneal nerve density was analyzed in a subgroup of patients, but still achieved statistical significance. Finally, adverse events were not assessed in detail, and patients were not asked to specify the type of ocular discomfort related to rhNGF therapy. Nevertheless, the current study on the safety and efficacy of rhNGF in stage 1 NK demonstrated improvement in vision in patients, suggesting that early treatment may prevent vision loss. In conclusion, topical rhNGF therapy was well tolerated and resulted in significant improvement in BCVA and CFS scores for patients with stage 1 NK. Download .pdf (.1 MB) Help with pdf files Table1 Download .pdf (.1 MB) Help with pdf files Table2

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