Cutting Edge: Topical Recombinant Nerve Growth Factor for the Treatment of Neurotrophic Keratopathy (NK)—Biologicals as a Novel Therapy for NK

Abstract

Ophthalmologists find management of neurotrophic keratopathy (NK) challenging, as conventional therapy lacks efficacy and may result in permanent loss of vision. Recombinant nerve growth factor (rhNGF, Cenegermin) targets the underlying pathogenesis of NK by regenerating corneal nerves and healing the corneal epithelium through promotion of proliferation, maturing corneal epithelial cells. It has been approved as FDA-approved treatment for NK. Herein, the background, clinical trials and impact of rhNGF as the first neurotrophic factor for the restoration of corneal integrity, homeostasis and corneal nerve regeneration are discussed.

INTRODUCTION

The discovery of nerve growth factor (NGF) by Rita Levi-Montalcini 70 years ago resulted in the award of the Nobel Prize in 1986. In her experiments with chick embryos, she observed that transplanted murine tumor fragments were releasing a soluble molecule that induced potent growth and differentiation of sensory and sympathetic nerves. These initial studies resulted in significant interest in NGF in the scientific community, eventually leading to studies on the potential therapeutic impact of topical murine NGF for neurotrophic ulcers by Lambiase et al. ¹

NGF is a growth factor from the neurotrophin family, which maintains myelin synthesis in the nervous system. Neurotrophins stimulate axonal growth through activation of transcription factors that regulate gene expression and subsequent synthesis of proteins necessary for axonal growth. The mechanisms of action of NGF are extremely complex and are dependent on two specific receptors, tropomyosin receptor kinase (Trk) A receptor (Trk family of tyrosine kinase receptors: with high affinity) and the p75 neurotrophic receptor (p75NTR) (TNF receptor family; with low affinity). NGF-sensitive neurons generally express both TrkA and p75NTR receptors, and increased functional interaction is related to the changes in their expression levels. In physiological states, NGF, TrkA and p75NTR are expressed in the cornea, and play a critical role for corneal epithelial cell migration and proliferation. The activation of these receptors mediates neuronal survival and differentiation, as well as promotion of axonal elongation for both sensory and sympathetic nerves.⁹

Based upon NGF’s neurotrophic and neuroprotective effects, the systemic administration of recombinant human NGF (rhNGF, through cloning of human genes) was assessed as a treatment option for different types of neurodegenerative diseases, such as Alzheimer’s Disease or Huntington Disease. More recently, an ophthalmic solution rhNGF was developed (20 μg/mL Cenegermin), and became the first topical drug to be approved for the treatment of all stages of neurotrophic keratopathy (keratitis) (NK), with the aim of restoring the corneal integrity.^2–4 Herein we describe how the development and approval of rhNGF for NK may change the management of NK for clinicians and patients alike, as well as lead to future treatments with biologicals for NK.

Neurodegeneration in the Cornea

Background and Historical Overview

The cornea is densely innervated by sensory nerves (400 times more than skin), predominantly originating from ophthalmic division of the trigeminal nerve. These sensory nerve endings help protect the ocular surface by triggering the blink reflex and tear production. Equally important, these nerves provide neurotrophins (e.g. NGF, brain-derived neurotrophic factor [BDNF]), neuropeptides (e.g., substance P [SP], calcitonin gene-related peptide [CGRP]), and growth factors (e.g. epidermal growth factor [EGF]), which mediate corneal epithelial differentiation, proliferation, migration, and corneal collagen production.^2–4

In 1824, Magendie described that damage to the trigeminal nerve can lead to degenerative changes of the cornea. Decreased corneal nerve density and/or function causes impairment of tear reflex, blink reflex, and ocular surface homeostasis, leading to severe epitheliopathy and stromal pathology. Thus, any insult that alters the corneal sensory innervation impeding the function of post-ganglionic trigeminal nerve fibers can cause NK.^2–4 The prevalence of NK is estimated between 1.6–4.2/10,000, thus it is classified as an orphan disease (ORPHA137596, www.orpha.net).⁵

NK is associated with several ocular and non-ocular conditions, all of which result in damage to the trigeminal ganglion or post-ganglionic nerve fibers. Ocular conditions including chronic inflammation (e.g. ocular surface diseases), infections (e.g. herpetic keratitis), iatrogenic (e.g. ocular surgeries, or contact lens wear), trauma (e.g. physical, chemical, or thermal) are associated with NK. Furthermore, systemic diseases (e.g. Diabetes mellitus, leprosy, or vitamin A deficiency), central nervous system diseases (e.g. neoplasms, aneurysms, stroke, surgical injury to the trigeminal nerve), and genetic conditions (e.g. Riley-Day, Goldenhar-Gorlin, or Moebius syndromes, or familial corneal hypoesthesia) are also associated with NK.⁶

Ocular Symptoms and Signs in Corneal Neurodegeneration

Unlike dry eye disease (DED) and other ocular surface diseases, ocular discomfort is not one of the typical symptoms of NK, due to the damage to sensory nerves. Instead, patients commonly report visual complaints due to surface epitheliopathy and a poor tear film.⁶

Punctate staining in NK is most frequently found in the central cornea, which is different than in DED and exposure keratopathy (inferior and/or interpalpebral respectively). Further, the presence of a persistent epithelial defect is characteristic of NK, which can be differentiated from an infectious ulcer by the absence of infiltrates and the presence of loose epithelium with rolled edges around the ulcer.⁵ Stromal involvement may arise in the late stages of the disease; however Descemet’s membrane folds and stromal edema under the area of the ulcer may be observed even in the absence of stromal involvement.⁶ Alternative findings that may be found in NK include limited conjunctival inflammation compared to what would be expected from corneal findings, and focal superficial neovascularization caused by previous epithelial defects.⁶ Suspicion of NK should be confirmed by testing corneal sensation with corneal esthesiometry (e.g. cotton wisp test, Cochet-Bonnet, and Belmonte esthesiometers).⁵ Finally, decrease in corneal subbasal nerve density may be confirmed with in vivo confocal microscopy (IVCM). Increased stromal reflectivity with reduced or absence of subbasal corneal nerves are typically seen in advanced disease.^5,6 The most commonly used classification for NK is the Mackie classification, which divides the disease into three stages based on clinical findings. In stage 1 NK, patients generally show unilateral or bilateral staining of the inferior palpebral conjunctiva and central or diffuse superficial punctate staining of corneal epithelium. Stage 2 NK is characterized by the non-healing corneal epithelial defect. Stage 3 NK includes persistent epithelial defects with presence of stromal lysis and/or perforation.⁶ This classification system has been used in proposing the treatment modalities for NK.

Treatment and Success of Conventional NK Therapy

Treatment of NK is generally initiated according to disease stage and severity.⁵ Table 1 shows conventional treatment methods in different stages of NK. The treatment goals are to support epithelial healing, avoid involvement of corneal stroma, and/or to induce corneal nerve growth.^5,6

Table 1.

Conventional treatment of neurotrophic keratopathy (modified from Dua et al.)¹³

Stage	Objective	Treatment Options
1 (Mild)	- Promote epithelial healing, improve epithelial quality and transparency. - Stabilize epithelium and reduce epithelial breakdown. - Prevent progression to stage 2.	- Discontinuation of preservative containing topical medications. - Treatment of concomitant ocular surface diseases. - Anti-inflammatory therapy. - Tear substitution/ Administration of topical preservative-free lubricants. - Autologous serum eye drops, platelet-rich plasma - Corneal or scleral therapeutic contact lenses. - Punctal occlusion. - Correction of lid abnormalities. - Epithelial debridement.
2 (Moderate)	- Improve epithelial healing. - Prevent the occurrence/recurrence of the epithelial breakdown. - Prevent progression to stage 3.	All measures for stage 1 and; - Prophylactic topical preservative-free antibiotics. - Prevention of melting with Citrate/tetracycline/macrolides (if stromal involvement is threatened) - Non-surgical Eyelid closure, tarsorrhaphy. - Debridement of epithelial defect. - Amniotic membrane transplantation. - Conjunctival flaps.
3 (Severe)	- Promote corneal healing - Prevent further stromal lysis and perforation.	All measures for stage 1 and 2 and; - Amniotic membrane. - Corneal grafts. - Tissue adhesive. - Amniotic membrane transplantation or corneal grafts.

Stage 1

The first step in the management of NK is discarding any topical medications, preservatives, and cosmetics, which can impair corneal sensation and interfere with regeneration of the corneal epithelium. Use of non-preserved topical medication should be prioritized. Any eyelid abnormalities that may alter the lid function and homeostasis of the ocular surface (e.g., facial nerve palsy, nocturnal lagophthalmos, entropion, ectropion, and trichiasis) should also be treated. If there is suspicion, microbiological assessment should be done, and concomitant infectious keratitis should be treated. Epithelialization is promoted by preservative free artificial tears with their ability to lubricate the interface between the lids and cornea as well as to dilute the pro-inflammatory cytokines in the tear film. Punctal occlusion complements corneal epithelial healing by increasing the natural tear volume and can be achieved by punctal plugs, or thermal cauterization. However, punctal occlusion may cause retention of the tear film and lead to accumulation of pro-inflammatory mediators along with bacterial overload.^5,6

The first line of treatment for concurrent inflammation in NK is topical steroids, preferably non-preserved topical corticosteroids, such as dexamethasone and prednisolone or steroids with lower preservative concentration, including loteprednol etabonate formulations. Androgens, medroxyprogesterone 1%−2%, topical cyclosporine 0.05%, lifitegrast 5%, or tacrolimus 0.03–0.1% may reduce complications related to steroids and serve as steroid-sparing therapies.⁷ The use of matrix metalloproteinase inhibitors (e.g., oral/topical tetracyclines and topical acetylcysteine) is also advised to reduce inflammation and prevent stromal lysis.⁵

Blood derived tear substitutes that also have nutritional support can be used in all stages of NK (e.g., autologous serum tears [AST], platelet-rich plasma [PRP], plasma rich in growth factors [PRGF], and human umbilical cord blood serum). These blood derivatives resemble natural tears in terms of growth factors (e.g., NGF, EGF), vitamins (A and C), molecules that contribute to natural immunity (secretory IgA, defensins, lysozyme), glucose, and proteins associated with wound healing (fibronectin). AST are most commonly used and are relatively easy to prepare and effective in treating persistent epithelial defects in NK (average reported treatment success rate is 70%).⁶ Although PRP and PRGF have higher growth factor levels with undetectable leukocytes compared to AST, their outcomes were similar. In general, all blood derivatives used as tear substitutes have a good safety profile.^5,6

Nevertheless. despite these treatment modalities, patients may not respond to these conventional therapies, necessitating more advanced therapies.

Stage 2

All treatment options for stage 1, in particular blood-derived tear substitutes, may be combined with the therapies for stage 2 NK. In addition, amniotic membrane (AM) has been shown to be effective in NK of various stages (between 73.3% to 82.1% complete resolution).^6,8 Cryopreserved amniotic membrane lenses have been shown to be similarly effective in the treatment of stage 2 NK.^5,6

For cases that are unresponsive to medical therapy, narrowing the interpalpebral opening provides an important tool in NK management, in order to protect the ocular surface against the effect of lid blinking, and environmental irritants, preserving natural tears. Eyelid closure can be achieved by many methods (e.g., tape, pressure patching, botulinum toxin A injection induced ptosis, and tarsorrhaphy), although they provide poor cosmetic results. Tarsorrhaphy may be used as an adjunct treatment in neurotrophic ulcers, however in the only randomized controlled trial to date, resolution of epithelial defect rate was reported at only 66.7%.⁷ In addition, contact lenses protect the cornea from lid rubbing and environment and can be used to help preserve the integrity of the ocular surface. The results are similar to eyelid closure methods without the cosmetic disadvantages but contact lenses should only be considered after infection is excluded. If they are utilized, prophylactic use of topical non-preserved antibiotics should also be prescribed, as they may result in de novo infections.^5,6 Contact lenses should be used with caution in stage 1 NK, because of the risk of infectious complications.

More recently, corneal neurotization, which is a complex surgical procedure, has been shown to promote corneal nerve regeneration. Contralateral supraorbital and supratrochlear nerves, greater auricular nerve, and sural nerve have been used for neurotization. Only few centers, however, have been using this technique due to its surgical complexity and lack of comparative clinical results.^5,6

Although there are many treatment options for stage 2, as high as 33% of NK patients do not respond to treatment, and epithelial defect may persist and even progresses to stage 3, therefore necessitating further advanced treatment modalities.

Stage 3

All treatment options for stages 1 and 2 may be combined with the therapies for stage 3 NK.

Conjunctival flap surgery restores the corneal integrity; however, it sacrifices visual function and cosmetics especially in central defects. However, it could be used as an option in peripheral cases.^5,6 Small perforations or corneal stromal lysis can be treated with cyanoacrylate glue, followed by application of bandage contact lens. Corneal transplants and patch grafts should be reserved for larger epithelial defects, however, epithelial healing may be impaired and corneal ulcers may recur in the graft due to NK.^5,6

Advanced medical treatments, which reduce the progression of stromal stromal lysis and address the pathophysiology of NK by inducing corneal nerve growth are needed in order to avoid the unwanted cosmetic results and complex surgeries that are described above for the treatment of stage 2 and 3 NK.

Topical Nerve Growth Factor for Neurotrophic Keratopathy

The first evidence that NGF has a protective role in the treatment of NK was published by Lambiase et al. in the late 1990s.^5,6 In 2 prospective clinical trials (total n=55) they demonstrated that topical murine NGF administration resulted in complete resolution of persistent epithelial defects (PEDs) that did not respond to conventional NK treatment within 3 to 6 weeks.^5,6 The application of topical murine NGF also improved corneal transparency and tear volume, which helped improve visual function. None of the studies reported significant ocular or systemic side effects of topical NGF. However, in a study with 11 patients, ocular discomfort (moderate and tolerable painful sensation for 1 hour after the instillation of NGF) has been reported.¹ However, topical NGF was not commercially available until recently.

Topical Recombinant Nerve Growth Factor for the Therapy of Neurotrophic Keratopathy

The recent development of topical ophthalmic rhNGF (cenegermin 20 μg/ml) has provided a novel treatment for the cases not responding conventional NK therapy, which include advanced non-responsive cases of stage I NK cases, particularly when impacting vision, as well as stage II and stage III NK cases not responsive to conventional therapies. The treatment is generally used six times daily for up to 8 weeks, Treatment may occasionally co-incide with ocular surface inflammation, in which case anti-inflammatory therapy might be required, such as low dose steroids. For ocular discomfort, cold preservative free artificial tears or cool compresses, together with anti-inflammatory therapy may be added. (Fig. 1). The approval of rhNGF therapy for NK was based on the results of 3 clinical trials in patients with stage 2 and stage 3 NK; NGF0212/REPARO (Phase I with 18 patients, phase II for 156 patients with 10 μg/ml-20 μg/ml rhNGF and placebo): randomized, double-masked, vehicle-controlled, dose-ranging study from Europe,^2,3 and NGF 0214 (Phase II with 48 patients with 20 μg/ml and placebo): a pivotal trial from United States.⁴ Based on the study population, there was no statistically significant association between demographic criteria, initial NK stage and disease duration since diagnosis. The most common causes of NK for both studies were herpetic eye disease, diabetes, DED, and neurosurgical procedures, with the most common prior medications being artificial tears and topical antibiotics.

Figure 1: Demonstrative images for cenegermin therapy in different stages of neurotrophic keratopathy (NK).

A: Diffuse central corneal fluorescein staining in stage 1 NK patient; B: Resolution of corneal staining after 8 weeks of cenegermin therapy; C: Central persistent epithelial defect in stage 2 NK patient; D: Complete healing of corneal epithelial defect after 8 weeks of cenegermin therapy; E: Corneal stromal lysis and corneal scar in stage 3 NK patient; F: Corneal healing after 8 weeks of cenegermin therapy; G: Severe corneal nerve loss in Stage 1 NK patient is shown in in vivo confocal microscopy; H: Corneal nerve regeneration after 8 weeks of therapy in Stage 1 NK patient

‘Topical rhNGF therapy was found to be effective for promoting epithelial healing for each concentration and treatment duration in the studies and showed significant improvement in healing as compared to placebo. (p=0.008, p=0.068 (Table 2). The studies suggested steady improvement over time with rhNGF therapy and demonstrated maximum corneal epithelial healing rates at the eighth weeks, independent of initial lesion size. After 8 weeks of treatment, up to 72% of patients achieved complete corneal epithelial healing. However, rhNGF demonstrated no statistically significant benefit over placebo in terms of best corrected distance vision acuity (BCDVA) or corneal sensitivity in Phase I and Phase II clinical trials yet.^2,3 The improvement of BCVDA was evaluated with the change from baseline with 15 letter gains in ETDRS chart, which was achieved in 50% of cases (10 μg/mL) and 41.5% of cases (20 μg/mL) in rhNGF-treated patients vs. 22.5% in vehicle treated patients (p=0.008 and p=0.68 respectively) in the NGF0212 study, and in 13.0% of rhNGF-treated patients vs. 16.7% of vehicle treated patients (p=0.727) in NGF0214 study.^2–4

Table 2.

Comparison of Clinical Trials: Phase I/II (Europe) and Phase II (USA)

	NGF0212/REPARO Phase I (EUROPE)2	NGF0212/REPARO Phase II (EUROPE)3	NGF0214 Phase II (USA)4
Patient Number (n)	18 (7a:7b:4c)	156 (52a:52b:52c)	48 (24b:24c)
Study Aim	Safety and systemic absorption of topical rhNGF to support proceeding with phase II	Safety and efficacy of rhNGF	Safety and efficacy of rhNGF
Primary NK Diagnosis (%)
Stage 2	42.9a/71.4b/50.0c	21.0a/27.0b/28.0c	62.5b/75.0c
Stage 3	57.1a/28.6b/50.0c	31.0a/25.0b/24.0c	37.5b/25.0c
Drug Dose	10 μg/ml rhNGF, 20 mg/ml rhNGF, Placebo	10 μg/ml rhNGF, 20 μg/ml rhNGF, Placebo	20 μg/ml rhNGF, Placebo
Treatment Duration	8 weeks	4 weeks/ 8 weeks	4 weeks/ 8 weeks
Follow-up Time	48–56 weeks	48–56 weeks	24 weeks
Most Common Underlying Causes (% of all causes)
Diabetes	14.3a/28.6b/25.0c	5.8a/7.7b/7.7c	0b/4.7c
Herpetic Eye Disease	14.3a/28.6b/50.0c	15.0a/11.0b/18.0c	37.5b/33.3c
Neurosurgical Procedure	28.6a/14.3b/0c	11.4a/15.2b/13.5c	4.2b/4.2c
Ocular Surgery	28.6a/28.6b/0c	17.2a/9.6b/13.4c	12.5b/16.7c
Prior Treatments (% of all treatments)
Artificial tears, gel, ointment-Preservative Free Artificial tears	14.3–57.1a/85.7–57.1b/75–50c	46.2–51.9a/55.8–38.5b/50.6–45.5c	-
Topical Antibiotics	57.1a/57.1b/50c	57.7a/61.5b/63.5c
Therapeutic Contact Lens	28.6a/14.3b/25c	25.0a/44.2b/21.2c	-
Autologous Serum Tears	14.3a/28.6b/25.0c	7.7a/9.6b/9.0c	-
Efficacy
Complete corneal healing ratio after treatment (%), p value	-	4 weeks: 54.9a/58.0b/19.6c p<0.001a-c, p<0.001b-c, p=0.754a-b 8 weeks: 74.5a/74.0b/43.1c p=0.001a-c, p=0.002b-c, p=0.953a-b	4 weeks: 54.2b/20.8c p=0.017b-c 8 weeks: 58.3b/12.5c p<0.001b-c
15 letters gain in BCDVA Change (%), p value	-	4 weeks: 36.7a/34.1b/20.9c p=0.097a-c, p=0.175b-c, p=0.008a-b 8 weeks: 50.0a/41.5b/22.5c p=0.008a-c, p=0.068b-c, p=0.421a-b	8 weeks: 13.0b/16.7c p=0.727b-c
Improvement in corneal sensitivity (%), p value	-	4 weeks: 68.9a/61.1b/63.4c p=0.592a-c, p=0.835b-c, p=0.465a-b 8 weeks: 78.6a/76.3b/68.4c p=0.303a-c, p=0.442b-c, p=0.809a-b	8 weeks: 72.2b/60.0c p=0.207b-c
Side effects (% of patients)
Any adverse event	14.3a/42.9b/25.0c	11.5a/17.3b/19.2c	43.5b/33.3c
Eye Pain	0a/28.6b/0c	0a/7.7b/3.8c	13.0b/4.2c
Conjunctival hyperemia	14.3a/0b/0c	0a/0b/1.0c	N/A
Eye Irritation	0a/14.3b/0c	1.9a/0b/1.9c	0b/8.3c

¹NK: Neurotrophic Keratopathy, NGF: Nerve Growth Factor, rhNGF = recombinant human nerve growth factor

²BCDVA: Best corrected distance vision acuity, ^aGroup with 10 μg/ml rhNGF treatment, ^bGroup with 20 μg/ml

³rhNGF treatment, ^cPlacebo Group, the significance level is 0.05, *p<0.05 ^** p<0.01 ^*** p<0.001

In NGF0214 study, corneal sensitivity measures (measured with Cochet-Bonnet esthesiometer) at baseline were 0.81 in the rhNGF group vs. 0.65 in the vehicle-treated patients. After 8 weeks of treatment, Cochet-Bonnet esthesiometry measurements were and 2.91 vs. 1.83 respectively. Comparisons between treatment groups did not reach statistical significance (p=0.207). Similarly, NGF0212 study did not show any significant improvement in corneal sensitivity compared to vehicle treated group (p=0.442).^2–4

Topical rhNGF was generally well tolerated. Side effects were reported in 14.3% (10 μg/mL) and 42.9% (20 μg/mL) in rhNGF-treated patients vs 25.0% in placebo in the REPARO Phase I study, and in 11.5 % (10 μg/mL) and 17.3% (20 μg/mL) of rhNGF-treated patients vs 19.2% in the placebo group of the REPARO Phase II study, as well as in 43.5% of rhNGF-treated patients vs 33.3% in the placebo group in the NGF0214 study.^2–4 The most common adverse event (AE) was eye pain (0% (10 μg/mL) and 2% (20 μg/mL) in rhNGF-treated patients vs 0% in placebo in the NGF0212/REPARO Phase I study, and in 0 % (10 μg/mL) and 7.7% (20 μg/mL) of rhNGF-treated patients vs 17.3% in the placebo group of the NGF0212/REPARO Phase II study) which did however not affect the completion of therapy. During the treatment period, there were no non-ocular or serious systemic AEs related to rhNGF therapy.^2–4 Comparative detailed information for efficacy and tolerability of rhNGF treatment and statistical analysis for each study are demonstrated in Table 2.

According to the results of these studies, the European Medicines Agency (July 2017) and Food and Drug Administration (August 2018) approved rhNGF (cenegermin 20μg/ml [Oxervate®, Dompe Pharmaceuticals]) for the treatment of NK.³ ).

Clinical Experience with Recombinant Nerve Growth Factor in The Field

The safety and efficacy of topical rhNGF have also been established in patients of 2 years of age and older children, as well as in adults of 65 years or older,^3,4 although there is no data for usage during pregnancy and lactation. Pedrotti et al. published a case report on the use of rhNGF for a non-healing corneal ulcer as a result of radiation therapy for rhabdomyosarcoma in a 3-year-old child after ten cycles of treatment combinations, including topical eye biopolymer containing a poly-carboxymethyl glucose sulfate solution and a total four amniotic membrane transplantations. rhNGF resulted in complete epithelial healing after 3 weeks of treatment.⁹ Further, in a retrospective case series, we demonstrated the efficacy and tolerability of rhNGF in Stage 1 NK in 14 patients (Fig. 1).¹⁰ Use of rhNGF was effective and well-tolerated, demonstrating the improvement of BCVA from 20/30 to 20/25 (p=0.02) and the mean CFS score from 3.6±1.0 to 1.1±0.8 (p<0.001). Further, the mean total, main and branch nerve densities significantly increased compared to baseline.

Recently, cenegermin is being used for the patients with stage 1 NK who are unresponsive to conventional treatment. When the cenegermin is being prescribed, it is important to document the right codes for NK, document loss of corneal sensation and clinical signs of NK in order to allow proper documentation for insurance coverage. During the treatment, ocular side effects generally occur because of ocular inflammation, for this reason, ocular anti-inflammatory therapy might be needed. For ocular discomfort, preservative free artificial tears can be added to cenegermin regimen.

Summary-Game Changing Aspects of Topical rhNGF Therapy

In summary, the management of NK is a challenging for ophthalmologists and lack of efficacy of conventional therapy may result in permanent loss of vision or blindness. Therefore, the treatment of NK requires effective management. The prescribed first-line treatments are generally palliative, including preservative-free ocular lubricants or ointment and eye patching, or require complex process with contact lenses or scleral lenses, autologous serum tears, or more aggressive therapies such as tarsorrhaphy and amnion membrane transplantations or corneal transplantation.⁹ Furthermore, other advanced conventional therapies, such as PRP or PRGF, may also partially address the underlying pathology, but they are not effective in all cases, and not commercially available as compared to rhNGF therapy. In terms of the surgical treatment modalities, they sacrifice visual function, and may have undesirable cosmetic effects. rhNGF (cenegermin) is the first FDA-approved treatment for NK, targeting the underlying pathogenesis of NK by promoting corneal re-innervation¹¹, proliferation, and maturation of corneal epithelial cells, and healing of the corneal epithelium.¹² For this reason, rhNGF is a promising therapy for restoring corneal integrity and corneal nerve regeneration.^10,11

The approval of rhNGF has opened the door for additional clinical for drug development and emerging biological treatment options for patients with NK other neurodegenerative diseases. As a result, there are now several ongoing trials (www.clinicaltrials.gov) for NK, such as CSB-001 (human recombinant dHGF, 5-amino acid deleted hepatocyte growth factor, NCT04909450), ST266 ophthalmic solution 0.1% for stage 2–3 NK (Noveome Biotherapeutics, Inc, NCT03687632), plasma rich in growth factors (PRGF-Endoret, NCT02707120) eye drops for the treatment of NK. Additionally, clinical trials are now underway with autologous platelet-rich plasma (APRP, NCT04604834). These studies demonstrate that the treatment of NK and other nerve-related corneal diseases are not only palliative in nature anymore, but that rhNGF opened the door for additional treatment alternatives to target the underlying cause of the disease.