Article

Nerve growth factor for NK

A new therapy targets the underlying cause of neurotrophic keratopathy.

The FDA’s recent approval of Oxervate (cenegermin-bkbj) 0.002% ophthalmic solution (Dompé) facilitates a potential shift in the management of patients with neurotrophic keratopathy (NK).

Oxervate is a recombinant form of human nerve growth factor (rhNGF) that targets the underlying pathology of NK rather than solely addressing symptoms. It also provides an alternative to the invasive treatment options that are currently available.1,2

BACKGROUND

NK is a degenerative corneal disorder caused by damage to the trigeminal nerve, which leads to the reduction of corneal sensation, spontaneous breakdown of the corneal epithelium and impairment of healing. The prevalence and incidence of NK has been estimated at less than 1.6/10,000.3

NK can result from conditions that impair trigeminal innervation such as systemic or ocular surface diseases and central or peripheral nervous system impairments. The most common cause is herpetic eye infections; NK develops in an average of 6% of patients with herpetic keratitis and 12.8% of patients with herpes zoster keratitis. Another common cause is neurosurgical procedures that damage the trigeminal nerve, where it has been reported that 2.8% of patients undergoing surgical intervention for trigeminal neuralgia develop NK.3 Other causes include chemical/physical injuries, topical drug toxicity, chronic ocular surface injury or inflammation, corneal dystrophy, diabetes, leprosy, multiple sclerosis, rare congenital syndromes and degenerative disorders of the central nervous system.3 Once the corneal nerve damage has been established, the development, clinical severity and progression of NK are independent of the various conditions that initially led to the impairment of corneal nerves.4

Corneal nerves play an important role in the maintenance of a healthy ocular surface by releasing neuromediators that provide trophic support to corneal epithelial cells and by eliciting protective reflexes, such as tear production and blinking, in response to ocular surface injury. When damage to the corneal sensory innervation occurs, these mechanisms are altered, leading to decreased epithelial renewal rate and reduced blinking and tear formation. In turn, corneal epithelial cells regulate the survival, differentiation and maturation of nerve fibers by releasing neurotrophins (ie, NGF). This homeostasis between the corneal epithelium and corneal nerves is key to maintaining a healthy ocular surface.2,4

CLINICAL PRESENTATION/DIAGNOSIS

The hallmark of NK is the loss or reduction of corneal sensitivity and is characterized by progressive changes to the ocular surface as a result.2 Traditionally, NK has been classified into three stages based on severity as described by the Mackie classification system:

  • Stage 1 (mild) NK. Characterized by corneal epithelial irregularity, superficial punctate keratopathy and mild stromal scarring (Figures 1 and 2).

    Figure 1. Stage 1 NK. HSV stromal keratitis in a 28-year-old patient who is stable on topical low dose steroid once daily and oral valacyclovir twice daily.

    Figure 2. NK Stage 1. A 58-year-old after PKP for keratoconus who underwent a corneal astigmatic keratotomy. Both the PKP and the astigmatic keratotomy led to a surgically induced NK Stage 1.

  • Stage 2 (moderate) NK. Characterized by a persistent epithelial defect with smooth and rolled edges, Descemet’s membrane folds and stromal swelling and possible anterior chamber inflammatory reaction (Figure 3).

    Figure 3. Stage 2 NK from prior HSV keratitis. The breakdown of the epithelium is within the prior HSV site and the scar from the HSV is faint but present.

  • Stage 3 (severe) NK. Characterized by corneal ulceration with stromal involvement, which can progress into stromal melting and corneal perforation (Figure 4).4

    Figure 4. Stage 3 NK. Peripheral neovascularization nasally and a diffuse anterior stromal scar inferonasally, spanning the mid-periphery from 3 to 6 o’clock.

Patients with NK are often asymptomatic, likely associated with their lack of sensation. However, in the presence of corneal ulceration, edema or scarring, patients may experience blurred vision.4 It is important to differentiate NK from similarly presenting ocular surface diseases that can lead to corneal staining, ulceration and/or thinning (ie, Sjogren’s syndrome, microbial or viral keratitis) and address any comorbid conditions. One of the most pertinent diagnostic tools in establishing an NK diagnosis is corneal sensitivity testing. This can be performed using the Cochet-Bonnet esthesiometer or a more conventional method of applying a cotton wisp to the corneal surface.2,4

MANAGEMENT OPTIONS

An ideal therapy for NK should stimulate corneal renewal and healing by improving trigeminal innervation and restoring the trophic supply to the corneal nerves. Until recently, treatment options — limited solely to promoting corneal healing — did not target the underlying cause.4 These treatments included preservative-free artificial tears and punctal occlusion to support the tear film, the cautious use of therapeutic contact lenses, tarsorrhaphy and amniotic membrane transplantation to protect the cornea from further damage and more invasive surgical options, such as the use of conjunctival flaps, direct neurotization and corneal transplantation.

BENEFITS OF OXERVATE

The recent approval of Oxervate introduces a treatment specifically indicated for NK that also promotes corneal integrity by targeting the underlying pathology of the disease.2

Oxervate (cenegermin-bkbj) 0.002% ophthalmic solution is an rhNGF indicated for the treatment of NK. It is structurally identical to the endogenous NGF protein found in human ocular tissue.2 Endogenous NGF acts through specific high-affinity (ie, TrkA) and low-affinity (ie, p75NTF) receptors to play an integral role in the development, maintenance, growth and differentiation of neurons to support corneal innervation and integrity. Endogenous NGF is also believed to support corneal integrity by stimulating proliferation, differentiation and survival of corneal epithelial cells as well as promoting sensory-mediated reflex tear secretion.3-6

The safety and efficacy of Oxervate was established in two pivotal trials (REPARO and NGF0214) in which patients with stage 2 and 3 NK received Oxervate 0.002% ophthalmic solution six times per day for 8 weeks. These studies showed that up to 72% of patients were completely healed (defined as absence of staining of the corneal lesion and no persistent staining in the rest of the cornea) at week 8. Additionally, researchers saw a durable treatment response, with 80% of patients who achieved complete corneal healing in the REPARO study still healed 48 weeks after completing just one 8-week cycle of Oxervate.1,7 In both trials, Oxervate was generally well tolerated, with the most common adverse reaction being eye pain following instillation, which was reported in approximately 16% of patients.1

Treatment relies on a stepwise approach based on clinical severity. Often, a combination of treatments is necessary to effectively treat NK.2 Worsening of NK can be asymptomatic, so it is important to carefully monitor patients and diagnose and treat early for optimal prognosis.3 Oxervate provides a noninvasive topical option for all stages of NK.1

CASE STUDY

A 68-year-old pseudophakic male patient presents for an urgent evaluation of a “right eye that is light sensitive and watery for the past few days.” Symptoms include minimal redness and only mild, occasional foreign-body sensation. The patient heeded caution and came in due to his long-standing past ocular history significant for unilateral HSV keratitis of the right eye, with a handful of recurrences. The last documented episode of epithelial keratitis occurred in 2017. The patient faithfully uses Valtrex 500 mg orally b.i.d.

Clinically, the patient has an uncorrected vision of 20/30 +2. There is trace conjunctival injection. The cornea (Figure 4) demonstrates peripheral neovascularization nasally and a diffuse anterior stromal scar inferonasally, spanning the mid-periphery from 3 to 6 o’clock. There is an epithelial defect within the bed of the stromal scar, measuring 2.5 mm x 1.5 mm, with upwards of 80% thinning and very mild WBC recruitment without a formed infiltrate. The anterior chamber is unremarkable, without cell or flare.

This gentleman has stage 3 NK (ulceration with thinning). Prognostically, this 68-year-old has many years ahead of him and has good to excellent vision potential to preserve (UCDVA 20/30 on presentation). This appears to be the first severe breakdown of the epithelium due to the neurotrophic nature of the disease. It is likely, though, that the patient actually suffered from at least stage 1 NK chronically, given the long-standing and recurrent nature of the prior HSV keratitis. More severe, chronic dry eye disease from NK may lead to recurrent breakdown and worse stages of the disease.

Multiple modalities are targeted aggressively to heal this neurotrophic ulcer with thinning, including minimizing topical toxicities, frequent preservative-free lubrication, amniotic membrane therapy and oral vitamin C and/or tetracycline. The patient re-epithelializes after use of a self-retaining cryopreserved amniotic membrane (Prokera Slim, Bio-Tissue, Inc.) twice and protective ptosis with an upper lid temporary tape tarsorrhaphy. Valacyclovir 500 mg is maintained at the prophylactic dose of twice daily. Additionally, medically regenerating the corneal nerves with Oxervate to treat the root cause of the disease process is of utmost importance and is initiated upon insurance approval, which took about 3 weeks.

THE TAKE-HOME

Neurotrophic keratopathy is one of the most difficult and challenging ocular diseases to manage. The introduction of Oxervate into the armamentarium for NK treatment allows ophthalmologists to offer a less invasive and safe topical treatment that has a durable benefit.

With early diagnosis, careful monitoring and availability of effective treatment, we can halt progression to corneal melting/perforation and prevent the burden of managing these complications. OM

REFERENCES

  1. OXERVATE (cenegermin-bkbj) ophthalmic solution 0.002% (20 mcg/mL) [US package insert]. Boston, MA: Dompé US; 2018.
  2. Dua HS, Said DG, Messmer EM, et al. Neurotrophic keratopathy. Prog Retin Eye Res. 2018;66:107-131.
  3. Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571-579.
  4. Mastropasqua L, Massaro-Giordano G, Nubile M, Sacchetti M. Understanding the pathogenesis of neurotrophic keratitis: The role of corneal nerves. J Cell Physiol. 2017;232:717-724.
  5. Müller LJ, Marfut CF, Kruse F, Tervo TMT. Corneal nerves: structure, contents and function. Exp Eye Res. 2003; 76:521-542.
  6. Muzi S, Colafrancesco V, Sornelli F, et al. Nerve growth factor in the developing and adult lacrimal glands of rat with and without inherited retinitis pigmentosa. Cornea. 2010;29:1163-1168.
  7. 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.

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