The cornea is the most densely innervated tissue in the human body and is supplied by the ophthalmic branch of the trigeminal nerve and autonomic nerves. Corneal nerves release neuropeptides, such as substance P and calcitonin gene-related peptide, that promote epithelial cell proliferation, migration, adhesion, and differentiation. In turn, corneal epithelial cells release neurotrophic factors, such as nerve growth factor (NGF) and epidermal growth factor, which promote neuronal extension and survival. This balance is vital for corneal healing and maintenance. Corneal nerve damage results in loss of corneal sensation and trophic functions which consequently leads to epithelial breakdown and poor healing; a condition known as neurotrophic keratitis or neurotrophic keratopathy.
Neurotrophic keratitis is an underdiagnosed degenerative condition induced by impairment to the corneal nerves which may lead to persistent epithelial defects and corneal blindness. The diagnosis of neurotrophic keratitis is mainly based on clinical history and clinical signs such as presence of persistent epithelial defects or ulcers and decreased corneal sensitivity. According to the literature, the estimated prevalence of neurotrophic keratitis is less than 5/10,000 individuals, being classified as a rare orphan disease.
Neurotrophic Keratitis: Stages and Current Treatment
Based on the severity, neurotrophic keratitis is classified into three overlapping stages: epithelial alterations (stage 1), persistent epithelial defects (stage 2), and corneal ulcers (stage 3).
Management of neurotrophic keratitis can be divided into medical management, non-surgical intervention, and surgical management. The objective of treatment is to arrest progression and reverse neurotrophic keratitis changes that have occurred at the time of presentation. Conventional therapy for stage 1 aims to prevent epithelial breakdown, generally by administering lubricating agents such as preservative-free artificial tears, autologous serum drops, and discontinuing toxic topical medications specifically unnecessary use of antibiotics and anti-inflammatory agents. However, they all provide nonspecific symptomatic relief, which may be temporary. Stage 2 and 3 therapies aim to facilitate corneal healing and prevent corneal melting and perforation; these include procedures such as tarsorrhaphy, botulinum-induced ptosis, conjunctival flap, and amniotic membrane transplantation to restore ocular surface integrity. However, these procedures are usually performed late and therefore carry the risk of corneal scarring and poor vision. Collectively, current medical and surgical treatments poorly tackle the essential problem of corneal anesthesia and hence fail to provide a permanent cure.
Cenegermin is a newly introduced recombinant human nerve growth factor (rhNGF) to promote healing in neurotrophic keratitis. Cenegermin under the tradename (OXERVATETM) was approved for the treatment of neurotrophic keratitis in the United States on August 22, 2018, and for the treatment of moderate to severe neurotrophic keratitis in the European Union on July 20, 2017. Neurologist Dr. Rita Levi-Montalcini of Italy first discovered NGF in the 1950s, and this work won her the Nobel prize in 1986. NGF is known to support corneal integrity via many mechanisms, although its exact role in treating neurotrophic keratitis is not entirely clear.
Preliminary clinical trials have demonstrated the safety and efficacy of topical cenegermin in patients with moderate to severe neurotrophic keratitis; however, the clinical experience with this drug is still limited.
The most common adverse reaction of Cenegermin is eye pain following instillation, which was reported in approximately 16% of patients. Other adverse reactions occurring in 1-10% of patients included corneal deposits, foreign body sensation, ocular hyperemia. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies may not reflect the rates observed in practice.