The U.S. Food and Drug Administration approved the first drug, Oxervate (cenegermin), for the treatment of neurotrophic keratitis on August 22, 2018.
Oxervate received Orphan Drug Designation, Fast Track Status, and Breakthrough Therapy Designation, which led to Priority Review.
Oxervate represents the first-ever topical biologic medication approved in ophthalmology, and is the first ever application of a human nerve growth factor as drug or treatment.
Neurotrophic keratitis (NK) is a degenerative disease characterized by decreased corneal sensitivity and poor corneal healing. It results from impaired function of corneal nerves, which can be caused by herpetic or other infections, ocular surface injuries, ocular or neurologic surgeries, and some systemic conditions that can impair corneal sensation. If unchecked, the disease can progress in severity, leading to persistent epithelial defects, corneal ulcers, melting, perforation and vision loss.
Neurotrophic keratitis is classified as an orphan disease with an estimated prevalence of less than 5/10,000 individuals that affects fewer than 65,000 persons in the United States.
Neurotrophic keratitis is a challenging condition with high unmet medical need due to the lack of approved treatments that can restore corneal integrity. Current treatment options for neurotrophic keratitis were limited to symptomatic treatments, which do not target the underlying disease pathology. These include artificial tears, antibiotics, autologous serum-derived eye drops, tarsorrhaphy (a procedure in which the eyelids are partially sutured together) and botulinum-induced ptosis (closure of the eyelid). Other surgical interventions, designed to restore the integrity of the cornea, include conjunctival flap surgeries and corneal transplants, which are invasive and can compromise the appearance and function of the eye.
Cenegermin is a recombinant human nerve growth factor. The drug is based on cenegermin-bkbj, a novel recombinant human nerve growth factor (rhNGF) that is structurally identical to the nerve growth factor (NGF) protein that is made in the human body, including in the ocular tissues. The endogenous protein supports corneal integrity though several mechanisms. NGF acts directly on corneal epithelial cells to stimulate their growth and survival. In addition, NGF is known to bind receptors on lacrimal glands to promote tear production, which may provide the eye with lubrication and natural protection from pathogens and injury. The protein also has been shown experimentally to support corneal innervation, which is lost in neurotrophic keratitis.
The safety and efficacy of Oxervate, a topical eye drop containing cenegermin, was studied in a total of 151 patients with neurotrophic keratitis in two, eight-week, randomized controlled multi-center, double-masked studies. In the first study, patients were randomized into three different groups. One group received cenegermin, a second group received an eye drop with a different concentration of cenegermin, and the third group received an eye drop without cenegermin.
In the second study, patients were randomized into two groups. One group was treated with Oxervate eye drops and the other group was treated with an eye drop without cenegermin. All eye drops in both studies were given six times daily in the affected eye(s) for eight weeks. In the first study, only patients with the disease in one eye were enrolled, while in the second study, patients with the disease in both eyes were treated in both eyes (bilaterally).
Across both studies, complete corneal healing in eight weeks was demonstrated in 70-74 percent of patients treated with Oxervate compared to 28-43 percent of patients treated with vehicle. Results were statistically significant for Oxervate in both the studies at 8 weeks.
There was no statistically significant improvement in corneal lesion size, time to corneal healing, best-corrected distance visual acuity, corneal sensitivity and reflex testing although Oxervate treated patients exhibited greater improvement in all these parameters.
The most commonly reported adverse reactions in patients suffering from neurotrophic keratitis and treated with Oxervate during clinical studies include eye pain (11.1%), eye inflammation (8.3%), lacrimation (5.6%), eyelid pain (5.6%) and foreign body sensation in the eye (5.6%).
Patients considered completely healed at the end of 8 weeks of treatment with Oxervate did not tend to have recurrences within the 12 months follow-up period of study NGF0212. Specifically, more than 80 % of the 31 patients who were healed after initial Oxervate 20 µg/ml treatment and for whom a response was available, remained completely healed at the end of the 12 months follow up period.
People who were healed at week 8 but no longer healed at 32 or 56 weeks of the extended follow-ups of study NGF0212 and study NGF0214 were considered to have had a recurrence of neurotrophic keratitis. Recurrence rates at 32 weeks in the 2 studies varied from 0% to 3% in study NGF0212 and 0% to 14% in study NGF0214, depending on the arm to which people were originally randomised. At 56 weeks, recurrence rates were 3% to 5% in study NGF0212.
In both the studies the controlled follow-up period was short (8 weeks) and long term follow ups were performed for 56 weeks in study NGF0212 and for 32 weeks in study NGF0214. There is no clinical evidence to support the assumption that people who are completely healed at 1 year will remain healed for the rest of their lifetime, and that their disease is effectively cured. All the results of healing and recurrence discussed above were based on a small number of patients for whom response data were available. Also, there is a need to do a robust cost-effectiveness estimate for Oxervate compared with artificial tears that can help in QALY gained.
Many questions are still unanswered in management of neurotropic keratitis even after approval of Oxervate. Complete cure will remain a distant goal to achieve for current pipeline therapies. Long term healed cornea, low recurrence rate of disease, clinically and statistically significant data on corneal lesion size, time to corneal healing, best-corrected distance visual acuity, corneal sensitivity and reflex testing, and QALY gain as compared to current therapies are the new benchmark for pipeline therapies to achieve in future.
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