Eye drops containing a novel recombinant human nerve growth factor can now be used in U.S. patients to treat neurotrophic keratitis, a rare disease for which no treatment was previously available.
“It is a breakthrough therapy for a degenerative disease that is rare but eventually leads to loss of vision if untreated. Now that we have this new option available, doctors need to be aware of this condition, learn to recognize it and treat it early,” Healio/OSN Board Member Kenneth A. Beckman, MD, said.
Neurotrophic keratitis results from the impairment of corneal sensory innervation, leading to progressive loss of corneal sensitivity. Stage 1 is characterized by the classic signs and symptoms of dry eye, and the epithelium starts to break down showing presence of punctate erosion. At stage 2, the disease progresses to frank epithelial defect, and at stage 3, stromal ulceration thinning and perforation may occur.
Oxervate (cenegermin-bkbj, Dompé) was approved in the United States for stage 1, 2 and 3 neurotrophic keratitis, while in Europe it is approved for only stage 2 and 3.
“I like the fact that we can use it at stage 1 because these patients need to be treated early and aggressively to avoid progressing at the later stages,” Beckman said.
Differentiating neurotrophic keratitis from other conditions with similar symptoms is important so that the treatment is administered selectively and wisely.
“If you have a patient with damaged epithelium, you want to make sure it is not just dry eye or the toxic effects of drugs like glaucoma medications. You want to check on possible anatomic issues, such as poor blink, which is frequent in patients with Parkinson’s disease, for instance,” Beckman said.
Checking corneal sensation is key to determine whether the cornea is neurotrophic. If an esthesiometer is not available in the clinic, a simple cotton-tipped applicator or a rolled-up paper tissue are sufficiently good methods.
“If the cornea is neurotrophic, you have to heal not just the defect, but also the underlying problem or else the defect is going to recur,” Beckman said. “Over the years, I have seen patients treated with tarsorrhaphy who seemed to do well, but the defect recurred as soon as the tarsorrhaphy was taken down.”
If a significant loss of sensation is observed, prompt and aggressive treatment is needed.
“While I may try also other methods, such as bandage contact lens, punctal plug and amniotic membrane, I would be very proactive in giving Oxervate as early as possible,” he said.
Eight weeks to regenerate nerves
Nerve growth factor (NGF) is a signaling protein discovered by Nobel laureate Rita Levi-Montalcini in the 1950s.
“It allows the eye, by having sensation, to blink when you need to and to produce tears to wash away any environmental insult. With a neurotrophic cornea, you lose those protective reflexes. In addition, the NGF is critical for epithelial healing, as it stimulates epithelium proliferation and growth to heal the surface. If this system no longer works, the eye cannot protect itself and cannot heal,” Mark S. Milner, MD, said.
The recombinant NGF cenegermin promotes nerve regeneration and sensation, thus reestablishing epithelial healing and tear production.
“We treated patients who had multiple other therapies that did not resolve, and cenegermin really helped those patients to heal, to regain corneal sensation and to maintain it over time,” Milner said.
Since FDA approval of cenegermin in August 2018, Milner has administered the drug in several patients, two in combination with amniotic membrane.
Pivotal trials suggest that treatment should be administered for 8 weeks, even in cases that appear to heal earlier.
“One of my patients healed by 3 weeks, but we kept him on for 8 weeks because the surface heals earlier but we want to promote nerve regeneration in the deeper layers. Studies with confocal microscopy show a progressive increase in nerve density over the entire course of the treatment,” he said.
Pain is a positive sign
Eye discomfort and pain may occur during the treatment as symptoms of recovered corneal sensation. It is important to inform patients that these are positive signs and are transient.
“The majority of my patients report tolerable discomfort, but one or two reported pain at some point. Some took a short break when they skipped a day or used the drops less frequently for a couple of days. Supplementing the treatment with lubricants helps, but I would discourage the use of corticosteroids. Systemic management of the pain is a possibility and also gabapentin or even tricyclic antidepressants. You may work at this with the neurologist or primary care physician,” Beckman said.
Neurotrophic keratitis is an orphan, rare disease, seen more commonly in referral corneal practices. For this reason, Beckman was able to see and treat a relatively high number of patients with this condition. About a dozen have completed the 8-week course, and most of them are doing well. Two patients had to go on to a second course, one because of delayed healing and the other because of recurrence.
Obtaining the drug and having the cost covered by insurance are straightforward, Beckman said.
“Dompé has an excellent patient support program in the U.S. They provide the forms you need to fill out and have a hotline you can contact to make the arrangements. Typically, this is sufficient to obtain coverage by the patient’s insurance, but if it is not, the company has an appeal process and patients get the product for usually a low copay of no more than $100 for the entire course. The cost is very high for the complete course, and patients are not paying anything or very little,” Beckman said.
The processing time from signing the application to obtaining the treatment is usually 2 weeks, during which whatever treatment was used previously can be maintained.
“There is a lack of familiarity with the disease and with the product, but now doctors are being educated more on what to look for and who is a good candidate to treat, and we will start to see and treat more patients,” he said.
A practice that is interested in knowing more and adopting this treatment can contact Dompé.
“Once I had them in my office, they showed us how to train the patient to use the product and how to apply to the insurance. The company has set up a system that is really helpful and easy to work with,” Beckman said. – by Michela Cimberle
Disclosures: Beckman and Milner report they are consultants for Dompé.
This content was originally published here.