Neurotrophic keratitis landscape improving, yet many hurdles remain
Key takeaways:
- Oxervate, approved by the FDA in 2018, treats the underlying cause of neurotrophic keratitis.
- Other treatment options in development include gene therapies and deleted hepatocyte growth factor.
Neurotrophic keratitis is a relatively rare disease that can be difficult to manage, and treatment varies depending on disease stage.
In recent years, the development of Oxervate (cenegermin-bkbj ophthalmic solution 0.002%, Dompé U.S.) has transformed the treatment landscape, becoming one of the greatest advancements for patients with neurotrophic keratitis, according to Cory J. Lappin, OD, MS, FAAO, an optometrist at Phoenix Eye Care and the Dry Eye Center of Arizona.
Approved by the FDA in 2018, Oxervate is the first pharmaceutical therapy specifically indicated for the treatment of neurotrophic keratitis.
“What makes Oxervate unique is that it contains cenegermin-bkbj, a recombinant form of human nerve growth factor [NGF] which is responsible for repair and maintenance of corneal nerves. It also plays a role in corneal wound healing and routine epithelial cell maintenance,” Lappin told Healio. “Oxervate directly treats the underlying cause of neurotrophic keratitis by repairing the corneal nerves that are damaged in the disease.”
Other treatments
Other treatment options for neurotrophic keratitis are primarily aimed at stabilizing the condition and preventing progression, rather than treating the underlying cause.
“In mild cases, topical lubrication with preservative-free artificial tears and autologous serum tears are common treatments,” Lappin said. “Soft bandage contact lenses and amniotic membranes can also help stabilize the corneal surface, especially for stage 2 and stage 3 disease, in which patients experience persistent epithelial defects and ulcers.”
“Cryopreserved amniotic membranes, such as Prokera Slim (BioTissue), are especially helpful because they have anti-inflammatory and regenerative properties that help promote healing and prevent scarring, making their use beneficial at any stage of the disease.”
Regarding surgical treatments, Lappin said tarsorrhaphy may be implemented in more severe cases.
“For example, in the case of nonhealing ulcers, tarsorrhaphy is effective at stabilizing the corneal surface,” he said. “From a more restorative standpoint, we have corneal neurotization surgery where a healthy donor nerve is used to restore sensation of the cornea by surgically relocating the donor nerve to the cornea to take the place of damaged corneal nerves.”
In the pipeline
Other treatment options in the pipeline are in various stages of development and “represent a potential to improve our ability to treat neurotrophic keratitis,” Lappin said. “Each treatment is based around a novel therapeutic agent or a unique mechanism of action and some are targeting specific stages of the disease, including stage 1 disease.”
One that is furthest along in development is the nasal spray OC-01 (varenicline solution, Viatris) for stage 1 disease.
“The concept behind this treatment revolves around the fact that the lacrimal gland can secrete NGF and the use of this nasal spray is thought to enhance tearing from the lacrimal gland via stimulation of the trigeminal nerve, which may subsequently increase NGF production and promote healing of the cornea and nerves,” Lappin said.
In the preclinical arena, gene therapies are also being examined for stage 1 and stage 2 neurotrophic keratitis.
“In this setting, investigators are examining the use of an Enriched Tear Film Gene Therapy platform,” Lappin said. “OC-101 AAV-NGF (Viatris) utilizes adeno-associated virus vectors to deliver genes responsible for NGF production into the lacrimal gland, which theoretically upregulates NGF production through an intra-lacrimal gland injection.”
Another treatment under investigation is RGN-259 (RegeneRx).
“This treatment uses a topical form of thymosin beta-4, which improves tissue healing and regeneration through the promotion of cell migration and anti-inflammatory properties,” Lappin said. “Last but not least, Claris Biotherapeutics is investigating CSB-001, which uses a deleted form of hepatocyte growth factor that is antifibrotic, anti-inflammatory, neurotrophic, and also enhances corneal wound healing.”
Challenges
Despite the many advancements, challenges remain.
“One of the biggest issues in neurotrophic keratitis is that most treatments are primarily supportive in nature rather than restorative,” Lappin said. “Oxervate is the only pharmaceutical option that will address the underlying cause of neurotrophic keratitis, and corneal neurotization is the only surgical procedure that actually restores function. The only issue there is that the surgical procedure is very invasive and finding access to a surgeon who is capable of performing the surgery can be challenging.”
The pathophysiology of the disease itself is yet another challenge.
“Corneal nerves are responsible for many different functions of the ocular surface — they provide sensation to the cornea, maintain routine epithelial cell turnover, promote wound healing, and control blinking and lacrimation,” Lappin said. “One of the major obstacles in treating neurotrophic keratitis is once there is damage to the corneal nerves, there is impairment of those vital functions, which creates a significant disruption to the ocular surface. Most of these treatments are supportive and only stabilize the surface.”
Essentially, these treatments aim to promote healing in a condition in which the cornea has innately lost the ability to do so, he added.
“This is one of the reasons why neurotrophic ulcers are notoriously hard to treat because the cornea has lost the ability to repair these wounds or even promote regular epithelial cell maintenance and turnover,” Lappin said. “These patients experience interrupted blinking and tearing, which makes their ocular surface environment even less conducive to healing. The condition fights us every step of the way when trying to treat it.
“Because most treatments are aimed at stabilizing the ocular surface, once we stop treatment, many patients experience regression. Similarly, even though some of the surgical procedures, such as tarsorrhaphy or a conjunctival flap, may stabilize severe cases, once the procedures have been reversed, the condition often regresses again.”
Research underway
Research is now underway examining NGF as one of the main therapeutics for neurotrophic keratitis and long-term outcomes associated with it.
“We do have studies that have shown that about 80% of patients with stage 2 and stage 3 neurotrophic keratitis have maintained healing nearly 1 year after use of Oxervate,” Lappin said. “However, considering it is still a relatively new drug, we still do not have a lot of long-term data.
“In my personal experience, I have seen patients who have displayed significant improvement while on Oxervate, but once they discontinue treatment, they have regression and even after a second course they display the exact same pattern. I would like to see more research looking at whether there is a subset of patients that actually require long-term use of NGF to maintain sustained healing and function.”
Still, the treatment landscape for neurotrophic keratitis has come a long way, he said.
“A big part of that is the approval of Oxervate, mainly because neurotrophic keratitis has always been considered a very rare condition,” Lappin said. “Now that we have an effective treatment option for the disease, more eyecare providers are looking for it and we are finding it might not be as rare as we once thought.”
In addition, a larger focus is now on the health of the corneal nerves in general.
“As time goes on and we learn more about treating neurotrophic keratitis, we are likely going to find that there is broader implication of corneal neuropathy besides this one specific presentation of the disease, because the corneal nerves have so many different functions within the context of ocular surface homeostasis,” he said. “We might even come to learn that these nerves are implicated in dry eye and ocular surface disease more broadly. Treatments that were initially indicated specifically for neurotrophic keratitis might have utility in treatment of dry eye and ocular surface disease in general.
“With all of these treatment advancements in the development pipeline, we will continue to improve our ability to treat neurotrophic keratitis. We are getting better, but we still have many hurdles to overcome.”
For more information:
Cory J. Lappin, OD, MS, FAAO, can be reached at lappin@phxeyecare.com.
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