Neurotrophic Keratitis: Early Intervention is Key

As optometrists familiarize themselves with methods of testing for and diagnosing neurotrophic keratitis (NK), so too must they understand how intervention—particularly early intervention^1,2—may prevent disease progression. Approval of OXERVATE® (cenegermin-bkbj) ophthalmic solution 0.002% (20 mcg/mL) (Dompé U.S. Inc. [“Dompé”]) by the US FDA for the treatment of NK³represents the most recent era of care for patients affected by this disease. If NK, a corneal disease caused by impairment of trigeminal innervation, is untreated, it may lead to corneal ulceration, melting, perforation,¹ and, potentially, vision loss.²

In March 2021, Scott Schachter, OD, FBCLA, moderated a roundtable discussion with Lauren McLoughlin, OD; Tim Poirier, OD; Justin Schweitzer, OD, FAAO; and Walt Whitley, OD, MBA, FAAO, to review their strategies and tactics for diagnosing and treating NK. The expert panel discussed the utility of stratifying disease, methods of corneal sensitivity testing, and how the adoption of OXERVATE in their practices has affected outcomes for early-stage patients.

PRESENTATION OF NK IN THE OPTOMETRIC CLINIC

Scott Schachter, OD, FBCLA: Tracking the exact prevalence of NK has been a challenge. Prevalence is estimated at fewer than 65,000 patients in the US.¹ Over the last few years, awareness of NK has increased, and I’m seeing it more often in my practice than before.

Justin Schweitzer, OD, FAAO: Now that we have a better understanding of the signs, symptoms, and risk factors for NK, I am detecting and treating it earlier and at a greater rate. The literature tells us that history of herpetic keratitis, herpes zoster keratitis, and many other conditions we are going to discuss today are risk factors for developing NK.⁴ Since I have begun looking for NK more closely, I have also found that patients with a history of chronic dry eye disease (DED) are presenting with NK.^5,6

Walt Whitley, OD, MBA, FAAO: A vast majority of patients in my clinic with NK also have DED. The literature, and my experience, have shown that diabetes is a common cause of NK.⁴ I have seen multiple patients who report no symptoms but present with impaired corneal innervation, which is a good reminder of the value of corneal sensitivity testing (CST).

Dr. Schachter: It is incumbent upon us to educate about the relationship between comorbidities and NK. Dr. McLoughlin, have you noticed any other comorbidities in patients who present with NK?

Lauren McLoughlin, OD: Patients with glaucoma are a patient population that is easy to overlook when evaluating NK. Patients with glaucoma who have been on prolonged drop regimens are often referred to me for further evaluation. When performing CST during my examination, I sometimes find evidence of impaired trigeminal innervation and the subsequent lack of corneal sensation, which suggests that the patient may have NK. I rely on CST to screen for NK in most of the patients with glaucoma who are referred to me.

Tim Poirier, OD: Dr. McLoughlin brings up a good point: the more we know about the relationship between comorbidities and NK, the more we screen for it and the more cases we find. I began testing for NK in patients who have had cataract or refractive surgery after learning that a history of ocular surgery is linked with NK risk.⁶ The number of patients I identified as having NK among that population has surprised me.

Dr. Schachter: Do you weigh the risk of progression in early-stage NK patients?

Dr. McLoughlin: To me, the presence of NK itself is risky. When I determine that a patient has any stage of NK, I get them started on treatment as soon as possible. Rather than wait for a patient’s disease to progress to the point that their condition significantly worsens, I prefer to help them early.

Dr. Whitley: It’s important to remember that NK is a degenerative disease. Without appropriate treatment, NK can progress. I’m identifying more patients now that I know more about what to look for. I’m treating more, too.^1,2

Key Insight

Justin Schweitzer, OD, FAAO
Sioux Falls, South Dakota

Patient history is important when assessing the risk that an early stage NK patient may progress. Patients in my office whose clinical examination leads to a diagnosis of stage 1 NK, who I believe to be at higher risk of progression, often have a history of chronic contact lens wear, lid surgery, or a systemic disease such as diabetes.

PATIENT HISTORY AND CORNEAL SENSITIVITY TESTING

Dr. Schachter: Gathering patient history is one of the most important elements of a clinical evaluation. Dr. Schweitzer, what elements of patient history do you gather from patients who might have NK?

Dr. Schweitzer: Patient history is critical for proper diagnosis and guiding optometric treatment decisions. Systemically, I want to know if they have a history of diabetes or multiple sclerosis and, if so, how long it has been since they were first diagnosed with a systemic disease. Surgically, I investigate history related to lid, cataract, or refractive surgery. When it comes to ocular history, I gather information related to herpes simplex or herpes zoster infection, contact lens wear patterns, and history of DED. I will also inquire about the efficacy and duration of topical drops for DED. I am interested in knowing how drops, particularly prescription drops like cyclosporine, worked in a patient with DED.

Dr. Schachter: Some patients with DED are in my clinic often, as their disease has not responded to therapy and may be complicated by NK. Diagnosing NK in patients with DED is a unique challenge we face.

Dr. Schweitzer: That’s not to say that most patients with ocular surface disease have NK, but I have found in my practice that most of my patients with NK have ocular surface disease.⁴

Dr. McLoughlin: DED sometimes complicates diagnosis of NK⁶ because, as Dr. Schweitzer noted, the overlap of ocular surface disease and NK may be significant in some practices. When DED patients return to my office after a cycle of prescription drops has been ineffective, particularly if they have superficial punctate keratitis (SPK), I begin to suspect that NK is present. I perform CST in these patients to diagnose or rule out NK.

Dr. Poirier: History is important, and a clinical examination can help confirm or rule out NK. I perform CST on all patients in whom I suspect NK may be present. The most common etiologies I see include a history of ocular surface disease, diabetes, refractive surgery, and herpes keratitis (Table 1).

Dr. Schachter: Let’s take a moment to discuss the logistics of CST. How do you perform CST? Personally, I apply the tip of a cotton swab to the cornea and rely on my experience to determine if the patient has reacted. If they don’t notice that I’ve touched their cornea, then I am confident that the patient has impaired innervation.^1,6

Dr. Poirier: Instead of a cotton swab, I use the end of a rolled tissue. This is very quick and easy, as I have a box of tissues in all my lanes.

Dr. McLoughlin: Checking all quadrants of the cornea as well as the central cornea is crucial to a thorough test.

Dr. Whitley: Keeping CST as easy as possible is key to adding it seamlessly into your clinical workup. I classify corneal sensitivity into three categories: present, reduced, or absent.

Key Insight

Tim Poirier, OD
Raleigh, North Carolina

I do not think there’s an easier test we can do that gives us so much information. CST is very easy to incorporate into your clinical routine. No new equipment is needed. You already have cotton swabs and tissues. All you need to do is modify your practice patterns and perform a quick check of corneal sensitivity.

Dr. Schachter: Dr. Whitley is wise to point out that a smooth integration of CST into your routine is key. What pearls do you have for including CST in your examination?

Dr. Whitley: I’ve found it key to inform my staff that a patient should not have any numbing drops instilled prior to an evaluation that may include CST.

Dr. Schweitzer: That’s a very important point. Communication with your practice’s technicians is key to success on that front. We should mention to them that proparacaine or tetracaine should not be used prior to an examination of a suspected NK patient, as doing so will make CST inconclusive and you may need to ask the patient to return to the clinic for a CST evaluation.

Dr. Schachter: What other means of detecting NK are important?

Dr. Schweitzer: I am a big believer in vital dyes. I use fluorescein and lissamine green in my practice to determine if patients fall into the ‘stain without pain’ category. I feel like our field should not underutilize vital dyes as they’re a useful tool that we should employ often.⁶

STAGING NK AND EARLY INTERVENTION

Dr. Schachter: Based on discussions with this group, I know that everyone on this panel uses the Mackie Classification to stage severity of disease in patients with NK. (See Table 2 for more details). Do you treat patients strictly based on how they fit into the Mackie Classification?

Dr. Poirier: Early intervention is key. In my practice, I have found that treating patients early will make their disease easier to manage.⁶ For comparison, we don’t wait for optic nerves to become cupped before starting treatment for glaucoma. Using that same mindset, if we can keep stage 1 NK patients from progressing to stage 2 or stage 3, then we are taking the best possible care of our patients.

Dr. McLoughlin: I take a similar approach to Dr. Poirier. It’s much more difficult to treat a stage 3 case of NK than it is to address a stage 1 case early.⁶ In addition to the Mackie Classification, I consider underlying patient comorbidities when weighing risk stratification.

Dr. Schachter: Interventions for NK included use of preservative-free artificial tears, bandage contact lenses, steroid or NSAID eye drops, autologous serum eye drops, and application of amniotic membranes.

Early Intervention with OXERVATE: Breakthrough Therapy for NK

Treating Early With Oxervate

Dr. Schachter: Adoption of OXERVATE® (cenegermin-bkbj) ophthalmic solution 0.002% (20 mcg/mL) should encourage optometrists to have a better understanding of the relationship between corneal nerves and the epithelium. OXERVATE is the first FDA-approved pharmacologic treatment that targets the root pathogenesis of NK and is approved for all stages of NK for patients 2 years of age and older.³

Cenegermin-bkbj, the active ingredient in FDA-approved OXERVATE, is structurally identical to the human nerve growth factor (NGF) protein made in ocular tissues. Endogenous NGF is a protein involved in the differentiation and maintenance of neurons and is believed to support corneal integrity through three mechanisms (in preclinical models): corneal innervation, tear secretion, and epithelial cell growth.^1,5,7,8

Two clinical trials enrolled the largest combined population of NK patients ever examined in randomized controlled trials.³ In the REPARO (NGF0212) trial, 72% of patients receiving OXERVATE, compared to 33.3% receiving vehicle, achieved complete corneal healing at week 8.² In the NGF0214 trial, 65% of patients receiving OXERVATE had complete corneal healing compared to 16.7% of vehicle-treated patients.⁹ Complete corneal healing was defined as 0 mm staining in the lesion area and no persistent staining in the rest of the cornea.^2,9

Importantly, 80% of patients who achieved complete corneal healing in the REPARO trial were still completely healed 48 weeks after one 8-week course of OXERVATE.^2,10

As for side effects, the most common was eye pain following instillation (16%).³ Other adverse reactions, occurring in 1 to 10% of patients, were corneal deposits, foreign body sensation, ocular hyperemia, ocular inflammation, and tearing.³ There was no evidence of systemic absorption or immunogenicity in clinical trials.³

Dr. Schachter: Although alternative therapies can be effective at times, OXERVATE® (cenegermin-bkbj) ophthalmic solution 0.002% (20 mcg/mL) has been one of my interventions of choice since I started orienting part of my practice around NK detection and treatment. What will it take for optometry to begin considering OXERVATE as an intervention earlier in the treatment paradigm?

Dr. Poirier: Understanding why OXERVATE is such an evolution in our field will be key to adoption. Previous treatments for NK mainly addressed signs and symptoms.⁸ Although this is important for patient comfort, it limited our efficacy as clinicians. Before OXERVATE approval, I felt like I was only able to pat patients on the back and give them some words of encouragement as we treated them with palliative options. Now, with OXERVATE, I am able to actually target the root pathogenesis of their disease.

Dr. Whitley: Anyone who is learning more about NK will benefit from having photos that illustrate stage 1 disease, as diagnosing NK early can be a challenge. Photographs assisted me as I refined my knowledge of NK and are useful tools in educating my patients about their condition.

Dr. Schweitzer: I assume many clinicians have had my relationship with NK, which is that before OXERVATE, I was treating persistent SPK and DED, but neurotrophic keratitis was not at the top of my list. In many of these patients, disease recalcitrance led to irritated patients. Now that I screen more often for NK, I find that treating NK patients with OXERVATE is leading to complete corneal healing in most patients. When our colleagues who face similar frustrations learn about how effective OXERVATE is, I hope they will begin to adopt it as a treatment option for patients with NK.

Dr. McLoughlin: I realize with hindsight that I, too, was only treating persistent SPK.

Dr. Schachter: In which types of patients do you use OXERVATE therapy for early intervention?

Dr. Schweitzer: In patients with stage 1 NK, presence of systemic disease or some other confounding factor pushes me toward early intervention with OXERVATE. However, if a patient with stage 1 NK is not a contact lens wearer, has no history of herpetic infection, and has an otherwise healthy profile, I am likely to try traditional therapies first for the management of NK.

Key Insight

Scott Schachter, OD, FBCLA
Pismo Beach, California

We’re often tasked with treating patients for their lifetime when it comes to some ocular conditions. The beauty of OXERVATE is that we can now treat NK patients with a single 8-week course of therapy. Optometrists are in a unique position to identify NK early and improve the prognosis for a potentially debilitating disease.

Dr. Schachter: I also am likely to begin OXERVATE therapy in a patient with stage 1 NK if diabetes or herpetic infection is present, or if they have recalcitrant ocular surface disease after being treated with more traditional therapies. I have had success with many of my stage 1 patients with OXERVATE.

Dr. Poirier: I consider therapy with OXERVATE in all patients I diagnose with NK.

Dr. Schachter: Now, let’s take a look at some real-world cases from the panelists’ experience treating with OXERVATE.

CASE No. 1: Stage 1 NK

Dr. Schweitzer: An 82-year-old male patient with poorly controlled diabetes that was not responding to conventional therapies for ocular surface disease presented to the clinic. This patient was referred for a chief complaint of reduced visual acuity in his left eye. The patient’s history showed chronic dry eye disease for an extended period of time, long-term drops for his mild primary open-angle glaucoma (diagnosed in 2000), pseudophakia, cataract surgery, and blepharoplasty. He was previously treated with cyclosporine and multiple thermal pulsation treatments without any improvement.

Dr. Schachter: Given the patient’s history of poorly controlled diabetes and his decades-long use of glaucoma medications, I would suspect this patient had NK.

Dr. Schweitzer: I thought the same, and I performed CST with a cotton swab. The patient had zero response to the cotton swab. I observed SPK without a persistent epithelial defect leading me to diagnose this patient with stage 1 NK. Then I prescribed OXERVATE.

Key Insight

Lauren McLoughlin, OD
Portsmouth, New Hampshire

Starting therapy with OXERVATE in a patient with stage 1 NK is much easier than trying to treat a patient who has reached stage 2 or 3 disease.⁶ Rather than waiting for disease to progress and then treating it, help your patients in their earliest stages of disease so that they can avoid complications down the line.⁶ As soon as I flag a patient with even mild (stage 1) NK, I get them started on OXERVATE therapy because I find it much harder to backpedal if the patient progresses.

Dr. McLoughlin: What factors did you weigh when deciding to start this patient on OXERVATE® (cenegermin-bkbj) ophthalmic solution 0.002% (20 mcg/mL) versus other therapies for NK management?

Dr. Schweitzer: Poorly controlled diabetes, chronic recalcitrant DED, 20-year use of prostaglandin analogues, and a history of ocular surgeries were all important elements discovered during the medical history assessment that factored into my decision to use OXERVATE for stage 1 NK (Figure 1A).

Dr. Schachter: How did the patient respond to OXERVATE therapy?

Dr. Schweitzer: As prescribed, he applied 1 drop every 2 hours 6 times per day for 8 weeks to his affected eye. After 4 weeks of OXERVATE therapy, the patient’s SPK showed signs of resolving (Figure 1B). At week 8 there were some punctate epithelial erosions observed, but they were much improved from baseline (Figure 1C), and further resolution was observed after week 8.

Without OXERVATE therapy, this patient would have continued to be treated with palliative therapies. Instead, we performed CST, diagnosed him, and chose a treatment that targets the root pathogenesis of the patient’s disease.

CASE No. 2: Stage 1 NK

Dr. Schachter: I recently saw a young woman, 25 years old, with a history of chronic contact lens use. She had worn ortho-K lenses during her high school years, about 5 years prior. She had a persistent SPK, and we went through all of the traditional treatments. She did not have many complaints, but I didn’t like the way her cornea looked. Despite everything I did, I could not get her corneal surface to look better.

Key Insight

Walt Whitley, OD, MBA, FAAO
Norfolk, Virginia

As my awareness of NK increased, I began to reevaluate my dry eye disease recalcitrant patients with a better understanding of the NK disease state. Patient history and corneal sensitivity testing were key assessments that allowed me to diagnose these patients with NK.

Dr. Whitley: What was your turning point in realizing you’ve got an NK patient?

Dr. Schachter: During the course of an examination, I was going to put in dilating drops and told her they might sting a little. She made a comment to me that was so striking. She said, “I won’t feel it. I don’t feel anything in that eye ever.” So, before I put the drops in, I performed corneal sensitivity testing with a cotton swab, and she had no sensitivity.

I found decreased sensitivity in both eyes. The left eye we continued to treat with conventional methods, but there was persistent SPK in the right eye. We diagnosed her as stage 1 at the time.

Dr. Whitley: What were some of the deciding factors in this case that pushed you toward intervention with OXERVATE?

Dr. Schachter: There was nothing remarkable in her health history, but she spends a lot of time on the computer, and she has mild MGD. I had been treating her for that, and she now wears a soft contact lens. She had also been on cyclosporine, steroid ophthalmic solution, AT, advanced eyelid gel, and daily SCLs.

We put her on OXERVATE® (cenegermin-bkbj) ophthalmic solution 0.002% (20 mcg/mL). At week four, we saw a big improvement. When I saw her back at 8 weeks, her cornea was completely healed.

We would not typically be thinking about a 25-year-old woman that’s healthy as potentially suffering from NK. Although this patient did not have many complaints, she did have fluctuating vision. If a patient has symptoms, don’t rule them out.

ACCESS TO CARE

Dr. Schachter: Before we conclude our roundtable, we should consider that access to care can be a challenge for some patients. Because OXERVATE is a biologic, the process for prescribing it may be more involved than other medications and requires a prior authorization. What pearls do you have to make the process go smoothly?

Dr. Poirier: As soon as I identify a patient who could benefit from OXERVATE, I ask a technician to join the patient and me in the lane with the proper paperwork to begin the enrollment process. Technicians are the champions of this process, as they focus on the details to make sure it flows as smoothly as possible. For example, my technician is tasked with ensuring that all required signatures, including the patient’s signature, are acquired before the prescription process can move forward.

Dr. Whitley: The Dompé CONNECT to Care program helps facilitate the process for patients and offices through a single point of contact, and I find that the service is effective. The program has been very helpful in supporting the process to access OXERVATE for patients.

Dr. Schachter: I agree. Dompé CONNECT to Care is comprehensive and supports the patient with benefits verifications, financial resources, and delivery coordination. I usually tell my patients with commercial insurance that they are not likely to pay more than $100 out of pocket for a single 8-week course of therapy, as they may qualify for financial assistance through the program.

Dr. Schweitzer: I was skeptical that the CONNECT to Care program would make prescribing OXERVATE easier for the practice and the patient, but the program has proven to be effective and relatively easy. Like Dr. Poirier, we have a designated technician who serves as our OXERVATE champion and fully understands the Dompé CONNECT to Care process. This has increased our efficiency greatly.

Dr. Schachter: Programs like this are key to helping patient access and office support for important medications like OXERVATE. With the support Dompé provides, it makes it easier for patients to acquire and benefit from this pharmacological innovation.

Important Safety Information

Contact lenses should be removed before applying OXERVATE® because the presence of a contact lens (either therapeutic or corrective) could theoretically limit the distribution of cenegermin-bkbj onto the area of the corneal lesion. Lenses may be reinserted 15 minutes after administration.

OXERVATE may cause mild to moderate eye discomfort such as eye pain during treatment. The patient should be advised to contact their doctor if a more serious eye reaction occurs.

The most common adverse reaction in clinical trials that occurred more frequently with OXERVATE was eye pain (16% of patients). Adverse reactions included corneal deposits, foreign body sensations in the eye, ocular hyperemia (enlarged blood vessels in the white of the eyes), swelling (inflammation) of the eye, and increase of tears (1-10% of patients).

WHAT IS OXERVATE™?

OXERVATE™ (cenegermin-bkbj) ophthalmic solution 0.002% is indicated for the treatment of neurotrophic keratitis.

DOSAGE FORMS AND STRENGTHS

Ophthalmic solution for topical use in the eye: cenegermin-bkbj 0.002% (20 mcg/mL) is a clear, colorless solution in a multiple-dose vial.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Use With Contact Lenses

Contact lenses should be removed before applying OXERVATE because the presence of a contact lens (either therapeutic or corrective) could theoretically limit the distribution of cenegermin-bkbj onto the area of the corneal lesion. Lenses may be reinserted 15 minutes after administration.

Eye Discomfort

OXERVATE may cause mild to moderate eye discomfort such as eye pain during treatment. The patient should be advised to contact their doctor if a more serious eye reaction occurs.

ADVERSE REACTIONS

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be compared directly to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In 2 clinical trials of patients with neurotrophic keratitis, a total of 101 patients received cenegermin-bkbj eye drops at 20 mcg/mL at a frequency of 6 times daily in the affected eye(s) for a duration of 8 weeks. The mean age of the population was 61 to 65 years of age (18 to 95).

The most common adverse reaction in clinical trials that occurred more frequently with OXERVATE was eye pain (16% of patients). Other adverse reactions included corneal deposits, foreign body sensation in the eye, ocular hyperemia (enlarged blood vessels in the white of the eye), swelling (inflammation) of the eye, and increase in tears (1%-10% of patients).

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

There are no data from the use of OXERVATE in pregnant women to inform any drug-associated risks.

Administration of cenegermin-bkbj to pregnant rats or rabbits during the period of organogenesis did not produce adverse fetal effects at clinically relevant doses. In a pre- and postnatal development study, administration of cenegermin-bkbj to pregnant rats throughout gestation and lactation did not produce adverse effects in offspring at clinically relevant doses.

Data

Animal Data

In embryofetal development studies, daily subcutaneous administration of cenegermin-bkbj to pregnant rats and rabbits throughout the period of organogenesis produced a slight increase in postimplantation loss at doses greater than or equal to 42 mcg/kg/day (267 times the maximum recommended human ophthalmic dose [MRHOD]). A no-observed-adverse-effect level (NOAEL) was not established for postimplantation loss in either species. In rats, hydrocephaly and ureter anomalies were observed once each in fetuses at 267 mcg/kg/day (1709 times the MRHOD). In rabbits, cardiovascular malformations, including ventricular and atrial septal defects, enlarged heart, and aortic arch dilation, were observed once each in fetuses at 83 mcg/kg/day (534 times the MRHOD). No fetal malformations were observed in rats and rabbits at doses of 133 mcg/kg/day and 42 mcg/kg/day, respectively.

In a pre- and postnatal development study, daily subcutaneous administration of cenegermin-bkbj to pregnant rats during the period of organogenesis and lactation did not affect parturition and was not associated with adverse toxicity in offspring at doses up to 267 mcg/kg/day.

In parental rats and rabbits, an immunogenic response to  cenegermin-bkbj  was observed. Given that cenegermin-bkbj is a heterologous protein in animals, this response may not be relevant to humans.

Lactation

Risk Summary

There are no data on the presence of OXERVATE in human milk, the effects on breastfed infants, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OXERVATE and with any potential adverse effects on the breastfed infant.

Pediatric Use

The safety and effectiveness of OXERVATE have been established in the pediatric population. Use of OXERVATE in pediatric patients 2 years of age and older is supported by evidence from adequate and well-controlled trials of OXERVATE in adults with additional safety data in children.

Geriatric Use

Of the total number of subjects in clinical studies of OXERVATE, 43.5% were 65 years old and older. No overall differences in safety or effectiveness were observed between elderly and younger adult patients.

The risk information provided here is not comprehensive. To learn more, talk about OXERVATE with your health care provider or pharmacist.

For additional information and full prescribing information, go to www.oxervate.com. To report SUSPECTED ADVERSE REACTIONS, contact Dompé U.S. Inc. at 1-833-366-7387 or FDA at 1-800-FDA-1088 or www.fda.gov./medwatch

US-OXE-2100102 09/21