New era for rare corneal disorder

Reviewed by Stephen C. Pflugfelder, MD

The FDA approval of topical cenegermin (Oxervate, Dompé Farmaceutici SpA) for the treatment of moderate-to-severe neurotrophic keratitis (NK) last month represents a breakthrough for management of a disease that has been a frustrating problem for clinicians and devastating condition for patients.

Cenegermin, a recombinant form of human nerve growth factor (hNGF), was granted marketing authorization by the European Medicines Agency in July 2017.

“Topical cenegermin may represent a paradigm shift in the treatment of neurotrophic keratitis, a sight-threatening condition that has been treated with a variety of non-validated therapies with varying success,” said Stephen C. Pflugfelder, MD, an investigator in the cenegermin clinical trial.

“The clinical trial results for topical cenegermin showed that it was associated with statistically significant and clinically meaningful healing of neurotrophic keratitis due to different etiologies,” said Dr. Pflugfelder, professor and director of the ocular surface and the James and Margaret Elkins Chair, Department of Ophthalmology, Baylor College of Medicine, Houston.

It is the first FDA-approved therapy for this condition, and the evidence suggests that it will improve treatment outcomes and reduce the need for corneal transplantation, which has a high failure rate in these eyes, he added.

“Neurotrophic keratitis has been a real treatment challenge,” said Flavio Mantelli, MD, PhD, chief medical officer–biotech, Dompé Farmaceutici, Milan, Italy, and a trained cornea specialist

“Because affected patients lack corneal sensitivity, they cannot feel if their condition is worsening, and so they need frequent followup visits with their ophthalmologist,” said Dr. Mantelli, adjunct associate professor of biology, Temple University School of Medicine, Philadelphia. “Furthermore, the only intervention that could be offered to these patients were measures to protect the cornea and try to delay the course of this progressive condition.”

In refractory cases and advanced disease stages, interventions include tarsorraphy, amniotic membrane transplantation, and creation of a conjunctival flap, but these measures are not very acceptable to patients because they are invasive and disfiguring, he said.

“Results from two randomized, masked controlled clinical trials show that cenegermin is safe, well-tolerated, and significantly more effective than vehicle for restoring corneal epithelial integrity in eyes with stage 2 (moderate, persistent epithelial defect) or stage 3 (severe, corneal ulcer) NK. We believe evidence shows this biotechnology product targets the mechanisms of disease development and progression, and the FDA decision gives clinicians a valuable tool for addressing a truly unmet need.”

Topical cenegermin is formulated as a preservative-free preparation. The active ingredient is derived from Escherichia coli engineered with human genes to express a protein that is structurally identical to hNGF.

The rationale for using cenegermin for NK is based on understanding of the etiology of NK and the multiple biological activities of NGF. NK develops in association with conditions that impair corneal innervation. Consequently, there is loss of trophic support and corneal sensitivity that in turn leads to reduced blinking and tear production. These conditions set up a vicious detrimental cycle leading to disease progression

NGF, which is deficient in eyes with NK, has important roles for maintaining corneal homeostasis and promoting healing. “NGF is believed to promote corneal healing directly by stimulating the proliferation and differentiation of corneal epithelial cells,” Dr. Mantelli said.

In addition, NGF is known to bind receptors on lacrimal glands to promote tear secretion, which may provide the eye with lubrication and natural protection from pathogens and injury. The protein also has been shown experimentally to trigger corneal reinnervation, potentially targeting the root cause of NK.

“Through NGF’s known mechanisms of action (promoting the epithelial healing process, corneal nerve innervation, and tear production), treatment with cenegermin may break the detrimental loop that leads to NK progression,” Dr. Mantelli said.

Clinical trial evidence

Cenegermin is a form of human nerve growth factor (rhNGF) produced in E. coli and developed by Dompé Farmaceutici (Italy).

After results of a phase I study demonstrated the safety and tolerability of topical rhNGF/cenegermin in healthy individuals, a phase I/II trial, known as REPARO (Latin for “repair”), enrolled patients with NK across a combined total of 32 centers in 6 European countries.

Two articles reporting separately on the phase I and phase II segments of the study have been published jointly in the September 2018 issue of Ophthalmology [Bonini S, et al. Ophthalmology. 2018 Apr 10. pii: S0161-6420(17)33805-8. Bonini S, et al. Ophthalmology. 2018 April 10. pii: S0161-6420(17)31993-0.].

Patients were eligible for REPARO if they were adults with stage 2 or 3 NK affecting one eye only, showed no objective evidence of improvement in the lesion during the prior 2 weeks, and had decreased corneal sensitivity (<40 mm by Cochet-Bonnet aesthesiometer)

The dose-ranging phase II study randomly assigned 156 patients 1:1:1 to treatment with cenegermin 20 mcg/mL, cenegermin 10 mcg/ mL, or vehicle. Study treatment was used 6 times daily for 8 weeks. Patients in the vehicle group who experienced treatment failure during the 8-week controlled treatment period (i.e., their condition had worsened, not healed, or recurred) were eligible for an additional, uncontrolled treatment course with cenegermin 10 or 20 mcg/mL (a second randomization performed at baseline) for 8 weeks. All patients were followed for 48 weeks after completing treatment.

The primary endpoint was percentage of eyes achieving corneal healing at 4 weeks (defined as
< 0.5 mm maximum maximum diameter of corneal fluorescein staining in the area of the defect). The study results showed a highly statistically significant difference favoring both cenegermin 10 mcg/mL and 20 mcg/mL over vehicle (54.9% and 58.0% versus 19.6% p < 0.001 for both comparisons).

The active treatments also maintained their superiority over vehicle in analysis of the prespecified secondary endpoint, corneal healing rate at 8 weeks, when nearly three-fourths of eyes treated with either 10 mcg/ml or 20 mcg/ml cenegermin had healed compared with just 43% of eyes in the control group (p ≤ 0.002)

In a post hoc analysis using a more stringent definition of healing (0 mm staining in the lesion area and no persistent staining elsewhere), 49% of eyes treated with cenegermin 10 mcg/ mL, 58% of eyes in the 20 mcg/mL group and 13.7% of controls had achieved corneal healing (p < 0.001 versus placebo for both groups).

Evaluations at the end of the study showed the treatment benefit was maintained in the long term; 96% of patients whose defect healed with cenegermin remained healed at 48 weeks.

Other secondary and exploratory endpoints included measurement of corneal lesion size, time to corneal healing or onset of healing, best-corrected distance visual acuity, corneal sensitivity, and reflex tearing. Overall, the results from those assessments favored cenegermin versus vehicle, although the differences between groups were not always statistically significant at all time points, likely due to insufficient statistical power of the patient sample.

“The sample size for REPARO was chosen to demonstrate efficacy for the primary endpoint (corneal healing) and may not have been adequate to demonstrate statistically significant differences in the secondary and exploratory endpoints,” Dr. Mantelli said.

There were no clinically significant ocular or systemic adverse events during the treatment or follow-up periods. Eye pain and other similar complaints (e.g., abnormal sensation in the eye, excessive lacrimation, photophobia, eyelid pain, eye or eyelid irritation) were the most common treatment-related adverse events associated with cenegermin, but they could be interpreted as a sign of efficacy because they may reflect restoration of corneal innervation, corneal sensitivity, and reflex tearing.

A confirmatory trial conducted in the United States, NGF0214, enrolled 48 patients and compared cenegermin 20 mcg/mL with vehicle. It used the same enrollment criteria, treatment protocol, and endpoints as REPARO except that only NGF0214 allowed enrollment of patients with bilateral NK. Upon agreement with the FDA, patients were followed to just 6 months.

“In REPARO, the 10 and 20 mcg/mL cenegermin formulations had similar safety but the higher dose was more effective, and so it was chosen as the dose we wanted to pursue for commercialization,” Dr. Mantelli said. “The shorter follow-up in the confirmatory trial aimed to allow cenegermin to become commercially available sooner, and the healing responses observed in the confirmatory trial were strikingly similar to those seen in the first phase II study.”

Disclosures:

Stephen C. Pflugfelder, MD
E: stevenp@bcm.edu
Dr. Pflugfelder was an investigator in the Oxervate clinical trial and is consultant for Allergan and Shire. Cenegermin will be made available by Dompé in the United States by early 2019. Details regarding patient access will be announced prior to that time.