Approved Neurotrophic Keratitis Therapy Oxervate Requires Further Clinical Testing, According to Review

Approved Neurotrophic Keratitis Therapy Oxervate Requires Further Clinical Testing, According to Review

Despite its U.S. Food and Drug Administration approval, the safety and efficacy of Oxervate (cenegermin) as a treatment for the degenerative eye disease neurotrophic keratitis needs additional clinical testing, according to a recent review.

“Clinical experience with this drug is still limited. Further studies are needed to evaluate corneal nerve morphology and function,” the researchers said.

Titled “Update On Cenegermin Eye Drops In The Treatment Of Neurotrophic Keratitis,” the review was published in the journal Clinical Ophthamology.

Neurotrophic keratitis is a degenerative disease that affects the cornea, the transparent layer of the eye. The disease is caused by damage to the nerves that innervate the cornea, leading to a loss of sensation and breakdown of its epithelium, or outer layer.

Depending on the severity of degeneration, neurotrophic keratitis can be classified into three overlapping stages. Stage 1 is defined by epithelial alterations, while stage 2 is identified by persistent epithelial defects and stage 3 by corneal ulcers.

Management of neurotrophic keratitis includes both medical and surgical interventions to help stop disease progression and reverse damage. However, these strategies provide only relief of symptoms, and — in the case of surgical procedures — can cause corneal scarring and poor vision.

“Collectively, current medical and surgical treatments poorly tackle the essential problem of corneal anesthesia and hence fail to provide a permanent cure,” the researchers said.

Oxervate, marketed by Dompé, is a human recombinant nerve growth factor in the form of eye drops that could “fulfill the unmet need in the treatment of neurotrophic keratitis,” the researchers said.

The therapy was the first to be approved for the treatment of neurotrophic keratitis — in the U.S. in 2018 and in Europe in 2017.

Clinical studies suggest Oxervate could better help patients to restore corneal integrity. This nerve growth factor, or NGF, promotes the growth and survival of corneal epithelial cells and supports regeneration. Moreover, it promotes tear production known to be important for corneal re-innervation.

“It may be used as a first-line treatment for patients with stage 2 or 3 neurotrophic keratitis that have not responded to other conventional non-surgical treatments for [approximately] 2 weeks,” the researchers said.

Until now, the therapy’s safety and efficacy has been tested in just six clinical trials. This includes one Phase 1 study (NCT01744704) in healthy volunteers; one Phase 1/2 study, REPARO  (NCT01756456), in people with stage 2 and stage 3 neurotrophic keratitis; and four Phase 2 (NCT02227147, NCT02101281, NCT03019627, NCT03035864) trials.

During these studies, a higher proportion of patients treated with Oxervate achieved complete healing, compared with placebo.

In the Phase 1/2 study, the participants were randomly selected to receive 20 micrograms per milliliter (µg/ml) of Oxervate (higher dose), 10µg/mL Oxervate (lower dose), or placebo 6 times daily for eight weeks. After four weeks, complete healing was observed in 55% of patients receiving the lower dose, in 58% of those at the higher dose, and in 20% of those on placebo. These numbers increased to 75% at the lower dose, 74% at the higher dose, and 43% on placebo after eight weeks.

“Interestingly, there were no statistically significant differences in improvement in corneal sensitivity in patients of the treatment groups, who achieved complete corneal clearing at week 4, 6, or 8,” the researchers said.

Additionally, the recurrence of persistent epithelial defects or corneal ulcers during follow-up was more frequent in the Oxervate groups: 17% of those at the lower dose, 20% at the higher dose, and 10% of those on placebo had recurrences.

In one of the Phase 2 trials (NCT02227147), 48 participants were randomly selected to receive 20 µg/ml of Oxervate or placebo, six times a day for eight weeks. In this study, 70% of patients treated with Oxervate achieved complete corneal healing, compared with 28% of those in the placebo group.

Nonetheless, some adverse reactions have been reported in the clinical studies. Among the participants, 16% of those in the treatment group reported eye pain following the therapy compared with 7.9% in the placebo group. Meanwhile, some patients reported visual acuity reduction (10.7%), corneal deposits (4%), cataract (4%), foreign body sensation (2.7%), ocular hyperemia, or excess blood in eye vessels (6.7%, ), inflammation (5.3%), and tearing (5.3%).

The researchers noted that the long-term safety of Oxervate has not been established, with more studies necessary to evaluate changes in corneal nerves “in terms of morphology and function.”

In more practical matters, the storage and handling of Oxervate remains a significant concern, as the therapy must be kept stored in a freezer and needs about 30 minutes to warm up to be used at room temperature. “The multiple steps used to withdraw the eye drops and the multi-dose vial carry the risk of contamination,” the researchers said.

The therapy’s cost also is seen as a limitation. For example, in Europe, an eight-week course of Oxervate costs the equivalent of $8,606 U.S.

While Oxervate “has been demonstrated to be safe and effective in the treatment of neurotrophic keratitis based on conducted regulatory trials,” there is still limited clinical experience with the therapy, the researchers said. They called for further studies to evaluate the treatment’s safety and effectiveness.

“A single-dose generic medication with a controlled delivery and an affordable cost is necessary,” the investigators said.

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