Oxervate (cenegermin) and Cacicol (RGTA) are currently the primary treatments for persistent and difficult-to-treat corneal ulcers caused by neurotrophic keratitis (NK), a review study reports. Oxervate is approved in both the U.S. and the EU, and Cacicol is available only in Europe.

In the report, researchers describe other investigational therapies with promising results in preclinical and clinical studies that may represent future treatment options.

The study, “Recent innovations with drugs in clinical trials for neurotrophic keratitis and refractory corneal ulcers,” was published in the journal Expert Opinion on Investigational Drugs.

Neurotrophic keratopathy (NK) is a rare eye disorder that affects the cornea, the transparent front part of the eye that works like a window to focus the entry of light into the eye.

It is due to a malfunction of the nerves that supply the cornea, causing a loss of sensation and the breakdown of the outermost layer of the cornea, the epithelium, accompanied by scarring and impaired healing.

These lesions can evolve to a corneal ulcer, which can manifest as a thinning of the cornea, known as ‘melting’, and in more advanced stages a hole or opening to the inside of the eye, which can eventually lead to vision loss.

The management of NK aims to promote corneal healing and avoid complications. However, the disease can promote the formation of chronic ulcers that respond poorly to conventional therapy and are difficult to treat.

In such cases of refractory disease, surgical procedures or eyedrops prepared with the patients’ own serum may also be used. However, the high costs associated with complex preparation procedures, and the potential risk of infections limits its use in routine clinical practice.

New treatments available

Oxervate eye drops (cenegermin, a lab-made version of human nerve growth factor, rhNGF, sold by Dompé) “is a promising therapy” and was the first medicine approved by the U.S. FDA for the treatment of moderate to severe NK in adults. It has also been approved in Europe.

NGF, the active ingredient in Oxervate, promotes the formation and maintenance of nerve cells, aimed at restoring corneal integrity.

The efficacy and safety of Oxervate were assessed in two placebo-controlled Phase 2 trials in patients with moderate or severe (corneal ulcer) NK refractory to non-surgical treatments.

In the first trial, called REPARO (NCT01756456), 156 patients were randomly assigned one drop, six times a day, of Oxervate at either 10 μg/ml or 20 μg/ml, or a placebo.

At eight weeks, treatment with Oxervate led to complete corneal healing in a greater percentage of patients, compared to placebo: 43.1% of placebo-treated patients achieved corneal healing compared to 74.5% give Oxervate 10 μg/ml and 74.0% receiving the 20 μg/ml dose. Only mild side effects were reported, showing the medication was well-tolerated.

The second trial (NCT02227147) further confirmed these results. In 48 patients given either Oxervate 20 μg/ml or placebo, complete healing was seen in 69.6% of patients treated by Oxervate versus 29.2% on placebo.

An eye solution called Cacicol (ReGeneraTing Agent orRGTA, sold by Théa) has also recently reached the European market to treat chronic corneal ulcers.

Calcicol acts as a scaffold made of engineered sugar-based polymers that mimic natural sugars to promote the fixation and the protection of components involved in the tissue regeneration process. It is applied over the eye to promote the regeneration and healing of cornea, in order to delay or avoid more invasive surgical procedures.

Several observational and non-controlled studies have suggested the agent can speed up corneal healing and relief pain in patients with NK.

However, “randomized clinical trials are still necessary” to support these findings, the researchers wrote. A randomized double-blinded clinical trial (NCT01242839) evaluating Calcicol efficiency versus placebo has been recently completed in France, but results are not yet available.

Emergent options under research

A number of alternative treatments are currently being investigated in preclinical and clinical studies.

Examples include CODA001, an RNA therapy that inhibits connexion 43, a protein overproduced in chronic corneal wounds. The treatment has shown promising results for healing eye surface burns, but currently there is no ongoing clinical trial evaluating it for ulcers associated with NK.

Topical insulin has also been suggested as a treatment. A recent study reported complete corneal healing within seven to 25 days after topical insulin drops in six NK patients with refractory corneal ulcers.

Other researchers have proposed the use of substance P, a modulator of nerve cell communication, and insulin-like growth factor 1 (IGF-1), a hormone. A combination of the two agents is thought to act synergistically to aid cell migration to wound sites and promote healing.

In an open-label study, 25 patients with NK were treated with eye drops containing active parts of substance P and IGF-1, reaching complete corneal repair in 73% of the cases, within four weeks.

Another promising candidate for NK is an eye solution of RGN-259 (thymosin beta 4). Compassionate use of RGN-259 eye drops in nine NK patients for 28 or 49 days led to complete, dramatic epithelial corneal healing in six of them. A Phase 3, multi-center, randomized, placebo-controlled clinical study (NCT02600429) is currently ongoing to further access RGN-259’s efficacy and safety.

Other emerging treatment strategies include eye drops made of plasma rich in growth factors (PRGF) and fingerprick autologous blood.

An NK study of 38 eyes treated with PRGF eye drops reported a 97% complete resolution of the corneal defect/ulcer within a mean period of 11.4 weeks. A Phase 4 clinical trial (NCT02707120) is ongoing to evaluate this approach in patients with more advanced NK.

Finger prick blood has been suggested as a simpler alternative to drops of patients’ own serum (which contains regenerative factors). For this new procedure, patients clean one finger with alcohol, collect a drop of blood using a diabetic lancet, and apply the drop directly to the eye four times a day.

“Management of refractory corneal ulcers remains challenging. New drugs, acting in the maintenance of nerve cells or in restoration of the extracellular matrix architecture of the cornea, are the main therapeutic innovations. Current promising research could open new ways of drugs development and treatment perspectives for refractory corneal ulcers,” the researchers concluded.