New ways to treat NK

New nerve growth factor agent promising in early trials

Leigh Spielberg

Posted: Wednesday, November 1, 2017

Dr Paolo Rama speaking at the 8th EuCornea Congress in Lisbon, Portugal

Strategies for the treatment of neurotrophic keratopathy (NK) range from basic prophylaxis to surgery. Now a new agent, recombinant nerve growth factor, offers new hope to these patients, reported Paolo Rama MD at the 8th EuCornea Congress in Lisbon, Portugal.

NK is related to alterations in corneal nerves leading to impairment in sensory and trophic function, with consequent breakdown of the corneal epithelium. This affects the health and integrity of both the epithelium and stroma. It is well known that the permanent, non-healing epithelial defects in NK can be extremely difficult to manage, explained Dr Rama, San Raffaele Scientific Institute, Milan, Italy.

He outlined several different stages of treatment, starting with prophylaxis. He advised avoiding unnecessary topical drugs; prescribing only preservative-free artificial tears; using scleral or therapeutic soft contact lenses in patients at risk; and making sure the ocular surface is protected at night, either via ointment or occlusion.

Once mild NK has developed, autologous serum or platelet-rich plasma can be prescribed. However, the current treatment paradigm of more advanced NK is primarily surgical.

Besides treating the NK itself, the underlying cause of the loss of nerve function must also be addressed. This is most commonly herpetic eye disease, but a very wide range of aetiologies have been identified, including severe chemical burns, systemic diseases such as diabetes, and any cause of fifth cranial nerve palsy.

“Medical treatment is insufficient, and surgical treatments, like lateral tarsorrhaphy and amnion membrane grafting, are not primarily aimed at improving vision, but at preserving ocular integrity,” said Dr Rama.

In effect, the current treatments, both medical and surgical, simply treat the corneal damage secondary to NK without addressing the underlying neuronal deficit. The chronic problem of loss of corneal sensory innervation leads to decreased corneal epithelial renewal rate, reduced tear formation and a situation that is ultimately untreatable without resorting to surgery.

Dr Rama introduced delegates to the possibilities of using nerve growth factor (NGF) to treat difficult cases of NK.

“NGF is a molecule critically involved in differentiation, growth and survival of neurons. It also has known proliferative effects on epithelial cells,” he said.

Discovered in the 1950s and isolated from mice or produced via genetic engineering, NGF may dramatically alter the treatment of NK. It is, however, a molecule with a complex folding pattern that is difficult to manufacture.

As far back as 1998, Dr Rama and his team published an article in the New England Journal of Medicine to report that topically applied murine NGF restored corneal integrity in 12 patients with neurotrophic ulcers. These included patients who had developed corneal anaesthesia after neurosurgery, herpetic keratitis, topical anaesthetic drug abuse and even simple PRK.

“In many cases, seven days of topical murine NGF was sufficient for closure of the epithelial defects,” he said. Dr Rama showed pictures of beautifully clear corneas that had previously looked hopeless.

More than 100 severe patients have thus far been treated, and 100% have demonstrated complete healing, he said. Side-effects are mild, and include conjunctival hyperaemia, photophobia and periocular pain. Of the 11 patients tested for anti-NGF antibodies, none tested positive. All patients who relapsed suffered from NK due to fifth cranial nerve resection.

In 2011, the Dompé Group of Italy acquired the worldwide rights for the development and commercialisation of NGF. Despite the difficulty of producing NGF, the Dompé Group has succeeded in producing a recombinant molecule that is 10 times more potent in vitro than murine NGF.

A phase I study proved the safety of topical recombinant NGF. A phase I-II study, the REPARO study, enrolled 174 patients in 39 centres and was successfully completed. Marketing authorisation was granted in Europe in 2017, and recombinant human NGF, referred to as cenergemin, will be marketed as Oxervate.

“NGF may represent a future therapeutic approach to treat neurotrophic persistent epithelial defects, stromal ulcers and melting, as well as to promote reinnervation, prevent recurrence and improve the prognosis of keratoplasties in neurotrophic cases,” he concluded.

Paolo Rama:

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