The Ocular Surface with Marguerite McDonald

Topical recombinant human nerve growth factor an innovation in ocular surface disease treatment

Eye drops with cenegermin restore the normal healing process and repair corneal damage in eyes with neurotrophic keratitis.
Marguerite B. McDonald

On Aug. 22, the FDA approved Oxervate, the first drug for the treatment of neurotrophic keratitis; it is produced by the Italian pharmaceutical company Dompé. Cenegermin was approved in the European Union as an eye drop formulation for the treatment of moderate to severe neurotrophic keratitis in adults in July 2017.

Oxervate (cenegermin) was studied for the treatment of moderate to severe neurotrophic keratitis in adults; it is the first biotechnological treatment authorized for this indication.

Neurotrophic keratitis is a fairly rare eye disease, affecting fewer than five in 10,000 people. There have been no prior approved drugs to treat neurotrophic keratitis. Neurotrophic keratitis is caused by damage to the trigeminal nerve, which can lead to loss of corneal sensitivity. In its most severe form, neurotrophic keratitis can lead to ulcers, melting and corneal perforations, with severe reduction in vision.

Cenegermin is the active ingredient in Oxervate. It is the recombinant version of human nerve growth factor (NGF), discovered by biochemist and neurologist Dr. Rita Levi-Montalcini of Italy. Her groundbreaking work on cenegermin earned her the Nobel Prize.

Cenegermin is a protein naturally produced by the human body, responsible for the development, maintenance and survival of nerve cells. It is a neurotrophic factor and neuropeptide that is primarily involved in regulation of mitochondrial production of energy as well as the maintenance, growth, proliferation and survival of certain target neurons, including those in the brain.

NGF is similar to other neurotrophins in that it activates receptors in target cells called tyrosine receptor kinases (Trks). Trks are the proteins found on the surface of neurons. When activated by NGF, they cause a series of cellular events that stimulate immature neurons to grow axons and survive. The cells that do not find their target will undergo the programmed death process known as apoptosis, thereby maintaining their appropriate connections and eliminating inappropriate ones. Therefore, when administered in eye drops in patients with neurotrophic keratitis, cenegermin — recombinant human nerve growth factor — restores the normal healing processes of the eye and repairs corneal damage.

Oxervate is produced with recombinant DNA technology; a gene (DNA) is introduced into bacteria, which allows them to produce human NGF.

The safety and efficacy of Oxervate, the topical eye drop containing cenegermin, was studied in 151 patients with neurotrophic keratitis in two 8-week randomized controlled multicenter double-masked studies. In the first study, patients were randomly assigned to one of three groups. One group received Oxervate, a second group received an eye drop with a different concentration of cenegermin, and the third group received an eye drop without cenegermin. In the second study, patients were randomly assigned to one of two groups. One group was treated with Oxervate eye drops, and the other group was treated with an eye drop without cenegermin. All eye drops in both studies were given six times daily in the affected eyes for 8 weeks. In the first study, only patients with the disease in one eye were enrolled, while in the second study, patients with the disease in both eyes were treated bilaterally. In both studies, complete corneal healing after 8 weeks was demonstrated in 70% of patients treated with Oxervate compared with 28% of patients treated without cenegermin.

Before approval, Oxervate was granted priority review designation, under which the FDA’s goal is to take action on an application within 6 months of application filing if the FDA determines that the drug, if approved, would provide a significant improvement in the safety or efficacy of the treatment, diagnosis or prevention of a serious malady. Oxervate also was granted orphan drug designation, which provides incentives to assist and encourage companies to develop drugs for rare conditions.

The most common adverse reactions in patients taking Oxervate are eye pain, ocular hyperemia, eye inflammation and increased lacrimation.

Since this watershed discovery by Levi-Montalcini, hundreds of studies have been performed with NGF. The results suggest that there are positive benefits that affect both the anterior and posterior segments of the eye, as well as the suppression of inflammation and the slowing of both age-related memory loss and cognitive decline.

Levi-Montalcini self-treated with NGF eye drops for years and died at the age of 103.

Disclosure: McDonald reports no relevant financial disclosures.

Marguerite B. McDonald

On Aug. 22, the FDA approved Oxervate, the first drug for the treatment of neurotrophic keratitis; it is produced by the Italian pharmaceutical company Dompé. Cenegermin was approved in the European Union as an eye drop formulation for the treatment of moderate to severe neurotrophic keratitis in adults in July 2017.

Oxervate (cenegermin) was studied for the treatment of moderate to severe neurotrophic keratitis in adults; it is the first biotechnological treatment authorized for this indication.

Neurotrophic keratitis is a fairly rare eye disease, affecting fewer than five in 10,000 people. There have been no prior approved drugs to treat neurotrophic keratitis. Neurotrophic keratitis is caused by damage to the trigeminal nerve, which can lead to loss of corneal sensitivity. In its most severe form, neurotrophic keratitis can lead to ulcers, melting and corneal perforations, with severe reduction in vision.

Cenegermin is the active ingredient in Oxervate. It is the recombinant version of human nerve growth factor (NGF), discovered by biochemist and neurologist Dr. Rita Levi-Montalcini of Italy. Her groundbreaking work on cenegermin earned her the Nobel Prize.

Cenegermin is a protein naturally produced by the human body, responsible for the development, maintenance and survival of nerve cells. It is a neurotrophic factor and neuropeptide that is primarily involved in regulation of mitochondrial production of energy as well as the maintenance, growth, proliferation and survival of certain target neurons, including those in the brain.

NGF is similar to other neurotrophins in that it activates receptors in target cells called tyrosine receptor kinases (Trks). Trks are the proteins found on the surface of neurons. When activated by NGF, they cause a series of cellular events that stimulate immature neurons to grow axons and survive. The cells that do not find their target will undergo the programmed death process known as apoptosis, thereby maintaining their appropriate connections and eliminating inappropriate ones. Therefore, when administered in eye drops in patients with neurotrophic keratitis, cenegermin — recombinant human nerve growth factor — restores the normal healing processes of the eye and repairs corneal damage.

Oxervate is produced with recombinant DNA technology; a gene (DNA) is introduced into bacteria, which allows them to produce human NGF.

The safety and efficacy of Oxervate, the topical eye drop containing cenegermin, was studied in 151 patients with neurotrophic keratitis in two 8-week randomized controlled multicenter double-masked studies. In the first study, patients were randomly assigned to one of three groups. One group received Oxervate, a second group received an eye drop with a different concentration of cenegermin, and the third group received an eye drop without cenegermin. In the second study, patients were randomly assigned to one of two groups. One group was treated with Oxervate eye drops, and the other group was treated with an eye drop without cenegermin. All eye drops in both studies were given six times daily in the affected eyes for 8 weeks. In the first study, only patients with the disease in one eye were enrolled, while in the second study, patients with the disease in both eyes were treated bilaterally. In both studies, complete corneal healing after 8 weeks was demonstrated in 70% of patients treated with Oxervate compared with 28% of patients treated without cenegermin.

PAGE BREAK

Before approval, Oxervate was granted priority review designation, under which the FDA’s goal is to take action on an application within 6 months of application filing if the FDA determines that the drug, if approved, would provide a significant improvement in the safety or efficacy of the treatment, diagnosis or prevention of a serious malady. Oxervate also was granted orphan drug designation, which provides incentives to assist and encourage companies to develop drugs for rare conditions.

The most common adverse reactions in patients taking Oxervate are eye pain, ocular hyperemia, eye inflammation and increased lacrimation.

Since this watershed discovery by Levi-Montalcini, hundreds of studies have been performed with NGF. The results suggest that there are positive benefits that affect both the anterior and posterior segments of the eye, as well as the suppression of inflammation and the slowing of both age-related memory loss and cognitive decline.

Levi-Montalcini self-treated with NGF eye drops for years and died at the age of 103.

Disclosure: McDonald reports no relevant financial disclosures.