Dompé’s team manufactured Oxervate®, the first topical biologic FDA-approved treatment for neurotrophic keratitis. Neurotrophic keratitis is a rare, degenerative corneal disease marked by loss of corneal sensitivity, which if left untreated can lead to corneal epithelium breakdown and even corneal perforation.
Nerve Growth Factor (NGF) was discovered by the Italian neurobiologist, Professor Rita Levi-Montalcini, and her colleague Dr. Stanley Cohen. For this discovery, they were awarded the Nobel Prize in Physiology or Medicine in 1986. Nerve Growth Factor (NGF) is an endogenous protein involved in the differentiation and maintenance of neurons. In their research, Drs. Levi-Montalcini and Cohen uncovered that NGF plays a crucial role in the proliferation, differentiation and survival of sympathetic and sensory neurons.
At Dompé, our goal is to improve the lives of patients living with challenging conditions. We strive to focus on areas of unmet medical need. 2010 was a momentous year when Dompé acquired the rights to produce and market NGF. Following several years of research, our committed team of scientists developed cenegermin-bkbj, a recombinant human Nerve Growth Factor (rhNGF). Cenegermin-bkbj is produced using an innovative biotechnological process in which genetic material comprised of sequences coding for NGF is transformed into bacteria. These bacteria then produce a recombinant protein, which is structurally identical to the NGF protein naturally produced by the human body.
Neurotrophic keratitis, a hard to manage disease, had no FDA-approved treatments available for patients; thus, we embarked on a clinical development path to create cenegermin-bkbj to fill this need. The cornea is a transparent, highly innervated tissue, devoid of blood vessels and with a highly organized collagenous matrix to ensure optical transparency for clear vision.
Corneal health and trophism relies in part on innervation. Sensory corneal nerves provide trophic support to the corneal epithelium while facilitating and maintaining ocular surface homeostasis. Alteration in the morphology and function of these corneal nerves disrupts the fine balance needed for corneal integrity and health of the cornea. In a disease like NK, the corneal nerves and corneal epithelium are compromised. Even though most patients with NK may not complain of symptoms due to reduced corneal sensitivity, they suffer from corneal epithelial breakdown, which when left untreated, can lead to further deterioration over time.
Cenegermin-bkbj, the active ingredient in Oxervate®, is a recombinant form of human NGF (rhNGF). NGF is an endogenous protein involved in the differentiation and maintenance of neurons, which acts through specific high-affinity (i.e., TrkA) and low-affinity (i.e., p75NTR) Nerve Growth Factor receptors in the anterior segment of the eye to support corneal innervation and integrity.
Dompé’s advanced developmental capabilities formulated cenegermin-bkbj into a topical treatment for neurotrophic keratitis that can be delivered via an eye drop.
In clinical trials, the most common adverse reaction was eye pain following instillation which was reported in approximately 16% of patients. Eye pain may arise as corneal healing occurs.
Central to realizing the value of our research has been the industrial-scale biotech production process set up at our L’Aquila manufacturing plant.
Having created the first rhNGF-based drug for the treatment of neurotrophic keratitis, we then had to create a production process that could produce the recombinant protein on an industrial scale. The complex production process of this biotech drug was set up at our L’Aquila production site in Italy, the operational heart of cenegermin-bkbj production.The production process is complex and requires a team of highly skilled technicians and biotechnologists to manufacture cenegermin-bkbj. A key challenge in the process is ensuring that the active ingredient is kept at very low temperatures within specially designed cold stores.
Therefore, we also set up a cold chain to ensure that once produced, the drug is distributed to patients in containers kept at -20°C. We were unwavering in our vision of taking rhNGF protein from bench to bedside as treatment for neurotrophic keratitis, offering an effective treatment for patients who had no FDA-approved, commercially available treatment options. This led to European Medicines Agency (EMA) approval in 2017, U.S. Food and Drug Administration (FDA) approval a year later in 2018, and National Medical Products Administration (NMPA) approval in 2020. FDA granted cenegermin-bkbj ophthalmic solution “Breakthrough Therapy” designation, fast-tracking the review and approval of the drug, recognizing neurotrophic keratitis as a serious condition without FDA-approved drug treatments.
We are currently investigating applications in other ocular diseases. Our success in ophthalmics is only a stepping stone for rhNGF-based applications. We are now exploring potential opportunities to treat other diseases. We have expanded our research efforts into neurotrophins, including manufacturing, formulation, and administration, to better understand their potential for patients. We believe that continuous improvements can evolve into meaningful therapeutic innovations.
Use with Contact Lens
Contact lenses should be removed before applying OXERVATE® because the presence of a contact lens (either therapeutic or corrective) could theoretically limit the distribution of cenegermin-bkbj onto the area of the corneal lesion. Lenses may be reinserted 15 minutes after administration.
Eye Discomfort
OXERVATE® may cause mild to moderate eye discomfort such as eye pain during treatment. The patient should be advised to contact their doctor if a more serious eye reaction occurs.
Contact lenses should be removed before applying OXERVATE® because the presence of a contact lens (either therapeutic or corrective) could theoretically limit the distribution of cenegermin-bkbj onto the area of the corneal lesion. Lenses may be reinserted 15 minutes after administration.
Pregnancy
There are no data from the use of OXERVATE® in pregnant women to inform any drug associated risks.
Lactation
The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for OXERVATE®, and any potential adverse effects on the breastfed infant from OXERVATE®.
Pediatric Use
The safety and effectiveness of OXERVATE® have been established in the pediatric population. Use of OXERVATE® in pediatric patients 2 years of age and older is supported by evidence from adequate and well-controlled trials of OXERVATE® in adults with additional safety data in children.
OXERVATE® (cenegermin-bkbj) ophthalmic solution 0.002% (20 mcg/mL) is indicated for the treatment of neurotrophic keratitis.
Instill one drop of OXERVATE in the affected eye(s), 6 times a day at 2-hour intervals for eight weeks. To report ADVERSE REACTIONS, contact Dompé U.S. Inc. at 1-833-366-7387 or FDA at 1-800-FDA-1088 or https://www.dompe.com/http://www.fda.gov/medwatch.
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