- 4.1 General
- 4.2 Carcinogenesis/Mutagenesis/Impairment of Fertility
- 4.3 Pregnancy
- 4.4 Nursing Mothers
- 4.5 Pediatric Use
- 7.1 REPARO
- 7.2 NGF0214
- 7.3 DEFENDO
- 7.4 PROTEGO
Overview
Oxervate TM (cenegermin-bkbj) is a recombinant human nerve growth factor (rhNGF) that was approved for neurotrophic keratitis1 by the FDA in August 2018 (Food and Drug Administration, USA). It is the first FDA-approved treatment for neurotrophic keratitis and the first ophthalmic topical biologic [1] .
Neurotrophic Keratitis (NK) is a rare degenerative disease that results from defective corneal innervation by the trigeminal nerve [2] . Patients with this disease typically have decreased corneal sensation and develop nonhealing corneal epithelial defects and ulcers [2] . Surgical intervention was the only available treatment for NK prior to the approval of Oxervate [1] .
Patient Selection
Oxervate has been approved by the United States Food and Drug Administration (FDA) for the treatment of neurotrophic keratitis. [1]
Patients with cenegermin hypersensitivity to avoid its use. Patients using eye drops with corticosteroids or preservatives should avoid doing so while using cenegermin, as they may interfere with cenergermin’s efficacy. [1]
Mechanism of Action
Oxervate contains cenegermin-bkbj as its active ingredient. Cenegermin-bkbj is a recombinant nerve growth factor that is produced in recombinant Escherichia coli [1] . It is produced as an inactive propeptide and when instilled topically, it undergoes cleavage [1] . The mature protein works through specific nerve growth factor receptors (high-affinity tropomyosin receptor kinase A and low-affinity neurotrophin receptor) [1] which are located in the anterior segment of the eye [3] . Activation of these receptors allows for the differentiation and maintenance of neurons, which would support the innervation of the cornea [3] . The growth factor allows for corneal epithelial cells to maintain some stem cell potential and allows for tear production through lacrimal gland receptor activation [1] .
Warnings/Precautions
General
Contact lenses should not be worn while instilling Oxervate. Patients should wait 15 minutes after instillation of the drops before inserting contact lenses. [3]
Carcinogenesis/Mutagenesis/Impairment of Fertility
There is no data on potential carcinogenic or mutagenic effects. [3]
Animal studies involving subcutaneous administration demonstrated no fertility effects. However, toxicology studies involving subcutaneous and ocular administration showed some ovarian changes in females at doses of 19 mcg/kg/day such as ovarian follicular cysts, atrophy of corpora lutea, ovarian weight changes and persistent estrus. [3]
Pregnancy
There is no data on whether use of Oxervate is harmful to pregnant women or the developing fetus. Animal data demonstrated that cenegermin-bkbj did not adversely affect the fetus during the gestational period. [3]
Nursing Mothers
There is no data on whether cenegermin is secreted in human milk, affects milk production or is absorbed by or harmful to an infant [3] . However, cenegermin is a large protein molecule and absorption from the eye is minimal, it is likely that the amount secreted in milk and absorbed by the infant is low [4] . In order to decrease any risks of cenegermin milk secretion or cenegermin absorption by the infant, the patient may put pressure on the tear duct for about a minute and clean any excess solution to prevent systemic absorption of the drop [4] .
Pediatric Use
Oxervate is approved for use in pediatric patients 2 years of age and older. [3]
Adverse Reactions
The most common adverse reaction is eye pain during treatment. Other adverse reactions include visual acuity reduction, corneal deposits, foreign body sensation, ocular hyperemia, ocular inflammation, cataracts, and tearing. [1]
Administration, Dosing, and Preparation
Oxervate contains the active ingredient cenegermin-bkbji 0.002% (20 mcg/mL). It is a clear, colorless solution in a multi-dose vial. [3]
According to the FDA Label: “Instill one drop of Oxervate in the affected eye(s), 6 times a day at 2-hour intervals for eight weeks.” [3]
Oxervate should be stored in the refrigerator (for up to 14 days) and should not be left sitting out for more than 5 hours once retrieved from the pharmacy. At the pharmacy, Oxervate is stored in the freezer and should be allowed to thaw before use. [3]
Before each instillation, a sterile disinfectant wipe should be used to clean the surface of the connector on the vial. A new pipette should be obtained and screwed into the vial with the pipette plunger pushed all the way down. Once attached, the vial should be flipped upside down and the plunger should be pulled to the stop point. Once the pipette is filled with the solution, the vial should be set right side up and the pipette should be unscrewed from the vial. The patient should sit or lie down, hold the pipette above the affected eye and push the plunger down. The patient should blink a few times to ensure that the medication coats the eye. The pipette should be thrown away immediately and not reused. If the patient needs to use the drops in their other eye, a new pipette should be used. The patient should ensure that the vial is placed in the refrigerator throughout the day between uses. [3]
Clinical Trials
REPARO
REPARO is a 8 week phase II multicenter, randomized, double-masked, vehicle-controlled trial of 156 patients with Stage 2 or Stage 3 Neuropathic Keratitis. The patients were randomized into three cohorts with treatment 6 times daily for 8 weeks: cenegermin ophthalmic solution 10 mcg/mL, cenegermin ophthalmic solution 20 mcg/mL, and vehicle. Corneal healing was evaluated at 4 weeks and 8 weeks. At week 4, 58% of the 20 mcg/mL cohort achieved healing, 54.9% of the 10 mcg/mL cohort achieved healing, and 19.6% of the vehicle cohort achieved healing. At week 8, 74% of the 20 mcg/mL cohort achieved healing, 74.5% of the 10 mcg/mL cohort achieved healing, and 43.1% of the vehicle cohort achieved healing. [5]
NGF0214
NGF0214 is a 8 weeks multicenter, randomized, double-masked, vehicle-controlled trial of 48 patients with neurotrophic persistent epithelial defect. The patients were randomized into two cohorts with treatment 6 times daily for 8 weeks: cenegermin ophthalmic solution 20 mcg/mL, and vehicle. At week 8, 69.6% of the cenegermin cohort achieved healing and 29.2% of the vehicle cohort achieved healing using conventional assessment measures. Using conservative assessment measures, 65.2% of the cenegermin cohort achieved healing and 16.7% of the vehicle cohort achieved healing. [6]
DEFENDO
DEFENDO is an 8 week, open label, prospective study of 37 patients with Stage 1 Neurotrophic Keratitis. Patients were all assigned to one study group who received cenergermin-bkbj ophthalmic solution 20 mcg/mL every 2 hours 6 times daily for 8 weeks. The study measured corneal epithelial healing at week 8. [7]
The long-term safety and efficacy of the solution will be evaluated in these 37 patients through follow up visits at 24 months and 30 months to assess corneal epithelial healing. The estimated completion date of the study is September 2024. [8]
PROTEGO
PROTEGO-1 is a phase III, 4-week, multicenter, double-masked, vehicle-controlled study of 104 patients with severe dry eye disease due to Sjögren’s Syndrome. The patients were randomized into two cohorts: cenegermin ophthalmic solution 20 mcg/mL three times daily for 4 weeks or a vehicle treatment three times daily for 4 weeks. The patients will be followed to evaluate efficacy until week 16 and to evaluate safety until week 24. The estimated completion date of the study is July 2023. [9]
PROTEGO-2 is a similar study to PROTEGO-1 with 85 patients who are chronically treated with topical Cyclosporine A and remain on this treatment throughout the study duration. The estimated completion date of the study is October 2023. [10]
References
- ↑ 1.01.11.21.31.41.51.61.71.8 Adams BS, Patel AR. Cenegermin. [Updated 2022 May 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK573069/. Accessed June 21, 2023.
- ↑ 2.02.1 Sacchetti M, Bruscolini A, Lambiase A. Cenegermin for the treatment of neurotrophic keratitis. Drugs Today (Barc). 2017;53(11):585-595. doi:10.1358/dot.2017.53.11.2722395.
- ↑ 3.003.013.023.033.043.053.063.073.083.093.103.11 Highlights of Prescribing Information: OxervateTM (cenergermin-bkbj) ophthalmic solution for topical ophthalmic use. AccessDataFDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761094s000lbl.pdf. Accessed June 21, 2023.
- ↑ 4.04.1 Cenegermin. In: Drugs and Lactation Database (LactMed®). Bethesda (MD): National Institute of Child Health and Human Development; December 3, 2018.
- ↑ Bonini S, Lambiase A, Rama P, et al. Phase II Randomized, Double-Masked, Vehicle-Controlled Trial of Recombinant Human Nerve Growth Factor for Neurotrophic Keratitis. Ophthalmology. 2018;125(9):1332-1343. doi:10.1016/j.ophtha.2018.02.022
- ↑ Pflugfelder SC, Massaro-Giordano M, Perez VL, et al. Topical Recombinant Human Nerve Growth Factor (Cenegermin) for Neurotrophic Keratopathy: A Multicenter Randomized Vehicle-Controlled Pivotal Trial. Ophthalmology. 2020;127(1):14-26. doi:10.1016/j.ophtha.2019.08.020
- ↑ Study to Evaluate OXERVATE™ in Patients With Stage 1 Neurotrophic Keratitis (DEFENDO). Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04485546?intr=Oxervate&rank=8. Accessed June 21, 2023.
- ↑ DEFENDO Long Term Follow-up Study in Stage 1 NK Patients (DEFENDO). Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT05552261?intr=Oxervate&rank=7. Accessed June 21, 2023.
- ↑ Study to Evaluate Safety and Efficacy of Cenegermin (Oxervate®) vs Vehicle in Severe Sjogren's Dry Eye Disease (NGF0121 - PROTEGO-1 Study) (NGF0121). Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT05133180?intr=Oxervate&rank=1. Accessed June 21, 2023.
- ↑ Study to Evaluate Safety and Efficacy of Cenegermin (Oxervate®) vs Vehicle in Severe Sjogren's Dry Eye Disease (NGF0221 - PROTEGO-2 Study) (NGF0221). Clinicaltrials.gov. https://clinicaltrials.gov/study/NCT05136170?intr=Oxervate&rank=2. Accessed June 21, 2023.
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