About OXERVATE®

OXERVATE is the only pharmacologic therapy that targets the root pathogenesis of neurotrophic keratitis.1

Cenegermin-bkbj, the active ingredient in OXERVATE, is a recombinant nerve growth factor (NGF) that is structurally identical to human NGF protein made in ocular tissues (endogenous NGF).2

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) NGF receptors in the anterior segment of the eye to support corneal innervation and integrity.1

Endogenous NGF is believed to support corneal integrity through 3 mechanisms (shown in preclinical models).3,4

1

Corneal Innervation

The cornea, a highly sensitive tissue, is densely innervated with sensory nerve fibers via the ophthalmic branch of the trigeminal nerve. In neurotrophic keratitis, this corneal innervation is impaired, ultimately impacting the health and function of the cornea.4,5

2

Tear Secretion

NGF binds receptors on lacrimal glands to promote tear secretion and facilitates sensory-mediated reflex tearing, potentially protecting from pathogens and injury.3,6

3

Cell Proliferation and Differentiation

NGF stimulates proliferation, differentiation, and survival of corneal epithelial cells.3

Endogenous NGF contributes to ocular surface homeostasis as a key part of the dynamic interplay between corneal epithelial cells and sensory nerves. Sensory nerves produce neuromediators supporting corneal epithelial cell health, and corneal epithelial cells produce NGF supporting sensory nerve health.3,7

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    Important Safety Information

    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.

    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.

    The most common adverse reaction in clinical trials that occurred more frequently with OXERVATE was eye pain (16% of patients). Adverse reactions included corneal deposits, foreign body sensation in the eye, ocular hyperemia (enlarged blood vessels in the white of the eye), swelling (inflammation) of the eye, and increase of tears (1-10% of patients).

    INDICATION
    OXERVATE (cenegermin-bkbj) ophthalmic solution 0.002% is indicated for the treatment of neurotrophic keratitis.

    DOSAGE FORMS AND STRENGTHS
    Ophthalmic solution for topical use in the eye: cenegermin-bkbj 0.002% (20 mcg/mL) is a clear, colorless solution in a multiple-dose vial.

    CONTRAINDICATIONS
    None.

    WARNINGS AND PRECAUTIONS
    Use With Contact Lenses
    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.

    ADVERSE REACTIONS
    Clinical Studies Experience
    Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be compared directly to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

    In 2 clinical trials of patients with neurotrophic keratitis, a total of 101 patients received cenegermin-bkbj eye drops at 20 mcg/mL at a frequency of 6 times daily in the affected eye(s) for a duration of 8 weeks. The mean age of the population was 61 to 65 years of age (18 to 95).

    The most common adverse reaction in clinical trials that occurred more frequently with OXERVATE was eye pain (16% of patients). Other adverse reactions included corneal deposits, foreign body sensation in the eye, ocular hyperemia (enlarged blood vessels in the white of the eye), swelling (inflammation) of the eye, and increase in tears (1%-10% of patients).

    USE IN SPECIFIC POPULATIONS
    Pregnancy
    Risk Summary
    There are no data from the use of OXERVATE in pregnant women to inform any drug-associated risks.

    Administration of cenegermin-bkbj to pregnant rats or rabbits during the period of organogenesis did not produce adverse fetal effects at clinically relevant doses. In a pre- and postnatal development study, administration of cenegermin-bkbj to pregnant rats throughout gestation and lactation did not produce adverse effects in offspring at clinically relevant doses.

    Data
    Animal Data
    In embryofetal development studies, daily subcutaneous administration of cenegermin-bkbj to pregnant rats and rabbits throughout the period of organogenesis produced a slight increase in postimplantation loss at doses greater than or equal to 42 mcg/kg/day (267 times the maximum recommended human ophthalmic dose [MRHOD]). A no-observed-adverse-effect level (NOAEL) was not established for postimplantation loss in either species. In rats, hydrocephaly and ureter anomalies were observed once each in fetuses at 267 mcg/kg/day (1709 times the MRHOD). In rabbits, cardiovascular malformations, including ventricular and atrial septal defects, enlarged heart, and aortic arch dilation, were observed once each in fetuses at 83 mcg/kg/day (534 times the MRHOD). No fetal malformations were observed in rats and rabbits at doses of 133 mcg/kg/day and 42 mcg/kg/day, respectively.

    In a pre- and postnatal development study, daily subcutaneous administration of cenegermin-bkbj to pregnant rats during the period of organogenesis and lactation did not affect parturition and was not associated with adverse toxicity in offspring at doses up to 267 mcg/kg/day.

    In parental rats and rabbits, an immunogenic response to cenegermin-bkbj was observed. Given that cenegermin-bkbj is a heterologous protein in animals, this response may not be relevant to humans.

    Lactation
    Risk Summary
    There are no data on the presence of OXERVATE in human milk, the effects on breastfed infants, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OXERVATE and with any potential adverse effects on the breastfed infant.

    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.

    Geriatric Use
    Of the total number of subjects in clinical studies of OXERVATE, 43.5% were 65 years old and older. No overall differences in safety or effectiveness were observed between elderly and younger adult patients.

    The FDA-approved product labeling can be found here. You may report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Dompé at 1-833-366-7387 or Usmedinfo@dompe.com.

    References

    1. OXERVATE® (cenegermin-bkbj) ophthalmic solution 0.002% (20mcg/mL)[US package insert]. Boston, MA; Dompé U.S. Inc.; 2019.
    2. Voelker R. New drug treats rare, debilitating neurotrophic keratitis. JAMA. 2018;320(13):1309.
    3. Mastropasqua L, Massaro-Giordano G, Nubile M, Sachetti M. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J. Cell Physiol. 2017 Apr;232;(4):717-724.
    4. Müller LJ, Marfurt CF, Kruse F, et al. Corneal nerves: structure, contents and function. Exp Eye Res. 2003 May;76(5):521-542.
    5. Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol. 2014;8:571-579.
    6. Muzi S, Colafrancesco V, Sornelli F, et al. Nerve growth factor in the developing and adult lacrimal glands of rat with and without inherited retinitis pigmentosa. Cornea. 2010;29:1163-1168.
    7. Bonini S, Lambiase A, Rama P, Sinigaglia F, Allegretti M, Chao W, Mantelli F, for the REPARO Study Group. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology. 2018 Sep;125(9):1332-1343.
    8. Data on File. Dompé U.S. Inc.; 2020.

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