Clinical Trials

The efficacy and safety of OXERVATE were established in the largest clinical trial program conducted in patients with neurotrophic keratitis

Clinical Trials  / 

    OXERVATE study design

    Two independent, double-masked, randomized, multicenter, controlled clinical trials

    Study REPARO (NGF0212) (Europe, N=156*)3

    All patients enrolled had moderate (stage 2) or severe (stage 3) neurotrophic keratitis.


    *Phase II data only.
    †The formulation that was tested in REPARO (Study NGF0212) did not include the antioxidant methionine and is not the final formulation that is marketed as OXERVATE. Methionine is an excipient added to the commercial formulation to improve its stability. More than one study was conducted with the final commercial formulation. No difference in safety was seen in either of the trials.
    Twenty-three vehicle-treated patients were allowed to cross over, at their physicians’ discretion, to receive 8 weeks of uncontrolled treatment of cenegermin 10 mcg/mL or cenegermin-bkbj 20 mcg/mL.

    Select baseline characteristics from REPARO (NGF0212) study3

    OXERVATE pivotal trials included a diverse pool of neurotrophic keratitis patients

    Select baseline characteristics from REPARO (NGF0212) study*

    OXERVATE
    20 mcg/mL† (n=52)    		 Vehicle
    (n=52)
    Primary neurotrophic keratitis diagnosis, no. (%)
    Stage 2 (moderate)
    Stage 3 (severe)
    27 (51.9)
    25 (48.1)
    28 (53.8)
    24 (46.2)
    Underlying cause, no. (%)
    Herpetic eye disease 11 (21.2) 18 (34.6)
    Neurosurgical procedure 8 (15.2) 7 (13.5)
    Ocular surgery or procedure 5 (9.6) 7 (13.4)
    Dry eye disease 6 (11.5) 5 (9.6)
    Non-DED ocular surface injury/inflammation 5 (9.6) 5 (9.6)
    Other 5 (9.6) 3 (5.8)
    Topical medication (glaucoma) 1 (1.9) 1 (1.9)
    Stroke 2 (3.8) 0
    Unknown origin 1 (1.9) 0
    Systemic medication 0 0

    *Baseline characteristics were similar across all treatment arms.
    †The formulation that was tested in REPARO (Study NGF0212) did not include the antioxidant methionine and is not the final formulation that is marketed as OXERVATE. Methionine is an excipient added to the commercial formulation to improve its stability. More than one study was conducted with the final commercial formulation. No difference in safety was seen in either of the trials.

    NGF0214 (United States, n=48)5,8

    All patients enrolled had moderate (stage 2) or severe (stage 3) neurotrophic keratitis.

    Select Baseline Characteristics from NGF0214 Study5,*

    OXERVATE pivotal trials included a diverse pool of neurotrophic keratitis patients

    Select baseline characteristics from NGF0214 study

    OXERVATE
    20 mcg/mL (n=24)    		 Vehicle
    (n=24)
    Primary neurotrophic keratitis diagnosis, no. (%)
    Stage 2 (moderate)
    Stage 3 (severe)
    15 (62.5)
    9 (37.5)
    18 (75.0)
    6 (25.0)
    Underlying cause, no. (%)
    Herpetic eye disease 9 (37.5) 8 (33.3)
    Other 1 (4.2) 5 (20.8)
    Ocular surgery or procedure 3 (12.5) 4 (16.7)
    Dry eye disease 3 (12.5) 3 (12.5)
    Corneal dystrophy 2 (8.3) 1 (4.2)
    Ocular surface injury/inflammation 2 (8.3) 1 (4.2)
    Neurosurgical procedure 1 (4.2) 1 (4.2)
    Diabetes mellitus 0 1 (4.2)
    Multifactorial 2 (8.3) 0
    Topical medication (glaucoma) 1 (4.2) 0

    *Baseline characteristics were similar across all treatment arms.

    OXERVATE clinical efficacy

    With OXERVATE, up to 72% of patients achieved complete corneal healing1,3

    Primary efficacy analysis: complete corneal healing at 8 weeks

    Complete corneal healing was defined as the absence of staining of the corneal lesion and no persistent staining in the rest of the cornea after 8 weeks of treatment.3

    *The formulation that was tested in REPARO (Study NGF0212) did not include the antioxidant methionine and is not the final formulation that is marketed as OXERVATE. Methionine is an excipient added to the commercial formulation to improve its stability. More than one study was conducted with the final commercial formulation. No difference in safety was seen in either of the trials.

    OXERVATE Clinical Trials– Efficacy, Safety & Side Effects 8
    Up to 72% of patients treated with an 8-week course of OXERVATE achieved complete healing. 80% of those patients remained completely healed at 1 year.*
    *Based on results from REPARO (NGF0212) trial only.

    NGF0214 and additional studies with formulations also containing L-methionine were conducted and well-tolerated.

    OXERVATE was well-tolerated in clinical trials

    Most adverse events were local, mild, transient, and did not require treatment discontinuation.3

    OXERVATE Clinical Trials– Efficacy, Safety & Side Effects 16 %

    The most common adverse reaction was eye pain following instillation, which was reported in approximately 16% of patients.

    OXERVATE Clinical Trials– Efficacy, Safety & Side Effects 1 -10 % %

    Other adverse reactions occurring in 1% to 10% of patients taking OXERVATE and more frequently than in the vehicle-treated patients included corneal deposits, foreign body sensation, ocular hyperemia, ocular inflammation, and tearing.

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    (cenegermin-bkbj) ophthalmic solution 0.002%
    (20 mcg/mL)

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    Important Safety Information

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

    Important Safety Information

    MORE LESS

    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.

    Important Safety Information

    MORE LESS

    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% (20 mcg/mL) [US package insert]. Boston, MA: Dompé U.S. Inc.; 2018.
    2. Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin Ophthalm. 2014 Mar;8:571-579.
    3. 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.
    4. Mastropasqua L, Massaro-Giordano G, Nubile M, Sacchetti M. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J Cell Physiol. 2017 Apr;232;(4):717-724.
    5. Data on File. NGF0214.
    6. Müller LJ, Marfurt CF, Kruse F, et al. Corneal nerves: structure, contents and function. Exp Eye Res. 2003 May;76(5):521-542.
    7. Friedman NJ, Kaiser PK, Trattler B. Review of Ophthalmology. 3rd ed. Edinburgh: Elsevier; 2018.
    8. Drug approval package: OXERVATE (cenegermin-bkbj) [Internet]. U.S. Food and Drug Administration. 2018 Sep [cited 2018 Nov 13]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761094Orig1s000TOC.cfm

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