Cenegermin

Identification

Summary

Cenegermin is a recombinant human nerve growth factor used to treat neurotrophic keratitis.

Brand Names
Oxervate
Generic Name
Cenegermin
DrugBank Accession Number
DB13926
Background

Cenegermin is a human beta-nerve growth factor (beta-ngf)-(1-118)- peptide (non-covalent dimer) produced in escherichia coli. It received European Union Approval in July 2017 for the treatment of moderate to severe neurotrophic keratitis. Cenegermin received approval from the US FDA a year later in August of 2018. 1

Neurotrophic keratitis is a degenerative disease resulting from a loss of corneal sensation. The loss of corneal sensation impairs corneal health, causing progressive damage to the top layer of the cornea, including corneal thinning, ulceration, and perforation in severe cases. The prevalence of neurotrophic keratitis has been estimated to be less than five in 10,000 individuals. 1

While the prevalence of neurotrophic keratitis is low, the impact of this serious condition and its associated sequelae on an individual patient can be debilitating. Many currently available therapeutic options for treating the condition involve surgical interventions - surgeries that are typically only palliative 1. The approval of cenegermin consequently provides a novel topical treatment that has the potential capacity to offer total corneal healing for many patients who may use the agent.1

In particular, cenegermin was granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months of application filing where the agency determines that the drug, if approved, would provide a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious condition. Cenegermin also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Protein Chemical Formula
C583H908N166O173S8
Protein Average Weight
13226.0 Da
Sequences
Not Available
Synonyms
  • Cenegermin
  • cenegermin-bkbj

Pharmacology

Indication

Cenegermin is indicated for the treatment of moderate (persistent epithelial defect) or severe (corneal ulcer) neurotrophic keratitis in adults by the FDA and EMA.4,3

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofCorneal ulceration•••••••••••••••••••••••••
Treatment ofNeurotrophic keratitis••••••••••••••••••••
Treatment ofPersistent corneal epithelial defects•••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

No pharmacodynamic studies have been conducted in humans.3

Mechanism of action

Cenegermin is a recombinant form of human nerve growth factor.4

Neurotrophic keratitis is a degenerative disease resulting from a loss of corneal sensation. The loss of corneal sensation impairs corneal health, causing progressive damage to the top layer of the cornea, including corneal thinning, ulceration, and perforation in severe cases.1

Nerve growth factor is subsequently 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. Nerve growth factor receptors are expressed in the anterior segment of the eye (cornea, conjunctiva, iris, ciliary body, and lens), by the lacrimal gland, and by posterior segment intraocular tissues. The treatment with cenegermin, administered as eye drops, is intended to allow restoration of corneal integrity.4

TargetActionsOrganism
AHigh affinity nerve growth factor receptor
stimulator
Humans
ATumor necrosis factor receptor superfamily member 16
stimulator
Humans
Absorption

Cenegermin is mostly removed from the eye with the tear production and through the naso-lacrimal duct; the minor portion that is absorbed occurs mostly in the conjunctiva and peri-orbital tissue and to a minor extent through the cornea following ocular administration [F1502]. Pharmacokinetic profiling of patients included in studies found no accumulation effect of cenegermin [F1502]. In general, the systemic absorption of cenegermin is negligible.4

Volume of distribution

After eye drop administration, cenegermin is distributed particularly in the anterior portion of the eye, although a study with radiolabelled cenegermin in rats has shown that it also reaches the retina and other posterior parts of the eye at doses significantly higher than those administered by eye drops in humans to treat neurotrophic keratitis. At the ocular doses, cenegermin is not distributed throughout body tissues as there is no systemic absorption above the natural baseline levels.4

Protein binding

In general, the systemic absorption of cenegermin is negligible.4

Metabolism

As a protein, rhNGF is catabolised by standard proteolytic pathways with its constituent amino acids being added to the general body pool likely by local tissue proteases.5

Route of elimination

Cenegermin is mostly removed from the eye with the tear production and through the naso-lacrimal duct: a good portion of the protein through the nasolacrimal duct reaches the nasal and then the oropharyngeal cavity and is then degraded by proteases.4,5

Half-life

Half-life data specific to human administration is not readily accessible or available.4,5

Clearance

Although the systemic absorption of cenegermin is negligible in general, clearance data specific to human administration is not readily accessible or available.4,5

Adverse Effects
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Toxicity

There are no data from the use of cenegermin-bkbj 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.3

Animal studies have not been conducted to determine the carcinogenic and mutagenic potential of cenegermin-bkbj.3

Daily subcutaneous administration of cenegermin-bkbj to male and female rats for at least 14 days prior mating, and at least 18 days post-coitum had no effect on fertility parameters in male or female rats at doses up to 267 mcg/kg/day (1709 times the MRHOD).3

In general toxicology studies, subcutaneous and ocular administration of cenegermin-bkbj infemales was associated with ovarian findings including persistent estrus, ovarian follicular cysts, atrophy/reduction of corpora lutea, and changes in ovarian weight at doses greater than or equal to 19 mcg/kg/day (119 times the MRHOD).3

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OxervateSolution0.002 %OphthalmicDompé farmaceutici S.p.A.2022-02-18Not applicableCanada flag
OxervateSolution / drops20 ug/1mLOphthalmicDompé farmaceutici S.p.A.2018-11-26Not applicableUS flag
OxervateSolution / drops20 mcg/mlOphthalmicDompé farmaceutici S.p.A.2020-12-22Not applicableEU flag
OxervateKit; Solution / drops20 ug/1mLOphthalmicDompé farmaceutici S.p.A.2018-11-26Not applicableUS flag

Categories

ATC Codes
S01XA24 — Cenegermin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
B6E7K36KT8
CAS number
1772578-74-1

References

General References
  1. Dompe Farmaceutici SpA Cenegermin FDA Approval Press Release [Link]
  2. FDA Approved Drug Products: OXERVATE (cenegermin-bkbj) solution [Link]
  3. FDA Approved Drug Products: OXERVATE® (cenegermin-bkbj) ophthalmic solution, for topical ophthalmic use (Dec 2023) [Link]
  4. EMA Approved Drug Products: OXERVATE (cenegermin) solution, for opthalmic use [Link]
  5. EMA Cenegermin Assessment Report [Link]
RxNav
2104332
Wikipedia
Cenegermin
FDA label
Download (575 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentNeurotrophic Keratopathy1
3Active Not RecruitingTreatmentDry Eyes1
3CompletedTreatmentDry Eye Syndrome (DES)1
2CompletedTreatmentDry Eye Syndrome (DES)2
2CompletedTreatmentDry Eyes1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Kit; solution / dropsOphthalmic20 ug/1mL
SolutionOphthalmic0.002 %
Solution / dropsOphthalmic20 MCG/ML
Solution / dropsOphthalmic20 ug/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Stimulator
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympatheti...
Gene Name
NTRK1
Uniprot ID
P04629
Uniprot Name
High affinity nerve growth factor receptor
Molecular Weight
87496.465 Da
References
  1. FDA Approved Drug Products: OXERVATE® (cenegermin-bkbj) ophthalmic solution, for topical ophthalmic use (Dec 2023) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Stimulator
General Function
Low affinity receptor which can bind to NGF, BDNF, NTF3, and NTF4. Forms a heterodimeric receptor with SORCS2 that binds the precursor forms of NGF, BDNF and NTF3 with high affinity, and has much lower affinity for mature NGF and BDNF (PubMed:24908487). Plays an important role in differentiation and survival of specific neuronal populations during development (By similarity). Can mediate cell survival as well as cell death of neural cells. Plays a role in the inactivation of RHOA (PubMed:26646181). Plays a role in the regulation of the translocation of GLUT4 to the cell surface in adipocytes and skeletal muscle cells in response to insulin, probably by regulating RAB31 activity, and thereby contributes to the regulation of insulin-dependent glucose uptake (By similarity). Necessary for the circadian oscillation of the clock genes BMAL1, PER1, PER2 and NR1D1 in the suprachiasmatic nucleus (SCmgetaN) of the brain and in liver and of the genes involved in glucose and lipid metabolism in the liver (PubMed:23785138).
Specific Function
Amyloid-beta binding
Gene Name
NGFR
Uniprot ID
P08138
Uniprot Name
Tumor necrosis factor receptor superfamily member 16
Molecular Weight
45182.98 Da
References
  1. FDA Approved Drug Products: OXERVATE® (cenegermin-bkbj) ophthalmic solution, for topical ophthalmic use (Dec 2023) [Link]

Drug created at December 01, 2017 18:18 / Updated at February 05, 2024 00:28