Cenegermin
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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
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Corneal ulceration •••••••••••• ••••• •••••••• Treatment of Neurotrophic keratitis •••••••••••• •••••••• Treatment of Persistent 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
Target Actions Organism AHigh affinity nerve growth factor receptor stimulatorHumans ATumor necrosis factor receptor superfamily member 16 stimulatorHumans - 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
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Oxervate Solution / drops 20 ug/1mL Ophthalmic Dompe' Farmaceutici S.P.A. 2018-11-26 Not applicable US Oxervate Solution / drops 20 mcg/ml Ophthalmic Dompe' Farmaceutici S.P.A. 2020-12-22 Not applicable EU Oxervate Kit; Solution / drops 20 ug/1mL Ophthalmic Dompe' Farmaceutici S.P.A. 2018-11-26 Not applicable US Oxervate Solution 0.002 % Ophthalmic Dompe' Farmaceutici S.P.A. 2022-02-18 2024-07-17 Canada
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
- Dompe Farmaceutici SpA Cenegermin FDA Approval Press Release [Link]
- FDA Approved Drug Products: OXERVATE (cenegermin-bkbj) solution [Link]
- FDA Approved Drug Products: OXERVATE® (cenegermin-bkbj) ophthalmic solution, for topical ophthalmic use (Dec 2023) [Link]
- EMA Approved Drug Products: OXERVATE (cenegermin) solution, for opthalmic use [Link]
- EMA Cenegermin Assessment Report [Link]
- External Links
- 2104332
- Wikipedia
- Cenegermin
- FDA label
- Download (575 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Neurotrophic Keratopathy 3 somestatus stop reason just information to hide Not Available Recruiting Not Available Neurotrophic Corneal Ulcer / Neurotrophic Keratoconjunctivitis / Neurotrophic Keratopathy / Neurotrophic Ulcers 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Neurotrophic Keratopathy 1 somestatus stop reason just information to hide 4 Active Not Recruiting Treatment Keratitis, Ulcerative / Neurotrophic Keratopathy 1 somestatus stop reason just information to hide 4 Completed Treatment Neurotrophic Keratopathy 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Kit; solution / drops Ophthalmic 20 ug/1mL Solution Ophthalmic 0.002 % Solution / drops Ophthalmic 20 ug/1mL Solution / drops Ophthalmic 20 MCG/ML - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Stimulator
- General 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 sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand (PubMed:1281417, PubMed:15488758, PubMed:17196528, PubMed:1849459, PubMed:1850821, PubMed:22649032, PubMed:27445338, PubMed:8325889). Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival (By similarity). Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:1281417). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors
- Specific Function
- ATP binding
- Gene Name
- NTRK1
- Uniprot ID
- P04629
- Uniprot Name
- High affinity nerve growth factor receptor
- Molecular Weight
- 87496.465 Da
References
- 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
- 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