Identification

Name
Cenegermin
Accession Number
DB13926
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

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 [1]. 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]. 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 [1]. Cenegermin also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases [1].

Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
  • rhNGF
International/Other Brands
Oxervate (Dompe farmaceutici s.p.a.)
Categories
Not Available
UNII
B6E7K36KT8
CAS number
1772578-74-1

Pharmacology

Indication

Cenegermin is indicated for the treatment of moderate (persistent epithelial defect) or severe (corneal ulcer) neurotrophic keratitis in adults [Label].

Associated Conditions
Pharmacodynamics

Little to no pharmacodynamic studies have yet been conducted in humans [Label].

Mechanism of action

Cenegermin is a recombinant form of human nerve growth factor [Label].

Neurotrophic keratitis is a degenerative disease resulting from a loss of corneal sensation [1]. 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 [Label]. 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 [Label]. The treatment with cenegermin, administered as eye drops, is intended to allow restoration of corneal integrity [Label].

TargetActionsOrganism
UHigh affinity nerve growth factor receptor
stimulator
Human
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 [2]. Pharmacokinetic profiling of patients included in studies found no accumulation effect of cenegermin [2]. In general, the systemic absorption of cenegermin is negligible [2].

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 [2]. At the ocular doses, cenegermin is not distributed throughout body tissues as there is no systemic absorption above the natural baseline levels [2].

Protein binding

In general, the systemic absorption of cenegermin is negligible [2].

Metabolism

Ocularly administered cenegermin is mainly eliminated by tear secretion and the remainder mostly biotransformed by local tissue proteases [2].

Route of elimination

Cenegermin administered by eye drops is mostly eliminated with the tear secretion [2].

Half life

Half life data specific to human administration is not readily accessible or available [Label].

Clearance

ALthough the systemic absorption of cenegermin is negligible in general [2], clearance data specific to human administration is not readily accessible or available [Label].

Toxicity

There are no data from the use of cenegermin in pregnant women [Label]. Systemic exposure to cenegermin is negligible or does not occur [2]. As a precautionary measure, it is preferable to avoid the use of OXERVATE during pregnancy [2].

It is not known whether cenegermin is excreted in human milk [Label]. A risk to the suckling child cannot be excluded [2]. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from this therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman [2].

The safety and effectiveness of cenegermin have been established in the pediatric population [Label]. Use of cenegermin in this population is supported by evidence from adequate and well controlled trials of cenegermin in adults with additional safety data in pediatric patients from 2 years of age and older [Label].

Of the total number of subjects in clinical studies of cenegermin, 43.5 % were 65 years old and over [Label]. No overall differences in safety or effectiveness were observed between elderly and younger adult patients [Label].

There are no data on the effects of cenegermin on human fertility [Label].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Dompe Farmaceutici SpA Cenegermin FDA Approval Press Release [Link]
  2. Cenegermin EMA Label [File]
  3. Cenegermin EMA Assessment Report [File]
External Links
Wikipedia
Cenegermin
FDA label
Download (575 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentGlaucoma1
1, 2CompletedTreatmentCorneal Inflammation / Neurotrophic Keratitis / Ulcerative keratitis1
1, 2CompletedTreatmentRetinitis Pigmentosa (RP)1
2CompletedTreatmentDry Eye Syndrome (DES)1
2CompletedTreatmentEye Dryness1
2CompletedTreatmentNeurotrophic Keratitis1
2CompletedTreatmentOcular Discomfort1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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

Drug created on December 01, 2017 11:18 / Updated on November 02, 2018 07:47