Identification

Summary

Plasminogen is plasma-derived human plasminogen administered intravenously to treat type 1 plasminogen deficiency (hypoplasminogenemia).

Brand Names
Ryplazim
Generic Name
Plasminogen
DrugBank Accession Number
DB16701
Background

Plasminogen is a pro-enzyme (i.e. a zymogen) which is cleaved to form plasmin - also known as fibrinolysin - as part of the fibrinolytic pathway that breaks down fibrin blood clots.1 This pathway is activated when a clot is no longer needed or to prevent a clot from extending beyond the site of injury.6

In June 2021, the FDA approved a plasma-derived plasminogen (Ryplazim, human plasminogen-tvmh)4 for the treatment of type 1 plasminogen deficiency (hypoplasminogenemia).3 It is the first and only FDA-approved treatment for this condition, which causes wood-like lesions to form on the mucous membranes of patients, providing an unmet medical need for patients with this rare congenital disease.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Blood factors
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
>Human Plasminogen:
MEHKEVVLLLLLFLKSGQGEPLDDYVNTQGASLFSVTKKQLGAGSIEECAAKCEEDEEFT
CRAFQYHSKEQQCVIMAENRKSSIIIRMRDVVLFEKKVYLSECKTGNGKNYRGTMSKTKN
GITCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILE
CEEECMHCSGENYDGKISKTMSGLECQAWDSQSPHAHGYIPSKFPNKNLKKNYCRNPDRE
LRPWCFTTDPNKRWELCDIPRCTTPPPSSGPTYQCLKGTGENYRGNVAVTVSGHTCQHWS
AQTPHTHNRTPENFPCKNLDENYCRNPDGKRAPWCHTTNSQVRWEYCKIPSCDSSPVSTE
QLAPTAPPELTPVVQDCYHGDGQSYRGTSSTTTTGKKCQSWSSMTPHRHQKTPENYPNAG
LTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKKCSGTEASVVAPPPVVLLPDVETPSEED
CMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGG
PWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRT
RFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLE
PTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQ
LPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSW
GLGCARPNKPGVYVRVSRFVTWIEGVMRNN
References:
  1. UniProt: Human Plasminogen (PLMN_HUMAN) [Link]
Download FASTA Format
Synonyms
  • 1-glutamylplasminogen
  • Human plasminogen
  • Plasma trypsinogen
  • plasminogen, human-tvmh
  • Profibrinolysin

Pharmacology

Indication

Plasma-derived human plasminogen, marketed under the brand name Ryplazim, is indicated for the treatment of patients with plasminogen deficiency type 1 (hypoplasminogenemia).4

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

The intravenous administration of plasminogen temporarily increases levels of plasminogen in the blood, allowing for the reduction or resolution of the lignous lesions associated with plasminogen deficiency.4 Therapy is administered periodically, every 2 to 4 days, to prevent any significant build-up of these lesions between doses.

Plasminogen administration can lead to tissue sloughing at mucosal sites where lignous lesions have built up, which may lead to organ or airway obstruction depending on the site of the lesion(s). Patients should be monitored for at least 4 hours post-administration, especially patients with evidence of airway involvement, to ensure airway management and respiratory support is readily available.4

Mechanism of action

Plasminogen is a zymogen produced in the liver which, when cleaved into its active form, breaks down fibrin blood clots.1 This active form, called plasmin or fibrinolysin, is generated when tissue plasminogen activator (tPA) or urokinase-like plasminogen activator (uPA) cleave plasminogen to begin the fibrinolytic pathway.6 Blood clots are broken down by plasmin into soluble fibrin and fibrinogen degradation products when the clot is no longer needed.6

Type 1 plasminogen deficiency, also called hypoplasminogenemia, is a congenital disorder in which patients are deficient in plasminogen. Interestingly, this disease does not increase the risk of clotting, but rather results in the formation of lignous pseudomembranous lesions on the mucous membranes of the body.5 Lesions range in location and severity but can lead to severe long-term consequences if left untreated. For example, lignous conjunctivitis, the most common manifestation of type 1 plasminogen deficiency, may lead to corneal tearing and blindness.2

Human plasminogen is administered topically (e.g. in eye drops) or intravenously (i.e. Ryplazim) in order to temporarily increase local or serum levels of fibrinogen. When this therapy is administered every 2 to 4 days, it prevents the build-up of lignous lesions and allows existing lesions to be shed.

Absorption

Following 12 weeks of intravenous administration every 2 to 4 days, the mean AUCinf of Ryplazim was 5731.8 hr*% and its Cmax was approximately 125% of the mean physiological level (normal: 70-130%).4 After 12 weeks of therapy, physiological plasminogen levels were sustained for approximately 24 hours post-dose and patients maintained a 10% absolute increase in plasminogen concentration for up to 96 hours after administration.4

Volume of distribution

The mean steady-state volume of distribution of Ryplazim is approximately 49.3 mL/kg.4

Protein binding

Not Available

Metabolism

Plasminogen is a zymogen which is converted into the active fibrinolytic plasmin, or fibrinolysin, by tissue plasminogen activator (tPA) or urokinase-like plasminogen activator (uPA).6,1

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Route of elimination

Not Available

Half-life

The mean half-life of Ryplazim at steady-state is approximately 39.2 hours.4

Clearance

The clearance of Ryplazim appears to slow with extended use. Following the first intravenous dose the mean clearance of Ryplazim was 1.4 mL/hr/kg, while following an intravenous dose at week 12 the mean clearance was 0.9 mL/hr/kg.4

Adverse Effects
Adverseeffects
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Toxicity

There are no data regarding overdose of intravenously administered human plasminogen.

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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International/Other Brands
Ryplazim (Liminal BioSciences Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RyplazimInjection, powder, lyophilized, for solution68.8 mg/1IntravenousPrometic Biotherapeutics, Inc.2021-06-04Not applicableUS flag

Categories

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

Chemical Identifiers

UNII
1EF190B6M7
CAS number
9001-91-6

References

General References
  1. Katz JM, Tadi P: Physiology, Plasminogen Activation . [Article]
  2. Schuster V, Hugle B, Tefs K: Plasminogen deficiency. J Thromb Haemost. 2007 Dec;5(12):2315-22. doi: 10.1111/j.1538-7836.2007.02776.x. Epub 2007 Sep 26. [Article]
  3. FDA News Release: FDA Approves First Treatment for Patients with Plasminogen Deficiency, a Rare Genetic Disorder [Link]
  4. FDA Approved Drug Products: Ryplazim (plasminogen, human-tvmh) powder for reconsitution for intravenous injection [Link]
  5. National Organization for Rare Disorders: Congenital Plasminogen Deficiency [Link]
  6. Pathology Outlines: Anticoagulation / fibrinolytic pathway [Link]
UniProt
P00747
RxNav
2557200
Wikipedia
Plasmin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4TerminatedTreatmentPulmonary Embolism / Pulmonary Embolism Subacute Massive / Pulmonary Embolism With Acute Cor Pulmonale / Pulmonary Embolism With Pulmonary Infarction / Ventricular Dysfunction, Right / Ventricular Failure, Right1
4Unknown StatusTreatmentAcute Myocardial Infarction With ST Segment Elevation1
3Enrolling by InvitationTreatmentLigneous Conjunctivitis, Left Eye1
3RecruitingTreatmentStroke, Acute, Stroke Ischemic1
3Unknown StatusTreatmentCerebrovascular Accident1
2CompletedTreatmentAcute Peripheral Arterial Occlusion1
2Not Yet RecruitingTreatmentAcute Pulmonary Embolism (PE)1
2Not Yet RecruitingTreatmentStroke, Acute, Stroke Ischemic1
2, 3CompletedTreatmentCongenital Plasminogen Deficiency / Type I Plasminogen Deficiency1
2, 3CompletedTreatmentLigneous Conjunctivitis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous68.8 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Serine-type endopeptidase activity
Specific Function
Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen. By controlling plasmin-mediated proteolysis, it plays an important role in t...
Gene Name
PLAT
Uniprot ID
P00750
Uniprot Name
Tissue-type plasminogen activator
Molecular Weight
62916.495 Da
References
  1. Katz JM, Tadi P: Physiology, Plasminogen Activation . [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Serine-type endopeptidase activity
Specific Function
Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.
Gene Name
PLAU
Uniprot ID
P00749
Uniprot Name
Urokinase-type plasminogen activator
Molecular Weight
48507.09 Da
References
  1. Katz JM, Tadi P: Physiology, Plasminogen Activation . [Article]

Drug created at June 17, 2021 16:59 / Updated at June 22, 2021 18:16