NAV

Rozanolixizumab

Identification

Summary

Rozanolixizumab is a humanized monoclonal antibody targeting the human neonatal Fc receptor (FcRn) used to treat generalized myasthenia gravis.

Brand Names
Rystiggo
Generic Name
Rozanolixizumab
DrugBank Accession Number
DB14919
Background

Rozanolixizumab is a humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (IgG4P) targeting the immunoglobulin G (IgG). Rozonolixizumab itself is an IgG4P, an inactive isotype, to reduce the likelihood of unwanted chain exchange.1 It is investigated for use in autoimmune and alloimmune diseases with pathologic IgG, particularly generalized myasthenia gravis.2 Generalized myasthenia gravis is characterized by the formation of IgG antibodies against the nicotinic acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK).3,4,5 Approximately 80% of myasthenia gravis patients tested positive for the AChR autoantibodies, and 40% of these AChR-negative or seronegative patients were found to have MuSK autoantibodies.7

AChR is vital for signal transduction in the neuromuscular junctions (NMJ) by generating muscle end plate potentials to propagate action potential.4 Therefore, the presence of AChR-antibodies can interfere with the ACh-mediated downstream signaling, thus reducing the likelihood of end plate potentials reaching the threshold needed to trigger an action potential.4 As a result, the main clinical manifestation of myasthenia gravis is easily fatigable or persistent muscle weakness.4 On the other hand, MuSK activation can trigger the clustering of AChR at the NMJ, guide the innervation of motor neurons toward AChR-dense areas, and anchor acetylcholinesterase.3,6 Therefore, autoantibodies against MuSK can also affect the signal propagation at the NMJ.

Rozanolixizumab-noli is available under the brand name RYSTIGGO and was developed by UCB.9 It was granted orphan drug designation by the FDA in 2019, by the European Medicines Agency (EMA) in April 2020, and by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) in November 2020.9 In June 2023, Rozanolixizumab-noli was approved by the FDA under Priority Review for the treatment of adult patients with generalized myasthenia gravis who are positive for the anti-acetylcholine receptor (AchR) or anti-muscle-specific tyrosine kinase (MuSK) antibody.9 This is due to the efficacy demonstrated in the pivotal Phase 3 MycarinG study (NCT03971422).9

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
148000.0 Da
Sequences
Not Available
Synonyms
  • Rozanolixizumab
  • UCB7665
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Pharmacology

Indication

Rozanolixizumab-noli is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive.8

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofGeneralized myasthenia gravis••••••••••••••••••••••••••••••••••••• •••••••• •••••• •••••• •••••••• ••••••••• •••••••••••••••••• •••••••• •••••••• •••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

The pharmacological effect of rozanolixizumab-noli was assessed by measuring the decrease in serum IgG levels and AChR and MuSK autoantibody levels. In patients testing positive for AChR and MuSK autoantibodies who were treated with RYSTIGGO, there was a reduction in total IgG levels relative to baseline. Decreases in AChR autoantibody and MuSK autoantibody levels followed a similar pattern.8

Mechanism of action

Rozanolixizumab-noli is a humanized IgG4 monoclonal antibody that binds to the neonatal Fc receptor (FcRn), resulting in the reduction of circulating IgG.8

TargetActionsOrganism
AIgG receptor FcRn large subunit p51
antibody
Humans
Absorption

Rozanolixizumab-noli exhibited nonlinear pharmacokinetics. Rozanolixizumab-noli exposure increased in a greater than dose-proportional manner over a dose range from 1 mg/kg to 20 mg/kg (two times the maximum recommended dose) following subcutaneous administration.8

Following subcutaneous administration of rozanolixizumab-noli, peak plasma levels were achieved after approximately 2 days in healthy subjects.8

Volume of distribution

The apparent volume of distribution of rozanolixizumab-noli is 6.6 L.8

Protein binding

Not Available

Metabolism

Rozanolixizumab-noli is expected to be degraded by proteolytic enzymes into small peptides and amino acids.8

Route of elimination

Not Available

Half-life

Not Available

Clearance

The apparent clearance for the rozanolixizumab-noli is 0.89 L/day.8

Adverse Effects
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Toxicity

There are limited data on rozanolixizumab-noli use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Following the administration of rozanolixizumab-noli to pregnant monkeys at doses greater than those used clinically, increases in embryonic death, reduced body weight, and impaired immune function were observed in the absence of maternal toxicity.8

Subcutaneous administration of rozanolixizumab-noli (0 or 150 mg/kg) every 3 days for 26 weeks to sexually mature cynomolgus monkeys resulted in no adverse effects on sperm parameters (count, motility, or morphology) or estrus cyclicity. The dose tested in monkeys is 30 times the maximum recommended human dose of approximately 10 mg/kg, on a mg/kg/week basis.8

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.
DrugInteraction
Integrate drug-drug
interactions in your software
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Rozanolixizumab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Rozanolixizumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Rozanolixizumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Rozanolixizumab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Rozanolixizumab.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RystiggoInjection, solution140 mg/1mLSubcutaneousUCB, Inc.2023-06-26Not 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
Not Available

Chemical Identifiers

UNII
P7186074QC
CAS number
1584645-37-3

References

General References
  1. Kiessling P, Lledo-Garcia R, Watanabe S, Langdon G, Tran D, Bari M, Christodoulou L, Jones E, Price G, Smith B, Brennan F, White I, Jolles S: The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study. Sci Transl Med. 2017 Nov 1;9(414):eaan1208. doi: 10.1126/scitranslmed.aan1208. [Article]
  2. Smith B, Kiessling A, Lledo-Garcia R, Dixon KL, Christodoulou L, Catley MC, Atherfold P, D'Hooghe LE, Finney H, Greenslade K, Hailu H, Kevorkian L, Lightwood D, Meier C, Munro R, Qureshi O, Sarkar K, Shaw SP, Tewari R, Turner A, Tyson K, West S, Shaw S, Brennan FR: Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration. MAbs. 2018 Oct;10(7):1111-1130. doi: 10.1080/19420862.2018.1505464. Epub 2018 Sep 12. [Article]
  3. Rivner MH, Pasnoor M, Dimachkie MM, Barohn RJ, Mei L: Muscle-Specific Tyrosine Kinase and Myasthenia Gravis Owing to Other Antibodies. Neurol Clin. 2018 May;36(2):293-310. doi: 10.1016/j.ncl.2018.01.004. [Article]
  4. Gable KL, Guptill JT: Antagonism of the Neonatal Fc Receptor as an Emerging Treatment for Myasthenia Gravis. Front Immunol. 2020 Jan 10;10:3052. doi: 10.3389/fimmu.2019.03052. eCollection 2019. [Article]
  5. Rodolico C, Bonanno C, Toscano A, Vita G: MuSK-Associated Myasthenia Gravis: Clinical Features and Management. Front Neurol. 2020 Jul 23;11:660. doi: 10.3389/fneur.2020.00660. eCollection 2020. [Article]
  6. Cao M, Koneczny I, Vincent A: Myasthenia Gravis With Antibodies Against Muscle Specific Kinase: An Update on Clinical Features, Pathophysiology and Treatment. Front Mol Neurosci. 2020 Sep 2;13:159. doi: 10.3389/fnmol.2020.00159. eCollection 2020. [Article]
  7. Huijbers MG, Zhang W, Klooster R, Niks EH, Friese MB, Straasheijm KR, Thijssen PE, Vrolijk H, Plomp JJ, Vogels P, Losen M, Van der Maarel SM, Burden SJ, Verschuuren JJ: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20783-8. doi: 10.1073/pnas.1313944110. Epub 2013 Dec 2. [Article]
  8. FDA Approved Drug Products: RYSTIGGO® (rozanolixizumab-noli) injection, for subcutaneous use [Link]
  9. UCB announces U.S. FDA approval of RYSTIGGO® (rozanolixizumab-noli) for the treatment of adults with generalized myasthenia gravis [Link]
RxNav
2642274
Wikipedia
Rozanolixizumab

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentGeneralized Myasthenia Gravis1
3CompletedTreatmentGeneralized Myasthenia Gravis3
3RecruitingTreatmentMyelin Oligodendrocyte Glycoprotein Antibody-associated Disease (MOG-AD)1
3TerminatedTreatmentPrimary Immune Thrombocytopenia (ITP)3
2Active Not RecruitingTreatmentFibromyalgia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous140 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Details1. IgG receptor FcRn large subunit p51
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Cell surface receptor that transfers passive humoral immunity from the mother to the newborn. Binds to the Fc region of monomeric immunoglobulin gamma and mediates its selective uptake from milk (PubMed:7964511, PubMed:10933786). IgG in the milk is bound at the apical surface of the intestinal epithelium. The resultant FcRn-IgG complexes are transcytosed across the intestinal epithelium and IgG is released from FcRn into blood or tissue fluids. Throughout life, contributes to effective humoral immunity by recycling IgG and extending its half-life in the circulation. Mechanistically, monomeric IgG binding to FcRn in acidic endosomes of endothelial and hematopoietic cells recycles IgG to the cell surface where it is released into the circulation (PubMed:10998088). In addition of IgG, regulates homeostasis of the other most abundant circulating protein albumin/ALB (PubMed:24469444, PubMed:28330995).
Specific Function
Beta-2-microglobulin binding
Gene Name
FCGRT
Uniprot ID
P55899
Uniprot Name
IgG receptor FcRn large subunit p51
Molecular Weight
39742.99 Da
References
  1. FDA Approved Drug Products: RYSTIGGO® (rozanolixizumab-noli) injection, for subcutaneous use [Link]

Drug created at May 20, 2019 14:35 / Updated at June 30, 2023 06:40