Identification

Summary

Lumasiran is lumasiran is an interfering RNA that silences hydroxyacid oxidase 1 for the treatment of primary hypoxaluria type 1.

Brand Names
Oxlumo
Generic Name
Lumasiran
DrugBank Accession Number
DB15935
Background

Lumasiran is a small interfering RNA used in the treatment of primary hyperoxaluria type 1 (PH1).6 This condition, caused by a deficiency in the enzyme alanine-glyoxylate aminotransferase, leads to an accumulation of oxalate, causing calcium crystal formation.6 These patients experience frequent kidney stones, nephrocalcinosis, and renal failure.6

Oxlumo, producted by Alnylam Pharmaceuticals, represents the first approved treatment for PH1.3 Prior to this approval, therapy consisted of symptomatic treatment such as hyperhydration, inhibitors of crystallization, pyridoxine, and renal transplant.6

Lumasiran was granted FDA approval on 23 November 2020.3

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Gene Therapies
Antisense oligonucleotides
Synonyms
  • Lumasiran
External IDs
  • AD-65585
  • ALN-65585
  • ALN-G01
  • ALN-GO1
  • WHO 10684

Pharmacology

Indication

Lumasiran is indicated for the treatment of primary hyperoxaluria type 1.3,5

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Lumasiran is a small interfering RNA that prevents the translation of glycolate oxidase, which reduces levels of glyoxylate, reducing metabolism of glyoxylate to oxalate.4,5 The duration of action is long as it is given every 3 months.5 Patients should be counselled regarding the risk of worsening metabolic acidosis in severe or end stage renal disease, as well as potentially decreased efficacy in moderate to severe hepatic impairment.5

Mechanism of action

Patients with primary hyperoxaluria type 1 produce an excess of oxalate due to a deficiency in the enzyme alanine-glyoxylate aminotransferase.2,4

Lumasiran is a small interfering RNA that silences the gene hydroxyacid oxidase 1 (HOA1).4 Lumasiran targets HOA1 mRNA, preventing translation to the enzyme glycolate oxidase (GO).5 Reduced levels of GO, reduce levels of glyoxylate, leaving less reactants available for metabolism to oxalate.5 In the ILLUMINATE trials, lumasiran reduced oxalate levels in 84% of adults and children over 6 years to at or below 1.5 times the upper limits of normal.4

TargetActionsOrganism
AHydroxyacid oxidase 1
antisense oligonucleotide
Humans
Absorption

In patients ≥20 kg; a 3 mg/kg subcutaneous dose of lumasiran reacheas a Cmax of 529 ng/mL, with a Tmax of 4.0 hours, and an AUC of 7400 ng*h/mL.5 In patients <20 kg; a 6 mg/kg subcutaneous dose of lumasiran reaches a Cmax of 912 ng/mL and an AUC of 7960 ng*h/mL.5

Volume of distribution

The apparent central volume of distribution based on population estimate is 4.9 L.5

Protein binding

Lumasiran is 77% to 85% bound to protein in plasma.5

Metabolism

Lumasiran is metabolized to smaller oligonucleotides by endo- and exonucleases.5 The sense strand is less prone to metabolism due to protection by the GalNac group at the 3' end.6

Lumasiran weakly inhibits CYP2C8 with an IC50 of 461 µM, 14000 times pharmacologically relevant concentrations.6 It is not a substrate or inducer of any CYP450 enzymes.6

Route of elimination

7-26% of a dose of lumasiran is recovered in the urine as the unmetabolized parent compound.5

A radiolabelled dose administered to rats was 19.5% recovered in urine and 33.9% recovered in feces.6

Half-life

The mean terminal half life of lumasiran is 5.2 hours.5

Clearance

The apparent plasma clearance of lumasiran based on population estimate is 26.5 L/h for an average 70 kg adult.5 The mean renal clearance is 2.0-3.4 L/h.5

Adverse Effects
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Toxicity

Data regarding overdoses of lumasiran are not readily available.5 In the event of an overdose, patients should be monitored for signs of adverse reactions and be treated symptomatically.5

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
Oxlumo
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OxlumoInjection, solution94.5 mg/0.5mLSubcutaneousAlnylam Netherlands B.V.2020-12-16Not applicableEU flag
OxlumoInjection, solution94.5 mg/0.5mLSubcutaneousAlnylam Pharmaceuticals, Inc.2020-11-23Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
RZT8C352O1
CAS number
1834610-13-7

References

General References
  1. McGregor TL, Hunt KA, Yee E, Mason D, Nioi P, Ticau S, Pelosi M, Loken PR, Finer S, Lawlor DA, Fauman EB, Huang QQ, Griffiths CJ, MacArthur DG, Trembath RC, Oglesbee D, Lieske JC, Erbe DV, Wright J, van Heel DA: Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria. Elife. 2020 Mar 24;9. pii: 54363. doi: 10.7554/eLife.54363. [Article]
  2. Dindo M, Conter C, Oppici E, Ceccarelli V, Marinucci L, Cellini B: Molecular basis of primary hyperoxaluria: clues to innovative treatments. Urolithiasis. 2019 Feb;47(1):67-78. doi: 10.1007/s00240-018-1089-z. Epub 2018 Nov 14. [Article]
  3. FDA News Release: FDA Approves First Drug to Treat Rare Metabolic Disorder [Link]
  4. Alylam Pharmaceuticals: Lumasiran Clinical Development Program [Link]
  5. EMA Summary of Product Characteristics: Oxlumo (Lumasiran) Subcutaneous Injection [Link]
  6. EMA Assessment Report: Oxlumo (Lumasiran) Subcutaneous Injection [Link]
RxNav
2467140
Wikipedia
Lumasiran

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentPrimary Hyperoxaluria Type 1 (PH1)1
3Active Not RecruitingTreatmentPrimary Hyperoxaluria / Primary Hyperoxaluria Type 1 (PH1)2
2Active Not RecruitingTreatmentAGT / PH1 / Primary Hyperoxaluria / RNAi Therapeutic / SiRNA1
2RecruitingTreatmentElevated Urinary Oxalate Levels / Recurrent Calcium Oxalate Kidney Stone Disease1
1, 2CompletedTreatmentPrimary Hyperoxaluria Type 1 (PH1)1
Not AvailableApproved for MarketingNot AvailablePrimary Hyperoxaluria1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous94.5 mg/0.5mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10131907No2018-11-202028-08-24US flag
US8106022No2012-01-312029-12-12US flag
US8828956No2014-09-092028-12-04US flag
US10478500No2019-11-192035-10-09US flag
US10612024No2020-04-072035-08-14US flag
US10612027No2020-04-072035-08-14US flag
US10465195No2019-11-052034-12-26US flag
US10435692No2019-10-082034-12-26US flag
US10487330No2019-11-262034-12-26US flag
US9828606No2017-11-282034-12-26US flag
US11060093No2014-12-262034-12-26US flag
US11261447No2018-11-202038-11-20US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility387 mg/mLEMA Assessment Report

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antisense oligonucleotide
General Function
Very-long-chain-(s)-2-hydroxy-acid oxidase activity
Specific Function
Has 2-hydroxyacid oxidase activity. Most active on the 2-carbon substrate glycolate, but is also active on 2-hydroxy fatty acids, with high activity towards 2-hydroxy palmitate and 2-hydroxy octano...
Gene Name
HAO1
Uniprot ID
Q9UJM8
Uniprot Name
Hydroxyacid oxidase 1
Molecular Weight
40923.945 Da
References
  1. McGregor TL, Hunt KA, Yee E, Mason D, Nioi P, Ticau S, Pelosi M, Loken PR, Finer S, Lawlor DA, Fauman EB, Huang QQ, Griffiths CJ, MacArthur DG, Trembath RC, Oglesbee D, Lieske JC, Erbe DV, Wright J, van Heel DA: Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria. Elife. 2020 Mar 24;9. pii: 54363. doi: 10.7554/eLife.54363. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. EMA Assessment Report: Oxlumo (Lumasiran) Subcutaneous Injection [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Geselowitz DA, Neckers LM: Bovine serum albumin is a major oligonucleotide-binding protein found on the surface of cultured cells. Antisense Res Dev. 1995 Fall;5(3):213-7. doi: 10.1089/ard.1995.5.213. [Article]

Drug created at November 24, 2020 23:54 / Updated at February 21, 2021 18:55