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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 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients.3,5,7
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Primary hyperoxaluria type i •••••••••••• •••••• ••••••••• ••••••••• - Contraindications & Blackbox Warnings
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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
Target Actions Organism A2-Hydroxyacid oxidase 1 antisense oligonucleotideHumans - 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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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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Ingredient UNII CAS InChI Key Lumasiran sodium 67P6XH37HD 1834612-06-4 Not applicable - International/Other Brands
- Oxlumo
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Oxlumo Injection, solution 94.5 mg/0.5mL Subcutaneous Alnylam Pharmaceuticals, Inc. 2020-11-23 Not applicable US 
Oxlumo Injection, solution 94.5 mg/0.5mL Subcutaneous Alnylam Netherlands B.V. 2020-12-16 Not applicable EU 
Oxlumo Solution 94.5 mg / 0.5 mL Subcutaneous Alnylam Netherlands B.V. 2022-05-05 Not applicable Canada 
Categories
- ATC Codes
- A16AX18 — Lumasiran
- Drug Categories
- Alimentary Tract and Metabolism
- Antisense Elements (Genetics)
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (weak)
- Cytochrome P-450 Enzyme Inhibitors
- Genitourinary Agents
- HAO1-directed Small Interfering Ribonucleic Acid (siRNA)
- Nucleic Acids
- Nucleic Acids, Nucleotides, and Nucleosides
- Renal Agents
- RNA, Antisense
- RNA, Small Untranslated
- RNA, Untranslated
- Small Interfering RNA
- Various Alimentary Tract and Metabolism Products
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- RZT8C352O1
- CAS number
- 1834610-13-7
References
- General References
- 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]
- 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]
- FDA News Release: FDA Approves First Drug to Treat Rare Metabolic Disorder [Link]
- Alylam Pharmaceuticals: Lumasiran Clinical Development Program [Link]
- EMA Summary of Product Characteristics: Oxlumo (Lumasiran) Subcutaneous Injection [Link]
- EMA Assessment Report: Oxlumo (Lumasiran) Subcutaneous Injection [Link]
- FDA Approved Drug Products: OXLUMO (lumasiran) injection, for subcutaneous use (October 2022) [Link]
- External Links
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 data3 Active Not Recruiting Treatment Primary Hyperoxaluria / Primary Hyperoxaluria Type 1 (PH1) 2 somestatus stop reason just information to hide 3 Completed Treatment Primary Hyperoxaluria Type 1 (PH1) 1 somestatus stop reason just information to hide 2 Completed Treatment AGT / PH1 / Primary Hyperoxaluria / RNAi Therapeutic / SiRNA 1 somestatus stop reason just information to hide 2 Recruiting Treatment Cardiovascular Disease (CVD) / Cardiovascular Risk / Chronic Kidney Disease Requiring Chronic Dialysis / Hemodialysis Treatment / Hyperoxalemia 1 somestatus stop reason just information to hide 2 Terminated Treatment Elevated Urinary Oxalate Levels / Recurrent Calcium Oxalate Kidney Stone Disease 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Subcutaneous 94.5 mg/0.5mL Solution Subcutaneous 94.5 mg / 0.5 mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10131907 No 2018-11-20 2028-08-24 US US8106022 No 2012-01-31 2029-12-12 US US8828956 No 2014-09-09 2028-12-04 US US10478500 No 2019-11-19 2035-10-09 US US10612024 No 2020-04-07 2035-08-14 US US10612027 No 2020-04-07 2035-08-14 US US10465195 No 2019-11-05 2034-12-26 US US10435692 No 2019-10-08 2034-12-26 US US10487330 No 2019-11-26 2034-12-26 US US9828606 No 2017-11-28 2034-12-26 US US11060093 No 2021-07-13 2034-12-26 US US11261447 No 2018-11-20 2038-11-20 US US11401517 No 2015-08-14 2035-08-14 US US11446380 No 2015-10-09 2035-10-09 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility 387 mg/mL EMA Assessment Report
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antisense oligonucleotide
- General Function
- Broad substrate specificity (S)-2-hydroxy-acid oxidase that preferentially oxidizes glycolate (PubMed:10777549, PubMed:10978532, PubMed:17669354, PubMed:18215067). The glyoxylate produced by the oxidation of glycolate can then be utilized by alanine-glyoxylate aminotransferase for the peroxisomal synthesis of glycine; this pathway appears to be an important step for the detoxification of glyoxylate which, if allowed to accumulate, may be metabolized to oxalate with formation of kidney stones (PubMed:10978532, PubMed:17669354). Can also catalyze the oxidation of glyoxylate, and long chain hydroxyacids such as 2-hydroxyhexadecanoate and 2-hydroxyoctanoate, albeit with much lower catalytic efficiency (PubMed:10777549, PubMed:17669354, PubMed:18215067). Active in vitro with the artificial electron acceptor 2,6-dichlorophenolindophenol (DCIP), but O2 is believed to be the physiological electron acceptor, leading to the production of H2O2 (PubMed:10777549, PubMed:10978532, PubMed:17669354, PubMed:18215067). Is not active on L-lactate and 2-hydroxybutanoate (PubMed:10777549)
- Specific Function
- (s)-2-hydroxy-acid oxidase activity
- Gene Name
- HAO1
- Uniprot ID
- Q9UJM8
- Uniprot Name
- 2-Hydroxyacid oxidase 1
- Molecular Weight
- 40923.945 Da
References
- 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
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- Arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- EMA Assessment Report: Oxlumo (Lumasiran) Subcutaneous Injection [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- Antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- 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 April 26, 2024 04:15