Oxlumo
lumasiran
Species
MonkeyRatRabbit
Longest study
36 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (both pharmacologically relevant); rabbit for EFD
“The target site of lumasiran in the HAO1 mRNA is conserved across mammalian species and both rodent and monkey are pharmacologically relevant species.”
Why that species
HAO1 target site conserved across mammals; active in rodents, lagomorphs and NHP
“Lumasiran is pharmacologically active in both rodents, lagomorphs and nonhuman primates.”
Surrogate molecule
No surrogate; clinical siRNA pharmacologically active in rodent and monkey tox species
“The target site of lumasiran in the HAO1 mRNA is conserved across mammalian species and both rodent and monkey are pharmacologically relevant species.”
Species: general tox
Rat (up to 25 weeks) and monkey (up to 36 weeks)
“Chronic administration of lumasiran was assessed in good laboratory practice (GLP) repeat-dose toxicology studies up to 25- and 36-weeks in rats and monkeys, respectively.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Lumasiran did not show any adverse effects on male and female fertility and pre- and post-natal development in rats. In embryo-foetal development studies in rats and rabbits, skeletal abnormalities were observed, but at high exposure multiples relative to human therapeutic exposures.”
Species: carcinogenicity
Tg-rasH2 mouse and Sprague Dawley rat
“Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats. Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”
Surrogate used in
No surrogate used; HAO1 target site conserved, rodent and monkey pharmacologically relevant
“The target site of lumasiran in the HAO1 mRNA is conserved across mammalian species and both rodent and monkey are pharmacologically relevant species.”
Study lengthopen answer page →
Longest pivotal study
36 weeks
“Chronic administration of lumasiran was assessed in good laboratory practice (GLP) repeat-dose toxicology studies up to 25- and 36-weeks in rats and monkeys, respectively.”
Pivotal GLP studies
Rat 25-week SC monthly; monkey 36-week SC every 4 weeks (10 doses); plus 8-week weekly monkey study
“Dose and frequency of dosing: 30, 100, or 300 mg/kg lumasiran once every 4 weeks for a total of 10 doses Route of administration: SC”
Route in tox
Subcutaneous, weekly or monthly, matching clinical route
“Dose and frequency of dosing: 0, 20, 50 and 200 mg/kg Once/month for 25 weeks Route of administration: SC”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
“Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or in vivo micronucleus assay in rats.”
Carcinogenicity
Postmarketing requirement; later completed: 26-week Tg-rasH2 mouse and 2-year rat both negative
“Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”
Reproductive & developmental
Full DART: rat fertility, rat and rabbit EFD, rat PPND, plus juvenile rat study; no serious effects
“Reproductive toxicology studies did not reveal any serious fertility or teratogenic effects of lumasiran.”
Safety pharmacology
Standalone monkey CV/respiratory telemetry (10, 100 mg/kg weekly x4), no effects; CNS in 8-week monkey study
“In a standalone cardiovascular safety pharmacology study in the monkey, the administration of lumasiran at 10 and 100 mg/kg weekly for a total of four doses had no immediate or delayed effects on clinical observations, qualitative or quantitative electrocardiogram parameters,”
Genotox: Ames
Bacterial reverse mutation (Ames): negative
“Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or in vivo micronucleus assay in rats.”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral blood lymphocytes: negative
“Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or in vivo micronucleus assay in rats.”
Genotox: in vivo
Rat micronucleus: negative
“Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or in vivo micronucleus assay in rats.”
Carcinogenicity model
26-week Tg-rasH2 mouse (up to 1500 mg/kg monthly) and rat study; not carcinogenic in mice
“Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats. Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”
Carcinogenicity timing
2-year rat and 6-month transgenic mouse studies underway at approval; postmarketing requirements
“Two-year rat and 6-month transgenic mouse carcinogenicity studies are underway. The available data do not raise concern for a risk of carcinogenicity that should delay approval given the apparent clinical benefit and unmet need. As such, these studies will be postmarketing requirements.”
hERG / QT
Monkey safety pharmacology: no QT or QTc prolongation after four SC doses of 10 and 100 mg/kg
“Safety pharmacology studies in monkeys did not demonstrate prolongation in QT or QTc (using the individual animal correction factor) after four subcutaneous doses of 10 and 100 mg/kg administered in a 3-week period.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Oxlumo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAELs = highest doses (200 mg/kg rat, 300 mg/kg monkey monthly); non-adverse liver, kidney, coagulation, injection site, lymph node findings (FDA integrated review, p. 56)
NOAEL / key findings
NOAELs = highest doses (200 mg/kg rat, 300 mg/kg monkey monthly); non-adverse liver, kidney, coagulation, injection site, lymph node findings
“The no observed adverse effect levels (NOAELs) in the chronic repeat-dose toxicity studies with once monthly dosing were the highest doses tested, 200 and 300 mg/kg for rats and monkeys, respectively.”
Risksopen answer page →
Immune & cytokine safety
Low-titre ADA in 3/36 monkeys, no impact on exposure or tox; no ADA in rats; not immunostimulatory
“A low incidence, 3 out of 36 treated monkeys in the 36- week repeat-dose toxicity study (GO1-GLP15-036) were confirmed to have a low titre of anti-lumasiran antibodies.”
Biodistribution & persistence
Rat: liver, kidney cortex/medulla highest; not detected in brain/spinal cord; long liver half-life (585 h) in monkey
“Relatively high tissue concentrations (in descending order) were observed in the liver, kidney cortex, kidney medulla, cecum, salivary gland, bone marrow, thyroid and pancreas.”
Modality-specific risk
Rodent-specific hepatocellular changes (vacuolation, necrosis); renal basophilic granules; GalNAc-siRNA class effects (ISR, LFTs, ADA)
“AEs or toxicities associated with GalNAC-conjugated siRNA products include injection site reactions, ALT and AST elevations, mild increases in serum creatinine and decreases in eGFR, positive ADA, and hypersensitivity (including anaphylactic reactions).”
Anti-drug antibodies: animals
Low-titre ADA in 3/36 monkeys (36-week); no effect on exposure or toxicity; no ADA in rats
“A low incidence, 3 out of 36 treated monkeys in the 36- week repeat-dose toxicity study (GO1-GLP15-036) were confirmed to have a low titre of anti-lumasiran antibodies. Plasma exposure of lumasiran was not impacted and there were no toxicological findings attributed to the presence of ADAs in these animals. No ADAs were detected in treated rats.”
Anti-drug antibodies: patients
ADA in 7/120 (6%) lumasiran-treated individuals; no clinically significant impact
“Across all clinical studies in the lumasiran development program, including patients with PH1 and healthy volunteers dosed with OXLUMO, 7 of 120 (6%) lumasiran-treated individuals with mean follow-up duration of 8.9 months, tested positive for ADA, as early as from Day 29.”
Tox packageopen answer page →
Before first-in-human
First-in-human: where
UK: single ascending dose in healthy subjects (Study 001 Part A)
“Part A: SAD study (001A) in healthy subjects to evaluate safety, tolerability, PK, PD and ADA of lumasiran Country: UK”
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Oxlumo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAELs = highest doses (200 mg/kg rat, 300 mg/kg monkey monthly); non-adverse liver, kidney, coagulation, injection site, lymph node findings (FDA integrated review, p. 56)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
36-week cynomolgus monkey (SC); recovery phase not stated
“Chronic administration of lumasiran was assessed in good laboratory practice (GLP) repeat-dose toxicology studies up to 25- and 36-weeks in rats and monkeys, respectively.”
Pivotal GLP studies
Rat 25-week SC monthly; monkey 36-week SC every 4 weeks (10 doses); plus 8-week weekly monkey study
“Dose and frequency of dosing: 30, 100, or 300 mg/kg lumasiran once every 4 weeks for a total of 10 doses Route of administration: SC”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Lumasiran did not show any adverse effects on male and female fertility and pre- and post-natal development in rats. In embryo-foetal development studies in rats and rabbits, skeletal abnormalities were observed, but at high exposure multiples relative to human therapeutic exposures.”
Reproductive & developmental
Full DART: rat fertility, rat and rabbit EFD, rat PPND, plus juvenile rat study; no serious effects
“Reproductive toxicology studies did not reveal any serious fertility or teratogenic effects of lumasiran.”
PPND / ePPND: when
PPND study completed before the marketing application; NOAEL 50 mg/kg
“A pre- and postnatal development study had a NOAEL of 50 mg/kg with a safety margin of >2X.”
Carcinogenicity
Species: carcinogenicity
Tg-rasH2 mouse and Sprague Dawley rat
“Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats. Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”
Carcinogenicity model
26-week Tg-rasH2 mouse (up to 1500 mg/kg monthly) and rat study; not carcinogenic in mice
“Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats. Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”
Carcinogenicity timing
2-year rat and 6-month transgenic mouse studies underway at approval; postmarketing requirements
“Two-year rat and 6-month transgenic mouse carcinogenicity studies are underway. The available data do not raise concern for a risk of carcinogenicity that should delay approval given the apparent clinical benefit and unmet need. As such, these studies will be postmarketing requirements.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL 200 mg/kg ~44x and monkey NOAEL 300 mg/kg ~150x human AUC
“25-week rat 200 378 44 X
36-week monkey 300 1290 150 X”
NOAEL / key findings
NOAELs = highest doses (200 mg/kg rat, 300 mg/kg monkey monthly); non-adverse liver, kidney, coagulation, injection site, lymph node findings
“The no observed adverse effect levels (NOAELs) in the chronic repeat-dose toxicity studies with once monthly dosing were the highest doses tested, 200 and 300 mg/kg for rats and monkeys, respectively.”
Efficacy evidenceopen answer page →
Efficacy evidence
Genetic PH1 mouse model (AGXT-/-): dose-dependent urinary oxalate reduction (~50% at 3 mg/kg)
“In vivo study in a genetic PH1 mouse model (AGXT-/-) (single dose): Single doses of 0.3, 1 and 3 mg/kg lumasiran resulted in a dose-dependent reduction of urinary oxalate and an increase in urinary glycolate. A single 3 mg/kg dose of lumasiran resulted in a reduction of urinary oxalate by approximately 50%.”
Why that model
HAO1 target site conserved across mammals; rodent and monkey pharmacologically relevant
“The target site of lumasiran in the HAO1 mRNA is conserved across mammalian species and both rodent and monkey are pharmacologically relevant species.”
Reviewer's view of the efficacy data
FDA: nonclinical data support efficacy in decreasing HAO1 mRNA, GO enzyme and oxalate production
“The nonclinical data support the efficacy of lumasiran to decrease levels of HAO1 mRNA, GO enzyme levels and the production of oxalate, based on the following data:”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Rat 2-year and transgenic mouse 6-month carcinogenicity studies incomplete at approval; deferred to postmarketing requirements
Why: No carcinogenicity concern in available data; clinical benefit and unmet need · Rare disease / unmet need · Weight of evidence
“Two-year rat and 6-month transgenic mouse carcinogenicity studies are underway. The available data do not raise concern for a risk of carcinogenicity that should delay approval given the apparent clinical benefit and unmet need. As such, these studies will be postmarketing requirements.”
Safety pharmacologyAcceptedBeyond the letter
No in vitro hERG assay
Why: Physicochemical properties of lumasiran and targeted liver delivery · Pharmacology or kinetics
“Not performed, given the physiochemical property of lumasiran and targeted liver delivery, this was determined to be acceptable.”
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