Givlaari
givosiran
Species
MonkeyRatRabbit
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (both pharmacologically active); rabbit inactive (EFD only)
“In addition to being pharmacologically active in humans, based on the nonclinical data described below, givosiran is also pharmacologically active in both rats and monkeys but is not pharmacologically active in rabbits.”
Why that species
Lead duplex has complete sequence homology to human and monkey ALAS1; ALAS1 knockdown shown in rat and monkey
“This parent duplex, with complete sequence homology to human and monkey ALAS1, and is therefore expected to be pharmacologically active in each of the indicated species.”
Surrogate molecule
No surrogate; clinical siRNA tested in rat, monkey and (non-responsive) rabbit
“Pharmacodynamics measurement on GD 22 indicated that givosiran did not reduce hepatic ALAS1 transcript levels in pregnant rabbits at any dose level, confirming that givosiran is not pharmacologically active in rabbits.”
Species: general tox
Rat and monkey (rat most sensitive)
“In the repeat-dose toxicity studies conducted in rats and monkeys, the rat was identified as the most sensitive species to givosiran-related effects, with the liver being identified as the primary target organ of toxicity in both the rat and monkey.”
Species: DART
Rat and rabbit
“Maximal exposure was low in pregnant rats (maximally 1.7x human exposure based on AUC) and slightly higher in rabbits (maximally 5x human exposure).”
Species: carcinogenicity
Tg-rasH2 mouse (26-week) and Sprague Dawley rat (2-year)
“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”
Surrogate used in
No surrogate used; givosiran pharmacologically active in rat and monkey (not rabbit)
“In addition to being pharmacologically active in humans, based on the nonclinical data described below, givosiran is also pharmacologically active in both rats and monkeys but is not pharmacologically active in rabbits.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“In a 39-week monkey study, cynomolgus monkeys were subcutaneously administered vehicle or givosiran (10, 30, or 100 mg/kg) once weekly for 39 weeks followed by a 13-week recovery period.”
Pivotal GLP studies
Rat 26-week SC weekly (with male fertility arm), monkey 39-week SC weekly, both with 13-week recovery
“Dawley rats were subcutaneously administered vehicle or givosiran (3, 10, or 30 mg/kg) once weekly for 26 weeks followed by a 13-week recovery period.”
Route in tox
Subcutaneous, once weekly (vs monthly clinical schedule)
“The studies were conducted using the subcutaneous route of administration, which is consistent with the intended clinical route of administration; however, animals were dosed once weekly instead of the once monthly dose schedule used to treat patients.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
“Givosiran was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in the in vitro chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Conducted: 26-week Tg.rasH2 mouse negative; 2-year rat (post-approval) showed hepatocellular adenomas in males at 100 mg/kg
“A statistically significant increase in hepatocellular adenomas occurred in males at 100 mg/kg/month, the clinical significance of which is uncertain.”
Reproductive & developmental
Full DART: rat fertility/EFD, rabbit EFD (postimplantation loss with maternal toxicity), rat PPND; no malformations
“Givosiran showed marked maternal toxicity in rabbits (including mean maternal body weight loss) and resulted in increased post-implantation loss as a result of increased early resorptions and a low incidence of skeletal variations.”
Safety pharmacology
Standalone GLP CV/respiratory telemetry study in monkey (single 150 mg/kg SC); no clear effects
“A safety pharmacology study assessed the effects of a single subcutaneous dose of 150 mg/kg givosiran on cardiovascular and respiratory function in male telemetered cynomolgus monkeys.”
Genotox: Ames
Bacterial reverse mutation: negative
“Givosiran was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in the in vitro chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo bone marrow micronucleus assay in rats.”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral blood lymphocytes: negative
“Givosiran was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in the in vitro chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo bone marrow micronucleus assay in rats.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Givosiran was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in the in vitro chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity model
Sprague Dawley rat, SC every 28 days up to 89 weeks: hepatocellular adenomas in males at 100 mg/kg/month
“In a carcinogenicity study in Sprague Dawley rats administered 25, 50, or 100 mg/kg givosiran by subcutaneous injection every 28 days for up to 89 weeks (males) or 85 weeks (females), givosiran doses in rats were 2, 3, and 6 times, respectively, the MRHD based on body surface area. A statistically significant increase in hepatocellular adenomas occurred in males at 100 mg/kg/month, the clinical significance of which is uncertain.”
Carcinogenicity timing
26-week Tg-rasH2 mouse completed (negative); 2-year Sprague Dawley rat ongoing at approval
“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”
hERG / QT
Monkey CV/respiratory telemetry (single 150 mg/kg SC): no clear drug-related effects
“A safety pharmacology study assessed the effects of a single subcutaneous dose of 150 mg/kg givosiran on cardiovascular and respiratory function in male telemetered cynomolgus monkeys. Givosiran produced no clear drug-related effects on cardiovascular and respiratory function under the conditions tested.”
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 Givlaari 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: Liver primary target in rat and monkey (single-cell necrosis, enzyme increases); no adverse findings at 3.5x (rat) and 26.3x (monkey) exposure (EMA assessment report, p. 47)
NOAEL / key findings
Liver primary target in rat and monkey (single-cell necrosis, enzyme increases); no adverse findings at 3.5x (rat) and 26.3x (monkey) exposure
“No adverse findings were associated with chronic, weekly administration of givosiran to rats and monkeys at doses that achieved exposure multiples of 3.5- and 26.3 fold, respectively when compared to exposures achieved in patients receiving the maximum recommended human dose.”
Risksopen answer page →
Immune & cytokine safety
Low ADA incidence: rat negative, one monkey ADA-positive; no dedicated antigenicity studies
“All samples in the rat were negative. In the monkey study one sample was positive at 30 mg/kg/week (on day 169) and 3 samples were positive at 100 mg/kg/week, all from one animal (on days 85, 169 and 253).”
Biodistribution & persistence
Rat QWBA: liver, kidney cortex, lymph nodes highest; long liver/kidney half-lives; persists in liver, kidney, injection site at 28 days
“Quantitative whole-body autoradiography confirmed that givosiran is distributed to a limited number of tissues, with high exposures observed in the liver, kidneys, kidney cortex, and lymph nodes.”
Modality-specific risk
Hepatotoxicity, renal oligonucleotide accumulation (basophilic granules), injection-site reactions; off-target hybridization screened
“Tubular basophilic granules were observed in the kidney and may be related to accumulation of polyanionic oligonucleotide molecules in lysosomes.”
Anti-drug antibodies: animals
Rat (26-week): all negative; monkey (39-week): ADA-positive samples at 30 and 100 mg/kg/week, mostly from one animal
“All samples in the rat were negative. In the monkey study one sample was positive at 30 mg/kg/week (on day 169) and 3 samples were positive at 100 mg/kg/week, all from one animal (on days 85, 169 and 253).”
Anti-drug antibodies: patients
Treatment-emergent ADA in 1/111 (0.9%) AHP patients
“In placebo-controlled and open-label clinical studies, 1 of 111 patients with AHP (0.9%) developed treatment-emergent anti-drug antibodies (ADA) during treatment with GIVLAARI.”
Label warnings
- Anaphylactic Reaction
- Hepatic Toxicity
- Renal Toxicity
- Injection Site Reactions
- Blood Homocysteine Increased
- Pancreatitis
Hypersensitivity & infusion reactionsHepatotoxicityNephrotoxicityGastrointestinal
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US, UK and Sweden: 6 clinical study centers (4 US, 1 UK, 1 Sweden)
“6 clinical study centers (4 in US, 1 in UK, 1 in Sweden)”
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 Givlaari 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: Liver primary target in rat and monkey (single-cell necrosis, enzyme increases); no adverse findings at 3.5x (rat) and 26.3x (monkey) exposure (EMA assessment report, p. 47)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week SC cynomolgus monkey with 13-week recovery
“In a 39-week monkey study, cynomolgus monkeys were subcutaneously administered vehicle or givosiran (10, 30, or 100 mg/kg) once weekly for 39 weeks followed by a 13-week recovery period.”
Pivotal GLP studies
Rat 26-week SC weekly (with male fertility arm), monkey 39-week SC weekly, both with 13-week recovery
“Dawley rats were subcutaneously administered vehicle or givosiran (3, 10, or 30 mg/kg) once weekly for 26 weeks followed by a 13-week recovery period.”
DART package
Species: DART
Rat and rabbit
“Maximal exposure was low in pregnant rats (maximally 1.7x human exposure based on AUC) and slightly higher in rabbits (maximally 5x human exposure).”
Reproductive & developmental
Full DART: rat fertility/EFD, rabbit EFD (postimplantation loss with maternal toxicity), rat PPND; no malformations
“Givosiran showed marked maternal toxicity in rabbits (including mean maternal body weight loss) and resulted in increased post-implantation loss as a result of increased early resorptions and a low incidence of skeletal variations.”
PPND / ePPND: when
PPND in rat completed and reviewed in the marketing application: dosing GD 7-19 and LD 6-18
“In a pre- and postnatal development study in rats, givosiran (0, 3, 10, or 30 mg/kg) was administered to pregnant rats approximately every 6 days on GD 7, 13, and 19 and lactation days (LD) 6, 12, and 18 .”
Carcinogenicity
Species: carcinogenicity
Tg-rasH2 mouse (26-week) and Sprague Dawley rat (2-year)
“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”
Carcinogenicity model
Sprague Dawley rat, SC every 28 days up to 89 weeks: hepatocellular adenomas in males at 100 mg/kg/month
“In a carcinogenicity study in Sprague Dawley rats administered 25, 50, or 100 mg/kg givosiran by subcutaneous injection every 28 days for up to 89 weeks (males) or 85 weeks (females), givosiran doses in rats were 2, 3, and 6 times, respectively, the MRHD based on body surface area. A statistically significant increase in hepatocellular adenomas occurred in males at 100 mg/kg/month, the clinical significance of which is uncertain.”
Carcinogenicity timing
26-week Tg-rasH2 mouse completed (negative); 2-year Sprague Dawley rat ongoing at approval
“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”
Safety marginopen answer page →
Safety margin at NOAEL
No adverse findings at 3.5-fold (rat) and 26.3-fold (monkey) the exposure at the maximum recommended human dose
“No adverse findings were associated with chronic, weekly administration of givosiran to rats and monkeys at doses that achieved exposure multiples of 3.5- and 26.3 fold, respectively when compared to exposures achieved in patients receiving the maximum recommended human dose.”
NOAEL / key findings
Liver primary target in rat and monkey (single-cell necrosis, enzyme increases); no adverse findings at 3.5x (rat) and 26.3x (monkey) exposure
“No adverse findings were associated with chronic, weekly administration of givosiran to rats and monkeys at doses that achieved exposure multiples of 3.5- and 26.3 fold, respectively when compared to exposures achieved in patients receiving the maximum recommended human dose.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse and rat AIP disease models: givosiran prevented and reduced phenobarbital-induced ALA and PBG
“Four weekly administrations of the subcutaneous 3 mg/kg dose of givosiran prevented the production of ALA and PBG and a single subcutaneous dose (20 mg/kg in mice and 10 mg/kg in rats) of givosiran reduced ALA and PBG in both the mouse and rat models of AIP.”
Why that model
Givosiran is pharmacologically active in rats and monkeys (not rabbits)
“In addition to being pharmacologically active in humans, based on the nonclinical data described below, givosiran is also pharmacologically active in both rats and monkeys but is not pharmacologically active in rabbits.”
Reviewer's view of the efficacy data
EMA: proof of principle supported (ALAS1, ALA, PBG reduction), but monthly clinical regimen not tested in animals
“The pharmacodynamic studies support the proof of principle that givosiran can reduce liver ALAS1 mRNA and subsequently serum ALA and PGB levels. However, the intended clinical treatment regimen of once per month has not been tested in animals.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityVerdict not stated
2-year rat carcinogenicity study still ongoing at approval; only the 26-week Tg-rasH2 mouse study completed
“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”
Juvenile toxAcceptedBeyond the letter
No dedicated juvenile animal studies; young monkeys (13 to 17 months old) in the 39-week study used to support adolescents
Why: Monkeys aged 13 to 17 months at study start cover the developmental age of adolescents 12 years and older · Weight of evidence
“Dedicated studies were not conducted in juvenile animals. In the chronic monkey GLP toxicology study, givosiran was administered once weekly at dose levels between 10 and 100 mg/kg for 39 weeks, followed by a 13-week recovery phase.”
“At initiation of the treatment, monkeys were 13 to 17 months old. Monkeys at 24 to 36 months old are generally considered the corresponding development age of adolescent up to 12 years of age in human.”
OtherVerdict not stated
Repeat-dose toxicity studies dosed once weekly rather than the once-monthly clinical schedule
“The studies were conducted using the subcutaneous route of administration, which is consistent with the intended clinical route of administration; however, animals were dosed once weekly instead of the once monthly dose schedule used to treat patients.”
SpeciesVerdict not stated
Rabbit embryo-fetal study conducted in a pharmacologically inactive species (no hepatic ALAS1 knockdown)
“Pharmacodynamics measurement on GD 22 indicated that givosiran did not reduce hepatic ALAS1 transcript levels in pregnant rabbits at any dose level, confirming that givosiran is not pharmacologically active in rabbits.”
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