Takhzyro
lanadelumab
Species
MonkeyRat
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (monkey only for chronic study)
“Due to high anti-drug antibody (ADA) response in rats that reduced drug exposure, and combined with the apparent similarity in toxicity profile in rats and cynomolgus monkey, the cynomolgus monkey was selected as the single species for the pivotal 6-month toxicity study.”
Why that species
Comparable inhibitory potency against human, rat and cynomolgus monkey plasma kallikrein
“DX-2930 inhibits human, rat, and cynomolgus monkey pKal activity with comparable potencies (Table 2). Rats and cynomolgus monkeys are pharmacologically relevant species.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rat and cynomolgus monkey
“Rat and cynomolgus monkey were used as toxicology species based on in vitro pharmacology potency studies which indicated that pKal inhibition in rat and monkey was similar to human pKal inhibition.”
Species: general tox
Rat (4-week) and cynomolgus monkey; monkey sole species for pivotal 6-month study due to rat ADA
“Due to high anti-drug antibody (ADA) response in rats that reduced drug exposure, and combined with the apparent similarity in toxicity profile in rats and cynomolgus monkey, the cynomolgus monkey was selected as the single species for the pivotal 6-month toxicity study.”
Species: DART
Cynomolgus monkey (13-week fertility and ePPND)
“Complete reviews of the pivotal 39-week general toxicology study in monkeys, 13-week fertility study in male and female monkeys, and an enhanced pre- and postnatal development (ePPND) toxicology study conducted in monkeys are included”
Species: carcinogenicity
Not conducted (rodent studies not feasible due to ADA in rats)
“The conduct of carcinogenicity studies in rodents was not feasible based on the development of ADA in SD rats after repeated dosing.”
Surrogate used in
No surrogate used; lanadelumab cross-reacts with rat and monkey pKal
“Rat and cynomolgus monkey were used as toxicology species based on in vitro pharmacology potency studies which indicated that pKal inhibition in rat and monkey was similar to human pKal inhibition.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The 27 lanadelumab doses administered in the 6-month study in juvenile to adolescent cynomolgus monkeys (2.7-3.3 years) receiving lanadelumab doses 5, 25 or 50 mg/kg/week were well-tolerated.”
Pivotal GLP studies
SC studies: up to 4 weeks in rat (4-week recovery) and 6 months in cynomolgus monkey
“Studies up to 4 weeks duration (with 4-week recovery) and 6 months were performed in rats and monkey respectively.”
Route in tox
SC
“The toxicology studies were performed with SC injection.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“No genotoxicity studies have been performed for lanadelumab in accordance with ICHS6. This is considered acceptable.”
Carcinogenicity
Not conducted (rat ADA); weight of evidence: chronic bradykinin inhibition unlikely to affect carcinogenic risk
“The conduct of carcinogenicity studies in rodents was not feasible based on the development of ADA in SD rats after repeated dosing. Based on the results of the 39-week study in monkeys as well as evidence from the available scientific literature, chronic inhibition of bradykinin production via DX-2930 treatment is unlikely to affect carcinogenic risk in HAE patients.”
Reproductive & developmental
Monkey 13-week fertility: no effects; monkey ePPND: no effects on pregnancy, delivery or offspring; NOAEL 50 mg/kg
“In the ePPND study in pregnant cynomolgus monkeys administered once weekly doses of 10 or 50 mg/kg (highest dose tested), there were no lanadelumab-related effects on pregnancy and parturition, embryo foetal development, survival, growth, and/or postnatal development of offspring.”
Safety pharmacology
Incorporated into repeat-dose studies: rat (CNS) and cynomolgus monkey (cardiovascular, respiratory)
“Standard safety pharmacology endpoints were incorporated into the repeat-dose toxicology studies in rats (CNS) and cynomolgus monkeys (CV and respiratory).”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity studies have been performed for lanadelumab in accordance with ICHS6. This is considered acceptable.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity studies have been performed for lanadelumab in accordance with ICHS6. This is considered acceptable.”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity studies have been performed for lanadelumab in accordance with ICHS6. This is considered acceptable.”
Carcinogenicity model
Not conducted; written weight-of-evidence assessment instead of rodent studies
“Shire submitted a written assessment of the carcinogenic potential of lanadelumab (DX-2930) in place of conducting rodent carcinogenicity studies.”
Carcinogenicity timing
Not required: 2-year rodent study not feasible (neutralizing ADA in rats); replaced by written assessment
“The conduct of a 2-year carcinogenicity study with DX-2930 in rodents was not feasible based on the evidence for development of neutralizing anti-drug antibodies in SD rats after repeated dosing for 4 weeks.”
hERG / QT
No hERG assay; no ECG effects by jacketed external telemetry in 4-week and 6-month monkey studies
“ECG data was collected by Jacketed External Telemetry in the 4-week and 6-month SC monkey toxicity studies. There was no evidence for DX-2930-related effects on ECG parameters”
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 Takhzyro 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: Monkey NOAEL 50 mg/kg; target organ SC injection site, monitorable clinically (FDA multi-discipline review, p. 26)
NOAEL / key findings
Monkey NOAEL 50 mg/kg; target organ SC injection site, monitorable clinically
“The target organs of toxicity were SC injection sites, although these findings were considered monitorable in a clinical setting. The mean AUClast at the no observed adverse effect level (NOAEL) of 50 mg/kg was 110,500 µg*hr/ml.”
Risksopen answer page →
Immune & cytokine safety
Neutralizing ADA in nearly all rats in the 4-week SC study
“DX-2930 was highly immunogenic in rats as evidenced by the development of neutralizing anti-drug antibodies (ADA) in nearly all treated animals in a 4-week SC toxicity study.”
Biodistribution & persistence
Crossed the placenta and detected in milk of lactating monkeys
“In the ePPND study, DX-2930 crossed the blood-placenta barrier and was also detected in the milk of lactating monkeys.”
Modality-specific risk
aPTT prolongation from kallikrein inhibition of the intrinsic coagulation pathway, without abnormal bleeding
“It can be considered an indirect pharmacological effect of lanadelumab because reduced kallikrein activity limits intrinsic coagulation pathway.”
Anti-drug antibodies: animals
ADA prominent in rats, less so in cynomolgus monkeys; animal ADA not reflective of clinical situation
“ADA development was prominent in the rat study, but less so in the cynomolgus monkey studies. While ADAs have been identified also in the clinical program, the data on ADA in animals are not reflective of the clinical situation.”
Anti-drug antibodies: patients
12% (10 patients) vs 5% placebo over 26 weeks in Trial 1; low titers
“In Trial 1 with adult and pediatric patients 12 years of age and older, 10 (12%) lanadelumab-flyo-treated and 2 (5%) placebo-treated patients had at least 1 anti-drug antibody (ADA)-positive sample during the 26-week treatment period; antibody titers were low (range: 20 to 1280).”
Label warnings
- Hypersensitivity Reactions
Hypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human single ascending dose study in 32 healthy adults (DX-2930-01)
“DX-2930-01 was a first-in-human, double-blind, placebo-controlled, Phase 1a, single-ascending dose study evaluating a single dose of lanadelumab (0.1, 0.3, 1.0, or 3.0 mg/kg) in 32 healthy adult subjects.”
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 Takhzyro 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: Monkey NOAEL 50 mg/kg; target organ SC injection site, monitorable clinically (FDA multi-discipline review, p. 26)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month (26-week) SC cynomolgus monkey study, the only long-term repeat-dose study; recovery not described
“Thus, the 6-month study in Cynomolgus monkey is the only longer term repeated-dose study in the program.”
Pivotal GLP studies
SC studies: up to 4 weeks in rat (4-week recovery) and 6 months in cynomolgus monkey
“Studies up to 4 weeks duration (with 4-week recovery) and 6 months were performed in rats and monkey respectively.”
DART package
Species: DART
Cynomolgus monkey (13-week fertility and ePPND)
“Complete reviews of the pivotal 39-week general toxicology study in monkeys, 13-week fertility study in male and female monkeys, and an enhanced pre- and postnatal development (ePPND) toxicology study conducted in monkeys are included”
Reproductive & developmental
Monkey 13-week fertility: no effects; monkey ePPND: no effects on pregnancy, delivery or offspring; NOAEL 50 mg/kg
“In the ePPND study in pregnant cynomolgus monkeys administered once weekly doses of 10 or 50 mg/kg (highest dose tested), there were no lanadelumab-related effects on pregnancy and parturition, embryo foetal development, survival, growth, and/or postnatal development of offspring.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed and reviewed before the marketing application
“Complete reviews of the pivotal 39-week general toxicology study in monkeys, 13-week fertility study in male and female monkeys, and an enhanced pre- and postnatal development (ePPND) toxicology study conducted in monkeys are included”
Carcinogenicity
Species: carcinogenicity
Not conducted (rodent studies not feasible due to ADA in rats)
“The conduct of carcinogenicity studies in rodents was not feasible based on the development of ADA in SD rats after repeated dosing.”
Carcinogenicity model
Not conducted; written weight-of-evidence assessment instead of rodent studies
“Shire submitted a written assessment of the carcinogenic potential of lanadelumab (DX-2930) in place of conducting rodent carcinogenicity studies.”
Carcinogenicity timing
Not required: 2-year rodent study not feasible (neutralizing ADA in rats); replaced by written assessment
“The conduct of a 2-year carcinogenicity study with DX-2930 in rodents was not feasible based on the evidence for development of neutralizing anti-drug antibodies in SD rats after repeated dosing for 4 weeks.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 6-month NOAEL: AUC 23-fold and Cmax 21-fold over MRHD of 300 mg
“Cmax and AUC0-2 wk values at the NOAEL dose in the 6-month SC cynomolgus monkey study exceed the clinical values at the maximum recommended human dose of 300 mg by 21-fold and 23-fold respectively.”
NOAEL / key findings
Monkey NOAEL 50 mg/kg; target organ SC injection site, monitorable clinically
“The target organs of toxicity were SC injection sites, although these findings were considered monitorable in a clinical setting. The mean AUClast at the no observed adverse effect level (NOAEL) of 50 mg/kg was 110,500 µg*hr/ml.”
Efficacy evidenceopen answer page →
Efficacy evidence
Carrageenan-induced rat paw oedema: dose-dependent inhibition, max 73% (SC) at 30 mg/kg
“Lanadelumab pretreatment was found to inhibit carrageenan induced rat oedema in a dose-dependent manner with a maximum inhibition at 30 mg lanadelumab/kg by 73% following SC and 62% following IV infusion, respectively, suggesting an inhibition of pKal functional effects in vivo.”
Why that model
No established nonclinical animal model of HAE; bradykinin-mediated rat paw oedema used for mechanism
“Due to the lack of established non-clinical animal models of HAE, the in vivo pharmacodynamics of lanadelumab was evaluated in the carrageenan-induced rat paw oedema model, in which bradykinin is a known proinflammatory mediator, and that can be used to access mechanistic aspects of pKal inhibition.”
Reviewer's view of the efficacy data
EMA: model shows activity but is not an HAE model; appropriately not used to predict clinical doses
“This demonstrated the activity of lanadelumab, however, as the rat carrageenan paw oedema model is not a non-clinical model of HAE, efficacious doses in this model were not used to predict clinical efficacious doses, which is considered appropriate.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No rodent carcinogenicity study for chronic HAE prophylaxis (neutralising ADA in rats); weight-of-evidence assessment instead
Why: ADA in rats made rodent studies infeasible; 39-week monkey study and literature indicate low carcinogenic risk · Weight of evidence · Pharmacology or kinetics
“The conduct of carcinogenicity studies in rodents was not feasible based on the development of ADA in SD rats after repeated dosing. Based on the results of the 39-week study in monkeys as well as evidence from the available scientific literature, chronic inhibition of bradykinin production via DX-2930 treatment is unlikely to affect carcinogenic risk in HAE patients.”
“Based on this, it is acceptable to assume that the carcinogenicity risk of lanadelumab would be low. Thus, no further studies are considered necessary.”
SpeciesAcceptedBeyond the letter
Pivotal 6-month toxicity in cynomolgus monkey only; rat dropped because of high immunogenicity and loss of exposure
Why: High immunogenicity in rats caused loss of exposure on repeated dosing · Pharmacology or kinetics
“In rats, lanadelumab was highly immunogenic, which resulted in the loss of exposure following repeated administration, limiting the utility of using rats for further toxicology studies, while immunogenicity was generally low in cynomolgus monkeys with both SC and IV routes of administration.”
“The selection of the cynomolgus monkey as a single species for the pivotal 6-month toxicity study is endorsed.”
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