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.”
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).”
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 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: 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.”
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