Crysvita
burosumab
Species
MonkeyRabbit
Longest study
40 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
Rabbit and cynomolgus monkey
“Hence, rabbits and cynomolgus monkeys were used in the in vivo nonclinical studies.”
Why that species
Similar high affinity (KD ~10-11 M) for human, cynomolgus and rabbit FGF23; no binding to mouse, rat or dog FGF23
“it was shown to bind with similar binding affinity (KD~10-11 M) to human, cynomolgus monkey and rabbit FGF23. KRN23 shows no binding to mouse, rat or dog FGF23.”
Surrogate molecule
Yes: murine anti-FGF23 antibody, used for a 2-week toxicity study in wild-type and Hyp mice
“A murine anti-FGF23 antibody at doses of 0, 3, 10 and 30 mg/kg was administered by SC injection twice a week for 2 weeks, or as a single dose, to male wild-type (WT) mice (C57BL/6J) and male hypophosphatemic (Hyp) mice (B6.Cg-PhexHyp/J).”
Study lengthopen answer page →
Longest pivotal study
40 weeks
“In repeat-dose toxicity studies in rabbits up to 14 weeks, and in adult and juvenile cynomolgus monkeys up to 40 weeks, a spectrum of effects related to the primary pharmacology of burosumab was observed.”
Pivotal GLP studies
Rabbit repeat-dose up to 14 weeks; adult and juvenile cynomolgus monkey studies up to 40 weeks
“In repeat-dose toxicity studies in rabbits up to 14 weeks, and in adult and juvenile cynomolgus monkeys up to 40 weeks, a spectrum of effects related to the primary pharmacology of burosumab was observed.”
Route in tox
Intravenous (rabbit and monkey) and subcutaneous (monkey)
“The toxicological profile of burosumab (KRN23) was characterized in rabbits and cynomolgus monkeys via single-dose IV (rabbit) injection, and via repeat-dose IV (both species) injection/infusion and SC (cynomolgus) injection.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (not appropriate for monoclonal antibodies)
“Genotoxicity and carcinogenicity studies are generally not appropriate for biotechnology-derived monoclonal antibodies such as burosumab. No genotoxicity or carcinogenicity studies have been conducted by the Applicant; this is endorsed.”
Carcinogenicity
Not conducted; weight-of-evidence risk assessment concluded carcinogenicity risk appears low
“Overall, it is agreed that the carcinogenicity risk of burosumab appears to be low.”
Reproductive & developmental
Monkey ePPND: no teratogenicity up to 30 mg/kg; pre-/postnatal developmental NOAEL 3 mg/kg
“The Applicant’s proposed NOAEL at 3 mg/kg for pre- and postnatal development in fetuses and offspring is agreed with. It is also agreed that burosumab did not induce teratogenicity in monkeys up to a dose of 30 mg/kg.”
Safety pharmacology
No separate studies; respiratory, ECG, blood pressure and cardiac function assessed in 14- and 40-week monkey studies
“Safety pharmacology studies were not performed in separate studies, but safety pharmacology parameters (respiratory rate, ECG, blood pressure and cardiac function) were assessed in 14- and 40- week repeat-dose toxicity studies in adult and juvenile cynomolgus monkeys”
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 Crysvita 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: Adult monkey NOAEL 0.3 mg/kg (0.9x adult human AUC) in both repeat-dose studies (FDA multi-discipline review, p. 45)
NOAEL / key findings
Adult monkey NOAEL 0.3 mg/kg (0.9x adult human AUC) in both repeat-dose studies
“The NOAEL was 0.3 mg/kg (0.9x adult human AUC) in both”
Risksopen answer page →
Immune & cytokine safety
ADA in some monkeys reduced burosumab exposure and attenuated phosphate and vitamin D increases
“In all monkeys with ADA, serum concentrations of burosumab were diminished and increases in serum inorganic phosphate and 1,25-dihydroxy vitamin D were also attenuated.”
Biodistribution & persistence
Crossed the placenta: detected in fetal serum at all dose levels in monkey ePPND
“Burosumab was detected in serum from fetuses at all dose levels, indicating transport across the placenta.”
Modality-specific risk
Hyperphosphataemia-driven ectopic mineralization (kidney, heart, vessels) from exaggerated FGF23 inhibition
“The main toxicological effect observed in the non-clinical studies was ectopic mineralization.”
Similar precedents
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