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).”
Species: general tox
Rabbit and cynomolgus monkey (adult and juvenile)
“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.”
Species: DART
Cynomolgus monkey only (enhanced pre/postnatal development study)
“The Applicant conducted an enhanced pre/post-natal development (ePPND) study in cynomolgus monkeys, evaluating the effects of dosing from the start of organogenesis (GD20) to late 3rd trimester.”
Species: carcinogenicity
Not conducted
“No genotoxicity or carcinogenicity studies have been conducted by the Applicant; this is endorsed.”
Surrogate used in
Yes: murine anti-FGF23 antibody in wild-type and Hyp mice (2-week toxicity and pharmacology)
“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”
Genotox: Ames
Not conducted (ICH S6)
“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.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“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.”
Genotox: in vivo
Not conducted (ICH S6)
“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 model
Not conducted; weight-of-evidence carcinogenicity risk assessment (literature and in-house toxicology data) submitted
“No genotoxicity or carcinogenicity studies have been conducted by the Applicant; this is endorsed. The Applicant has submitted a carcinogenicity risk assessment document, summarizing and discussing relevant literature data, as well as data from in house toxicology studies.”
Carcinogenicity timing
Not required; FDA ECAC concurred carcinogenicity studies are not needed
“The Executive Carcinogenicity Assessment Committee was consulted by the Division regarding the Sponsor’s carcinogenicity risk assessment on April 28, 2017, and concurred that carcinogenicity studies with burosumab are not needed.”
hERG / QT
No hERG assay or separate safety pharmacology; no ECG effects in 14-week adult or 40-week juvenile monkey studies
“No ECG effects were observed in the 14-week study or in the 40-week study in juvenile 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
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: 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.”
Anti-drug antibodies: animals
No ADA in rabbits; ADA in 2 monkeys (14-week) and 1 (40-week) reduced burosumab exposure and attenuated phosphate and vitamin D increases
“In the 14-week adult cynomolgus monkey study, ADA were detected in two males at 3 mg/kg from Day 28. In the 40 week adult monkey study, one male at 30 mg/kg showed ADA from Week 15. 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.”
Anti-drug antibodies: patients
XLH: 0% (0/13) age 1-4, 19% (10/52) age 5-12, 15% (20/131) adults; three children had neutralizing antibodies
“In XLH clinical studies, none (0/13) of the 1- to 4-year-old patients, 19% (10/52) of the 5- to 12-year- old patients, and 15% (20/131) of the adult patients tested positive for anti-drug antibodies (ADA) after receiving CRYSVITA. Among these, three 5- to 12-year-old patients tested positive for neutralizing antibodies.”
Label warnings
- Hypersensitivity
- Hyperphosphatemia and Risk of Nephrocalcinosis
- Hypercalcemia
- Injection Site Reactions
Hypersensitivity & infusion reactionsNephrotoxicityMetabolic & endocrine
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
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 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
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: Adult monkey NOAEL 0.3 mg/kg (0.9x adult human AUC) in both repeat-dose studies (FDA multi-discipline review, p. 45)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
40-week IV/SC studies in adult and juvenile cynomolgus monkeys, each with 13-week recovery
“A 40ͲWeek Intermittent (Once Every 2 Weeks) Intravenous/Subcutaneous Dose Toxicity and Toxicokinetic Study with KRN23 in Cynomolgus Monkeys with a 13ͲWeek Recovery (Study 303Ͳ044)”
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.”
DART package
Species: DART
Cynomolgus monkey only (enhanced pre/postnatal development study)
“The Applicant conducted an enhanced pre/post-natal development (ePPND) study in cynomolgus monkeys, evaluating the effects of dosing from the start of organogenesis (GD20) to late 3rd trimester.”
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.”
PPND / ePPND: when
ePPND in cynomolgus monkey completed before the marketing application
“In an enhanced preͲ and postͲnatal development (ePPND) study in pregnant cynomolgus monkeys with Q2W IV doses during gestation of 0, 0.3, 3, 30 mg/kg IV, there was no teratogenicity and there were no effects on preͲ and postnatal development.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No genotoxicity or carcinogenicity studies have been conducted by the Applicant; this is endorsed.”
Carcinogenicity model
Not conducted; weight-of-evidence carcinogenicity risk assessment (literature and in-house toxicology data) submitted
“No genotoxicity or carcinogenicity studies have been conducted by the Applicant; this is endorsed. The Applicant has submitted a carcinogenicity risk assessment document, summarizing and discussing relevant literature data, as well as data from in house toxicology studies.”
Carcinogenicity timing
Not required; FDA ECAC concurred carcinogenicity studies are not needed
“The Executive Carcinogenicity Assessment Committee was consulted by the Division regarding the Sponsor’s carcinogenicity risk assessment on April 28, 2017, and concurred that carcinogenicity studies with burosumab are not needed.”
Safety marginopen answer page →
Safety margin at NOAEL
Adult monkey NOAEL 0.3 mg/kg at 0.9x adult human AUC
“The NOAEL was 0.3 mg/kg (0.9x adult human AUC) in both”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Hyp mouse (XLH model) treated with a murine anti-FGF23 antibody
“A murine anti-FGF23 antibody was used to characterize the PD effects and mode of action of inhibiting FGF23 in Hyp mice.”
Why that model
Burosumab binds human, cynomolgus and rabbit FGF23 but not 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.”
Reviewer's view of the efficacy data
EMA: Hyp mouse considered a relevant animal model of human XLH
“The Hyp mouse is considered to be a relevant animal model of human XLH.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAcceptedBeyond the letter
Monkey NOAELs at 0.3-0.9x human AUC; no exposure margin at the NOAEL
Why: Normal animals more sensitive to mineralization than XLH patients; effects linked to serum phosphate, monitorable in the clinic · Pharmacology or kinetics · Human data
“The animal NOAELs were low (0.3Ͳ0.9x human AUC exposure) due to the sensitivity of normal animals to mineralization. However, this has limited significance, since, like Hyp mice, XLH patients are expected to be at a reduced risk of ectopic mineralization compared to normal animals or humans.”
“Since the adverse effects are linked to serum phosphate levels and thus can be monitorable in the clinic, the lack of margins is not considered to be a crucial issue.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for chronic therapy; weight-of-evidence assessment instead of two-year rodent studies
Why: Burosumab does not bind rodent FGF23; weight-of-evidence assessment; Executive Carcinogenicity Assessment Committee concurred · No relevant species · Weight of evidence
“Standard 2Ͳyear rodent carcinogenicity studies with burosumab are not feasible since burosumab does not bind rodent FGF23.”
“The Executive Carcinogenicity Assessment Committee was consulted by the Division regarding the Sponsor’s carcinogenicity risk assessment on April 28, 2017, and concurred that carcinogenicity studies with burosumab are not needed.”
DARTVerdict not stated
No dedicated fertility or separate embryo-fetal studies; single monkey ePPND study
“EmbryoǦFetal Development Separate EFD studies were not performed. However, an ePPND study was conducted in cynomolgus monkeys.”
OtherQuestioned
Hyp versus wild-type mouse mineralization study lacked toxicokinetic data
“However, a deficiency of this study is the lack of toxicokinetic data.”
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