Fabhalta
iptacopan
Species
RatDog
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 dog
“The safety of iptacopan was evaluated in a comprehensive nonclinical program consisting of good laboratory practice compliant toxicology studies in rats and dogs (most sensitive species), a short study in monkeys, reproductive toxicology studies in rats and rabbits, and carcinogenicity assessments in rats and transgenic mice.”
Why that species
Rats and dogs considered the most sensitive species
“The safety of iptacopan was evaluated in a comprehensive nonclinical program consisting of good laboratory practice compliant toxicology studies in rats and dogs (most sensitive species), a short study in monkeys, reproductive toxicology studies in rats and rabbits, and carcinogenicity assessments in rats and transgenic mice.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Iptacopan administered at the high-dose (~10 times the clinical exposure at the maximum recommended human dose [MRHD], based on plasma area under the concentration-time curve [AUC]) resulted in decreased leukocyte parameters in male dogs at the end of the recovery period.”
Species: general tox
Rat and dog (most sensitive species); short study in monkeys
“The safety of iptacopan was evaluated in a comprehensive nonclinical program consisting of good laboratory practice compliant toxicology studies in rats and dogs (most sensitive species), a short study in monkeys, reproductive toxicology studies in rats and rabbits, and carcinogenicity assessments in rats and transgenic mice.”
Species: DART
Rat and rabbit
“The safety of iptacopan was evaluated in a comprehensive nonclinical program consisting of good laboratory practice compliant toxicology studies in rats and dogs (most sensitive species), a short study in monkeys, reproductive toxicology studies in rats and rabbits, and carcinogenicity assessments in rats and transgenic mice.”
Species: carcinogenicity
Tg rasH2 mouse (6-month) and rat (2-year)
“Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential.”
Surrogate used in
No surrogate used; iptacopan inhibits the alternative pathway in rat, dog and rabbit serum
“Zymosan-induced MAC deposition assays exhibited IC50 of ~100nM in serum of mouse, rabbit, pig, and human (in serum and whole blood), and ~500nM in serum of rat and dog.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Reversible thyroid follicular cell hypertrophy and thyroid organ weight increases were observed at clinically relevant exposures in toxicology studies at doses ≥50 mg/kg/day in the 26-week study in rats and at ≥5 mg/kg/day in the 39-week study in dogs.”
Pivotal GLP studies
26-week rat and 39-week dog repeat-dose studies
“Reversible thyroid follicular cell hypertrophy and thyroid organ weight increases were observed at clinically relevant exposures in toxicology studies at doses ≥50 mg/kg/day in the 26-week study in rats and at ≥5 mg/kg/day in the 39-week study in dogs.”
Route in tox
Oral (gavage)
“Route of administration: Oral (gavage)”
Skipped studiesopen answer page →
Genotoxicity
Not genotoxic or mutagenic in a battery of in vitro and in vivo assays
“Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays.”
Carcinogenicity
6-month rasH2 mouse and 2-year rat: no carcinogenic potential
“Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential.”
Reproductive & developmental
Rat and rabbit EFD: no embryo-fetal toxicity at 4- to 6-times human exposure
“In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4- to 6-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity (see Data) .”
Safety pharmacology
Dog telemetry: blood pressure decreased up to 26 mmHg with heart rate increased up to 40 beats/min
“Iptacopan-related decrease in blood pressure up to 26 mmHg (23%) and a concurrent increase in heart rate up to 40 beats/min (43%) compared to baseline-adjusted values in the control group.”
Genotox: Ames
Negative
“There was no evidence of mutagenicity observed.”
Genotox: in vitro mammalian
Human peripheral blood lymphocyte micronucleus: negative
“The frequencies of micronucleated binucleated (MNBN) cells were within the normal ranges and iptacopan did not increase micronuclei in human lymphocyte micronucleus assay.”
Genotox: in vivo
Rat micronucleus (in 4-week toxicity study): negative
“Micronucleus assay • No iptacopan-related effects were observed.”
Carcinogenicity model
6-month RasH2 mouse (up to 1,000 mg/kg/day) and 2-year rat (up to 750 mg/kg/day): negative
“Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential.”
Carcinogenicity timing
6-month rasH2 mouse and 2-year rat studies completed before the marketing application; no carcinogenic potential
“Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential.”
hERG / QT
hERG IC50 >300 µM (30.7% inhibition at 300 µM)
“Concentration: 30, 100, or 300µM hERG current inhibition (Mean ± SEM%) 30: 4.0 ± 1.3 100: 15.5 ± 0.7 300: 30.7 ± 1.5 Positive Control Cisapride (90nM): 62.4 ± 0.3 IC50 > 300 μM”
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 Fabhalta 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 small molecules 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: 39-week dog targets: thyroid, male reproductive system, lymphoid tissues, liver, bone marrow (FDA integrated review, p. 196)
NOAEL / key findings
39-week dog targets: thyroid, male reproductive system, lymphoid tissues, liver, bone marrow
“Target organs of toxicity included thyroid, male reproductive system, lymphoid tissues, liver and bone marrow.”
Risksopen answer page →
Immune & cytokine safety
Minimal TDAR effects in 39-week dog study: reduced IgM/IgG titers to KLH
“T-Dependent Antibody Response (TDAR) assay conducted with blood from dogs in 39-week toxicology study presented minimal effects on the humoral responses with reduced IgM and/or IgG titers following primary response to KLH challenge in both genders.”
Biodistribution & persistence
Detected in melanin-containing eye tissues up to 168 h, suggesting ocular melanin affinity
“In pigmented animals, iptacopan was detected in melanin containing eye tissues (choroid and ciliary body) up to 168 hrs which suggests affinity to ocular melanin.”
Modality-specific risk
Infection risk; also heart, thyroid and male reproductive organ effects
“A primary concern identified early in product development was a signal for infection. Other systems/organs affected by iptacopan were the heart (dog, monkey), thyroid (rat, dog), and male reproductive organs (rat, dog).”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
Boxed warning: Serious infections caused by encapsulated bacteria
- Serious Infections Caused by Encapsulated Bacteria
- Fabhalta rems
- Monitoring of PNH Manifestations After FABHALTA Discontinuation
- Hyperlipidemia
InfectionsMetabolic & endocrine
US prescribing information, Boxed Warning and 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 Fabhalta 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 small molecules 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: 39-week dog targets: thyroid, male reproductive system, lymphoid tissues, liver, bone marrow (FDA integrated review, p. 196)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral dog study with 27-week recovery (a 52-week juvenile dog study was also conducted)
“Study 1570192/ LNP023: 39-Week Oral (Gavage) Administration Toxicity Study in the Dog Followed by a 27-Week Recovery Period”
Pivotal GLP studies
26-week rat and 39-week dog repeat-dose studies
“Reversible thyroid follicular cell hypertrophy and thyroid organ weight increases were observed at clinically relevant exposures in toxicology studies at doses ≥50 mg/kg/day in the 26-week study in rats and at ≥5 mg/kg/day in the 39-week study in dogs.”
DART package
Species: DART
Rat and rabbit
“The safety of iptacopan was evaluated in a comprehensive nonclinical program consisting of good laboratory practice compliant toxicology studies in rats and dogs (most sensitive species), a short study in monkeys, reproductive toxicology studies in rats and rabbits, and carcinogenicity assessments in rats and transgenic mice.”
Reproductive & developmental
Rat and rabbit EFD: no embryo-fetal toxicity at 4- to 6-times human exposure
“In animal reproduction studies, oral administration of iptacopan to pregnant rats and rabbits during organogenesis at exposures 4- to 6-times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily did not induce embryo or fetal toxicity (see Data) .”
PPND / ePPND: when
GLP PPND in rat completed and reviewed with the marketing application; NOAEL 1000 mg/kg/day
“The NOAEL for both maternal toxicity (F0) and pre- and postnatal developmental (PPND) toxicity in F1 generation rats developing into adulthood is defined at 1000 mg/kg/day”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (6-month) and rat (2-year)
“Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential.”
Carcinogenicity model
6-month RasH2 mouse (up to 1,000 mg/kg/day) and 2-year rat (up to 750 mg/kg/day): negative
“Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential.”
Carcinogenicity timing
6-month rasH2 mouse and 2-year rat studies completed before the marketing application; no carcinogenic potential
“Carcinogenicity studies conducted with oral administration of iptacopan in RasH2 transgenic mice with doses up to 1,000 mg/kg/day for 6 months and in rats with doses up to 750 mg/kg/day for 2 years did not identify any carcinogenic potential.”
Safety marginopen answer page →
Safety margin at NOAEL
9-month dog NOAEL 0.5x (male) and 2.2x (female) human AUC; 6-month rat NOAEL 1.4x
“6-month, Rat 150 29000 100000 1.4 9-month, Dog Male 5 4580 39300 0.5 Female 30 21000 155000 2.2”
NOAEL / key findings
39-week dog targets: thyroid, male reproductive system, lymphoid tissues, liver, bone marrow
“Target organs of toxicity included thyroid, male reproductive system, lymphoid tissues, liver and bone marrow.”
Efficacy evidenceopen answer page →
Efficacy evidence
PNH patient erythrocytes in vitro: inhibition of hemolysis and C3 deposition
“In vitro assays using erythrocytes from patients with PNH showed that iptacopan inhibited both hemolysis and C3 deposition, suggesting that iptacopan may prevent both IVH and EVH features of PNH.”
Why that model
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.
Reviewer's view of the efficacy data
FDA: in vitro and in vivo inhibition of hemolysis, C3 cleavage, MAC formation and AP activation suggests benefit on IVH and EVH in PNH
“The inhibitory effect of iptacopan on hemolysis, C3 cleavage, MAC formation, and AP activation suggests iptacopan might beneficially impact complement mediated IVH and EVH in patients with PNH.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Male dog NOAEL in the 9-month study at 0.5 times human AUC at the MRHD
“9-month, Dog Male 5 4580 39300 0.5”
DARTVerdict not stated
Rat fertility and pre- and postnatal development studies without toxicokinetics; margins derived from general toxicology studies
Why: Toxicokinetic data from general toxicology studies used instead
“Rat fertility and pre/postnatal studies had no toxicokinetic (TK) data, therefore, the TK data from toxicology studies were used”
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