Jascayd
nerandomilast
Species
MonkeyRatPig
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, minipig and cynomolgus monkey
“As listed in Table 46, the Applicant characterized the toxicity profile of nerandomilast with general toxicity studies in rats (13 weeks and 26 weeks), minipigs (13 weeks and 39 weeks), and monkeys (39 weeks).”
Why that species
Pharmacologically relevant species, including similar IC50 in minipig and human
“The nonclinical species used in toxicology assessment of nerandomilast are considered pharmacologically relevant for various reasons including data demonstrating similar IC50 values for human and minipig for nerandomilast.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Repeat-dose toxicity studies with nerandomilast were performed by the oral route of administration in rats, minipigs, and cynomolgus monkeys in studies of up to 26, 39, and 39 weeks, respectively.”
Species: general tox
Rat, minipig and cynomolgus monkey
“The toxicology program included repeat-dose toxicity in rats, minipigs, and cynomolgus monkeys”
Species: DART
Rat and rabbit (embryo-fetal development)
“Nerandomilast administered during the period of organogenesis was not teratogenic in rats and rabbits”
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and rat (104-week)
“Nerandomilast showed no evidence of carcinogenic potential when administered for 26 weeks to transgenic mice (Tg.rasH2) or for 104 weeks to rats”
Surrogate used in
No surrogate used; nerandomilast tested directly
“The toxicology program included repeat-dose toxicity in rats, minipigs, and cynomolgus monkeys”
Study lengthopen answer page →
Longest pivotal study
39 (39-week minipig and monkey)
“Repeat-dose toxicity studies with nerandomilast were performed by the oral route of administration in rats, minipigs, and cynomolgus monkeys in studies of up to 26, 39, and 39 weeks, respectively.”
Pivotal GLP studies
26-week rat, 39-week minipig and 39-week cynomolgus monkey studies
“As listed in Table 46, the Applicant characterized the toxicity profile of nerandomilast with general toxicity studies in rats (13 weeks and 26 weeks), minipigs (13 weeks and 39 weeks), and monkeys (39 weeks).”
Route in tox
Oral gavage
“In a GLP-compliant 39-week oral repeat-dose toxicology and toxicokinetic study in Gottingen minipigs, BI 1015550 was administered by oral gavage once daily at 0, 3, 10, and 25/20 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and in vivo micronucleus assays
“Nerandomilast was negative for mutagenic and clastogenic potential in a complete battery of genotoxicity assays (e.g., in vitro Ames assay, in vitro chromosome aberration assay, and an in vivo mammalian micronucleus assay).”
Carcinogenicity
104-week rat and 26-week Tg.rasH2 mouse: no carcinogenic potential
“Nerandomilast showed no evidence of carcinogenic potential when administered for 26 weeks to transgenic mice (Tg.rasH2) or for 104 weeks to rats up to dose levels of 60 (male)/ 100 (female) and 2 mg/kg/day, respectively.”
Reproductive & developmental
Rat and rabbit EFD: embryofetal loss in rats at 6 mg/kg/day (5-fold MRHD AUC); none in rabbits at 15 mg/kg/day
“Embryofoetal lethality in the form of prenatal embryo-foetal loss (post-implantation loss due to early resorptions) was observed in rats at 6 mg/kg/day (5-fold human AUC exposure at the MRHD) but was not observed in rats at 3 mg/kg/day (3-fold human AUC exposure at the MRHD) or in rabbits at 15 mg/kg/day (4-fold human AUC, unbound exposure at the MRHD).”
Safety pharmacology
No relevant adverse findings in GLP core battery; dose-dependent chronotropic heart-rate effect in minipigs, not clinically relevant
“No relevant adverse findings were associated with nerandomilast administration in the additional GLP core battery safety pharmacology assessments. A dose-dependent chronotropic effect on heart rate was observed in minipigs but was not considered clinically relevant.”
Genotox: Ames
Negative
“Nerandomilast was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo rat micronucleus assay.”
Genotox: in vitro mammalian
Chromosomal aberration assay in human peripheral blood lymphocytes: negative
“Nerandomilast was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and in vivo rat micronucleus assay.”
Genotox: in vivo
Rat micronucleus: negative (bone marrow toxicity at high dose)
“However, in an in vivo rat micronucleus assay, bone marrow toxicity was observed based on a significant decrease in immature erythrocytes at 1000/500 mg/kg (i.e., males/females) at 24 and 48 hr postdose.”
Carcinogenicity model
26-week Tg.rasH2 mouse and 104-week rat: no carcinogenic potential
“Nerandomilast showed no evidence of carcinogenic potential when administered for 26 weeks to transgenic mice (Tg.rasH2) or for 104 weeks to rats up to dose levels of 60 (male)/ 100 (female) and 2 mg/kg/day, respectively.”
Carcinogenicity timing
26-week Tg rasH2 mouse and 104-week rat completed before the marketing application
“Nerandomilast showed no evidence of carcinogenic potential when administered for 26 weeks to transgenic mice (Tg.rasH2) or for 104 weeks to rats up to dose levels of 60 (male)/ 100 (female) and 2 mg/kg/day, respectively.”
hERG / QT
hERG IC50 >10 µM (<30% block at 10 µM)
“The nerandomilast IC50 at hERG channels expressed in HEK293 cells was determined to be >10µM, since the highest tested concentration of 10µM nerandomilast blocked less than 30% of the hERG tail current amplitude.”
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 Jascayd 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: Vasculopathy (inflammation, haemorrhage, necrosis of blood vessels) in rats and minipigs was the primary adverse finding (EMA assessment report, p. 34)
NOAEL / key findings
Vasculopathy (inflammation, haemorrhage, necrosis of blood vessels) in rats and minipigs was the primary adverse finding
“In repeat-dose general toxicity studies, vasculopathy (inflammation, haemorrhage, and necrosis of in and around blood vessels) was the primary nerandomilast-related adverse finding observed in rats and minipigs.”
Risksopen answer page →
Immune & cytokine safety
IL-6 induction by high-dose PDE4 inhibition linked to rat mesenteric vasculitis
“An increased IL-6 expression (mRNA and protein) as a consequence of usage of high doses of pan-PDE4 inhibitors has been linked to the development of mesenteric vasculitis in rat [Dietsch 2006].”
Biodistribution & persistence
Fast, extensive tissue distribution; moderate binding to ocular melanin but not skin melanin
“Tissue distribution of radioactivity from whole blood into peripheral tissues appeared to be fast and extensive. In pigmented rats, there was moderate affinity of radioactivity to melanin-containing tissues of the eye, but no discernible affinity to melanin in the skin.”
Modality-specific risk
Vasculitis in rats and minipigs; absent in monkeys above clinical exposure
“As such, there were initial concerns for vasculitis in clinical studies, an unmonitorable condition. However, in a 39-week oral repeat-dose toxicology study in monkeys, no evidence of vascular inflammation was observed at exposures exceeding those of the maximum clinical dose.”
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.
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
13-week rat and minipig GLP oral studies in the IND-opening submission
“In an IND-opening submission, GLP-compliant 13-week oral repeat-dose toxicology and toxicokinetic studies in rats and minipigs provided adequate nonclinical support for clinical studies with nerandomilast for up to 13 weeks duration.”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Jascayd 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: Vasculopathy (inflammation, haemorrhage, necrosis of blood vessels) in rats and minipigs was the primary adverse finding (EMA assessment report, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week minipig (28-day recovery) and 39-week cynomolgus monkey (8-week recovery) oral studies
“A 39-Week Study of BI 1015550 by Oral Gavage in Minipigs with a 28-Day Recovery Period Doses: 0, 3, 10, or 25/20 mg/kg/day Yes 17R062 4520258 Cynomolgus Monkeys BI 1015550: A 39-Week Oral Gavage Toxicity and Toxicokinetic Study in Cynomolgus Monkeys with an 8-Week Recovery”
Pivotal GLP studies
26-week rat, 39-week minipig and 39-week cynomolgus monkey studies
“As listed in Table 46, the Applicant characterized the toxicity profile of nerandomilast with general toxicity studies in rats (13 weeks and 26 weeks), minipigs (13 weeks and 39 weeks), and monkeys (39 weeks).”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“Nerandomilast administered during the period of organogenesis was not teratogenic in rats and rabbits”
Reproductive & developmental
Rat and rabbit EFD: embryofetal loss in rats at 6 mg/kg/day (5-fold MRHD AUC); none in rabbits at 15 mg/kg/day
“Embryofoetal lethality in the form of prenatal embryo-foetal loss (post-implantation loss due to early resorptions) was observed in rats at 6 mg/kg/day (5-fold human AUC exposure at the MRHD) but was not observed in rats at 3 mg/kg/day (3-fold human AUC exposure at the MRHD) or in rabbits at 15 mg/kg/day (4-fold human AUC, unbound exposure at the MRHD).”
PPND / ePPND: when
Rat PPND completed before the marketing application
“In an oral PPND study, four groups of virgin-mated female Wistar Han rats (F0 generation) were treated by oral administration with 0 (vehicle), 0.3, 1, and 3 mg/kg/day BI 1015550 from GD6 through Lactation Day 20.”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and rat (104-week)
“Nerandomilast showed no evidence of carcinogenic potential when administered for 26 weeks to transgenic mice (Tg.rasH2) or for 104 weeks to rats”
Carcinogenicity model
26-week Tg.rasH2 mouse and 104-week rat: no carcinogenic potential
“Nerandomilast showed no evidence of carcinogenic potential when administered for 26 weeks to transgenic mice (Tg.rasH2) or for 104 weeks to rats up to dose levels of 60 (male)/ 100 (female) and 2 mg/kg/day, respectively.”
Carcinogenicity timing
26-week Tg rasH2 mouse and 104-week rat completed before the marketing application
“Nerandomilast showed no evidence of carcinogenic potential when administered for 26 weeks to transgenic mice (Tg.rasH2) or for 104 weeks to rats up to dose levels of 60 (male)/ 100 (female) and 2 mg/kg/day, respectively.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat 26-week NOAEL ~1x human AUC and Cmax at MRHD
“In the 26-week repeat-dose toxicity study in rats, the NOAEL of 2 mg/kg/day resulted in steady state Cmax and AUC0-24 levels that were 1-fold (equivalent) to human levels at the MRHD.”
NOAEL / key findings
Vasculopathy (inflammation, haemorrhage, necrosis of blood vessels) in rats and minipigs was the primary adverse finding
“In repeat-dose general toxicity studies, vasculopathy (inflammation, haemorrhage, and necrosis of in and around blood vessels) was the primary nerandomilast-related adverse finding observed in rats and minipigs.”
Efficacy evidenceopen answer page →
Efficacy evidence
Bleomycin lung fibrosis in mice and rats; IPF patient lung fibroblasts in vitro
“In the in vivo bleomycin model of lung fibrosis, nerandomilast was associated with reversal of bleomycin-induced changes in pulmonary remodelling, lung function in mice at 12.5 mg/kg bid and rats at 2.5 mg/kg bid.”
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
EMA: relevance of bleomycin data to progressive pulmonary fibrosis questionable (transient rodent fibrosis)
“However as single dose bleomycin-induced pulmonary fibrosis disease often transiently resolves in rodents, the relevance of the current in vivo data (i.e. mice/rats treated with nerandomilast 8-10 days after bleomycin challenge) for the clinical situation with progressive pulmonary fibrosis (PPF) is questionable.”
Flexibilityopen answer page →
Flexibility accepted
Safety pharmacologyCriticised but acceptedBeyond the letter
In vitro hERG assay not conducted under GLP and had several deficiencies
Why: No QT prolongation potential in a dedicated clinical QT assessment · Human data
“Several deficiencies were evident in the hERG assay, which was not conducted under GLP conditions as per ICH S7B.”
“However, given that nerandomilast did not show QT prolongation potential in a dedicated clinical QT assessment, the addition of a GLP in vitro hERG assay is not warranted.”
CarcinogenicityAccepted
Rat carcinogenicity high dose gave low exposure margins of 1.6 (males) and 2.2 (females) by AUC
Why: In line with the ICH S1(R1) addendum · Within the guideline
“The low exposure margins achieved in rats at the high dose of 2 mg/kg of 1.6 and 2.2 based on AUC in males and females was discussed and considered acceptable in line with ICH S1 (R1) addendum.”
Juvenile toxAcceptedBeyond the letter
Definitive juvenile rat toxicity study deferred under the paediatric investigation plan; only non-GLP range-finder available
Why: Agreed deferral in the paediatric investigation plan · Other reason
“A definitive juvenile toxicity rat study is agreed in the PIP, with the completion of this study deferred to September 2025.”
“Conclusions The nonclinical package submitted for nerandomilast for MAA is acceptable.”
Safety marginVerdict not stated
26-week rat NOAEL exposure equivalent (1-fold) to human Cmax and AUC at the MRHD
“In the 26-week repeat-dose toxicity study in rats, the NOAEL of 2 mg/kg/day resulted in steady state Cmax and AUC0-24 levels that were 1-fold (equivalent) to human levels at the MRHD.”
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