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.”
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.”
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.”