Ohtuvayre
ensifentrine
Species
RatDog
Longest study
40 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 Applicant has conducted subchronic and chronic toxicology studies with ensifentrine in both rats and dogs.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“In a good laboratory practice (GLP) study, Wistar Han rats (10 animals/sex/group) were administered ensifentrine (suspension) once daily at 0 (vehicle), 2.0, 6.97, and 15.5 mg/kg/day”
Species: general tox
Rat (up to 6 months) and dog (up to 9 months)
“As listed in Table 39, general toxicity studies with ensifentrine were conducted in rats and dogs with dosing durations up to 6 months and 9 months, respectively.”
Species: DART
Rat and rabbit (embryo-fetal development)
“In animal reproduction studies, no adverse developmental effects were observed with inhalation administration of ensifentrine to pregnant rats and rabbits during organogenesis at maternal exposures up to 79 and 9 times, respectively, the exposure at the maximum recommended human daily inhalation dose (MRHDID).”
Species: carcinogenicity
Han Wistar rat (2-year inhalation) and Tg.rasH2 mouse (6-month oral)
“A two-year inhalation study in Han Wistar rats and a 6-month oral study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of ensifentrine.”
Surrogate used in
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.
Study lengthopen answer page →
Longest pivotal study
40 (40-week dog)
“The Division noted that in the 40-week dog study (Study #PL15XK), a no observed adverse effect level (NOAEL) was not established with respect to coronary artery vasculopathy.”
Pivotal GLP studies
Repeat-dose studies up to 6 months in rats and 9 months in dogs
“As listed in Table 39, general toxicity studies with ensifentrine were conducted in rats and dogs with dosing durations up to 6 months and 9 months, respectively.”
Route in tox
Inhalation
“Coronary artery vasculopathy findings associated with hemodynamic changes (i.e., increased heart rate and decreased blood pressure) were observed in repeat-dose inhalation toxicology studies (from 6-week to 40-week) in dogs.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vivo rat comet (lung and liver) and mouse micronucleus assays
“Ensifentrine was negative for genotoxicity in the following assays: in vitro Ames test for bacterial gene mutation, in vivo comet test (lung and liver) with rats, and in vivo micronucleus assay with mice.”
Carcinogenicity
2-year rat inhalation and 6-month rasH2 mouse oral studies; no tumorigenicity in rats at ~40x MRHDID
“A two-year inhalation study in Han Wistar rats and a 6-month oral study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of ensifentrine. No evidence of tumorigenicity was observed in male and female rats at an exposure approximately 40 times the MRHDID.”
Reproductive & developmental
Male rat reproductive tract toxicity impaired fertility: lower mating/fertility indices, more implantation loss at 30x MRHDID
“The male reproductive tract toxicity observed in the rat repeat dose toxicity studies resulted in impaired reproductive performance including decreased mating index and decreased fertility index, increased pre- and post-implantation loss, and decreased live embryos per litter in untreated females at 30 times the MRDHID.”
Safety pharmacology
Complete safety pharmacology battery; hERG IC50 5.62 μM
“A complete battery of safety pharmacology studies has been conducted with ensifentrine. The ensifentrine half maximal inhibitory concentration (IC50) at hERG channels expressed in HEK293 cells was calculated to be 5.62 μM.”
Genotox: Ames
Negative
“Ensifentrine was negative for genotoxicity in the following assays: in vitro Ames test for bacterial gene mutation, in vivo comet test (lung and liver) with rats, and in vivo micronucleus assay with mice.”
Genotox: in vitro mammalian
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.
Genotox: in vivo
Negative: rat comet (lung and liver) and mouse micronucleus
“Ensifentrine was negative for genotoxicity in the following assays: in vitro Ames test for bacterial gene mutation, in vivo comet test (lung and liver) with rats, and in vivo micronucleus assay with mice.”
Carcinogenicity model
2-year inhalation study in Han Wistar rat and 6-month oral Tg.rasH2 mouse
“A two-year inhalation study in Han Wistar rats and a 6-month oral study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of ensifentrine.”
Carcinogenicity timing
2-year rat inhalation and 6-month Tg.rasH2 mouse oral studies completed before the marketing application
“A two-year inhalation study in Han Wistar rats and a 6-month oral study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of ensifentrine.”
hERG / QT
hERG IC50 5.62 μM (HEK293 cells)
“The ensifentrine half maximal inhibitory concentration (IC50) at hERG channels expressed in HEK293 cells was calculated to be 5.62 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 Ohtuvayre 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: Rat: salivary gland acinar hypertrophy, testis atrophy, epididymal germ cell debris; dog: coronary artery vasculopathy (FDA integrated review, p. 79)
NOAEL / key findings
Rat: salivary gland acinar hypertrophy, testis atrophy, epididymal germ cell debris; dog: coronary artery vasculopathy
“Target organs of toxicity were identified as mandibular and parotid salivary glands (acinar cell hypertrophy), testis (tubular degeneration/atrophy), and epididymis (intraluminal germ cell debris) in rats, and heart (coronary artery vasculopathy) in dogs.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
No radioactivity detected in rat brain or spinal cord
“Radioactivity was not detectable in the brain or spinal cord in the rats.”
Modality-specific risk
Coronary artery vasculopathy in dogs linked to increased heart rate and decreased blood pressure
“In the nonclinical development program, ensifentrine treatment in dogs resulted in coronary artery vasculopathy associated with an increased heart rate and decreased blood pressure.”
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
- Acute Episodes of Bronchospasm
- Paradoxical Bronchospasm
- Psychiatric Events Including Suicidality
Psychiatric
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 Ohtuvayre 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: Rat: salivary gland acinar hypertrophy, testis atrophy, epididymal germ cell debris; dog: coronary artery vasculopathy (FDA integrated review, p. 79)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
40-week dog (inhalation, GLP) with 4-week recovery
“RPL554: Toxicity study by inhalation administration to Beagle dogs for 40 weeks followed by a 4-week recovery period”
Pivotal GLP studies
Repeat-dose studies up to 6 months in rats and 9 months in dogs
“As listed in Table 39, general toxicity studies with ensifentrine were conducted in rats and dogs with dosing durations up to 6 months and 9 months, respectively.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“In animal reproduction studies, no adverse developmental effects were observed with inhalation administration of ensifentrine to pregnant rats and rabbits during organogenesis at maternal exposures up to 79 and 9 times, respectively, the exposure at the maximum recommended human daily inhalation dose (MRHDID).”
Reproductive & developmental
Male rat reproductive tract toxicity impaired fertility: lower mating/fertility indices, more implantation loss at 30x MRHDID
“The male reproductive tract toxicity observed in the rat repeat dose toxicity studies resulted in impaired reproductive performance including decreased mating index and decreased fertility index, increased pre- and post-implantation loss, and decreased live embryos per litter in untreated females at 30 times the MRDHID.”
PPND / ePPND: when
PPND in rat (inhalation, GLP) completed before the marketing application
“In a GLP pre- and postnatal development study (8438109), pregnant rats were administered ensifentrine at achieved inhalation doses of 2.04, 5.94, and 18.6 mg/kg/day”
Carcinogenicity
Species: carcinogenicity
Han Wistar rat (2-year inhalation) and Tg.rasH2 mouse (6-month oral)
“A two-year inhalation study in Han Wistar rats and a 6-month oral study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of ensifentrine.”
Carcinogenicity model
2-year inhalation study in Han Wistar rat and 6-month oral Tg.rasH2 mouse
“A two-year inhalation study in Han Wistar rats and a 6-month oral study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of ensifentrine.”
Carcinogenicity timing
2-year rat inhalation and 6-month Tg.rasH2 mouse oral studies completed before the marketing application
“A two-year inhalation study in Han Wistar rats and a 6-month oral study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of ensifentrine.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog NOAEL provided adequate margins (no multiple stated in text)
“While the no observed adverse effect level in dogs provided adequate nonclinical safety margins, cardiac and vascular disorders were evaluated as safety topics of interest.”
NOAEL / key findings
Rat: salivary gland acinar hypertrophy, testis atrophy, epididymal germ cell debris; dog: coronary artery vasculopathy
“Target organs of toxicity were identified as mandibular and parotid salivary glands (acinar cell hypertrophy), testis (tubular degeneration/atrophy), and epididymis (intraluminal germ cell debris) in rats, and heart (coronary artery vasculopathy) in dogs.”
Efficacy evidenceopen answer page →
Efficacy evidence
Exploratory in vivo models of allergic conditions and asthma; no COPD animal model
“However, the Applicant did not conduct any in vivo pharmacology studies using COPD animal models. The in vivo pharmacology studies were primarily for allergic conditions as well as asthma.”
Why that model
No animal model fully recapitulates COPD; smoke, LPS and elastase models induce only some features
“While there are no animal models that fully recapitulate all aspects of COPD, the most frequently employed animal models use cigarette smoke, lipopolysaccharide, and elastase to induce various features of COPD.”
Reviewer's view of the efficacy data
FDA: clinical relevance of allergic models unclear, but totality of in vitro and in vivo data sufficient to characterize pharmacology
“Given the differences in etiology between COPD and allergic conditions, the clinical relevance of these studies to the current application is not clear. Nevertheless, the totality of in vitro and in vivo pharmacology data submitted was considered sufficient to characterize the pharmacological activity of ensifentrine”
Flexibilityopen answer page →
Flexibility accepted
No departure named in the public reviews.
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