Sohonos
palovarotene
Sources:FDA integrated review ↗
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“A series of pharmacology, pharmacokinetics (PK)/absorption, distribution, metabolism, excretion (ADME), repeat dose general toxicology studies of up to 26- and 39-week duration in rats and dogs, respectively, as well as reproductive toxicology (male and female fertility and early embryonic development (FEED), single species (rat) embryofetal development EFD) and juvenile animal toxicity studies were conducted.”
Why that species
Similar in vivo metabolite profiles in rats and dogs; no human-unique metabolites
“The in vivo metabolite profiles were similar in rats and dogs. No metabolites unique to humans were identified.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Groups of Wistar rats were given oral daily doses of vehicle (Miglyol 812 with 0.01% BHA and 0.01% BHT), or palovarotene at 0.3, 0.6 and 1 mg/kg/day for 26 weeks, including groups terminated after 13-weeks.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“A series of pharmacology, pharmacokinetics (PK)/absorption, distribution, metabolism, excretion (ADME), repeat dose general toxicology studies of up to 26- and 39-week duration in rats and dogs, respectively, as well as reproductive toxicology (male and female fertility and early embryonic development (FEED), single species (rat) embryofetal development EFD) and juvenile animal toxicity studies were conducted.”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“A series of pharmacology, pharmacokinetics (PK)/absorption, distribution, metabolism, excretion (ADME), repeat dose general toxicology studies of up to 26- and 39-week duration in rats and dogs, respectively, as well as reproductive toxicology (male and female fertility and early embryonic development (FEED), single species (rat) embryofetal development EFD) and juvenile animal toxicity studies were conducted.”
Route in tox
Oral
“Groups of Wistar rats were given oral daily doses of vehicle (Miglyol 812 with 0.01% BHA and 0.01% BHT), or palovarotene at 0.3, 0.6 and 1 mg/kg/day for 26 weeks, including groups terminated after 13-weeks.”
Skipped studiesopen answer page →
Genotoxicity
Negative Ames and mouse micronucleus; in vitro chromosomal aberration positive only at cytotoxic concentrations
“The in vitro Ames assay and in vivo mouse micronucleus assays were negative. Although an in vitro chromosomal aberration assay was positive, a clastogenic response was only evident at cytotoxic concentrations (mitotic index ≥50%).”
Carcinogenicity
Not conducted; studies in two rodent species required postmarketing
“Carcinogenicity assessment in two rodent species is considered necessary as a post marketing requirement.”
Reproductive & developmental
Rat EFD: multiple fetal external, visceral and skeletal malformations at ≥0.25 mg/kg/day, below clinical exposure
“Administration of daily oral doses of palovarotene to pregnant rats during the period of organogenesis resulted in multiple fetal external, visceral, and skeletal malformations at ≥0.25 mg/kg/day (below clinical exposures), consistent with the pattern of retinoid-mediated embryopathy.”
Safety pharmacology
Cardiovascular, neurobehavioral, GI and urinary studies: no apparent acute safety concerns
“Based on safety pharmacology studies conducted to assess the potential for cardiovascular, neurobehavioral, gastrointestinal and urinary effects, palovarotene did not appear to pose any”
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 Sohonos 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: No NOAEL in 26-week rat: skin, growth plate (knee, sternum) and forestomach findings at all doses (FDA integrated review, p. 281)
NOAEL / key findings
No NOAEL in 26-week rat: skin, growth plate (knee, sternum) and forestomach findings at all doses
“The target organs were the skin, growth plate of stifle or knee joints and sternum, and nonglandular forestomach during the interim and terminal sacrifices at all doses.”
Risksopen answer page →
Immune & cytokine safety
No evidence of immunosuppression
“No evidence of hormonal effects or immunosuppression”
Biodistribution & persistence
Slow but extensive tissue distribution (autoradiography)
“In autoradiography tissue distribution studies, palovarotene exhibited a slow but extensive distribution into the tissues.”
Modality-specific risk
Skin lesions, growth suppression and premature physeal closure in juveniles
“The safety issues identified in the nonclinical studies, including skin lesions, growth suppression, and premature closure of physis in juveniles, have been observed in humans treated with palovarotene.”