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.”
Species: general tox
Rat (26-week) and dog (39-week)
“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.”
Species: DART
Rat only (male and female fertility, EFD); second-species EFD waived as palovarotene was teratogenic in rats
“The Agency agreed that there was no benefit in conducting an EFD study in pregnant animals of a second species, as palovarotene adversely affected fetal development in pregnant rats, which was consistent with the retinoid class known to carry fetal development risks.”
Species: carcinogenicity
Not conducted; 2-year rat and mouse studies recommended
“The nonclinical review team in consultation with the CDER Executive Carcinogenicity Assessment Committee (ECAC) concluded that the carcinogenic potential of palovarotene in humans is uncertain and assessment in a 2-year rat carcinogenicity study, in addition to a mouse in vivo carcinogenicity study, would add value to the assessment of human carcinogenic risk.”
Surrogate used in
No surrogate used; palovarotene itself tested in rats
“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”
Genotox: Ames
Negative
“The in vitro Ames assay and in vivo mouse micronucleus assays were negative.”
Genotox: in vitro mammalian
Chromosomal aberration (human lymphocytes): positive only at cytotoxic concentrations
“Although an in vitro chromosomal aberration assay was positive, a clastogenic response was only evident at cytotoxic concentrations (mitotic index ≥50%).”
Genotox: in vivo
Mouse micronucleus: negative
“The in vitro Ames assay and in vivo mouse micronucleus assays were negative.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment under ICH S1B(R1) instead
“Dedicated rodent carcinogenicity studies to assess the carcinogenic potential of palovarotene have not been conducted; instead, the Applicant assessed the carcinogenic potential of palovarotene using a weight of evidence (WoE) approach outlined in an amendment to International Council for Harmonization S1B(R1).”
Carcinogenicity timing
Rodent carcinogenicity studies in two species: postmarketing requirements, not started at approval
“Therefore, rodent carcinogenicity studies in two species to assesses the carcinogenic potential from long-term oral exposure to palovarotene are being recommended as post marketing requirements.”
hERG / QT
hERG IC50 7.2 µM in CHO cells, >30-fold free Cmax at MRHD
“Palovarotene significant reduced inward and outward K+ currents, with IC50 of 7.2μM (~2985 ng/mL), which results in wide safety margin (>30-fold between hERG IC50 and the free Cmax at the MRHD).”
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.”
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 applicable (small molecule)
“Immunogenicity (not applicable)”
Label warnings
Boxed warning: EMBRYO-FETAL TOXICITY and PREMATURE EPIPHYSEAL CLOSURE IN GROWING PEDIATRIC PATIENTS
- Embryo-Fetal Toxicity
- Premature Epiphyseal Closure in Growing Pediatric Patients
- Mucocutaneous Adverse Reactions
- Metabolic Bone Disorders
- Psychiatric Disorders
- Night Blindness
Embryo-fetal toxicitySkin reactionsMetabolic & endocrineMusculoskeletalPsychiatric
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog; mid-dose group dosed through Week 52; 13-week recovery in low- and high-dose groups
“Due to the lack of significant toxicity, the mid dose was increased from 25 to 120 μg/kg/day for at least 39 weeks (Week 13 through Week 52). Recovery was assessed for an additional 13 weeks in animals treated at 12 and 40 μg/kg/day.”
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.”
DART package
Species: DART
Rat only (male and female fertility, EFD); second-species EFD waived as palovarotene was teratogenic in rats
“The Agency agreed that there was no benefit in conducting an EFD study in pregnant animals of a second species, as palovarotene adversely affected fetal development in pregnant rats, which was consistent with the retinoid class known to carry fetal development risks.”
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.”
PPND / ePPND: when
PPND not conducted: not warranted because palovarotene was teratogenic in rats (retinoid class)
“As palovarotene adversely affected fetal development in pregnant rats, and retinoids as a class are known to carry a risk of affecting fetal development, neither an EFD study in pregnant animals of a second species nor a pre-/postnatal developmental toxicity study were warranted.”
Carcinogenicity
Species: carcinogenicity
Not conducted; 2-year rat and mouse studies recommended
“The nonclinical review team in consultation with the CDER Executive Carcinogenicity Assessment Committee (ECAC) concluded that the carcinogenic potential of palovarotene in humans is uncertain and assessment in a 2-year rat carcinogenicity study, in addition to a mouse in vivo carcinogenicity study, would add value to the assessment of human carcinogenic risk.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment under ICH S1B(R1) instead
“Dedicated rodent carcinogenicity studies to assess the carcinogenic potential of palovarotene have not been conducted; instead, the Applicant assessed the carcinogenic potential of palovarotene using a weight of evidence (WoE) approach outlined in an amendment to International Council for Harmonization S1B(R1).”
Carcinogenicity timing
Rodent carcinogenicity studies in two species: postmarketing requirements, not started at approval
“Therefore, rodent carcinogenicity studies in two species to assesses the carcinogenic potential from long-term oral exposure to palovarotene are being recommended as post marketing requirements.”
Safety marginopen answer page →
Safety margin at NOAEL
No safety margin: NOAELs <0.03 mg/kg/day (26-week rat) and <12 mg/kg/day (39-week dog) due to exaggerated pharmacology
“Because of the exaggerated pharmacology in healthy animal models, no safety margins were established at the palovarotene NOAEL doses of <0.03 mg/kg/day and <12 mg/kg/day in the 26-week rat and 39-week dog toxicity studies, respectively (Table 42).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Injury-induced HO and FOP mouse models: BMP-2 implant, ALK2Q207D and ALK2R206H transgenic mice
“Proof of concept in vivo studies with palovarotene were conducted in various injury-induced heterotopic ossification (HO) and FOP mice models, including BMP-2 implant, transgenic mice expressing constitutively active ALK2Q207D mutant and the human relevant ALK2R206H mutation (Shimono et al. 2011; Chakkalakal et al. 2012; Chakkalakal et al. 2016).”
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
Supports mechanism, but limited as confirmatory evidence of effectiveness due to species differences and study design
“Nevertheless, the utility of the nonclinical data to provide confirmatory evidence of clinical effectiveness on its own is limited by several factors, including species-specific differences and study design issues (Table 5).”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No rodent carcinogenicity studies before approval for chronic use; weight-of-evidence assessment submitted; two-species studies required postmarketing
Why: Unmet medical need in severely debilitating FOP · Rare disease / unmet need · Serious disease
“Carcinogenicity bioassays were not considered necessary prior to submission and review of a marketing application because of the unmet medical need for the severely debilitating nature of heterotopic ossification in patients with FOP.”
“Therefore, rodent carcinogenicity studies in two species to assesses the carcinogenic potential from long-term oral exposure to palovarotene are being recommended as post marketing requirements.”
DARTAcceptedBeyond the letter
Embryo-fetal study in rat only (no second species); no pre-/postnatal development study
Why: Teratogenic in rats; retinoid class known to affect fetal development · Class precedent · Weight of evidence
“As palovarotene adversely affected fetal development in pregnant rats, and retinoids as a class are known to carry a risk of affecting fetal development, neither an EFD study in pregnant animals of a second species nor a pre-/postnatal developmental toxicity study were warranted.”
Safety marginCriticised but acceptedBeyond the letter
No safety margins: NOAELs below lowest doses tested in 26-week rat and 39-week dog studies
Why: Exaggerated pharmacology in healthy animals; risks manageable through clinical monitoring and labelling · Pharmacology or kinetics
“Because of the exaggerated pharmacology in healthy animal models, no safety margins were established at the palovarotene NOAEL doses of <0.03 mg/kg/day and <12 mg/kg/day in the 26-week rat and 39-week dog toxicity studies, respectively (Table 42).”
“The human risks might be manageable through various clinical interventions, including use of skin ointment for skin changes, growth monitoring in pediatric patients, labelling (e.g., contraindication and pregnancy testing before/during/after treatment) and other risk mitigation strategies, as appropriate.”
Similar precedents
AgamreeSmall molecules · vamorolone · Glucocorticoid receptor (dissociative)Rodent + dog or minipig · 39 wkGomekliSmall molecules · mirdametinib · MEK1/2Rodent + dog or minipig · 13 wkDuvyzatSmall molecules · givinostat · Histone deacetylase (class I/II)Monkey + rodent · 39 wkEvrysdiSmall molecules · risdiplam · SMN2 splicingMonkey + rodent · 39 wkZokinvySmall molecules · lonafarnib · FarnesyltransferaseMonkey + rodent · 52 wkAdqueySmall molecules · difamilast · PDE4 (topical)Rodent + dog or minipig · 39 wk