Sofdra
sofpironium
Species
RatPig
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 and Göttingen minipig
“Sofpironium bromide (code name; BBI-4000) has been evaluated in repeat-dose subcutaneous toxicity studies in rats for up to 26 weeks, and in repeat-dose dermal toxicity studies in Göttingen minipigs for up to 39 weeks.”
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
“Semi-occluded doses of 0% (vehicle), 5%, 10% or 20% sofpironium bromide gel were topically administered in Göttingen minipigs (4 sex/group) for 6 hr/day daily for 39 weeks.”
Species: general tox
Rat (subcutaneous, up to 26 weeks) and Göttingen minipig (dermal, up to 39 weeks)
“Sofpironium bromide (code name; BBI-4000) has been evaluated in repeat-dose subcutaneous toxicity studies in rats for up to 26 weeks, and in repeat-dose dermal toxicity studies in Göttingen minipigs for up to 39 weeks.”
Species: DART
Rat and rabbit (subcutaneous): fertility, embryofetal and pre/postnatal development
“The effect of sofpironium bromide on reproductive and development toxicity, including fertility, embryofetal development, and prenatal and postnatal development was investigated in rats or rabbits following subcutaneous (sc) administration.”
Species: carcinogenicity
Mouse (2-year dermal) and rat (2-year subcutaneous)
“The carcinogenic potential of sofpironium bromide was assessed in a 2-year dermal mouse carcinogenicity study and a 2-year subcutaneous rat carcinogenicity study.”
Surrogate used in
No surrogate used; sofpironium bromide tested directly in rats and minipigs
“Sofpironium bromide (code name; BBI-4000) has been evaluated in repeat-dose subcutaneous toxicity studies in rats for up to 26 weeks, and in repeat-dose dermal toxicity studies in Göttingen minipigs for up to 39 weeks.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dermal minipig)
“Sofpironium bromide (code name; BBI-4000) has been evaluated in repeat-dose subcutaneous toxicity studies in rats for up to 26 weeks, and in repeat-dose dermal toxicity studies in Göttingen minipigs for up to 39 weeks.”
Pivotal GLP studies
26-week subcutaneous rat and 39-week dermal minipig studies
“Sofpironium bromide (code name; BBI-4000) has been evaluated in repeat-dose subcutaneous toxicity studies in rats for up to 26 weeks, and in repeat-dose dermal toxicity studies in Göttingen minipigs for up to 39 weeks.”
Route in tox
Subcutaneous (rat) and dermal (minipig)
“Sofpironium bromide (code name; BBI-4000) has been evaluated in repeat-dose subcutaneous toxicity studies in rats for up to 26 weeks, and in repeat-dose dermal toxicity studies in Göttingen minipigs for up to 39 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and rat micronucleus assays
“Sofpironium bromide was not mutagenic or clastogenic in the bacterial reverse mutation assay, in vitro mammalian chromosome aberration assay, and rat in vivo micronucleus assay.”
Carcinogenicity
2-year dermal mouse and 2-year subcutaneous rat studies; no drug-related neoplasms in mice up to 20% gel
“The carcinogenic potential of sofpironium bromide was assessed in a 2-year dermal mouse carcinogenicity study and a 2-year subcutaneous rat carcinogenicity study. There were no drug-related neoplasms associated with daily topical administration of sofpironium bromide topical gel to mice at doses of up to 20% sofpironium bromide”
Reproductive & developmental
Rat and rabbit sc EFD: rat NOAEL 10 mg/kg/day; rabbit EFD NOAEL 2 mg/kg/day, malformation NOAEL 10 mg/kg/day
“The maternal and fetal survival, growth and development NOAEL was 10 mg/kg/day in embryo-fetal development studies in rats following sc administration. In rabbits, the NOAEL for embryo-fetal development toxicity was 2 mg/kg/day sc sofpironium bromide and the NOAEL for fetal malformation was 10 mg/kg/day.”
Safety pharmacology
hERG IC50 >300 µM (~350-fold clinical exposure)
“In vitro, sofpironium bromide was shown to inhibit the Ikr current in a hERG assay with an IC50 value of >300 μM, an approximate 350-fold higher exposure than that was measured clinically.”
Genotox: Ames
Negative
“Sofpironium bromide was not mutagenic in a bacterial mutagenicity assay (Ames assay) or clastogenic in an in vitro mammalian chromosomal aberration assay (human peripheral blood lymphocytes) or in an in vivo micronucleus assay in rats.”
Genotox: in vitro mammalian
Negative chromosomal aberration assay in human peripheral blood lymphocytes
“Sofpironium bromide was not mutagenic in a bacterial mutagenicity assay (Ames assay) or clastogenic in an in vitro mammalian chromosomal aberration assay (human peripheral blood lymphocytes) or in an in vivo micronucleus assay in rats.”
Genotox: in vivo
Negative rat in vivo micronucleus assay
“Sofpironium bromide was not mutagenic in a bacterial mutagenicity assay (Ames assay) or clastogenic in an in vitro mammalian chromosomal aberration assay (human peripheral blood lymphocytes) or in an in vivo micronucleus assay in rats.”
Carcinogenicity model
2-year dermal mouse and 2-year subcutaneous rat; no drug-related neoplasms in mice up to 20% gel
“The carcinogenic potential of sofpironium bromide was assessed in a 2-year dermal mouse carcinogenicity study and a 2-year subcutaneous rat carcinogenicity study. There were no drug-related neoplasms associated with daily topical administration of sofpironium bromide topical gel to mice at doses of up to 20% sofpironium bromide”
Carcinogenicity timing
Subcutaneous rat and dermal mouse studies (about 104 weeks) completed and submitted with the NDA
“In this submission, the sponsor included reports of two animal carcinogenicity studies, one in rats and one in mice. These studies were intended to assess the carcinogenic potential of BBI-4000 when administered by subcutaneousinjection in rats and by dermal in mice at appropriate drug levels for about 104 weeks.”
hERG / QT
hERG IC50 >300 µM, ~350-fold above clinical exposure
“In vitro, sofpironium bromide was shown to inhibit the Ikr current in a hERG assay with an IC50 value of >300 μM, an approximate 350-fold higher exposure than that was measured clinically.”
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 Sofdra 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: Mainly administration-site findings; anticholinergic effects in rats at ≥1.5 mg/kg/day sc (FDA multi-discipline review, p. 34)
NOAEL / key findings
Mainly administration-site findings; anticholinergic effects in rats at ≥1.5 mg/kg/day sc
“The major treatment-related effects observed in repeat-dose studies were findings at the test article administration sites. Pharmacologic anticholinergic effects were observed in rats with subchronic or chronic subcutaneous administration at doses of ≥1.5 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Skin irritant but not a skin sensitizer
“Sofpironium bromide is a skin irritant but not a sensitizer.”
Biodistribution & persistence
Rat: low placental transfer; drug or metabolites excreted into milk
“The transfer of 14C-sofpironium and/or its metabolites across the placental barrier is low during both organogenesis (12th day of pregnancy) and late (18th day) pregnancy. Sofpironium or its metabolites were transferred into the milk after a single subcutaneous administration of 0.5 mg/kg to lactating rats on postpartum Day 10.”
Modality-specific risk
Local skin and ocular irritation of the topical gel
“Sofpironium bromide gel (20%) elicited ocular irritation based on the results of the Bovine Corneal Opacity and Permeability assay. Sofpironium bromide is a skin irritant but not a sensitizer.”
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
- Urinary Retention
- Control of Body Temperature
- Operating Machinery or an Automobile
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 Sofdra 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: Mainly administration-site findings; anticholinergic effects in rats at ≥1.5 mg/kg/day sc (FDA multi-discipline review, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dermal Göttingen minipig; no recovery phase described
“Semi-occluded doses of 0% (vehicle), 5%, 10% or 20% sofpironium bromide gel were topically administered in Göttingen minipigs (4 sex/group) for 6 hr/day daily for 39 weeks.”
Pivotal GLP studies
26-week subcutaneous rat and 39-week dermal minipig studies
“Sofpironium bromide (code name; BBI-4000) has been evaluated in repeat-dose subcutaneous toxicity studies in rats for up to 26 weeks, and in repeat-dose dermal toxicity studies in Göttingen minipigs for up to 39 weeks.”
DART package
Species: DART
Rat and rabbit (subcutaneous): fertility, embryofetal and pre/postnatal development
“The effect of sofpironium bromide on reproductive and development toxicity, including fertility, embryofetal development, and prenatal and postnatal development was investigated in rats or rabbits following subcutaneous (sc) administration.”
Reproductive & developmental
Rat and rabbit sc EFD: rat NOAEL 10 mg/kg/day; rabbit EFD NOAEL 2 mg/kg/day, malformation NOAEL 10 mg/kg/day
“The maternal and fetal survival, growth and development NOAEL was 10 mg/kg/day in embryo-fetal development studies in rats following sc administration. In rabbits, the NOAEL for embryo-fetal development toxicity was 2 mg/kg/day sc sofpironium bromide and the NOAEL for fetal malformation was 10 mg/kg/day.”
PPND / ePPND: when
PPND in rat (subcutaneous) completed and reviewed in the NDA
“The potential of sofpironium bromide (an anticholinergic) related effects on pre- and postnatal development was assessed following daily subcutaneous administration from GD 6 after mating until lactation day (LD) 20 in the Sprague Dawley rat at doses of 1, 3 or 6 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Mouse (2-year dermal) and rat (2-year subcutaneous)
“The carcinogenic potential of sofpironium bromide was assessed in a 2-year dermal mouse carcinogenicity study and a 2-year subcutaneous rat carcinogenicity study.”
Carcinogenicity model
2-year dermal mouse and 2-year subcutaneous rat; no drug-related neoplasms in mice up to 20% gel
“The carcinogenic potential of sofpironium bromide was assessed in a 2-year dermal mouse carcinogenicity study and a 2-year subcutaneous rat carcinogenicity study. There were no drug-related neoplasms associated with daily topical administration of sofpironium bromide topical gel to mice at doses of up to 20% sofpironium bromide”
Carcinogenicity timing
Subcutaneous rat and dermal mouse studies (about 104 weeks) completed and submitted with the NDA
“In this submission, the sponsor included reports of two animal carcinogenicity studies, one in rats and one in mice. These studies were intended to assess the carcinogenic potential of BBI-4000 when administered by subcutaneousinjection in rats and by dermal in mice at appropriate drug levels for about 104 weeks.”
Safety marginopen answer page →
Safety margin at NOAEL
Adequate systemic safety margins at pivotal NOAELs; dermal NOAEL generally 20% gel vs 15% clinical
“For the NOAEL determined in the pivitol toxicology studies with sofpironium bromide, there are adequate safety margins when systemic exposure of sofpironium bromide is compared between animals and humans topically treated with sofpironium bromide gel, 15%. The NOAEL of sofpironium bromide gel in animal dermal toxicology studies are generally 20% which is higher when compared to the 15% concentration in clinical studies.”
NOAEL / key findings
Mainly administration-site findings; anticholinergic effects in rats at ≥1.5 mg/kg/day sc
“The major treatment-related effects observed in repeat-dose studies were findings at the test article administration sites. Pharmacologic anticholinergic effects were observed in rats with subchronic or chronic subcutaneous administration at doses of ≥1.5 mg/kg/day.”
Efficacy evidenceopen answer page →
Efficacy evidence
Pilocarpine-induced perspiration in normal SD rats inhibited by topical 20% gel
“In comparison with a concurrent ethanol control group, a single topical application of sofpironium bromide gel at a 20% concentration statistically significantly inhibited perspiration induced by subcutaneous injection of the muscarinic receptor agonist pilocarpine.”
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
FDA: topical sofpironium effectively reduced sympathetic nerve over-activity at the application site
“This study demonstrated that topically applied sofpironium bromide effectively reduced sympathetic nerve over-activity at the site of application.”
Flexibilityopen answer page →
Flexibility accepted
No departure named in the public reviews.
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