Vizz
aceclidine
Species
Rabbit
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit
“Table 42. 6-Month Ocular Toxicity Study in Rabbits, Study 21-1257”
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
“No changes in ophthalmoscopic observations attributed to aceclidine.”
Species: general tox
Rabbit only (chronic topical ocular study)
“The chronic ocular toxicity of aceclidine hydrochloride was investigated in rabbits”
Species: DART
Rat and rabbit (organogenesis and lactation studies)
“In animal reproduction studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis and lactation did not produce adverse maternal, fetal or neonatal effects at clinically relevant doses.”
Species: carcinogenicity
Not conducted
“Long term studies in animals have not been performed to evaluate carcinogenic potential.”
Surrogate used in
No surrogate molecule; metabolite 3-quinuclidinol used as exposure surrogate
“Assays for systemic and ocular exposure to the metabolite 3-quinuclidinol were developed, and 3-quinuclidinol exposure was used as a surrogate to determine ocular distribution and quantify systemic exposure.”
Study lengthopen answer page →
Longest pivotal study
26 (6-month rabbit ocular)
“Table 42. 6-Month Ocular Toxicity Study in Rabbits, Study 21-1257”
Pivotal GLP studies
6-month GLP ocular study in rabbits
“Table 42. 6-Month Ocular Toxicity Study in Rabbits, Study 21-1257 Study Features and Methods Details GLP compliance Yes”
Route in tox
Topical ocular (bilateral instillation)
“Route of administration (dose volume): Bilateral topical ocular instillation”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames (Salmonella and E. coli), in vitro chromosome aberration and mouse micronucleus assays
“Aceclidine did not show any potential to cause genetic toxicity in a series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in cultured human peripheral blood lymphocytes; and 3) an in vivo chromosome aberration assay (micronucleus test) in mice.”
Carcinogenicity
Not conducted
“Long term studies in animals have not been performed to evaluate carcinogenic potential.”
Reproductive & developmental
Oral rat and rabbit EFD: no maternal toxicity, skeletal anomalies or reduced fetal weight at 1.5 mg/kg/day
“In embryofetal development studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis produced no maternal toxicity, skeletal anomalies, nor reduction in fetal body weight at 1.5 mg/kg/day”
Safety pharmacology
Not conducted for QT; QT risk considered low given very limited systemic exposure
“QT prolongation Not studied. Given that systemic exposure to aceclidine in the proposed dosage is very limited, the risk of QT prolongation with ocular administration would be low.”
Genotox: Ames
Negative (Salmonella and E. coli)
“Aceclidine did not show any potential to cause genetic toxicity in a series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in cultured human peripheral blood lymphocytes; and 3) an in vivo chromosome aberration assay (micronucleus test) in mice.”
Genotox: in vitro mammalian
Chromosome aberration in human lymphocytes: negative
“Aceclidine did not show any potential to cause genetic toxicity in a series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in cultured human peripheral blood lymphocytes; and 3) an in vivo chromosome aberration assay (micronucleus test) in mice.”
Genotox: in vivo
Mouse micronucleus: negative
“Aceclidine did not show any potential to cause genetic toxicity in a series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in cultured human peripheral blood lymphocytes; and 3) an in vivo chromosome aberration assay (micronucleus test) in mice.”
Carcinogenicity model
Not conducted
“Long term studies in animals have not been performed to evaluate carcinogenic potential.”
Carcinogenicity timing
Not conducted; no long-term carcinogenicity studies performed, no reason given
“Long term studies in animals have not been performed to evaluate carcinogenic potential.”
hERG / QT
QT not studied; risk considered low given very limited systemic exposure
“QT prolongation Not studied. Given that systemic exposure to aceclidine in the proposed dosage is very limited, the risk of QT prolongation with ocular administration would be low.”
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 Vizz 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: Chronic ocular rabbit study: no adverse ocular or systemic effects (FDA integrated review, p. 77)
NOAEL / key findings
Chronic ocular rabbit study: no adverse ocular or systemic effects
“The chronic ocular toxicity of aceclidine hydrochloride was investigated in rabbits, with no adverse ocular or systemic effects at a dose of”
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
Rabbit eye: metabolite distributed to all ocular tissues within 30 min; highest in cornea and iris
“3-quinuclidinol distributed to all ocular tissues analyzed within 30 minutes of treatment. The rank order of the exposure was: cornea > iris > choroid > aqueous humor > sclera > retina > lens ≈ vitreous humor.”
Modality-specific risk
Systemic exposure quantified via metabolite 3-quinuclidinol as surrogate
“Assays for systemic and ocular exposure to the metabolite 3-quinuclidinol were developed, and 3-quinuclidinol exposure was used as a surrogate to determine ocular distribution and quantify systemic exposure.”
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
- Blurred Vision
- Risk of Retinal Tear/Detachment
- Iritis
- Hypersensitivity
- Use with Contact Lenses
- Potential for Eye Injury or Contamination
Ocular toxicityHypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country of first human use not stated; all eight sponsor clinical studies ran in the United States
“LENZ conducted eight clinical studies in the United States under IND 120609.”
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 Vizz 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: Chronic ocular rabbit study: no adverse ocular or systemic effects (FDA integrated review, p. 77)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week (6-month) GLP ocular study in Dutch Belted rabbits with 4-week recovery
“Core study: 6/sex/group Recovery (4-weeks): 3/sex/group; control and Group 4 only”
Pivotal GLP studies
6-month GLP ocular study in rabbits
“Table 42. 6-Month Ocular Toxicity Study in Rabbits, Study 21-1257 Study Features and Methods Details GLP compliance Yes”
DART package
Species: DART
Rat and rabbit (organogenesis and lactation studies)
“In animal reproduction studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis and lactation did not produce adverse maternal, fetal or neonatal effects at clinically relevant doses.”
Reproductive & developmental
Oral rat and rabbit EFD: no maternal toxicity, skeletal anomalies or reduced fetal weight at 1.5 mg/kg/day
“In embryofetal development studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis produced no maternal toxicity, skeletal anomalies, nor reduction in fetal body weight at 1.5 mg/kg/day”
PPND / ePPND: when
PPND in rat completed and reviewed with the marketing application
“In a pre- and postnatal development (PPND) study in rats, no adverse effects on the dam or first-generation (F1) offspring were observed at doses up to”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Long term studies in animals have not been performed to evaluate carcinogenic potential.”
Carcinogenicity model
Not conducted
“Long term studies in animals have not been performed to evaluate carcinogenic potential.”
Carcinogenicity timing
Not conducted; no long-term carcinogenicity studies performed, no reason given
“Long term studies in animals have not been performed to evaluate carcinogenic potential.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat/rabbit EFD at 1.5 mg/kg/day (no maternal or fetal toxicity): ~110x and 70x human 3-quinuclidinol exposure
“In embryofetal development studies, oral administration of aceclidine to pregnant rats and rabbits throughout organogenesis produced no maternal toxicity, skeletal anomalies, nor reduction in fetal body weight at 1.5 mg/kg/day (approximately 110-fold and 70-fold the human plasma exposure to the metabolite, 3-quinuclidinol, in rats and rabbits, respectively, at the MRHOD, assuming administration of 2 drops/eye/day).”
NOAEL / key findings
Chronic ocular rabbit study: no adverse ocular or systemic effects
“The chronic ocular toxicity of aceclidine hydrochloride was investigated in rabbits, with no adverse ocular or systemic effects at a dose of”
Efficacy evidenceopen answer page →
Efficacy evidence
Pupil response (miosis) in normal New Zealand White rabbits after topical aceclidine 1.75%
“In an efficacy study (Study #21-130-0009), pupil response was measured in New Zealand White rabbits following a single topical administration of aceclidine 1.75% with or without”
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
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.
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteAccepted
Potential mutagenic drug-substance impurity specified above the default ICH M7 acceptable intake, without impurity-specific safety data
Why: ICH M7 allows a higher acceptable intake for this impurity class · Within the guideline
“However, ICH M7 specifically comments on as a class and states the acceptable intake for this class of impurities could be increased by fold to µg/day”
“The specification of NMT ppm is acceptable from a nonclinical perspective.”
DARTVerdict not stated
Rat pre/postnatal development study without toxicokinetics in dams or offspring
“Toxicokinetics in the dams or nursing F1 offspring were not measured in the study.”
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