Tryptyr
acoltremon
Species
RatDogRabbit
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 and dog (ocular); rat (intravenous)
“Alcon completed 6-month repeated dose ocular GLP toxicity studies in rabbits (Study AR-15512-AS03) and dogs (Study AR-15512-AS04) and 28-day repeated dose intravenous GLP toxicity studies in rats (Study STF-G10986 AVX-012).”
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 6-month repeat dose ocular GLP toxicity studies in the beagle dog and the New Zealand White rabbit with 14-day recovery periods, at the doses of 0.868, 1.736, and 4.793 µg/eye/day/OU acoltremon, the highest dose tested was the NOAEL in both species.”
Species: general tox
Rabbit and dog (6-month ocular)
“In 6-month repeat dose ocular GLP toxicity studies in the beagle dog and the New Zealand White rabbit with 14-day recovery periods, at the doses of 0.868, 1.736, and 4.793 µg/eye/day/OU acoltremon, the highest dose tested was the NOAEL in both species.”
Species: DART
Rat and rabbit (intravenous embryo-fetal development)
“The intravenous administration of acoltremon to pregnant rats and rabbits during organogenesis did not produce embryo-fetal toxicity at”
Species: carcinogenicity
Not conducted (waived; no systemic exposure)
“Carcinogenicity studies were not conducted with acoltremon.”
Surrogate used in
No surrogate used; acoltremon tested directly in rabbit and dog
“In 6-month repeat dose ocular GLP toxicity studies in the beagle dog and the New Zealand White rabbit with 14-day recovery periods, at the doses of 0.868, 1.736, and 4.793 µg/eye/day/OU acoltremon, the highest dose tested was the NOAEL in both species.”
Study lengthopen answer page →
Longest pivotal study
26 (6-month rabbit and dog ocular)
“Alcon completed 6-month repeated dose ocular GLP toxicity studies in rabbits (Study AR-15512-AS03) and dogs (Study AR-15512-AS04) and 28-day repeated dose intravenous GLP toxicity studies in rats (Study STF-G10986 AVX-012).”
Pivotal GLP studies
6-month ocular rabbit and dog studies; 28-day intravenous rat study
“Alcon completed 6-month repeated dose ocular GLP toxicity studies in rabbits (Study AR-15512-AS03) and dogs (Study AR-15512-AS04) and 28-day repeated dose intravenous GLP toxicity studies in rats (Study STF-G10986 AVX-012).”
Route in tox
Topical ocular (rabbit, dog); intravenous (rat)
“Alcon completed 6-month repeated dose ocular GLP toxicity studies in rabbits (Study AR-15512-AS03) and dogs (Study AR-15512-AS04) and 28-day repeated dose intravenous GLP toxicity studies in rats (Study STF-G10986 AVX-012).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration (human lymphocytes) and rat micronucleus assays
“All studies were valid and acoltremon was negative in the Ames test, an in vitro chromosomal aberration test in human peripheral blood lymphocytes, and an in vivo micronucleus assay in the rat.”
Carcinogenicity
Not conducted; waived given absent systemic exposure (ocular route)
“The committee agreed with the Division that in the absence of systemic exposure for acoltremon ophthalmic solution, 0.003%, there is no need to conduct carcinogenicity studies.”
Reproductive & developmental
Rat and rabbit IV EFD: no maternal or fetal toxicity at 806- and 2151-fold the MRHOD
“In embryofetal developmental studies in pregnant rats and rabbits dosed by intravenous injection daily during organogenesis from gestation days 6-17 and gestation days 7-19, respectively, no maternal or fetal toxicity was observed at 806- and 2151-fold the MRHOD of acoltremon on a mg/m 2 basis.”
Safety pharmacology
No adverse cardiovascular or CNS effects in GLP dog and rat toxicity studies
“There was no evidence of test-article-related adverse effects on cardiovascular and central nervous system functions, when evaluated during the good laboratory practice (GLP) toxicity studies in the dog and the rat.”
Genotox: Ames
Negative
“All studies were valid and acoltremon was negative in the Ames test, an in vitro chromosomal aberration test in human peripheral blood lymphocytes, and an in vivo micronucleus assay in the rat.”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral blood lymphocytes: negative
“All studies were valid and acoltremon was negative in the Ames test, an in vitro chromosomal aberration test in human peripheral blood lymphocytes, and an in vivo micronucleus assay in the rat.”
Genotox: in vivo
Rat micronucleus: negative
“All studies were valid and acoltremon was negative in the Ames test, an in vitro chromosomal aberration test in human peripheral blood lymphocytes, and an in vivo micronucleus assay in the rat.”
Carcinogenicity model
Not conducted; ocular route without significant systemic exposure (ICH S1A)
“ICH S1A indicates that pharmaceuticals administered by the ocular route may not require carcinogenicity studies unless there is cause for concern or unless there is significant systemic exposure (March 1996).”
Carcinogenicity timing
Waived: not needed given absent systemic exposure (Executive CAC)
“The committee agreed with the Division that in the absence of systemic exposure for acoltremon ophthalmic solution, 0.003%, there is no need to conduct carcinogenicity studies.”
hERG / QT
No cardiovascular or CNS effects in GLP dog and rat toxicity studies
“There was no evidence of test-article-related adverse effects on cardiovascular and central nervous system functions, when evaluated during the good laboratory practice (GLP) toxicity studies in the dog and the rat.”
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 Tryptyr 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: Reversible, nonadverse conjunctival redness and swelling (rabbit) and ocular discharge (dog) (FDA integrated review, p. 76)
NOAEL / key findings
Reversible, nonadverse conjunctival redness and swelling (rabbit) and ocular discharge (dog)
“Test-article-related, reversible, nonadverse conjunctival redness and swelling (rabbit) and/or ocular discharge (dog) were observed.”
Risksopen answer page →
Immune & cytokine safety
Not a skin sensitizer in mouse local lymph node assay
“The product was not a sensitizer in the local lymph node assay performed with CBA/Ca mice at up to 50% acoltremon applied on the dorsal surface of both ears once daily (25 µL/dose) for 3 days consecutively.”
Biodistribution & persistence
Rabbit ocular distribution: detected only in conjunctiva (2/8 eyes); other ocular tissues below LLOQ
“in an ocular distribution study in the rabbit where animals received 3 µg/eye/day (1.67-fold the therapeutic dose) for 28 days, acoltremon was detected in the conjunctiva of 2 out of 8 eyes, while cornea, conjunctiva, aqueous humor, iris/ciliary body, vitreous humor, and retina were below the LLOQ of 5.05 ng/mL in all animals.”
Modality-specific risk
Local ocular tolerability; systemic exposure negligible, so no systemic on- or off-target activity expected
“this reviewer judged that the systemic exposure to the test article (free maximum plasma concentration [Cmax]) can be considered negligible and hence, neither on- nor off-target activity of the test article could be expected other than locally in the ocular tissues.”
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
- Potential for Eye Injury and Contamination
- Use with Contact Lenses
Ocular toxicity
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 Tryptyr 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: Reversible, nonadverse conjunctival redness and swelling (rabbit) and ocular discharge (dog) (FDA integrated review, p. 76)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month ocular GLP studies in dog and rabbit, each with 14-day recovery
“In 6-month repeat dose ocular GLP toxicity studies in the beagle dog and the New Zealand White rabbit with 14-day recovery periods”
Pivotal GLP studies
6-month ocular rabbit and dog studies; 28-day intravenous rat study
“Alcon completed 6-month repeated dose ocular GLP toxicity studies in rabbits (Study AR-15512-AS03) and dogs (Study AR-15512-AS04) and 28-day repeated dose intravenous GLP toxicity studies in rats (Study STF-G10986 AVX-012).”
DART package
Species: DART
Rat and rabbit (intravenous embryo-fetal development)
“The intravenous administration of acoltremon to pregnant rats and rabbits during organogenesis did not produce embryo-fetal toxicity at”
Reproductive & developmental
Rat and rabbit IV EFD: no maternal or fetal toxicity at 806- and 2151-fold the MRHOD
“In embryofetal developmental studies in pregnant rats and rabbits dosed by intravenous injection daily during organogenesis from gestation days 6-17 and gestation days 7-19, respectively, no maternal or fetal toxicity was observed at 806- and 2151-fold the MRHOD of acoltremon on a mg/m 2 basis.”
PPND / ePPND: when
PPND not conducted: negligible systemic exposure and no systemic toxicity
“Fertility and pre- and postnatal development animal studies have not been performed because there is negligible clinical systemic exposure at the RHOD and lack of systemic toxicity.”
Carcinogenicity
Species: carcinogenicity
Not conducted (waived; no systemic exposure)
“Carcinogenicity studies were not conducted with acoltremon.”
Carcinogenicity model
Not conducted; ocular route without significant systemic exposure (ICH S1A)
“ICH S1A indicates that pharmaceuticals administered by the ocular route may not require carcinogenicity studies unless there is cause for concern or unless there is significant systemic exposure (March 1996).”
Carcinogenicity timing
Waived: not needed given absent systemic exposure (Executive CAC)
“The committee agreed with the Division that in the absence of systemic exposure for acoltremon ophthalmic solution, 0.003%, there is no need to conduct carcinogenicity studies.”
Safety marginopen answer page →
Safety margin at NOAEL
Rabbit and dog ocular NOAELs: ~3x RHOD ocular; 29x and 9x systemic (mg/m2)
“There were about 3-fold ocular safety margins with the RHOD compared to the rabbit and the dog ocular NOAELs and 29- and 9-fold systemic safety margins with the RHOD, in mg/m2 equivalent, compared to the rabbit and the dog systemic NOAELs, respectively.”
NOAEL / key findings
Reversible, nonadverse conjunctival redness and swelling (rabbit) and ocular discharge (dog)
“Test-article-related, reversible, nonadverse conjunctival redness and swelling (rabbit) and/or ocular discharge (dog) were observed.”
Efficacy evidenceopen answer page →
Efficacy evidence
Increased blink rate after a single topical ocular dose in guinea pigs (EC50 9.1 µM)
“A single topical ocular dose of acoltremon (10 µL/eye/OU at 0, 10, 50, or 200µM acoltremon into the lower conjunctival sac) increased blink rate in guinea pigs (measured over 5 minutes) and in parallel, a slight but not statistically significant increase in tear rate was measured compared to vehicle, with an EC50 of 9.1µM.”
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
TRPM8 agonism considered established by published literature (as WS-12), like menthol
“The published literature establishes that acoltremon (as WS-12) is a TRPM8 agonist like menthol.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityCriticised but accepted
Rodent carcinogenicity studies waived for a chronic topical ocular drug; reviewer noted unexplored literature on TRPM8 in cancer
Why: ICH S1A ocular-route provision and absence of significant systemic exposure · Within the guideline · Pharmacology or kinetics
“Carcinogenicity studies were not conducted with acoltremon. ICH S1A indicates that pharmaceuticals administered by the ocular route may not require carcinogenicity studies unless there is cause for concern or unless there is significant systemic exposure (March 1996).”
“Reviewer’s comment: While this reviewer agrees with the Applicant’s overall justification for waiving rodent carcinogenicity studies, this reviewer has noted that the Applicant neglected to explore the published literature on the role of TRPM8 in cancer.”
DARTAcceptedBeyond the letter
Fertility/early embryonic and pre- and postnatal development studies waived
Why: No systemic adverse findings and negligible systemic exposure in animals and patients · Pharmacology or kinetics
“Fertility and pre- and postnatal development animal studies have not been performed because there is negligible clinical systemic exposure at the RHOD and lack of systemic toxicity.”
“In the absence of test-article-related systemic adverse findings and given negligible systemic exposure observed in toxicity studies, this reviewer judged that the rationale for waiving fertility and pre- and postnatal development studies was justified, considering that the clinical systemic exposure was judged to be negligible.”
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