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.”
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.”
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.”