Xdemvy
lotilaner
Species
RatDogRabbit
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
Rabbit and dog (ocular); rat and dog (systemic)
“The nonclinical safety of Lotilaner and Lotilaner Ophthalmic Solution, 0.25% were evaluated in the rabbit, rat and dog which were considered appropriate.”
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
“1020-7114: Lotilaner: A 6-Month Repeat-Dose Topical Ocular Toxicity Study Followed by a 4-Week Recovery Period in Dutch Belted Rabbits”
Species: general tox
Rabbit and dog (ocular); rat and dog (oral systemic)
“In two ocular GLP toxicity studies with Lotilaner Ophthalmic Solution, 0.25%, in the Dutch Belted rabbit and in the Beagle dog for 6 and 9 months, respectively”
Species: DART
Rat (EFD, 2-generation incl. male fertility) and rabbit (EFD)
“Safety pharmacology and genotoxicity batteries were complete and acceptable as were embryofetal toxicity studies in 2 species, i.e., the rat and the rabbit, and a 2-generation reproductive toxicity study in the rat to cover both male fertility and reproductive and developmental toxicity of the product.”
Species: carcinogenicity
Not conducted (waiver agreed with FDA)
“As agreed with the Sponsor during their pre-NDA interaction with the Division, carcinogenicity studies were not conducted to support the approval of Lotilaner Ophthalmic Solution, 0.25%, for the treatment of Demodex blepharitis.”
Surrogate used in
No surrogate used
“In the preclinical development studies, Lotilaner is also referred to as TP-03, IOB920 and AHC2224920 as the same active compound.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog ocular)
“1020-7122: Lotilaner: A 9-Month Repeat-Dose Topical Ocular Toxicity Study Followed by a 4-Week Recovery Period in the Beagle Dog”
Pivotal GLP studies
6-month rabbit and 9-month dog topical ocular GLP studies
“In two ocular GLP toxicity studies with Lotilaner Ophthalmic Solution, 0.25%, in the Dutch Belted rabbit and in the Beagle dog for 6 and 9 months, respectively”
Route in tox
Topical ocular
“In two ocular GLP toxicity studies with Lotilaner Ophthalmic Solution, 0.25%, in the Dutch Belted rabbit and in the Beagle dog for 6 and 9 months, respectively”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and rat micronucleus assays
“AHC 2224920 was negative for genotoxic potential in a complete battery of genotoxicity GLP studies (i.e., Ames test, in vitro chromosome aberration test in cultured human lymphocytes and in vivo micronuclei assay in rats).”
Carcinogenicity
Not conducted; waiver agreed with FDA for the Demodex blepharitis indication
“As agreed with the Sponsor during their pre-NDA interaction with the Division, carcinogenicity studies were not conducted to support the approval of Lotilaner Ophthalmic Solution, 0.25%, for the treatment of Demodex blepharitis.”
Reproductive & developmental
Rat EFD: marked fetal weight reduction and delayed (incomplete) ossification at 50 mg/kg/day
“There was a marked effect on mean fetal weight at 50 mg/kg/day and there was an indication of a developmental delay characterized by an increased number of fetuses with incomplete ossification of individual bones of the skeleton.”
Safety pharmacology
CNS, respiratory and cardiovascular (hERG, dog ECG) assessments: no clinically relevant effects
“The central nervous system, respiratory and cardiovascular assessments of Lotilaner were evaluated in GLP studies in vitro (hERG assay) and in vivo in rats and dogs. No clinically relevant adverse effects were noted in any of the studies.”
Genotox: Ames
Negative
“Lotilaner was not genotoxic in the following assays: Ames assay for bacterial gene mutation, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, and in vivo rat micronucleus test.”
Genotox: in vitro mammalian
Chromosomal aberration (human lymphocytes): negative
“Lotilaner was not genotoxic in the following assays: Ames assay for bacterial gene mutation, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, and in vivo rat micronucleus test.”
Genotox: in vivo
Rat micronucleus: negative
“Lotilaner was not genotoxic in the following assays: Ames assay for bacterial gene mutation, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, and in vivo rat micronucleus test.”
Carcinogenicity model
Not conducted; weight-of-evidence waiver (short, non-chronic treatment)
“Based on the totality of Sponsor’s arguments, this reviewer judged the waiver request for carcinogenicity studies receivable since the weight of evidence indicated no cause for concerns in the animals or humans, nor significant systemic exposure for a long period of time”
Carcinogenicity timing
No carcinogenicity studies; sponsor's rationale for not conducting them accepted
“No studies were performed. The Sponsor provided a rationale for not conducting carcinogenicity studies with Lotilaner that was found to be acceptable by this reviewer”
hERG / QT
No significant hERG block up to 100 µM (60 µg/mL)
“Lotilaner did not induce any significant block of hERG current at concentrations up to 100 µM (60 µg/mL).”
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 Xdemvy 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: Rat oral: skin/mucosa, ovary, lung, adrenal, pituitary and thymus findings; mortality at ≥40 mg/kg/day (males) and 60 mg/kg/day (females) (FDA pharmacology/toxicology review, p. 9)
NOAEL / key findings
Rat oral: skin/mucosa, ovary, lung, adrenal, pituitary and thymus findings; mortality at ≥40 mg/kg/day (males) and 60 mg/kg/day (females)
“Test-article related microscopic findings were noted in body weight, skin/mucosa, ovary, lung, adrenal, pituitary (males only) and thymus in rats. Mortality due to early sacrifice of moribund animals occurred at 60 mg/kg/day in female rats and at ≥40 mg/kg/day in male rats.”
Risksopen answer page →
Immune & cytokine safety
Not a skin sensitizer in the mouse local lymph node assay
“In a Local Lymph Node Assay in the mouse, ACH 2224920 did not have the potential to cause skin sensitization.”
Biodistribution & persistence
Accumulates in eyelid margins, with lowest clearance and AUC 10-fold higher than other ocular tissues
“Overall, the data indicated that inferior and superior eyelid margins were prone to drug accumulation, coupled with the lowest clearance in these tissues and an AUC inf 10-fold higher than in all other ocular tissues.”
Modality-specific risk
Local ocular/nasal toxicity: nasal turbinate and nasopharynx not examined histologically in ocular studies
“Nasal turbinate and nasopharynx were not examined under the microscope in any of the ocular studies which was a drawback to the complete evaluation of the potential ocular toxicity of Lotilaner Ophthalmic Solution, 0.25%, but does not influence the decision on approvability of this product.”
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
- Risk of Contamination
- Use with Contact Lenses
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 Xdemvy 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: Rat oral: skin/mucosa, ovary, lung, adrenal, pituitary and thymus findings; mortality at ≥40 mg/kg/day (males) and 60 mg/kg/day (females) (FDA pharmacology/toxicology review, p. 9)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month topical ocular dog study with 4-week recovery
“1020-7122: Lotilaner: A 9-Month Repeat-Dose Topical Ocular Toxicity Study Followed by a 4-Week Recovery Period in the Beagle Dog”
Pivotal GLP studies
6-month rabbit and 9-month dog topical ocular GLP studies
“In two ocular GLP toxicity studies with Lotilaner Ophthalmic Solution, 0.25%, in the Dutch Belted rabbit and in the Beagle dog for 6 and 9 months, respectively”
DART package
Species: DART
Rat (EFD, 2-generation incl. male fertility) and rabbit (EFD)
“Safety pharmacology and genotoxicity batteries were complete and acceptable as were embryofetal toxicity studies in 2 species, i.e., the rat and the rabbit, and a 2-generation reproductive toxicity study in the rat to cover both male fertility and reproductive and developmental toxicity of the product.”
Reproductive & developmental
Rat EFD: marked fetal weight reduction and delayed (incomplete) ossification at 50 mg/kg/day
“There was a marked effect on mean fetal weight at 50 mg/kg/day and there was an indication of a developmental delay characterized by an increased number of fetuses with incomplete ossification of individual bones of the skeleton.”
PPND / ePPND: when
No separate PPND; 2-generation rat study (covering reproductive and developmental toxicity) completed before the marketing application
“a 2-generation reproductive toxicity study in the rat to cover both male fertility and reproductive and developmental toxicity of the product.”
Carcinogenicity
Species: carcinogenicity
Not conducted (waiver agreed with FDA)
“As agreed with the Sponsor during their pre-NDA interaction with the Division, carcinogenicity studies were not conducted to support the approval of Lotilaner Ophthalmic Solution, 0.25%, for the treatment of Demodex blepharitis.”
Carcinogenicity model
Not conducted; weight-of-evidence waiver (short, non-chronic treatment)
“Based on the totality of Sponsor’s arguments, this reviewer judged the waiver request for carcinogenicity studies receivable since the weight of evidence indicated no cause for concerns in the animals or humans, nor significant systemic exposure for a long period of time”
Carcinogenicity timing
No carcinogenicity studies; sponsor's rationale for not conducting them accepted
“No studies were performed. The Sponsor provided a rationale for not conducting carcinogenicity studies with Lotilaner that was found to be acceptable by this reviewer”
Safety marginopen answer page →
Safety margin at NOAEL
Rabbit and dog ocular NOAEL ~2.66x clinical dose (direct dose comparison)
“Ocular safety margins to the clinical dose are 2.66X in both rabbit and dog, based on direct dose comparison”
NOAEL / key findings
Rat oral: skin/mucosa, ovary, lung, adrenal, pituitary and thymus findings; mortality at ≥40 mg/kg/day (males) and 60 mg/kg/day (females)
“Test-article related microscopic findings were noted in body weight, skin/mucosa, ovary, lung, adrenal, pituitary (males only) and thymus in rats. Mortality due to early sacrifice of moribund animals occurred at 60 mg/kg/day in female rats and at ≥40 mg/kg/day in male rats.”
Efficacy evidenceopen answer page →
Efficacy evidence
No proof-of-concept studies for Demodex blepharitis; mechanism (mite GABA-Cl inhibition) only
“Proof of concept studies were not conducted for the indication of Demodex blepharitis.”
Why that model
Relied on published efficacy against Demodex mites in dogs and veterinary approval
“Lotilaner has been shown to be effective against Demodex mites in dogs (Snyder 2017) and has been developed and approved as a veterinary drug for the eradication of skin parasites such as ticks and fleas.”
Reviewer's view of the efficacy data
Approvable from a pharmacology/toxicology perspective despite no proof-of-concept studies
“It is the opinion of this reviewer that the product is approvable from a pharmacology and toxicology perspective.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
Carcinogenicity studies waived on a weight-of-evidence basis
Why: Weight of evidence showed no concern in animals or humans and no prolonged significant systemic exposure · Weight of evidence · Pharmacology or kinetics
“Based on the totality of Sponsor’s arguments, this reviewer judged the waiver request for carcinogenicity studies receivable since the weight of evidence indicated no cause for concerns in the animals or humans, nor significant systemic exposure for a long period of time that would justify evaluating the cancer risk with Lotilaner Ophthalmic Solution, 0.25%, for the indication sought.”
OtherCriticised but acceptedBeyond the letter
Nasal turbinates and nasopharynx not examined histologically in any ocular toxicity study
Why: No clinical signs in any animal study suggesting nasal or throat irritation · Weight of evidence
“Nasal turbinate and nasopharynx were not examined under the microscope in any of the ocular studies which was a drawback to the complete evaluation of the potential ocular toxicity of Lotilaner Ophthalmic Solution, 0.25%, but does not influence the decision on approvability of this product.”
“No clinical signs were observed in any animal study that could suggest nasal cavities and/or throat irritation.”
Efficacy modelVerdict not stated
No nonclinical proof-of-concept studies for Demodex blepharitis
“Proof of concept studies were not conducted for the indication of Demodex blepharitis.”
DARTAcceptedBeyond the letter
No dedicated fertility study; male fertility NOAEL derived from the rat 2-generation study
Why: 2-generation study provided a male fertility NOAEL · Other reason
“There was no designated fertility study conducted, however the results of the 2- generation study suggested that the NOAEL for male fertility was 20 mg/kg/day, which provides a safety margin of X with the MRHD of mg/kg for a 60 kg human.”
“Safety pharmacology and genotoxicity batteries were complete and acceptable as were embryofetal toxicity studies in 2 species, i.e., the rat and the rabbit, and a 2-generation reproductive toxicity study in the rat to cover both male fertility and reproductive and developmental toxicity of the product.”
OtherAcceptedBeyond the letter
Chronic oral systemic toxicity study in dogs used once-monthly dosing
Why: Lotilaner exposure in dogs was relatively constant with monthly oral dosing · Pharmacology or kinetics
“Considering the exposure to Lotilaner was relatively constant in the dog study by oral exposure, this reviewer found the design of monthly administration in the dog acceptable for assessing systemic toxicity in the context of a daily ocular exposure in humans for 6 weeks.”
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