Reyvow
lasmiditan
Species
RatDog
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 dog
“General Toxicology: the oral toxicity of lasmiditan was tested in Sprague-Dawley rat (4-week + 2-week recovery, 13-week + 4-week recovery, and 26-week + 8-week recovery) and Beagle dog (2-week, 4-week + 2-week recovery, 13-week + 4-week recovery, and 39-week + 8-week recovery).”
Why that species
Major human metabolites M8 and M18 are produced in mouse, rat, rabbit and dog
“In humans, the major circulating metabolites are M8 and[S,R]-M18, which account for 47.5 and 10.5% of drug-related material in circulation. Both metabolites were produced in mouse, rat, rabbit, and dog.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In rat, lasmiditan was administered at doses up to 100 (4-week study) or 200 (13- and 26-week studies) mg/kg/day.”
Species: general tox
Rat (26-week) and dog (39-week)
“General Toxicology: the oral toxicity of lasmiditan was tested in Sprague-Dawley rat (4-week + 2-week recovery, 13-week + 4-week recovery, and 26-week + 8-week recovery) and Beagle dog (2-week, 4-week + 2-week recovery, 13-week + 4-week recovery, and 39-week + 8-week recovery).”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“A standard battery of reproductive and developmental toxicology studies was conducted for lasmiditan (fertility and early embryonic development in male and female Sprague-Dawley rat; embryofetal development in Sprague-Dawley rat and New Zealand White rabbit; pre- and postnatal development in Sprague-Dawley rat).”
Species: carcinogenicity
Rat (2-year) and Tg.rasH2 mouse (26-week)
“The carcinogenic potential of orally-administered lasmiditan was tested in a 26-week study in Tg.rasH2 mice (0, 20, 50, or 150 mg/kg/day in males; 0, 25, 80, or 250 mg/kg/day in females) and in a 2-year study in rats (0, 10, 25, or 75 mg/kg/day).”
Surrogate used in
No surrogate used; 5-HT1F binding affinity similar across test species and human
“Binding affinity was similar among mouse, rat, rabbit, dog, and human 5-HT1F receptors.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“In the 39-week study, the high dose was reduced to 40 mg/kg/day because of intolerability.”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“General Toxicology: the oral toxicity of lasmiditan was tested in Sprague-Dawley rat (4-week + 2-week recovery, 13-week + 4-week recovery, and 26-week + 8-week recovery) and Beagle dog (2-week, 4-week + 2-week recovery, 13-week + 4-week recovery, and 39-week + 8-week recovery).”
Route in tox
Oral
“All pivotal in vivo nonclinical studies were conducted using oral administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and mouse bone marrow micronucleus assays
“Lasmiditan was negative in adequately designed and conducted in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.”
Carcinogenicity
2-year rat and 6-month Tg rasH2 mouse: not carcinogenic
“Lasmiditan was not carcinogenic in 2-year rat or 6-month Tg rasH2 mouse studies.”
Reproductive & developmental
Rabbit EFD: malformations, embryofetal mortality and reduced fetal weight at a maternally toxic dose
“Oral administration of lasmiditan (0, 50, 75, or 115 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in malformations (skeletal and visceral), increases in skeletal variations and embryofetal mortality, and decreased fetal body weight were observed at the highest dose tested, which was associated with maternal toxicity.”
Safety pharmacology
hERG IC50 ~3.0 µM (>4-fold human Cmax); ECG, respiratory and vasoactivity assessments negative
“In hERG assays, IC50s for lasmiditan (~3.0 µM) and metabolites M8 and M18 (>30 µM) exceeded 4-fold the plasma Cmax in humans following oral administration of 200 mg. ECG, respiratory, and vasoactivity assessments were negative.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Lasmiditan was negative in adequately designed and conducted in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vitro mammalian
In vitro chromosomal aberration in mammalian cells: negative
“Lasmiditan was negative in adequately designed and conducted in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Lasmiditan was negative in adequately designed and conducted in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.”
Carcinogenicity model
2-year rat; 26-week Tg.rasH2 mouse; no drug-related neoplasms
“Both studies were adequately conducted, and no drug-related neoplasms were identified in either species (see Executive CAC minutes, dated June 20, 2019).”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 2-year rat completed before the marketing application
“A 26-week study in transgenic RasH2 mice and a 2-year study in Sprague-Dawley rats were conducted.”
hERG / QT
hERG IC50 ~3.0 µM (metabolites >30 µM), >4-fold human Cmax at 200 mg; ECG negative
“In hERG assays, IC50s for lasmiditan (~3.0 µM) and metabolites M8 and M18 (>30 µM) exceeded 4-fold the plasma Cmax in humans following oral administration of 200 mg. ECG, respiratory, and vasoactivity assessments were negative.”
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 Reyvow 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: 39-week dog: tremors and hypoactivity; NOAEL 30 mg/kg (8-fold AUC margin) (FDA pharmacology/toxicology review, p. 11)
NOAEL / key findings
39-week dog: tremors and hypoactivity; NOAEL 30 mg/kg (8-fold AUC margin)
“In the 39-week toxicology study in dog, there were lasmiditan-related tremors and hypoactivity. The safety margin was 8-fold compared to the maximum human dose based on AUC at the NOAEL of 30 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
Splenic marginal-zone lymphoid depletion and thymic involution at high dose in rats
“In all HD animals, hepatocellular hypertrophy, foamy alveolar macrophages, epithelial vacuolation in the seminal vesicle, vacuolation and lymphoid depletion of the marginal zone in the spleen, cortical hypertrophy of the adrenals, decreased hematopoietic tissue in the bone marrow, and thymic involution were also observed”
Biodistribution & persistence
Crosses blood-brain barrier (brain:plasma ~3); highest concentrations in urinary bladder and uveal tract
“Distribution studies (with [14C]lasmiditan) in rat show that lasmiditan crosses the blood brain barrier, with brain to plasma ratios of approximately 3 over a 24-hour period after IV dosing. The highest concentrations of [14C]lasmiditan were found in the urinary bladder and uveal tract of the eye.”
Modality-specific risk
Potential for coronary artery vasoconstriction
“In addition, the sponsor conducted nonclinical studies to address concerns regarding the potential for lasmiditan to cause coronary artery vasoconstriction.”
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
- Driving Impairment
- Central Nervous System Depression
- Serotonin Syndrome
- Medication Overuse Headache
NeurotoxicityPsychiatric
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 Reyvow 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: 39-week dog: tremors and hypoactivity; NOAEL 30 mg/kg (8-fold AUC margin) (FDA pharmacology/toxicology review, p. 11)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog with 8-week recovery (26-week rat also with 8-week recovery)
“General Toxicology: the oral toxicity of lasmiditan was tested in Sprague-Dawley rat (4-week + 2-week recovery, 13-week + 4-week recovery, and 26-week + 8-week recovery) and Beagle dog (2-week, 4-week + 2-week recovery, 13-week + 4-week recovery, and 39-week + 8-week recovery).”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“General Toxicology: the oral toxicity of lasmiditan was tested in Sprague-Dawley rat (4-week + 2-week recovery, 13-week + 4-week recovery, and 26-week + 8-week recovery) and Beagle dog (2-week, 4-week + 2-week recovery, 13-week + 4-week recovery, and 39-week + 8-week recovery).”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“A standard battery of reproductive and developmental toxicology studies was conducted for lasmiditan (fertility and early embryonic development in male and female Sprague-Dawley rat; embryofetal development in Sprague-Dawley rat and New Zealand White rabbit; pre- and postnatal development in Sprague-Dawley rat).”
Reproductive & developmental
Rabbit EFD: malformations, embryofetal mortality and reduced fetal weight at a maternally toxic dose
“Oral administration of lasmiditan (0, 50, 75, or 115 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in malformations (skeletal and visceral), increases in skeletal variations and embryofetal mortality, and decreased fetal body weight were observed at the highest dose tested, which was associated with maternal toxicity.”
PPND / ePPND: when
PPND in rat completed before the marketing application; stillbirth and neonatal mortality at high dose
“Pre- and postnatal development: Oral administration of lasmiditan (0, 100, 150, or 225 mg/kg/day) to rats throughout pregnancy and lactation resulted in increases in stillbirth and neonatal mortality at the highest dose tested, which was associated with maternal toxicity.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg.rasH2 mouse (26-week)
“The carcinogenic potential of orally-administered lasmiditan was tested in a 26-week study in Tg.rasH2 mice (0, 20, 50, or 150 mg/kg/day in males; 0, 25, 80, or 250 mg/kg/day in females) and in a 2-year study in rats (0, 10, 25, or 75 mg/kg/day).”
Carcinogenicity model
2-year rat; 26-week Tg.rasH2 mouse; no drug-related neoplasms
“Both studies were adequately conducted, and no drug-related neoplasms were identified in either species (see Executive CAC minutes, dated June 20, 2019).”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 2-year rat completed before the marketing application
“A 26-week study in transgenic RasH2 mice and a 2-year study in Sprague-Dawley rats were conducted.”
Safety marginopen answer page →
Safety margin at NOAEL
39-week dog NOAEL (30 mg/kg/day) ~7x human AUC at MRHD
“The NOAEL was 30 mg/kg/day, which was associated with plasma lasmiditan exposure (AUC of 15368 ng*hr/mL) ∼7 times that in humans at the MRHD.”
NOAEL / key findings
39-week dog: tremors and hypoactivity; NOAEL 30 mg/kg (8-fold AUC margin)
“In the 39-week toxicology study in dog, there were lasmiditan-related tremors and hypoactivity. The safety margin was 8-fold compared to the maximum human dose based on AUC at the NOAEL of 30 mg/kg.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rat trigeminovascular models: dural protein extravasation, c-fos induction, dural-evoked nociception, dural vasodilation
“In rodent efficacy models, lasmiditan inhibited trigeminovascular protein extravasation (neuroinflammatory response), induction of c-fos, dural-evoked nociception transmission, α-CGRP release, and vasodilation.”
Why that model
Trigeminal nociceptive transmission is implicated as origin of migraine pain and expresses 5-HT1F
“In vivo studies focused on trigeminal ganglia nociceptive neurotransmission because it is implicated as the origin of migraine pain and expresses 5-HT1F receptors.”
Reviewer's view of the efficacy data
Reviewer concluded the nonclinical data are adequate to support approval
“Based on the reviews, Dr. Nesti concludes the nonclinical data are adequate to support approval of the NDA.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityCriticised but acceptedBeyond the letter
In vivo mouse micronucleus assay judged inadequate by the primary reviewer: exposure to major human metabolites not demonstrated
Why: Supervisory review considered the genotoxicity battery adequately designed and negative
“Lasmiditan was negative in a bone marrow micronucleus assay in ICR mice (IV); however, the study was not adequate because systemic exposure to all major human metabolites was not demonstrated.”
“Lasmiditan was negative in adequately designed and conducted in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.”
Safety marginVerdict not stated
No exposure margin at the NOAEL in the pivotal rabbit embryo-fetal development study
“There was no safety margin based on AUC at the NOAEL of 50 mg/kg relative to that at the maximum human dose.”
Safety marginVerdict not stated
No exposure margin at the NOAEL in the rat pre- and postnatal development study (mg/m2 basis)
“On a mg/m2 basis, there was no safety margin at the NOAEL of 150 mg/kg, relative to that at the maximum human dose, for the F0 or F1 generations.”
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