Xolremdi
mavorixafor
Sources:FDA integrated review ↗
Species
RatDog
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
Rat and dog
“Both rats and dogs were considered pharmacologically relevant species for conducting toxicology assessments of mavorixafor based on the observation of the desired pharmacology and similar metabolite profiles compared to humans.”
Why that species
Pharmacological activity and metabolite profiles similar to human
“Both rats and dogs were considered pharmacologically relevant species for conducting toxicology assessments of mavorixafor based on the observation of the desired pharmacology and similar metabolite profiles compared to humans.”
Surrogate molecule
No surrogate; the clinical compound (free base) was tested
“The safety of mavorixafor (free base form) was evaluated in good laboratory practice-compliant, repeated dose toxicology studies in rats (28 days) and dogs (up to 39 weeks).”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“The safety of mavorixafor (free base form) was evaluated in good laboratory practice-compliant, repeated dose toxicology studies in rats (28 days) and dogs (up to 39 weeks).”
Pivotal GLP studies
28-day rat and 39-week dog GLP oral studies with the free base
“The safety of mavorixafor (free base form) was evaluated in good laboratory practice-compliant, repeated dose toxicology studies in rats (28 days) and dogs (up to 39 weeks).”
Route in tox
Oral (gavage in rats, capsule in dogs)
“General toxicology studies of mavorixafor (free base) were conducted for up to 4-weeks in rats and 4, 13 and 39-weeks in dogs with daily oral doses by gavage and by capsule, respectively.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and rat micronucleus assays
“Mavorixafor (free base) was not mutagenic in the Ames assay (bacterial reverse mutation assay), or clastogenic in vitro (chromosome aberration assay in human peripheral lymphocytes) or in vivo (rat bone marrow micronucleus assay).”
Carcinogenicity
Not conducted; postmarketing requirement
“Carcinogenicity studies with mavorixafor have not been conducted. There was a prior agreement with the Applicant regarding the need for postmarketing requirement (PMR) studies to assess the carcinogenicity potential of mavorixafor.”
Reproductive & developmental
No dedicated fertility, EFD or pre/postnatal studies; literature-based weight-of-evidence assessment
“No dedicated fertility and early embryonic development, definitive embryo-fetal development, or pre- and post-natal development toxicity studies were conducted with mavorixafor. The Applicant provided a weight-of-evidence assessment informing potential reproductive risks associated with mavorixafor treatment.”
Safety pharmacology
hERG inhibition, estimated IC50 19.2 µM (30-fold margin to free Cmax)
“Likewise, the estimated hERG IC50 (19.2 μM) provides a safety margin of 30-fold using the free drug Cmax.”
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 Xolremdi 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 target organs: liver, gallbladder, testes, epididymides and eyes (FDA integrated review, p. 126)
NOAEL / key findings
39-week dog target organs: liver, gallbladder, testes, epididymides and eyes
“Mavorixafor (free base) target organs of toxicity included the liver, gallbladder, testes, epididymides, and eyes (based on histopathological examination only).”
Risksopen answer page →
Immune & cytokine safety
No immunosuppression in 28-day rat KLH antibody response study
“Twice daily oral administration of mavorixafor for up to 250 mg/kg/day for 28 consecutive days to Sprague-Dawley rats did not result in immunosuppression.”
Biodistribution & persistence
Rat QWBA: persistent binding to melanin-containing uveal tract up to 840 h
“In partially pigmented rats, measurable radioactivity was observed in the uveal tract/whole eye from 8 hours until the final sampling time of 840 hours, suggesting irreversible binding to melanin-containing tissues.”
Modality-specific risk
Hepatotoxicity, embryofetal risk, male fertility impairment, QTc prolongation and retinal damage
“The primary safety concerns associated with mavorixafor in animals were liver, embryo-fetal developmental risk, impairment of male fertility, potential for corrected QT interval (QTc) prolongation, and retinal damage.”