Xolremdi
mavorixafor
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).”
Species: general tox
Rat (28-day) and dog (up to 39-week)
“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).”
Species: DART
No definitive DART 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.”
Species: carcinogenicity
Not conducted; rat and mouse studies required postmarketing
“Postmarketing requirements for the conduct of rat and mouse carcinogenicity studies will be issued.”
Surrogate used in
Literature only: CXCR4 antagonist plerixafor in Cxcr4+/1013 (WHIM) mice
“Intraperitoneal administration of a selective and competitive CXCR4 antagonist plerixafor or a CXCL12-neutraliser chalcone 4 increased the absolute numbers of total leukocytes including neutrophils, B and T cells both in the blood of mice carrying WT CXCR4 and in blood of Cxcr4+/1013 mice.”
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.”
Genotox: Ames
Negative
“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).”
Genotox: in vitro mammalian
Chromosome aberration (human lymphocytes): negative
“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).”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“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 model
Not conducted; PMR 26-week Tg.RasH2 mouse study
“PMR 3: Conduct a 26-week GLP carcinogenicity study by oral gavage administration in Tg.RasH2 mice to assess the carcinogenic potential from chronic exposure to mavorixafor.”
Carcinogenicity timing
None conducted before approval; rat and mouse carcinogenicity studies are postmarketing requirements
“Postmarketing requirements for the conduct of rat and mouse carcinogenicity studies will be issued.”
hERG / QT
hERG inhibition, estimated IC50 19.2 µM (30-fold over 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.”
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
- Embryo-Fetal Toxicity
- QTc Interval Prolongation
Embryo-fetal toxicityCardiovascular
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral (capsule) dog study, no recovery phase
“In the 39-week study in dogs, no recovery phase was included.”
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).”
DART package
Species: DART
No definitive DART 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.”
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.”
PPND / ePPND: when
No PPND conducted; accepted given difficulty reaching human-relevant exposures and CXCR4/SDF-1 knockout mouse data
“No prenatal and postnatal development (PPND) toxicity studies were conducted with mavorixafor. However, given the difficulties to perform animal reproduction toxicity studies with human relevant exposure and based on the results from CXCR4/SDF-1 knock out mice which showed high peri-postnatal lethality and adverse effects on developmental, this was acceptable to the CHMP.”
Carcinogenicity
Species: carcinogenicity
Not conducted; rat and mouse studies required postmarketing
“Postmarketing requirements for the conduct of rat and mouse carcinogenicity studies will be issued.”
Carcinogenicity model
Not conducted; PMR 26-week Tg.RasH2 mouse study
“PMR 3: Conduct a 26-week GLP carcinogenicity study by oral gavage administration in Tg.RasH2 mice to assess the carcinogenic potential from chronic exposure to mavorixafor.”
Carcinogenicity timing
None conducted before approval; rat and mouse carcinogenicity studies are postmarketing requirements
“Postmarketing requirements for the conduct of rat and mouse carcinogenicity studies will be issued.”
Safety marginopen answer page →
Safety margin at NOAEL
39-week dog female NOAEL 3.8 mg/kg/day ~0.3x MRHD exposure; no NOAEL in males
“The no observed adverse effect level (NOAEL) of mavorixafor in female dogs was defined at 3.8 mg/kg/day based on mavorixafor-related adverse findings at higher doses and corresponds to exposures 0.3-times the exposures at the MRHD.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Human K562 cells expressing WT and WHIM-mutant CXCR4 (CXCL12-binding IC50 6.1 nM WT; 3.2-11 nM mutants)
“The compound inhibited CXCL12 binding to CXCR4 with an IC50 of 6.1 nM in K562 lymphoblast cells stably overexpressing wild type (WT) CXCR4 and IC50 ranging between 3.2 and 11 nM in cells overexpressing different WHIM mutant variants.”
Why that model
No WHIM animal-model studies with mavorixafor; reason not given
“No studies in WHIM syndrome animal models were conducted with mavorixafor.”
Reviewer's view of the efficacy data
EMA: data did not demonstrate in vivo nonclinical efficacy in WHIM; no animal PK/PD data for dose finding
“Nevertheless, considering the compounds used in these studies, the data provided did not demonstrate non-clinical efficacy of mavorixafor in the WHIM syndrome in vivo. No PK/PD correlation data in animal models to support clinical dose finding were presented either.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; rat and mouse carcinogenicity studies deferred to postmarketing requirements
Why: High unmet need in WHIM syndrome · Rare disease / unmet need
“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.”
“There was prior agreement with the Applicant for postmarketing requirement studies to assess the carcinogenicity potential given the high unmet need for WHIM syndrome.”
Study lengthVerdict not stated
No chronic rat study with the marketed free base; chronic rat data only from a 26-week study of the PHB salt form
“As no chronic rat toxicity studies were conducted with the free base of mavorixafor, the 26-weeks rat study conducted with the PHB salt form of mavorixafor, referred to as AMD11070PHB, provided only supportive data for the chronic toxicity of mavorixafor in rats.”
DARTAcceptedBeyond the letter
No fertility, embryo-fetal or pre/postnatal development studies; literature weight-of-evidence (CXCR4/SDF-1 knockout mice) instead
Why: Human-relevant exposures hard to reach in animals; CXCR4/SDF-1 knockout mice already show developmental toxicity · Weight of evidence · Pharmacology or kinetics
“No dedicated fertility and early embryonic development, definitive embryo-fetal development, or pre- and post-natal development toxicity studies were conducted with mavorixafor.”
“However, given the difficulties to perform animal reproduction toxicity studies with human relevant exposure and based on the results from CXCR4/SDF-1 knock out mice which showed high peri-postnatal lethality and adverse effects on developmental, this was acceptable to the CHMP.”
Safety marginVerdict not stated
No exposure margin at the NOAELs in most pivotal rat and dog studies
“The CHMP concluded that, for the most parts, there were no margins from the NOAELs to clinical exposure.”
Juvenile toxAcceptedBeyond the letter
No definitive juvenile toxicity study in rats because of poor tolerance in juvenile rats
Why: Poor tolerance in juvenile rats at low exposures · Other reason
“It was agreed that a definitive juvenile toxicity study in rats is not feasible due to poor tolerance of mavorixafor at low exposures in juvenile rats.”
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