Relyvrio
sodium phenylbutyrate and taurursodiol
Species
RatPig
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 minipig
“The pivotal (GLP-compliant) oral toxicity studies were conducted in Sprague Dawley rat and minipig (Gottingen, Hanford).”
Why that species
Minipig used as non-rodent after a dog study was stopped for emesis, tremors and other signs at all doses
“An additional study was initiated in beagle dog but was discontinued due to emesis, retching, tremors, loose feces, and increases in respiratory rate at all doses, including the low dose of 62.5 mg/kg PB/20.83 mg/kg TUDCA.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In vivo toxicology studies were conducted using AMX0035.”
Species: general tox
Sprague Dawley rat and minipig
“The pivotal (GLP-compliant) oral toxicity studies were conducted in Sprague Dawley rat and minipig (Gottingen, Hanford).”
Species: DART
CD-1 mouse and Sprague Dawley rat (full reproductive and developmental battery)
“A full battery of reproductive and developmental toxicology studies was conducted for AMX0035. In the pivotal studies in CD-1 mouse and Sprague Dawley rat, AMX0035 was administered by oral gavage at doses of 0, 187.5, 375, and 750 mg/kg BID (0, 375, 750, and 1500 mg/kg/day).”
Species: carcinogenicity
Not conducted; mouse and rat studies to be done post-approval
“Carcinogenicity studies have not been conducted. Carcinogenicity studies in mouse and rat may be conducted post-approval, as agreed to by the Division (Meeting Minutes, April 7, 2020, and July 22, 2021) because of the seriousness of the indication.”
Surrogate used in
No surrogate used; the clinical combination was tested
“In vivo toxicology studies were conducted using AMX0035.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month minipig)
“Pivotal toxicity studies consisted of daily oral dosing in SD rat (840 mg/kg AMX0035) and Gottingen minipig (845 mg/kg AMX0035) for 26 or 39 weeks, respectively.”
Pivotal GLP studies
26-week rat and 39-week minipig daily oral studies
“Pivotal toxicity studies consisted of daily oral dosing in SD rat (840 mg/kg AMX0035) and Gottingen minipig (845 mg/kg AMX0035) for 26 or 39 weeks, respectively.”
Route in tox
Oral gavage
“In rat, NaBP/TUDCA were administered orally (gavage) at doses of 0/0, 250/83.32, 750/250, and 1000/333.28 mg/kg QD for 28 days, and AMX0035 was administered orally (gavage) at doses of 0, 250, 420, and 840 mg/kg QD for 26 weeks (+ 28-day recovery period).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and in vivo mouse micronucleus assays
“The genotoxic potential of AMX0035 was tested in a standard battery of in vitro (Ames, chromosomal aberration in human lymphocytes) and in vivo (micronucleus in CD-1 mouse) assays, which were adequate and negative.”
Carcinogenicity
Not conducted; mouse and rat studies are postmarketing requirements
“Carcinogenicity studies have not been conducted. Carcinogenicity studies in mouse and rat may be conducted post-approval, as agreed to by the Division (Meeting Minutes, April 7, 2020, and July 22, 2021) because of the seriousness of the indication.”
Reproductive & developmental
No adverse effects on maternal or offspring health and development in fertility, EFD or PPND studies
“There were no adverse effects on maternal health or offspring health and development in fertility, EFD, or PPND studies.”
Safety pharmacology
No CNS study; minipig CV and rat respiratory studies showed no adverse effects
“CNS safety pharmacology was not assessed; however, cardiovascular and respiratory safety pharmacology endpoints were assessed in standalone studies in Gottingen minipig and SD rat, respectively, following administration of 1000 mg/kg PB/333.3 mg/kg TUDCA and did not indicate any adverse effects.”
Genotox: Ames
Negative (phenylbutyrate and TUDCA tested individually)
“PB and TUDCA were individually assessed in Ames and in vitro chromosomal aberration assays and were found to be negative.”
Genotox: in vitro mammalian
Chromosomal aberration in human lymphocytes: negative
“The genotoxic potential of AMX0035 was tested in a standard battery of in vitro (Ames, chromosomal aberration in human lymphocytes) and in vivo (micronucleus in CD-1 mouse) assays, which were adequate and negative.”
Genotox: in vivo
Mouse micronucleus: negative up to 2000 mg/kg
“AMX0035 was tested at oral doses up to 2000 mg/kg and found to be negative in an in vivo micronucleus assay in CD mice.”
Carcinogenicity model
Not conducted; mouse and rat studies to be done post-approval given seriousness of indication
“Carcinogenicity studies have not been conducted. Carcinogenicity studies in mouse and rat may be conducted post-approval, as agreed to by the Division (Meeting Minutes, April 7, 2020, and July 22, 2021) because of the seriousness of the indication.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies not conducted before approval; postmarketing requirements
“If the NDA is approved, carcinogenicity studies in two species (mouse and rat) should be conducted as post-marketing requirements, as previously agreed to by the Division and communicated to the sponsor.”
hERG / QT
Minipig cardiovascular safety pharmacology: no adverse effects
“CNS safety pharmacology was not assessed; however, cardiovascular and respiratory safety pharmacology endpoints were assessed in standalone studies in Gottingen minipig and SD rat, respectively, following administration of 1000 mg/kg PB/333.3 mg/kg TUDCA and did not indicate any adverse effects.”
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 Relyvrio 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: No notable toxicity in rat (26-week) or minipig (9-month) studies (FDA pharmacology/toxicology review, p. 46)
NOAEL / key findings
No notable toxicity in rat (26-week) or minipig (9-month) studies
“There was no notable toxicity in either species; however, it was unclear why the high dose in the 6- and 9-month studies was reduced to 845 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Rat: phenylbutyrate highest in kidney with minimal CNS levels; taurursodiol below quantification in CNS
“Based on radioactivity, PB-related material accumulated in kidney while CNS levels were minimal (i.e., 10-fold lower than kidney); radiolabeled TUDCA-related material was below the limits of quantification in CNS tissue.”
Modality-specific risk
High doses gave plasma exposures below human clinical exposure
“The 845 mg/kg dose is not a limit, maximum feasible, or maximum tolerated dose, and it resulted in plasma Cmax and AUC below those in humans administered the clinical dose.”
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.
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 Relyvrio 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: No notable toxicity in rat (26-week) or minipig (9-month) studies (FDA pharmacology/toxicology review, p. 46)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week minipig oral study with recovery phase (length not stated)
“ECG was evaluated prior to the initiation of dosing, Dosing Day 269, and on Recovery Day 23.”
Pivotal GLP studies
26-week rat and 39-week minipig daily oral studies
“Pivotal toxicity studies consisted of daily oral dosing in SD rat (840 mg/kg AMX0035) and Gottingen minipig (845 mg/kg AMX0035) for 26 or 39 weeks, respectively.”
DART package
Species: DART
CD-1 mouse and Sprague Dawley rat (full reproductive and developmental battery)
“A full battery of reproductive and developmental toxicology studies was conducted for AMX0035. In the pivotal studies in CD-1 mouse and Sprague Dawley rat, AMX0035 was administered by oral gavage at doses of 0, 187.5, 375, and 750 mg/kg BID (0, 375, 750, and 1500 mg/kg/day).”
Reproductive & developmental
No adverse effects on maternal or offspring health and development in fertility, EFD or PPND studies
“There were no adverse effects on maternal health or offspring health and development in fertility, EFD, or PPND studies.”
PPND / ePPND: when
PPND in SD rat completed before the marketing application; no adverse effects
“Drug effects on pre- and postnatal development (PPND) were assessed in SD rats administered up to 1500 mg/kg/day (BID) AMX0035 from GD 6 to postnatal day (PND) 20.”
Carcinogenicity
Species: carcinogenicity
Not conducted; mouse and rat studies to be done post-approval
“Carcinogenicity studies have not been conducted. Carcinogenicity studies in mouse and rat may be conducted post-approval, as agreed to by the Division (Meeting Minutes, April 7, 2020, and July 22, 2021) because of the seriousness of the indication.”
Carcinogenicity model
Not conducted; mouse and rat studies to be done post-approval given seriousness of indication
“Carcinogenicity studies have not been conducted. Carcinogenicity studies in mouse and rat may be conducted post-approval, as agreed to by the Division (Meeting Minutes, April 7, 2020, and July 22, 2021) because of the seriousness of the indication.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies not conducted before approval; postmarketing requirements
“If the NDA is approved, carcinogenicity studies in two species (mouse and rat) should be conducted as post-marketing requirements, as previously agreed to by the Division and communicated to the sponsor.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: highest pivotal doses gave Cmax and AUC below human clinical exposure
“The 845 mg/kg dose is not a limit, maximum feasible, or maximum tolerated dose, and it resulted in plasma Cmax and AUC below those in humans administered the clinical dose.”
NOAEL / key findings
No notable toxicity in rat (26-week) or minipig (9-month) studies
“There was no notable toxicity in either species; however, it was unclear why the high dose in the 6- and 9-month studies was reduced to 845 mg/kg.”
Efficacy evidenceopen answer page →
Efficacy evidence
SOD1 G93A transgenic mouse model of ALS (no effect on lifespan or disease progression)
“An in vivo primary pharmacology study was conducted in the SOD1 G93A transgenic mouse model of ALS in which oral BID doses of 100/200 mg/kg PB/TUDCA were administered for 50 days. There was no effect on lifespan or markers of disease progression that would suggest any therapeutic potential for AMX0035.”
Why that model
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.
Reviewer's view of the efficacy data
Inconsistent results that failed to demonstrate beneficial effects of AMX0035
“Overall, the results of these studies were inconsistent or failed to demonstrate beneficial effects of AMX0035.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; mouse and rat studies deferred to post-marketing requirements
Why: Seriousness of the indication (ALS) · Serious disease
“Carcinogenicity studies have not been conducted. Carcinogenicity studies in mouse and rat may be conducted post-approval, as agreed to by the Division (Meeting Minutes, April 7, 2020, and July 22, 2021) because of the seriousness of the indication.”
“If the NDA is approved, carcinogenicity studies in two species (mouse and rat) should be conducted as post-marketing requirements, as previously agreed to by the Division and communicated to the sponsor.”
Safety marginCriticised but acceptedBeyond the letter
No exposure margin: highest doses in rat and minipig gave plasma exposures below human exposure at the maximum recommended dose
Why: Available clinical safety data · Human data
“It is, however, of note that the data available from the general toxicology studies indicate that the plasma exposures for PB and TUDCA achieved in animals at the highest doses tested in the nonclinical studies were lower than those in humans at the maximum recommended human doses (6 gm NaPB and 3 mg TUDCA).”
“From a safety standpoint, taking into consideration the available clinical safety data, the nonclinical studies support approval of the NDA.”
Impurity or metaboliteQuestioned
No human mass balance study; qualification of major human metabolites unknown
“According to the Clinical Pharmacology team, a mass balance study in humans was not conducted for AMX0035. In the absence of data on the in vivo metabolic profile in humans, it is not known whether any major human metabolites are qualified by the nonclinical data.”
Safety pharmacologyVerdict not stated
No CNS safety pharmacology assessment
“CNS safety pharmacology was not assessed; however, cardiovascular and respiratory safety pharmacology endpoints were assessed in standalone studies in Gottingen minipig and SD rat, respectively, following administration of 1000 mg/kg PB/333.3 mg/kg TUDCA and did not indicate any adverse effects.”
Efficacy modelQuestioned
One in vivo ALS model study plus in vitro assays; results inconsistent or failed to show benefit
“A number of in vitro assays and one in vivo study in an ALS-relevant animal model of disease were conducted to characterize the pharmacological activity and potential efficacy of AMX0035 for the treatment of ALS. Overall, the results of these studies were inconsistent or failed to demonstrate beneficial effects of AMX0035.”
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