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.”
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.”
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.”