Zokinvy
lonafarnib
Species
MonkeyRat
Longest study
52 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 cynomolgus monkey
“The Sprague Dawley rat and cynomolgus monkey were selected as the main rodent and non-rodent species in the general toxicity studies.”
Why that species
Farnesyltransferase sequence highly conserved between humans and rat, mouse, rabbit and monkey
“The lack of in vitro potency comparison between species was justified by referring to data showing that the amino acid sequence was highly conserved between humans and the relevant nonclinical species rat, mouse, rabbit and monkey.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The results of the 1-year oral toxicity study in monkeys indicated that treatment with lonafarnib resulted in histological changes in the male reproductive tract at all doses (10, 20, and 40 mg/kg/day), and in the eye at 40 mg/kg/day.”
Species: general tox
Rat (up to 6 months) and cynomolgus monkey (up to 1 year)
“The nonclinical safety profile of lonafarnib was evaluated in cardiovascular safety pharmacology studies in monkeys, repeated dose oral toxicology studies in rats for up to 6 months and in monkeys for up to 1 year”
Species: DART
Rat and New Zealand White rabbit
“Sprague Dawley rat and New Zeeland White rabbits were selected for reproduction and developmental studies.”
Species: carcinogenicity
Not conducted
“Long-term carcinogenicity studies have not been conducted.”
Surrogate used in
Yes: other farnesyltransferase inhibitors used in supporting progeria mouse model studies
“Supporting bridging studies in progeria animal models were provided as studies of treatments with other Farnesyl transfer inhibitors (FTIs).”
Study lengthopen answer page →
Longest pivotal study
52 (1-year monkey)
“The nonclinical safety profile of lonafarnib was evaluated in cardiovascular safety pharmacology studies in monkeys, repeated dose oral toxicology studies in rats for up to 6 months and in monkeys for up to 1 year”
Pivotal GLP studies
Repeat-dose studies up to 6 months in rats and 12 months in cynomolgus monkeys
“Overall, the toxicity profile of lonafarnib has been characterized via single-dose toxicity studies in mice and rats, repeat-dose toxicity studies (up to 6 months in Sprague Dawley rats and 12 months in cynomolgus monkeys)”
Route in tox
Oral
“The oral route of administration was utilized in all pivotal toxicity studies to match the intended clinical administration route.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosomal aberration and mouse micronucleus assays
“Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.”
Carcinogenicity
Not conducted; postmarketing requirement
“The Applicant will be required to conduct a carcinogenicity study postapproval.”
Reproductive & developmental
Rat EFD: post-implantation loss at ~human exposure; rabbit EFD: skeletal malformations below human exposure
“In pregnant rats, post-implantation loss (resorptions) was seen at plasma drug exposures approximately equal to that achieved in humans. In pregnant rabbits, skeletal malformations were seen at plasma drug exposures lower than human exposures.”
Safety pharmacology
hERG IC50 1.3 µM, about 3-fold below total clinical Cmax
“The hERG IC50 was 1.3 µM (0.83 µg/mL), which is approximately 3 times below the clinical Cmax (2.64 µg/mL).”
Genotox: Ames
Negative
“Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.”
Genotox: in vitro mammalian
Chromosomal aberration in human lymphocytes: negative
“Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.”
Genotox: in vivo
Mouse micronucleus: negative
“Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.”
Carcinogenicity model
Not conducted; carcinogenicity study required postapproval
“The Applicant will be required to conduct a carcinogenicity study postapproval.”
Carcinogenicity timing
Not conducted before approval; carcinogenicity study to be conducted after approval (PMR), as agreed at the pre-IND meeting
“As agreed at the pre-IND meeting held on August 22, 2018 (PIND 139923), the Applicant will conduct a carcinogenicity study postapproval.”
hERG / QT
hERG IC50 32 times above free clinical Cmax (0.026 µg/mL; >99% protein bound)
“However, when considering the plasma protein binding of lonafarnib, which was very high (>99%), the free fraction concentration in the patient (0.01 x 2.64 µg/mL = 0.026 µg/mL) is 32 times lower than the hERG IC50.”
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 Zokinvy 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: 6-month rat: renal toxicity (inner medulla necrosis, mineralization) at 30 and 60 mg/kg/day; NOAEL 15 mg/kg/day (FDA integrated review, p. 66)
NOAEL / key findings
6-month rat: renal toxicity (inner medulla necrosis, mineralization) at 30 and 60 mg/kg/day; NOAEL 15 mg/kg/day
“The results of the 6-month oral toxicity study in rats indicated that treatment with lonafarnib (at doses of 30 and 60 mg/kg/day) produced renal toxicity, including necrosis and mineralization in the inner medulla and mononuclear cell infiltrates. The no-observed-adverse-effect level (NOAEL) was 15 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid hypocellularity in spleen, thymus and mesenteric lymph node after 3 months in rats
“In rats, toxicity was seen after 3-months administration of lonafarnib and were attributed as lymphoid hypocellularity and with corresponding weight loss and the affected organs/tissues included spleen, thymus and mesenteric lymph node”
Biodistribution & persistence
Low to moderate brain penetration (brain:plasma AUC ~6.5%)
“The AUC ratio of brain to plasma was about 6.5% at each dose level, indicating a low to moderate brain penetration of Lonafarnib.”
Modality-specific risk
Nephrotoxicity, retinal toxicity, impaired fertility and embryo-fetal toxicity
“Nephrotoxicity, retinal toxicity, impaired fertility, and embryo-fetal toxicity were observed in nonclinical studies.”
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
- QTc Interval Prolongation
- Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions
- Laboratory Abnormalities
- Nephrotoxicity
- Retinal Toxicity
- Impaired Fertility
- Embryo-Fetal Toxicity
CardiovascularNephrotoxicityOcular toxicityEmbryo-fetal toxicity
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 Zokinvy 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: 6-month rat: renal toxicity (inner medulla necrosis, mineralization) at 30 and 60 mg/kg/day; NOAEL 15 mg/kg/day (FDA integrated review, p. 66)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week oral gavage study in cynomolgus monkeys; recovery not stated
“A 52-Week Oral (Gavage) Toxicity and Toxicokinetic Study of SCH 66336 in Cynomolgus Monkeys/ Study No. 96036”
Pivotal GLP studies
Repeat-dose studies up to 6 months in rats and 12 months in cynomolgus monkeys
“Overall, the toxicity profile of lonafarnib has been characterized via single-dose toxicity studies in mice and rats, repeat-dose toxicity studies (up to 6 months in Sprague Dawley rats and 12 months in cynomolgus monkeys)”
DART package
Species: DART
Rat and New Zealand White rabbit
“Sprague Dawley rat and New Zeeland White rabbits were selected for reproduction and developmental studies.”
Reproductive & developmental
Rat EFD: post-implantation loss at ~human exposure; rabbit EFD: skeletal malformations below human exposure
“In pregnant rats, post-implantation loss (resorptions) was seen at plasma drug exposures approximately equal to that achieved in humans. In pregnant rabbits, skeletal malformations were seen at plasma drug exposures lower than human exposures.”
PPND / ePPND: when
Rat PPND (oral gavage) completed and reviewed with the marketing application
“A Pre- and Postnatal Developmental Toxicity and Maternal Function Study of SCH 66336 Administered Orally by Gavage in Rats / Study No. 96047”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Long-term carcinogenicity studies have not been conducted.”
Carcinogenicity model
Not conducted; carcinogenicity study required postapproval
“The Applicant will be required to conduct a carcinogenicity study postapproval.”
Carcinogenicity timing
Not conducted before approval; carcinogenicity study to be conducted after approval (PMR), as agreed at the pre-IND meeting
“As agreed at the pre-IND meeting held on August 22, 2018 (PIND 139923), the Applicant will conduct a carcinogenicity study postapproval.”
Safety marginopen answer page →
Safety margin at NOAEL
Chronic rat NOAEL 15 mg/kg/day: 0.06x (males) and 0.36x (females) human AUC at 150 mg/m2 BID
“The no-observed-adverse-effect level (NOAEL) was 15 mg/kg/day. AUC0-24hr at 15 mg/kg/day was 2.31 ȝJ·hr/mL in males and 14.1 ȝJ·hr/mL in females, which are 0.06 and 0.36 times the human AUC0-24hr (39.1 ȝJ·hr/mL) observed with 150 mg/m2 BID, respectively.”
NOAEL / key findings
6-month rat: renal toxicity (inner medulla necrosis, mineralization) at 30 and 60 mg/kg/day; NOAEL 15 mg/kg/day
“The results of the 6-month oral toxicity study in rats indicated that treatment with lonafarnib (at doses of 30 and 60 mg/kg/day) produced renal toxicity, including necrosis and mineralization in the inner medulla and mononuclear cell infiltrates. The no-observed-adverse-effect level (NOAEL) was 15 mg/kg/day.”
Efficacy evidenceopen answer page →
Efficacy evidence
Hutchinson-Gilford progeria mouse model (homozygous LmnaG609G/G609G): lonafarnib prolonged survival
“which shows how lonafarnib in a mouse model of Hutchinson-Gilford Progeria Syndrome (homozygous LmnaG609G/G609G mice) prolonged survival”
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
EMA: sufficient nonclinical support for the hypothesized mechanism, though full understanding of effects not yet possible
“Sufficient non-clinical support for the hypothesized MoA is provided, although a full understanding of the lonafarnib induced effects on the set of complex mechanisms potentially affected is not possible to reach at this point.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity study before approval; deferred to a postapproval study as agreed at the pre-IND meeting
Why: Agreed at the pre-IND meeting · Other reason
“As agreed at the pre-IND meeting held on August 22, 2018 (PIND 139923), the Applicant will conduct a carcinogenicity study postapproval.”
Juvenile toxCriticised but acceptedBeyond the letter
No juvenile toxicity studies for a paediatric product; toxicology animals' ages did not cover patients from 12 months
Why: Previously agreed · Other reason
“No juvenile toxicity studies were conducted, although lonafarnib is in this application intended for children. The lack of juvenile toxicity studies has previously been agreed upon. In addition, the age of the animals in the toxicological studies corresponded to human ages from approximately 12 years and older and did not cover the ages of the intended paediatric patients (from 12 months and older).”
Safety marginVerdict not stated
Chronic rat NOAEL at 0.06 (males) and 0.36 (females) times human AUC
“The no-observed-adverse-effect level (NOAEL) was 15 mg/kg/day. AUC0-24hr at 15 mg/kg/day was 2.31 ȝJ·hr/mL in males and 14.1 ȝJ·hr/mL in females, which are 0.06 and 0.36 times the human AUC0-24hr (39.1 ȝJ·hr/mL) observed with 150 mg/m2 BID, respectively.”
Impurity or metaboliteAccepted with a conditionBeyond the letter
Major human metabolite M33 below 50% of human exposure in rats, the species used for pivotal embryo-fetal studies
Why: Lonafarnib already teratogenic at clinically relevant exposures; SmPC section 4.6 recommendation sufficient · Weight of evidence
“In the rat toxicity studies, mainly the M33 is lower than 50% of the human exposure. Since monkeys were not used in the pivotal EFD studies, the low exposure of M33 in rats is uncertain which may impact the results and conclusion of the reproductive toxicity studies.”
“However, since Lonafarnib has shown reproductive toxicity in animals, demonstrating teratogenic potential at clinically relevant exposures, the current recommendation in section 4.6 of the SmPC is considered sufficient.”
Impurity or metaboliteCriticised but acceptedBeyond the letter
Impurity Compound W not tested on its own for genotoxicity; QSAR assessment used instead
Why: QSAR assessment using statistical and expert-rule based methodology · Other reason
“To better investigate the genotoxic potential of Compound W, the substance itself should have been tested and preferably in a bacterial reverse mutation assay.”
“The QSAR analysis report was submitted upon request in the first round of the procedure. The assessment included a statistical and an expert-rule based methodology. It is agreed that Compound W can be considered non-mutagenic.”
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