Piqray
alpelisib
Species
RatDog
Longest study
13 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
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs, consistent with the clinical route of administration and intended dosing schedule.”
Why that species
Pharmacodynamic target and major human metabolic pathways represented in rat and dog
“The pharmacodynamic target and the major pathways of alpelisib metabolism in humans were all represented in these species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs, consistent with the clinical route of administration and intended dosing schedule.”
Species: general tox
Rat and dog
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs”
Species: DART
Rat (GLP EFD) and rabbit (non-GLP EFD dose-range finding)
“A GLP embryofetal toxicity study in rat and a non-GLP embryofetal toxicity extended dose-range finding study in rabbit were conducted in order to elucidate effects on the developing foetus.”
Species: carcinogenicity
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Surrogate used in
No surrogate used; alpelisib itself tested in rats and dogs
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“The toxicity of alpelisib after repeated oral administration was studied in rats and dogs with dosing up to 13 weeks.”
Pivotal GLP studies
GLP oral repeat-dose studies up to 3 months in rats and dogs
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs, consistent with the clinical route of administration and intended dosing schedule. The pivotal repeat-dose toxicology studies were conducted in compliance with Good Laboratory Practice regulations (21 CFR part 58).”
Route in tox
Oral
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs, consistent with the clinical route of administration and intended dosing schedule.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro micronucleus and chromosome aberration, and in vivo rat micronucleus assays
“Alpelisib did not induce mutations in the bacterial reverse mutation (Ames) assays and was not genotoxic in either the in vitro micronucleus and chromosome aberration tests or the in vivo rat micronucleus assay at 20 mg/kg, the top dose tested (1.7x human exposure based on AUC).”
Carcinogenicity
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Reproductive & developmental
Rat EFD: maternal toxicity and no viable fetuses (post-implantation loss) at 30 mg/kg/day (~3x human AUC)
“In rats, oral administration of alpelisib resulted in maternal toxicity (body weight loss, low food consumption) and no viable fetuses (post-implantation loss) at 30 mg/kg/day (approximately 3 times the exposure in humans at the recommended dose of 300 mg/day based on AUC).”
Safety pharmacology
Dose-independent blood pressure increase in dogs; no adverse ECG, respiratory or neurological effects
“A single oral administration of alpelisib induced a dose-independent increase in systolic and diastolic blood pressure in dogs at all doses tested (5, 15, 30 mg/kg) in the conducted safety pharmacology study. Alpelisib had no adverse effects on ECG, respiration, or neurological behavior in animals.”
Genotox: Ames
Negative (Ames)
“Alpelisib did not induce mutations in the bacterial reverse mutation (Ames) assays and was not genotoxic in either the in vitro micronucleus and chromosome aberration tests or the in vivo rat micronucleus assay at 20 mg/kg, the top dose tested (1.7x human exposure based on AUC).”
Genotox: in vitro mammalian
In vitro micronucleus and chromosome aberration tests: negative
“Alpelisib did not induce mutations in the bacterial reverse mutation (Ames) assays and was not genotoxic in either the in vitro micronucleus and chromosome aberration tests or the in vivo rat micronucleus assay at 20 mg/kg, the top dose tested (1.7x human exposure based on AUC).”
Genotox: in vivo
Rat micronucleus: negative at 20 mg/kg (1.7x human AUC)
“Alpelisib did not induce mutations in the bacterial reverse mutation (Ames) assays and was not genotoxic in either the in vitro micronucleus and chromosome aberration tests or the in vivo rat micronucleus assay at 20 mg/kg, the top dose tested (1.7x human exposure based on AUC).”
Carcinogenicity model
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Carcinogenicity timing
Not required for the proposed indication
“The FDA agrees that no carcinogenicity studies are required for the proposed indication.”
hERG / QT
hERG IC50 9.4 µM, ~13-fold above human exposure at 300 mg/day
“In vitro inhibition of hERG channels (IC50 of 9.4 µM) was shown at concentrations ~13-fold higher than the exposure in humans, at the recommended dose of 300 mg/day.”
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 Piqray 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 oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Targets: GI tract, hemolymphoid system, skin, metabolic (glucose/insulin) and reproductive system (FDA multi-discipline review, p. 38)
NOAEL / key findings
Targets: GI tract, hemolymphoid system, skin, metabolic (glucose/insulin) and reproductive system
“Administration of alpelisib to rats and dogs resulted in adverse effects in the GI tract, hemolymphoid system, skin, metabolic, and reproductive system.”
Risksopen answer page →
Immune & cytokine safety
Inflammation and/or suppression in bone marrow, spleen, thymus and lymph nodes
“The effects in the hemolymphoid system included inflammation and/or suppressive effects in the bone marrow, spleen, thymus, or lymph nodes.”
Biodistribution & persistence
Distribution to hair and eyes of pigmented rats; melanin binding
“Nonclinical ADME studies indicated distribution of radioactivity to hair and eyes of pigmented rats, thus alpelisib and/or its metabolites can bind melanin.”
Modality-specific risk
On-target hyperglycemia and hyperinsulinemia with pancreatic endocrine changes
“Administration of alpelisib to rats and dogs increased blood insulin and glucose levels, which correlated with histopathologic changes in the pancreas (vacuolation or hyperplasia of endocrine cells).”
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 assessed; not expected
“Immunogenicity The Applicant’s Position: Not applicable as this was not assessed nor expected. The FDA’s Assessment: The FDA agrees with the applicant’s assessment.”
Label warnings
- Severe Hypersensitivity
- Severe Cutaneous Adverse Reactions
- Hyperglycemia
- Pneumonitis
- Diarrhea or Colitis
- Embryo-Fetal Toxicity
Hypersensitivity & infusion reactionsSkin reactionsMetabolic & endocrineImmune-mediated reactionsGastrointestinalEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human study X2101 was a dose-escalation study in adults with advanced solid malignancies
“Study X2101 was a multicenter, Phase IA, dose-escalation/expansion study of oral alpelisib in adult subjects with advanced solid malignancies.”
Repeat-dose tox before first-in-human
4-week GLP rat oral study with 4-week recovery, designed to support the first clinical trials
“4-Week Study in rats followed by 4 week recovery period (0970325) (GLP) The purpose of this GLP toxicity study in rats [Study 0970325] was to determine the toxicity of alpelisib after repeated oral administration, aid in the selection of appropriate dose levels for subsequent repeated dose toxicity studies and to support first clinical trials in man.”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Piqray 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 oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Targets: GI tract, hemolymphoid system, skin, metabolic (glucose/insulin) and reproductive system (FDA multi-discipline review, p. 38)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week beagle dog oral study with 4-week recovery
“13-week oral administration toxicity study in the dog followed by a 4-week treatment-free period/ Study 1070416”
Pivotal GLP studies
GLP oral repeat-dose studies up to 3 months in rats and dogs
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs, consistent with the clinical route of administration and intended dosing schedule. The pivotal repeat-dose toxicology studies were conducted in compliance with Good Laboratory Practice regulations (21 CFR part 58).”
DART package
Species: DART
Rat (GLP EFD) and rabbit (non-GLP EFD dose-range finding)
“A GLP embryofetal toxicity study in rat and a non-GLP embryofetal toxicity extended dose-range finding study in rabbit were conducted in order to elucidate effects on the developing foetus.”
Reproductive & developmental
Rat EFD: maternal toxicity and no viable fetuses (post-implantation loss) at 30 mg/kg/day (~3x human AUC)
“In rats, oral administration of alpelisib resulted in maternal toxicity (body weight loss, low food consumption) and no viable fetuses (post-implantation loss) at 30 mg/kg/day (approximately 3 times the exposure in humans at the recommended dose of 300 mg/day based on AUC).”
PPND / ePPND: when
No PPND study; not warranted for advanced cancer per ICH S9
“As per ICH S9, pre-and postnatal and juvenile toxicology studies are generally not warranted to support marketing of pharmaceuticals for the treatment of patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Carcinogenicity timing
Not required for the proposed indication
“The FDA agrees that no carcinogenicity studies are required for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: repeat-dose effects occurred below human exposure at the maximum recommended dose
“All effects were observed at doses that resulted in total plasma exposure levels lower than those reached in patients treated with the maximum recommended dose and were reversible or showed a tendency towards reversibility after a 4- or 8-week treatment-free recovery period.”
NOAEL / key findings
Targets: GI tract, hemolymphoid system, skin, metabolic (glucose/insulin) and reproductive system
“Administration of alpelisib to rats and dogs resulted in adverse effects in the GI tract, hemolymphoid system, skin, metabolic, and reproductive system.”
Efficacy evidenceopen answer page →
Efficacy evidence
Breast cancer xenografts in mice, incl. ER-positive PIK3CA-mutant models and PDX
“These data were confirmed when alpelisib was administered to mice bearing a diverse range of breast cancer tumor xenografts, including the ER-positive breast cancer mouse models with PIK3CA mutations as well as additional breast cancer patient-derived xenograft (PDX) models (Fritsch et al 2014).”
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
FDA: in vitro and in vivo pharmacology provided a scientific basis for alpelisib plus fulvestrant in PIK3CA-mutated HR+/HER2- breast cancer
“Overall, the available in vitro and in vivo pharmacology data provided a scientific basis and mechanism of action of using alpelisib in combination with fulvestrant in HR-positive, HER2-negative advanced breast cancer with a PIK3CA mutation.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityQuestioned
In vitro genotoxicity concentrations below ICH S2 requirements; in vivo micronucleus exposure only 2-fold or 1.4-fold human exposure
“However, it should be noted that the value of the these studies is limited since the concentrations of alpelisib used in in vitro studies were lower than those required in the ICH S2 guideline and systemic exposures to alpelisib achieved in the in vivo study were only 2 fold or 1.4 fold higher than therapeutic exposure in adult humans.”
“Therefore, the genotoxicity potential of alpelisib in human cannot be ruled out (see SmPC section 5.3).”
Safety marginVerdict not stated
No exposure margin: all repeat-dose toxicity effects occurred below human exposure at the maximum recommended dose
“All effects were observed at doses that resulted in total plasma exposure levels lower than those reached in patients treated with the maximum recommended dose and were reversible or showed a tendency towards reversibility after a 4- or 8-week treatment-free recovery period.”
Impurity or metaboliteAcceptedBeyond the letter
Most impurity mutagenicity data from non-GLP Ames tests; three impurities Ames-positive
Why: Tested impurities not detectable in drug substance or purged to below 25 ppm · Other reason
“Only four studies on genotoxic potential of impurities were conducted in compliance with GLP. Three of the impurities were tested positive in the non-GLP AMES tests and three impurities were tested negative.”
“However, the tested impurities are either not detectable in the drug substance or controlled via a purging step in the manufacturing process, which ensures amounts of less than 25 ppm for mutagenic impurities at drug substance level based on a treatment duration of up to 10 years and a maximum daily dose of 400 mg alpelisib. Hence, the non-GLP Ames tests are accepted in support of the genotoxic testing of alpelisib.”
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