Polivy
polatuzumab vedotin
Species
MonkeyRat
Longest study
10 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (monkey with clinical ADC plus monkey-CD79b surrogate ADC)
“Polatuzumab does not bind to its target epitope on species typically used in toxicology studies. Both polatuzumab vedotin and a surrogate ADC that binds monkey CD79b were used in the toxicology studies.”
Why that species
Polatuzumab does not bind non-human primate or rodent CD79b (3 amino-acid epitope difference); surrogate binds cyno CD79b
“Peptide sequence alignment of CD79b between humans and cynomolgus monkeys showed a variation in three amino acids in the N-terminal epitope region.”
Surrogate molecule
Yes: surrogate ADC DCDS5017A (chimeric anti-cyno CD79b IgG1-vcMMAE, DAR 3.5) for target-mediated effects
“Therefore, a surrogate ADC (DCDS5017A) that binds specifically to cynomolgus monkey CD79b was generated for testing target-mediated effects.”
Species: general tox
Rat and cynomolgus monkey (polatuzumab vedotin, surrogate ADC and MMAE)
“The toxicological profile of polatuzumab vedotin has been evaluated during single and repeat-dose toxicity studies in rats and Cynomolgus monkeys using polatuzumab vedotin, surrogate ADC or unconjugated MMAE, genotoxicity studies, reproductive and developmental toxicity studies in rats and phototoxicity.”
Species: DART
Rat (MMAE embryo-fetal development only); no fertility study
“In an embryo-fetal developmental study, pregnant rats were given 2 intravenous doses of 0.2 mg/kg MMAE during the period of organogenesis on gestation Days 6 and 13.”
Species: carcinogenicity
Not conducted (not warranted for the indication)
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
Surrogate used in
Yes: surrogate ADC binding monkey CD79b used in monkey repeat-dose toxicity
“Both polatuzumab vedotin and a surrogate ADC that binds monkey CD79b were used in the toxicology studies.”
Study lengthopen answer page →
Longest pivotal study
10 weeks
“Cardiovascular, respiratory, and neurologic assessments were included in the 10-week repeat-dose toxicology study in cynomolgus monkeys, using polatuzumab vedotin or the surrogate ADC (10-0044).”
Pivotal GLP studies
Rat 4 weekly IV doses (6-week recovery); monkey Q3W x4 IV ADC and surrogate (9-week recovery); MMAE rat and monkey
“In Cynomolgus monkeys, IV doses of 1, 3, and 5 mg/kg polatuzumab vedotin or 3 and 5 mg/kg of the surrogate ADC were administered Q3W for a total of 4 doses, followed by a 9-week recovery period.”
Route in tox
IV bolus
“In the repeat-dose rat study, polatuzumab vedotin was administered by intravenous (IV) injection once weekly for 4 weeks at doses of 2, 6, and 10 mg/kg.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted with ADC; MMAE Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
“MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism.”
Carcinogenicity
Not conducted (not warranted for indication; ICH S9)
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
Reproductive & developmental
No fertility study (ICH S9); MMAE rat EFD embryolethal and teratogenic; testicular toxicity in rat repeat-dose
“A designated fertility study was not conducted with polatuzumab vedotin or MMAE and is not needed for the proposed indication.”
Safety pharmacology
Incorporated into rat and monkey repeat-dose studies; MMAE hERG IC50 >100 uM; no adverse effects
“Safety pharmacology assessments (neurobehavioral, cardiovascular, and respiratory) that were incorporated into the repeat-dose toxicology studies showed no polatuzumab vedotin- or surrogate ADC-induced adverse effects in monkeys.”
Genotox: Ames
MMAE: negative in Ames assay
“MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178Y mouse lymphoma forward mutation assay.”
Genotox: in vitro mammalian
MMAE: negative in L5178Y mouse lymphoma forward mutation assay
“MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178Y mouse lymphoma forward mutation assay.”
Genotox: in vivo
MMAE: positive in rat bone marrow micronucleus (aneugenic)
“MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study through an aneugenic mechanism.”
Carcinogenicity model
Not conducted with polatuzumab vedotin or MMAE (not warranted for the indication)
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
Carcinogenicity timing
Not conducted with polatuzumab vedotin or MMAE; not warranted for the indication
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
hERG / QT
MMAE hERG IC50 >100 µM (no appreciable inhibition)
“MMAE alone did not appreciably inhibit the human ether-à-go-go-related gene (hERG) channel (IC50 > 100 µM) in voltage-clamped human embryonic kidney cells”
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 Polivy 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 ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: Rat STD10 10 mg/kg; monkey surrogate HNSTD 3 mg/kg; bone marrow, lymphoid, liver, male reproductive organs (testes irreversible) (EMA assessment report, p. 55)
NOAEL / key findings
Rat STD10 10 mg/kg; monkey surrogate HNSTD 3 mg/kg; bone marrow, lymphoid, liver, male reproductive organs (testes irreversible)
“The main target organs are bone marrow, lymphoid organs, reproductive organs and liver with less severe effects on eye, skin and pancreas.”
Risksopen answer page →
Immune & cytokine safety
Surrogate ADC depleted B cells (expected pharmacology); ADA in monkeys without exposure impact
“Anti-drug-antibodies to polatuzumab vedotin or the surrogate ADC did not appear to impact exposure at any dose level and the toxicokinetic (TK) profiles were similar between ADA-positive and ADA-negative animals.”
Biodistribution & persistence
Rat: non-specific distribution to highly perfused tissues peaking ~2 h; MMAE eliminated >95% in feces
“In a combined distribution and elimination study, MMAE and MMAE-related catabolites of polatuzumab vedotin were primarily eliminated through the hepatobiliary pathway in rats: >95% in feces, ~5% in urine.”
Modality-specific risk
MMAE payload toxicity: myelosuppression, hepatotoxicity, testicular toxicity, genotoxicity; target-mediated B-cell depletion
“Toxicity of polatuzumab vedotin and MMAE observed in rats and Cynomolgus monkeys is consistent with the expected toxicity of a tubulin-binding agent, causing arrest of the cell cycle and apoptosis especially in rapidly dividing tissues.”
Anti-drug antibodies: animals
Monkey ADA 43% (polatuzumab vedotin repeat dose), 20-67% (surrogate ADC); no impact on exposure
“ADA incidence was 67% after a single dose of the surrogate ADC, 20% in Cynomolgus given repeat doses of the surrogate ADC; and 43% in Cynomolgus given repeat-doses of polatuzumab vedotin. Importantly, ADA did not appear to impact the PK/TK of total antibody and unconjugated MMAE exposures.”
Anti-drug antibodies: patients
1.4% (POLARIX) and 6% (GO29365) ADA-positive; none neutralizing
“In studies POLARIX and GO29365, 1.4% (6/427) and 6% (8/134) of patients tested positive for antibodies against polatuzumab vedotin-piiq, respectively, of which none were positive for neutralizing antibodies.”
Label warnings
- Peripheral Neuropathy
- Infusion-Related Reactions
- Myelosuppression
- Serious and Opportunistic Infections
- Progressive Multifocal Leukoencephalopathy (PML)
- Tumor Lysis Syndrome
- Hepatotoxicity
- Infusion Site Extravasation Injury
- Embryo-Fetal Toxicity
NeurotoxicityHypersensitivity & infusion reactionsCytopeniasInfectionsSecondary malignancyHepatotoxicityEmbryo-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 Polivy 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 ADCs
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: Rat STD10 10 mg/kg; monkey surrogate HNSTD 3 mg/kg; bone marrow, lymphoid, liver, male reproductive organs (testes irreversible) (EMA assessment report, p. 55)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Cynomolgus monkey, polatuzumab vedotin or surrogate ADC IV Q3W for 4 doses, with 9-week recovery
“In Cynomolgus monkeys, IV doses of 1, 3, and 5 mg/kg polatuzumab vedotin or 3 and 5 mg/kg of the surrogate ADC were administered Q3W for a total of 4 doses, followed by a 9-week recovery period.”
Pivotal GLP studies
Rat 4 weekly IV doses (6-week recovery); monkey Q3W x4 IV ADC and surrogate (9-week recovery); MMAE rat and monkey
“In Cynomolgus monkeys, IV doses of 1, 3, and 5 mg/kg polatuzumab vedotin or 3 and 5 mg/kg of the surrogate ADC were administered Q3W for a total of 4 doses, followed by a 9-week recovery period.”
DART package
Species: DART
Rat (MMAE embryo-fetal development only); no fertility study
“In an embryo-fetal developmental study, pregnant rats were given 2 intravenous doses of 0.2 mg/kg MMAE during the period of organogenesis on gestation Days 6 and 13.”
Reproductive & developmental
No fertility study (ICH S9); MMAE rat EFD embryolethal and teratogenic; testicular toxicity in rat repeat-dose
“A designated fertility study was not conducted with polatuzumab vedotin or MMAE and is not needed for the proposed indication.”
PPND / ePPND: when
No dedicated pre- and postnatal development study conducted
“No dedicated pre- and postnatal development studies have been conducted (see discussion on Non-Clinical aspects).”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted for the indication)
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
Carcinogenicity model
Not conducted with polatuzumab vedotin or MMAE (not warranted for the indication)
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
Carcinogenicity timing
Not conducted with polatuzumab vedotin or MMAE; not warranted for the indication
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
Rat STD10 10 mg/kg; monkey surrogate HNSTD 3 mg/kg; bone marrow, lymphoid, liver, male reproductive organs (testes irreversible)
“The main target organs are bone marrow, lymphoid organs, reproductive organs and liver with less severe effects on eye, skin and pancreas.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human DLBCL and B-cell lymphoma xenografts in mice; in vitro Ramos cytotoxicity
“Polatuzumab vedotin demonstrated anti-tumor activity in vitro in CD79b expressing human Burkitt lymphoma (Ramos) cells (IC50 = 0.071 nM) and in vivo in DLBCL and human B-cell lymphoma mouse xenograft models.”
Why that model
Xenograft line co-expressing human and cynomolgus CD79b allowed comparison of clinical and surrogate ADC
“The anti-tumour activity of polatuzumab Ab, polatuzumab vedotin and of the surrogate Ab and ADC was compared in a murine xenograft model with the BJAB Burkitt lymphoma transfectant cell line which expresses comparable amounts of human CD79b and recombinant Cynomolgus CD79b.”
Reviewer's view of the efficacy data
EMA: proof of concept demonstrated in vitro and in DLBCL xenografts, as monotherapy and in combination
“The pharmacological profile of polatuzumab vedotin was demonstrated in in vitro assays and in vivo DLBCL model xenografted in rodents. The proof of concept was successfully demonstrated, an anti tumor efficacy was shown both as monotherapy or combination with rituximab and bendamustine.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
Polatuzumab does not bind monkey CD79b; target-mediated toxicity assessed with a surrogate ADC binding monkey CD79b
Why: Three amino-acid difference in the CD79b epitope between humans and cynomolgus monkeys · No relevant species
“Peptide sequence alignment of CD79b between humans and cynomolgus monkeys showed a variation in three amino acids in the N-terminal epitope region. Therefore, a surrogate ADC (DCDS5017A) that binds specifically to cynomolgus monkey CD79b was generated for testing target-mediated effects.”
DARTVerdict not stated
No embryo-fetal study with the ADC; embryo-fetal toxicity assessed with the MMAE payload in rats
“Dedicated embryo-fetal developmental toxicity studies were not conducted with polatuzumab vedotin. However, MMAE (SGD-1010) was evaluated in rats in a GLP embryo-fetal developmental and TK study (Study 8204397) to determine maternal and embryo-fetal toxicity and teratogenic potential.”
DARTAccepted
No fertility study with the ADC or MMAE; male fertility risk inferred from repeat-dose rat studies
Why: Not needed for the proposed indication; repeat-dose rat studies indicate potential male fertility impairment · Within the guideline · Weight of evidence
“A designated fertility study was not conducted with polatuzumab vedotin or MMAE and is not needed for the proposed indication. However, results of repeat-dose toxicity studies in rats indicate the potential for polatuzumab vedotin to impair fertility in males.”
Similar precedents
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