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.”
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.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
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.”