Ten real questions, answered the way Ask Atlas answers: a short answer with real counts, then the regulator's own sentences with the page they're on. These examples are assembled only from Atlas's verified quotes. Ask Atlas does the same for your exact question.
“Cynomolgus monkey was selected as the appropriate animal species for assessing the nonclinical safety, pharmacokinetic (PK), and pharmacodynamic (PD) properties of mosunetuzumab and 2H7v16/40G5c.”
How was the first-in-human dose set for approved bispecifics?
3 of 18 public reviews say how the first human dose was set.
Stated3/18
Not stated publicly15/18
The evidence · 3 of 21 regulator sentences
LunsumioBispecifics · CD20 x CD3 · First-in-human starting dose
MABEL-type: EC20 from in vitro human PBMC cytokine release / T-cell activation assay
“The results (EC20 values) were used to inform the starting dose in the first in human study.”
✓ VerifiedFDA multi-discipline review, p. 60Source ↗
ColumviBispecifics · CD20 x CD3 · First-in-human starting dose
MABEL: monkey PK/PD IL-6 excursion model plus in vitro human/monkey whole-blood cytokine data; 5 ug flat dose
“A pharmacokinetic-pharmacodynamic (PK/PD) model for cytokine excursions in cynomolgus monkeys, particularly interleukin 6 (IL-6), was built and translated to humans. The human starting dose was selected to keep the predicted IL-6 excursion below a predefined…”
✓ VerifiedFDA multi-discipline review, p. 50Source ↗
RybrevantBispecifics · EGFR x MET · NOAEL / key findings
“The no-observed-adverse-effect level (NOAEL) in the toxicology studies was 120 mg/kg/week (highest tested dose) for the 6-week and 3-month toxicity GLP studies.”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗
1/6 HNSTD in cynomolgus monkey cited as rationale for species choice; actual FIH calculation not detailed
“The cynomolgus monkey was selected as nonclinical species for safety evaluation of loncastuximab tesirine, given the greater predictive value of PK data generated in this species for humans, potential for reduced impact of antidrug antibody (ADA) formation…”
✓ VerifiedFDA multi-discipline review, p. 49Source ↗
HNSTD-based: monkey HNSTD 10 mg/kg (q3w x4), below 1/10 rat severely toxic dose, used to set Phase I start
“the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys was 10 mg/kg for four injections every 3 weeks which was below the no observable adverse effect level in that species and below one-tenth of the severely toxic dose in rats, this information…”
1/12 HED of monkey HNSTD (0.8 mg/kg), also matching minimum effective trough concentration
“The FIH dose of 0.8 mg/kg was selected based on one-twelfth of the human equivalent dose of the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys in toxicology studies and was also estimated to provide trough concentration in humans comparable to…”
✓ VerifiedFDA multi-discipline review, p. 80Source ↗
Conducted: calicheamicin positive in Ames and in vitro micronucleus; ADC clastogenic in mouse micronucleus
“Inotuzumab ozogamicin was clastogenic in mice at doses ≥28 µg/kg (approximately 1.1 mg/m2 of the ADC), consistent with the known DNA-reactive activity of the calicheamicin payload.”
✓ VerifiedFDA multi-discipline review, p. 36Source ↗
Not conducted with ADC; DXd Ames negative, clastogenic in vitro chromosome aberration and in vivo rat micronucleus
“In genetic toxicology studies, deruxtecan was not mutagenic in an Ames assay but demonstrated clastogenic potential in an in vitro Chinese hamster lung chromosome aberration assay and an in vivo rat bone marrow micronucleus assay.”
✓ VerifiedFDA multi-discipline review, p. 47Source ↗
How long were the pivotal tox studies for approved oligonucleotides?
Median longest pivotal study: 39 weeks (range 36–53).
Over 26 weeks24/24
The evidence · 3 of 72 regulator sentences
MacugenOligos · VEGF-165 (aptamer) · Longest pivotal study
39 weeks
“Pivotal long term-studies in up to 9 months with intravitreous injections every 2 weeks did not cause any apparent toxic effects and there was no evidence of increased intra-ocular inflammation during the course of the studies.”
AmvuttraOligos · TTR (siRNA) · Longest pivotal study
40 weeks
“In the pivotal general toxicology studies of SC vutrisiran in rat (13- and 26-week) and cynomolgus monkey (13- and 40-week), non-adverse findings were observed in the liver (both species), kidneys (rat), and lymph nodes (monkey).”
✓ VerifiedFDA pharmacology/toxicology review, p. 9Source ↗
39-week IV male monkey; 10-week IV juvenile rat (PND14-77); 26-week IV mdx mouse with surrogate AVI-4225
“Pivotal toxicology studies of eteplirsen were conducted in male monkeys (39-week study) and juvenile male rats (10-week study). A 26-week study was conducted with a mouse-specific surrogate (AVI-4225) in male transgenic mdx mice.”
✓ VerifiedFDA pharmacology/toxicology review, p. 25Source ↗
Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
“Casimersen was tested in a standard battery of in vitro (bacterial reverse mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) genetic toxicology assays. The studies were adequately conducted and negative.”
✓ VerifiedFDA pharmacology/toxicology review, p. 6Source ↗
Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
“A standard battery of genetic toxicology assays was conducted for vutrisiran (in vitro bacterial mutagenicity, in vitro chromosomal aberration in human peripheral blood lymphocytes, and in vivo rat (bone marrow) micronucleus assay. All assays were adequate…”
✓ VerifiedFDA pharmacology/toxicology review, p. 4Source ↗
“The CRL also included a recommendation for the applicant to provide additional data to address the risks of vector integration and insertional mutagenesis.”
✓ VerifiedFDA pharmacology/toxicology review, p. 6Source ↗
Anti-AAV antibodies in mice; NHP: capsid/transgene T-cell responses, liver enzymes, anaphylaxis on redosing with rituximab/sirolimus
“increased antibody titers against AAVrh74 vector capsid from Weeks 5 to 12, increased cellular immune response against AAVrh74 vector capsid and micro-dystrophin at Week 2 compared to baseline”
✓ VerifiedFDA pharmacology/toxicology review, p. 30Source ↗
Not conducted (agreed with CHMP; low integration risk in post-mitotic neurons)
“It was previously agreed with CHMP that genotoxicity, carcinogenicity and evaluation of insertional mutagenesis studies were not required (EMEA/CHMP/SAWP/236092/2018).”
No relevant species; in vitro and NSG mouse xenograft only
“In particular, suitable animal models are not available for accurately assessing the non-clinical characteristics of a human cell-based product such as JCAR017.”
No relevant species; in vitro cross-reactivity/alloreactivity and murine xenograft pharmacology only
“Standard in vivo single-dose or repeat-dose toxicity studies were not conducted with afamitresgene autoleucel due to the lack of appropriate animal models for testing of human TCR engineered T-cells.”
✓ VerifiedFDA multi-discipline review, p. 39Source ↗