Ten real questions, answered the way Ask Lidia 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 Precedia's verified quotes. Ask Lidia does the same for your exact question.
“The cynomolgus monkey was utilized as the only pharmacologically relevant species for toxicity testing, in view of cross reactivity of MCLA-128 with the HER2/HER3 targets in this species.”
✓ VerifiedFDA multi-discipline review, p. 77Source ↗
Chimpanzee (only relevant species, limited non-terminal studies) plus mouse with murine surrogate
“General toxicology studies included non-terminal repeat-dose studies of intravenous administration of blinatumomab in chimpanzees and repeat-dose studies of subcutaneous and intravenous administration of a murine surrogate in mice.”
✓ VerifiedFDA pharmacology/toxicology review, p. 12Source ↗
How was the first-in-human dose set for approved multispecifics?
Rarely public: 3 of 18 reviews say how the first human dose was set.
Stated3/18
Not stated publicly15/18
The evidence · 3 of 21 regulator sentences
LunsumioMultispecifics · 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 ↗
ColumviMultispecifics · CD20 x CD3 · NOAEL / key findings
HNSTD 30/100 ug/kg step-up (2-week); B-cell depletion, cytokine release, lymphoid hypocellularity; CRS deaths at 100 ug/kg first dose
“Key findings with glofitamab identified in single- and repeat-dose toxicity studies up to 4 weeks in duration in cynomolgus monkeys included B-cell depletion, transient postdose cytokine release, primarily after the first dose,”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗
VabysmoMultispecifics · VEGF-A x Ang-2 · First-in-human starting dose
Starting dose 0.5 mg/eye IVT supported by monkey tox data (6 mg/eye high dose not initially supported; dose escalation gated)
“The proposed clinical starting dose of 0.5 mg/eye is supported by the nonclinical data but the high dose of 6.0 mg/eye is not.”
✓ VerifiedFDA pharmacology/toxicology review, p. 26Source ↗
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…”
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 ↗
“Title: SRP-4045: A 39-week intravenous infusion toxicity study in male cynomolgus monkeys with an 8-week recovery period”
✓ VerifiedFDA pharmacology/toxicology review, p. 40Source ↗
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 ↗
DawnzeraOligos · Prekallikrein / KLKB1 (ASO) · Longest pivotal study
39 weeks
“repeat dose studies in CD-1 mice and cynomolgus monkeys of up to 26- and 39-week duration, respectively”
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 ↗
Neutralizing anti-adenovirus and anti-IFNa2b antibodies in most high-dose monkeys, persisting through observation period
“Development of neutralizing antibodies to the adenovirus and anti-IFNα2b antibodies occurred in the majority of animals in the high dose group and to a lesser extent in the low dose group”
✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗
BeqvezGene therapy · Factor IX · Immune & cytokine safety
Anti-hFIX and anti-capsid antibodies in most NHPs, rising over time, correlated with declining hFIX
“The levels of both anti-hFIX and anti-AAV antibodies increased with time, which correlated with a decline in plasma hFIX protein levels.”
✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗
Which nonclinical studies did approved gene therapies skip?
26 of 26 skipped carcinogenicity; 21 of 26 skipped genotoxicity.
No genotoxicity studies21/26
No carcinogenicity study26/26
No dedicated repro tox20/26
The evidence · 3 of 243 regulator sentences
WaskyraGene therapy · WAS (LVV, ex vivo HSC) · Genotox: Ames
Not conducted (conventional mutagenicity studies not required for gene therapy)
“Conventional mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have not been conducted, which is in accordance with scientific and regulatory recommendations related to gene therapies.”
No animal studies with product; published murine and human TIL literature only
“No nonclinical studies were conducted with AMTAGVI. Instead, the applicant cited published nonclinical data evaluating similar murine and human tumor-derived T lymphocytes to provide support for AMTAGVI.”
✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗
No ADA incidence reported; immunological events (antibody formation) to be followed post-authorisation
“In addition, the MAH will follow-up on the risks of Graft versus Host Disease (GvHD), Severe systemic infection CMV and EBV reactivation, Febrile neutropenia, Hepatic failure, Carcinogenicity, Genotoxicity, Late complications (malignancies, autoimmunity),…”