Cyfendus
anthrax vaccine adsorbed, adjuvanted
Species
Rat
Longest study
4 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat only
“All these GLP-compliant toxicology studies were performed in rats.”
Why that species
Widely used toxicology species; rats responded to the vaccine and CpG 7909, confirmed by immunogenicity in each study
“The rat model was chosen for the safety evaluation of AV7909 as it is a widely used species for toxicology studies and rats were shown to respond appropriately to AV7909 and its component, CPG 7909, as confirmed by immunogenicity assessments conducted in each of the studies.”
Surrogate molecule
No surrogate; the clinical vaccine and CpG 7909 adjuvant alone were tested side by side
“Test article-related findings were observed in the adjuvant alone (CPG 7909) group as well as the Anthrax Vaccine Adsorbed (AVA), adjuvanted group with similar frequency and similar severity, which suggests that the findings were mostly induced by the adjuvant.”
Species: general tox
Rat only
“All these GLP-compliant toxicology studies were performed in rats.”
Species: DART
Female rat (pre/postnatal study with embryo-fetal phase, full human dose 0.5 mL)
“In a pre- and post-natal developmental study with an embryo-fetal development toxicity phase performed in female rats, a full human dose (0.5 mL) of CYFENDUS was administered by intramuscular injection on three occasions: 14 days prior to start of cohabitation, on the day of cohabitation, and on Gestation Day 7.”
Species: carcinogenicity
Not conducted
“CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.”
Surrogate used in
No surrogate used; CYFENDUS itself dosed in rats
“The applicant conducted a single-dose acute toxicity study, a repeat-dose safety toxicity study, a pre- and post-natal developmental and reproductive toxicity (DART) study, as well as a juvenile repeat-dose toxicology study. All these GLP-compliant toxicology studies were performed in rats, and animals were dosed with CYFENDUS via IM injection, the intended route for human use.”
Study lengthopen answer page →
Longest pivotal study
4 (adult rat repeat-dose study, full human dose on SD 1, 15, 29)
“The treatment-related effects were very similar in the single dose toxicity study as well as in the repeat dose toxicity study in adult (full human dose given on Study Day [SD] 1, 15, 29) and juvenile rats (1/5th of the human dose given on SD 21, 28, 35).”
Pivotal GLP studies
GLP rat studies, all IM: single-dose, repeat-dose, pre/postnatal DART and juvenile repeat-dose
“The applicant conducted a single-dose acute toxicity study, a repeat-dose safety toxicity study, a pre- and post-natal developmental and reproductive toxicity (DART) study, as well as a juvenile repeat-dose toxicology study. All these GLP-compliant toxicology studies were performed in rats, and animals were dosed with CYFENDUS via IM injection, the intended route for human use.”
Route in tox
Intramuscular (clinical route)
“In all studies, animals were dosed via intramuscular (IM) injection, the intended route for human use.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.”
Carcinogenicity
Not conducted
“CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.”
Reproductive & developmental
Rat DART study: no effects on mating, fertility, pregnancy, embryo-fetal viability or postnatal survival and development
“No reproductive or developmental toxicity was noted in the DART study. There was no effect on mating, fertility, pregnancy, embryo-fetal viability, growth, or morphologic development, parturition, maternal care of offspring or postnatal survival, growth, or development.”
Safety pharmacology
Covered by repeat-dose clinical observations: no effects of CpG 7909 or the vaccine
“Treatment with adjuvant CPG 7909 or CPG 7909 combined with AVA (AV7909) had no effect on cage-side, clinical, or dermal Draize observations.”
Genotox: Ames
Not conducted
“CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.”
Genotox: in vitro mammalian
Not conducted
“CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.”
Genotox: in vivo
Not conducted
“CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.”
Carcinogenicity model
Not conducted
“CYFENDUS has not been evaluated for carcinogenicity, mutagenic potential, or male infertility in animals.”
Carcinogenicity timing
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.
hERG / QT
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Cyfendus 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 oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Injection-site necrosis and granulomatous inflammation judged adverse but expected to resolve (FDA summary basis for approval, p. 16)
NOAEL / key findings
Injection-site necrosis and granulomatous inflammation judged adverse but expected to resolve
“The necrosis and granulomatous inflammation at the injection sites were considered adverse reactions and were expected to resolve over time.”
Risksopen answer page →
Immune & cytokine safety
Transient neutrophil, monocyte, basophil and inflammatory-marker increases; spleen weight increase and lymphoid hyperplasia
“Systemically, treated animals showed a transient increase in neutrophil, monocyte and basophil counts, as well as inflammatory markers. Additionally, increases in spleen weights, and hyperplasia in lymphoid tissues of the spleen and draining lymph nodes were observed.”
Biodistribution & persistence
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.
Modality-specific risk
Local and systemic inflammatory responses driven mainly by CpG 7909 immunostimulation
“The observed local and systemic inflammatory responses and findings are primarily due to the immunostimulatory effect of CPG 7909.”
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 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.
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
Injection-site necrosis and granulomatous inflammation judged adverse but expected to resolve
“The necrosis and granulomatous inflammation at the injection sites were considered adverse reactions and were expected to resolve over time.”
Efficacy evidenceopen answer page →
Efficacy evidence
Guinea pig and cynomolgus macaque lethal aerosolized B. anthracis spore challenge after two IM vaccinations
“Efficacy studies for CYFENDUS were conducted in guinea pigs and cynomolgus macaques. Animals received two intramuscular vaccinations two weeks apart with various dilutions of CYFENDUS and were challenged with a lethal dose of aerosolized B. anthracis spores on Day 28 or 70.”
Why that model
CpG 7909 activity significantly weaker in rabbits, so a guinea pig inhalational anthrax model was developed
“The activity of the CpG 7909 adjuvant has been observed to be significantly weaker in rabbits; therefore, to provide a suitable additional animal to demonstrate the effectiveness of CYFENDUS, the applicant developed and used a guinea pig model of inhalational anthrax.”
Reviewer's view of the efficacy data
FDA identified no deficiencies with the nonclinical animal studies
“No deficiencies were identified with the nonclinical animal studies”
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