Beqvez
fidanacogene elaparvovec
Species
MonkeyMouseDogRabbit
Longest study
104 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey and mouse (tox); hemophilia B dog and mouse (pharmacology); rabbit (shedding)
“A toxicology study was also conducted evaluating IV administration of AAVRh74var Padua in nonhuman primates (NHP) at dose levels ranging from 1 x 1012 vg/kg to 5 x 1012 vg/kg.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For biologics, ICH S6(R1) asks for species in which the product is pharmacologically active (target binding and activity), usually a cynomolgus monkey.
“A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies).”
✓ VerifiedICH 2011: ICH S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived…, p. 7Source ↗
Surrogate molecule
Yes: canine FIX surrogate vector for dog pharmacology; tox used closely related predecessor vector
“In vivo pharmacology was evaluated using a surrogate BEQVEZ product, AAVRh74var-cFIX-R338L, which expresses a transgene encoding canine factor IX, in a juvenile hemophilia B dog model.”
Species: general tox
Nonhuman primate and mouse
“The biodistribution (BD) profile following administration of BEQVEZ in mice and NHPs was evaluated in toxicology Study Nos. 12 and 14 and within a select panel of tissues in Study No. 16.”
Species: DART
Not conducted (hemophilia B almost exclusively male; not intended for women)
“Per applicant, hemophilia B is almost exclusively limited to male subjects, and BEQVEZ is not intended for administration in women.”
Species: carcinogenicity
Not conducted (not warranted given product characteristics, BD/toxicology results, patient population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted. These studies are not warranted based on the product characteristics, results from the biodistribution and toxicology studies, and patient population.”
Surrogate used in
Yes: canine FIX surrogate vector (AAVRh74var-cFIX-R338L) for in vivo pharmacology in hemophilia B dogs
“In vivo pharmacology was evaluated using a surrogate BEQVEZ product, AAVRh74var-cFIX-R338L, which expresses a transgene encoding canine factor IX, in a juvenile hemophilia B dog model.”
Study lengthopen answer page →
Longest pivotal study
104 weeks
“Single-Dose Intravenous Study of PF 06838435 in Monkeys with a 13- or 104-Week Observation Phase”
Pivotal GLP studies
GLP single IV NHP study (30/90-day recovery, to day 542); 12-month mouse study; GLP 2-year NHP integration study
“A GLP Toxicity Study of -hFIX-Padua by Intravenous Infusion in Monkeys with a 30- or 90- day Recovery Period”
Route in tox
Single intravenous infusion / slow bolus
“Route of Administration IV infusion (30 minute) via saphenous vein”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (classical); vector integration site analysis in dog and NHP liver instead
“Based on the IS profile, genotoxicity from vector integration appears to be a low risk.”
Carcinogenicity
Not conducted (not warranted given product characteristics, BD/tox data, population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted.”
Reproductive & developmental
Not conducted (male-only population); rabbit semen shedding/germline study only
“This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”
Safety pharmacology
Not conducted
“No safety pharmacology studies with BEQVEZ were conducted.”
Genotox: Ames
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.
Genotox: in vitro mammalian
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.
Genotox: in vivo
Vector integration site analysis in NHP liver: no clonal expansion; genotoxicity from integration judged low risk
“The number of detected IS in the liver was broadly similar or declined between interim and terminal time points, suggesting an absence of clonal expansion. Although IS were detected in the vicinity of cancer genes, these genes were not identified as vector CIS.”
Carcinogenicity model
Not conducted; 2-year NHP vector integration study showed no hepatocellular hyperplasia or carcinoma
“In a 2-year vector integration study in NHPs administered 5 × 1012 vg/kg, there was no indication that integration of vector DNA into host cell DNA resulted in altered liver function, hepatocellular hyperplasia or carcinoma.”
Carcinogenicity timing
Not conducted: not warranted (product characteristics, biodistribution and toxicology results)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted. These studies are not warranted based on the product characteristics, results from the biodistribution and toxicology studies”
hERG / QT
No safety pharmacology studies conducted
“No safety pharmacology studies with BEQVEZ were conducted.”
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 Beqvez 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 gene therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: NHP 1-5x10^12 vg/kg (2-10x clinical): no adverse findings, no thrombosis; mouse deaths linked to brain/skin findings (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
NHP 1-5x10^12 vg/kg (2-10x clinical): no adverse findings, no thrombosis; mouse deaths linked to brain/skin findings
“No test article-related adverse findings were observed in this study, including any findings of thrombosis by microscopic histopathology.”
Risksopen answer page →
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.”
Biodistribution & persistence
Vector in all NHP tissues incl. brain/testes; highest liver, spleen, lymph nodes; liver to day 542; rabbit semen to 4 months
“The highest vector DNA concentrations were detected in the liver, spleen, and inguinal lymph nodes.”
Modality-specific risk
AAV vector integration/hepatic oncogenicity; <0.1% integrated, no clonal expansion; thrombosis; germline transmission
“In a 2-year vector integration study in NHPs administered 5 × 1012 vg/kg, there was no indication that integration of vector DNA into host cell DNA resulted in altered liver function, hepatocellular hyperplasia or carcinoma.”
Anti-drug antibodies: animals
NHP: anti-hFIX and anti-AAV capsid antibodies in most animals, rising over time and correlating with declining hFIX levels
“Antibodies that targeted the hFIX protein and the AAV capsid were detected in most dosed animals. The levels of both anti-hFIX and anti-AAV antibodies increased with time, which correlated with a decline in plasma hFIX protein levels.”
Anti-drug antibodies: patients
Sustained neutralizing anti-AAVRh74var antibody increase in all assessed subjects; no FIX inhibitors
“No patients developed FIX inhibitors during the clinical studies using BEQVEZ. A sustained increase in neutralizing anti-AAVRh74var antibodies has been observed after administration of BEQVEZ in all subjects who participated in clinical studies and had neutralizing antibody (nAb) assessment.”
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 Beqvez 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 gene therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: NHP 1-5x10^12 vg/kg (2-10x clinical): no adverse findings, no thrombosis; mouse deaths linked to brain/skin findings (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single administration)
“Repeat-dose toxicity studies were not performed because fidanacogene elaparvovec is intended for single administration to patients.”
Pivotal GLP studies
GLP single IV NHP study (30/90-day recovery, to day 542); 12-month mouse study; GLP 2-year NHP integration study
“A GLP Toxicity Study of -hFIX-Padua by Intravenous Infusion in Monkeys with a 30- or 90- day Recovery Period”
DART package
Species: DART
Not conducted (hemophilia B almost exclusively male; not intended for women)
“Per applicant, hemophilia B is almost exclusively limited to male subjects, and BEQVEZ is not intended for administration in women.”
Reproductive & developmental
Not conducted (male-only population); rabbit semen shedding/germline study only
“This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”
PPND / ePPND: when
Not conducted: hemophilia B population almost exclusively male; not intended for women
“Per applicant, hemophilia B is almost exclusively limited to male subjects, and BEQVEZ is not intended for administration in women. This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted given product characteristics, BD/toxicology results, patient population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted. These studies are not warranted based on the product characteristics, results from the biodistribution and toxicology studies, and patient population.”
Carcinogenicity model
Not conducted; 2-year NHP vector integration study showed no hepatocellular hyperplasia or carcinoma
“In a 2-year vector integration study in NHPs administered 5 × 1012 vg/kg, there was no indication that integration of vector DNA into host cell DNA resulted in altered liver function, hepatocellular hyperplasia or carcinoma.”
Carcinogenicity timing
Not conducted: not warranted (product characteristics, biodistribution and toxicology results)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted. These studies are not warranted based on the product characteristics, results from the biodistribution and toxicology studies”
Safety marginopen answer page →
Safety margin at NOAEL
NHP: no adverse findings at doses 2- to 10-fold the recommended clinical dose
“No test article-related adverse findings were observed in this study, including any findings of thrombosis by microscopic histopathology. The dose levels in this study were between 2 to 10-fold higher than the recommended clinical dose level for BEQVEZ.”
NOAEL / key findings
NHP 1-5x10^12 vg/kg (2-10x clinical): no adverse findings, no thrombosis; mouse deaths linked to brain/skin findings
“No test article-related adverse findings were observed in this study, including any findings of thrombosis by microscopic histopathology.”
Efficacy evidenceopen answer page →
Efficacy evidence
Hemophilia B mice given BEQVEZ: liver hFIX-R338L expression and hemostatic FIX activity
“Mice with a hemophilia B phenotype that were administered BEQVEZ at the recommended clinical dose level expressed the hFIX-R338L transgene in the liver and exhibited hemostatic FIX activity, supporting the expected activity and mechanism of action of the product.”
Why that model
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.
Reviewer's view of the efficacy data
FDA judged canine-FIX surrogate data in dogs expected to be representative of BEQVEZ
“Animals in this study were administered an AAVRh74var vector encoding the canine factor IX gene. However, safety and activity data resulting from administration of this surrogate would be expected to be representative of BEQVEZ.”
Flexibilityopen answer page →
Flexibility accepted
OtherVerdict not stated
Definitive 3-month monkey GLP toxicity study used a closely related predecessor vector, not the clinical product
“The definitive 3-month GLP toxicity study in cynomolgus monkeys used AAVRh74var-hFIX19-R338L, while a 2-year genetic toxicity vector integration study in monkeys used fidanacogene elaparvovec.”
Efficacy modelAcceptedBeyond the letter
In vivo efficacy in hemophilia B dogs used a canine-FIX surrogate vector, not the clinical product
Why: Surrogate data expected to be representative of the clinical product · Pharmacology or kinetics
“This study did not evaluate the intended clinical product. Animals in this study were administered an AAVRh74var vector encoding the canine factor IX gene. However, safety and activity data resulting from administration of this surrogate would be expected to be representative of BEQVEZ.”
DARTAcceptedBeyond the letter
No embryo-fetal or pre-/postnatal development studies
Why: Hemophilia B almost exclusively affects males; product not intended for women · Other reason
“Per applicant, hemophilia B is almost exclusively limited to male subjects, and BEQVEZ is not intended for administration in women. This reviewer agrees that the omission of dedicated embryo-fetal development studies and pre- and postnatal development studies is acceptable.”
CarcinogenicityAcceptedBeyond the letter
No dedicated carcinogenicity studies; integration-site analyses relied on instead
Why: Integration analyses raise no specific carcinogenicity concern · Weight of evidence
“Dedicated studies on carcinogenicity were not conducted with fidanacogene elaparvovec. Results obtained from integration analyses might not raise any specific carcinogenicity concern so far.”
BiodistributionVerdict not stated
Semen shedding in rabbits only; no assessment of fertility impact or transmission to offspring
“Vector DNA was detectable in semen until 4 months after dosing. No analysis of potential impact on fertility or transmission to offspring was performed.”
Similar precedents
HemgenixGene therapy · etranacogene dezaparvovec · Factor IXMonkey + rodent · 26 wkRoctavianGene therapy · valoctocogene roxaparvovec · Factor VIIIMonkey + rodent · 26 wkAdstiladrinGene therapy · nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Monkey + rodent · 22 wkHympavziAntibodies · marstacimab · TFPIMonkey + rodent · 26 wkQfitliaOligos · fitusiran · Antithrombin / SERPINC1 (siRNA)Monkey + rodent · 39 wkSylvantAntibodies · siltuximab · IL-6Monkey + rodent · 26 wk