Roctavian
valoctocogene roxaparvovec
Species
MonkeyMouse
Longest study
26 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
Mouse (CD1, Rag2-/-, hemophilia A models) and cynomolgus/rhesus monkey; all males
“As the clinical schedule foresees one unique injection of BMN 270, all non-clinical studies supporting the safety of BMN 270 are single-dose toxicity studies conducted by the IV route, in male animals, in different animal species (Rag2-/- mice, Rag2-/- x FVIII-/- mice, CD1 mice, monkeys), which is acceptable.”
Why that species
Hemophilia A (Rag2-/- x FVIII-/-) mouse model for pharmacology; no explicit species-relevance argument; males because >99% of patients male
“All animals used in the nonclinical programme to evaluate BMN 270 were males because > 99% of HA patients are male.”
Surrogate molecule
No surrogate; clinical vector tested, though one pivotal GLP mouse study used early process B material
“The first GLP toxicity study (Study BMN 270-14-030) conducted in CD1 normal male mice used a batch of BMN 270 produced according to process B, which far diverges from process D and D’ used in phase III clinical trials and commercial process.”
Species: general tox
Mouse (CD1, Rag2-/-, Rag2-/- x FVIII-/-) and monkey; single-dose IV studies in males
“As the clinical schedule foresees one unique injection of BMN 270, all non-clinical studies supporting the safety of BMN 270 are single-dose toxicity studies conducted by the IV route, in male animals, in different animal species (Rag2-/- mice, Rag2-/- x FVIII-/- mice, CD1 mice, monkeys), which is acceptable.”
Species: DART
Not conducted (>99% of patients male); male mouse germline transmission/mating studies only
“As concerns fertility, dedicated fertility studies/embryofoetal studies have not been performed; the applicant argued that males comprise the majority (>99%) of the patient population to be treated with BMN 270”
Species: carcinogenicity
Not conducted
“As regards carcinogenicity: no carcinogenicity studies were performed with BMN 270.”
Surrogate used in
No surrogate used; BMN 270 tested directly (one pivotal CD1 mouse study used early process B material)
“The first GLP toxicity study (Study BMN 270-14-030) conducted in CD1 normal male mice used a batch of BMN 270 produced according to process B, which far diverges from process D and D’ used in phase III clinical trials and commercial process.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In single-dose toxicology studies conducted in adult male :CD1 mice with study durations up to 6 months, the IV administration of ROCTAVIAN at dose levels of 6.53 × 1013 vg/kg and higher resulted in dose-dependent adverse histopathologic findings in the heart”
Pivotal GLP studies
Two GLP single-dose IV studies in CD1 male mice (up to 26 weeks); 3-month single-dose male monkey study; germline transmission studies
“Then, two GLP single-dose studies were conducted in normal CD1 mice with observation periods of up to 26 weeks, and with doses ranging from 6E12 to 2E14 vg/kg.”
Route in tox
Single intravenous bolus/infusion
“All in vivo studies were single dose and used the intravenous (IV) route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (literature on AAV); NHP liver integration site analysis: 1.55x10^-3 IS/cell, no clonal expansion
“In terms of genotoxicity, no studies were performed with BMN 270.”
Carcinogenicity
Not conducted (product characteristics, tox results, population)
“As regards carcinogenicity: no carcinogenicity studies were performed with BMN 270.”
Reproductive & developmental
Not conducted (DART); male mouse germline transmission/mating studies showed no F1 transmission or fertility effects
“There were no ROCTAVIAN-related adverse changes on mating rates, maternal behavior, and fertility indices.”
Safety pharmacology
Not conducted; no CNS/respiratory/CV/renal findings in toxicity studies
“Safety pharmacology studies were not performed because BMN 270 components (capsid, vector DNA, corresponding RNA and hFVIII-SQ protein) are not expected to impact major organ systems’ (central nervous system, cardiovascular, renal or respiratory) function.”
Genotox: Ames
Not conducted (literature-based argument of low AAV genotoxicity risk)
“In terms of genotoxicity, no studies were performed with BMN 270.”
Genotox: in vitro mammalian
Not conducted
“In terms of genotoxicity, no studies were performed with BMN 270.”
Genotox: in vivo
Not conducted (vector integration site analysis in monkey liver instead)
“In terms of genotoxicity, no studies were performed with BMN 270.”
Carcinogenicity model
No carcinogenicity study; monkey liver vector integration analysis plus mouse/monkey toxicology showed no clonal expansion, preferential integration or tumors
“In summary, the vector integration data in nonhuman primates and toxicology data obtained in mice and nonhuman primates (e.g., BMN270-16-045 and BMN270-16-046) indicate no evidence of BMN 270-related clonal expansion, preferential vector integration site(s), or tumor formation.”
Carcinogenicity timing
Not warranted (product characteristics, toxicology results, target population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, carcinogenicity/tumorigenicity of ROCTAVIAN were not conducted. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
hERG / QT
Not conducted; no CNS, respiratory, cardiovascular or renal findings in toxicity studies
“Safety pharmacology studies were not performed because BMN 270 components (capsid, vector DNA, corresponding RNA and hFVIII-SQ protein) are not expected to impact major organ systems’ (central nervous system, cardiovascular, renal or respiratory) function.”
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 Roctavian 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: No NOAEL stated; CD1 mice >=6.53x10^13 vg/kg: mortality, cardiac hemorrhage/necrosis from anti-hFVIII antibodies; NHP: APTT prolongation (FDA summary basis for approval, p. 12)
NOAEL / key findings
No NOAEL stated; CD1 mice >=6.53x10^13 vg/kg: mortality, cardiac hemorrhage/necrosis from anti-hFVIII antibodies; NHP: APTT prolongation
“ROCTAVIAN-related mortality, adverse clinical observations, and changes in gross pathology were observed at dose levels of 6.53 × 1013 vg/kg and higher, and were associated with fibrosis, hemorrhage, and necrosis in the heart.”
Risksopen answer page →
Immune & cytokine safety
Anti-AAV5 antibodies in all species; anti-hFVIII antibodies cross-reacting with murine FVIII caused bleeding phenotype (species-specific)
“These anti-hFVIII antibodies cross-reacted with the murine endogenous FVIII, leading to a loss of endogenous FVIII activity, a bleeding phenotype, and subsequent visceral lesions (in heart, lungs and epididymis) associated with haemorrhages.”
Biodistribution & persistence
Liver highest, then lung, heart, lymph nodes, kidney, spleen, marrow, testis, brain; mRNA mainly liver; NHP brain <1% of liver
“Following IV administration of 2.13 × 1014 vg/kg ROCTAVIAN, the highest vector DNA concentration was detected in the liver, followed by the lung, heart, lymph nodes, kidney, spleen, bone marrow, testis, and brain through 6 months post-administration.”
Modality-specific risk
Vector integration/insertional mutagenesis (CRL request; BMN307 mouse liver tumors), anti-transgene immunity, germline transmission
“The CRL also included a recommendation for the applicant to provide additional data to address the risks of vector integration and insertional mutagenesis.”
Anti-drug antibodies: animals
Anti-AAV5 antibodies in mice and monkeys at all doses; anti-hFVIII-SQ antibodies caused loss of FVIII activity and bleeding coagulopathy in CD1 mice
“Immunogenicity to the vector capsid was assessed in both species, and this revealed that, independent of the dose, one unique injection of BMN 270 vector elicited anti-AAV5 antibodies. In the same way, animals elicited immune humoral responses against hFVIII-SQ, leading to loss of FVIII activity, and in some cases with coagulopathy associated with bleeding phenotype (normal CD1 mice).”
Anti-drug antibodies: patients
All subjects developed anti-AAV5 TAb and transduction inhibition from Week 8, peaking around Weeks 36-40
“following administration of ROCTAVIAN, all subjects developed anti-AAV5 TAb and reported positive AAV5 TI test results from the first assessment time point at 8-week post dosing and peaked around 36 - 40 weeks post dosing.”
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human dose-escalation study 270-201 in patients with severe hemophilia A
“Study 270-201 was a first-in-human, Phase 1/2 open-label, dose-escalation study of ROCTAVIAN”
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 Roctavian 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: No NOAEL stated; CD1 mice >=6.53x10^13 vg/kg: mortality, cardiac hemorrhage/necrosis from anti-hFVIII antibodies; NHP: APTT prolongation (FDA summary basis for approval, p. 12)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single-dose administration gene therapy)
“No repeat-dose toxicity studies were performed because BMN 270 is a single-dose administration gene”
Pivotal GLP studies
Two GLP single-dose IV studies in CD1 male mice (up to 26 weeks); 3-month single-dose male monkey study; germline transmission studies
“Then, two GLP single-dose studies were conducted in normal CD1 mice with observation periods of up to 26 weeks, and with doses ranging from 6E12 to 2E14 vg/kg.”
DART package
Species: DART
Not conducted (>99% of patients male); male mouse germline transmission/mating studies only
“As concerns fertility, dedicated fertility studies/embryofoetal studies have not been performed; the applicant argued that males comprise the majority (>99%) of the patient population to be treated with BMN 270”
Reproductive & developmental
Not conducted (DART); male mouse germline transmission/mating studies showed no F1 transmission or fertility effects
“There were no ROCTAVIAN-related adverse changes on mating rates, maternal behavior, and fertility indices.”
PPND / ePPND: when
Not conducted; not warranted given product characteristics, toxicology results and target population
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, carcinogenicity/tumorigenicity of ROCTAVIAN were not conducted. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“As regards carcinogenicity: no carcinogenicity studies were performed with BMN 270.”
Carcinogenicity model
No carcinogenicity study; monkey liver vector integration analysis plus mouse/monkey toxicology showed no clonal expansion, preferential integration or tumors
“In summary, the vector integration data in nonhuman primates and toxicology data obtained in mice and nonhuman primates (e.g., BMN270-16-045 and BMN270-16-046) indicate no evidence of BMN 270-related clonal expansion, preferential vector integration site(s), or tumor formation.”
Carcinogenicity timing
Not warranted (product characteristics, toxicology results, target population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, carcinogenicity/tumorigenicity of ROCTAVIAN were not conducted. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
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
No NOAEL stated; CD1 mice >=6.53x10^13 vg/kg: mortality, cardiac hemorrhage/necrosis from anti-hFVIII antibodies; NHP: APTT prolongation
“ROCTAVIAN-related mortality, adverse clinical observations, and changes in gross pathology were observed at dose levels of 6.53 × 1013 vg/kg and higher, and were associated with fibrosis, hemorrhage, and necrosis in the heart.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rag2-/- x FVIII-/- haemophilia A mice: blood loss and bleeding time almost corrected to wild-type levels
“In mice administered 1.0E14 vg/kg BMN 270, blood loss and bleeding time was almost corrected to wild-type levels, comparable to the correction achieved with Xyntha® treatment.”
Why that model
Immunocompetent mice mount antibodies against heterologous human FVIII, abolishing FVIII activity
“The applicant specified that the study was conducted in CD1 mice, a immunocompetent mice, thus able to mount an antibody response against a heterologous human protein. Results indicated that animals with higher anti-hFVIII TAb titers had FVIII activity that was BLQ.”
Reviewer's view of the efficacy data
EMA: adequate set of pharmacology experiments across mouse strains and monkeys; proof of concept in Rag2-/- x FVIII-/- mice
“From a pharmacology point of view, it is acknowledged that an adequate set of experiments have been conducted in different animals species, eg normal C57BL/6J and Crl:CD1(ICR) mice, Rag2-/- mice, Rag2-/- x FVIII-/- mice, and Rhesus and Cynomolgus monkeys. Proof of concept has been determined in the Rag2-/- x FVIII-/- mice in the course of Study BMN 270-14-014.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity or tumorigenicity studies (nor safety pharmacology or DART studies)
Why: Product characteristics, toxicology results and target population; tumorigenicity risk handled by labelling and long-term patient monitoring · Other reason
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, carcinogenicity/tumorigenicity of ROCTAVIAN were not conducted. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
“This has been implemented into physicians and patient’s information (as part of the SmPC/PL as well as the guides for HCP and patients) and covered through long term monitoring of patients.”
DARTAccepted with a conditionBeyond the letter
No fertility or embryo-fetal studies; justified by a mostly male patient population
Why: Males comprise more than 99% of the patient population; product not to be used in women of childbearing potential · Other reason
“As concerns fertility, dedicated fertility studies/embryofoetal studies have not been performed; the applicant argued that males comprise the majority (>99%) of the patient population to be treated with BMN 270”
“According to the applicant, Roctavian should not be used in women of childbearing potential, because the conditions for use in these patients have not yet been established.”
BiodistributionVerdict not stated
Sperm and semen not tested in the biodistribution studies
“To note, sperm and semen have not been tested in both biodistribution studies BMN 270-14-030 and BMN 270-16-045.”
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