Roctavian (valoctocogene roxaparvovec): what was done before first-in-human, and what came after?

Precedia/Gene therapy/Roctavian/Tox package

Roctavian: what was done before first-in-human, and what came after?

valoctocogene roxaparvovec · Factor VIII

Check my plan vs. these

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”

✓ VerifiedFDA summary basis for approval, p. 17Source ↗

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)

Full method, every step sourced →

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”

✓ VerifiedEMA assessment report, p. 34Source ↗

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.”

✓ VerifiedEMA assessment report, p. 31Source ↗

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”

✓ VerifiedEMA assessment report, p. 36Source ↗

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.”

✓ VerifiedFDA summary basis for approval, p. 12Source ↗

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.”

✓ VerifiedFDA summary basis for approval, p. 13Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“As regards carcinogenicity: no carcinogenicity studies were performed with BMN 270.”

✓ VerifiedEMA assessment report, p. 35Source ↗

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.”

✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

Carcinogenicity timing

Not warranted (product characteristics, toxicology results, target population)

✓ VerifiedFDA summary basis for approval, p. 13Source ↗

Summary across all 26 gene therapies →

Roctavian: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

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