Roctavian

“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.”

“All animals used in the nonclinical programme to evaluate BMN 270 were males because > 99% of HA patients are male.”

“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.”

“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”

“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.”

“All in vivo studies were single dose and used the intravenous (IV) route of administration.”

“In terms of genotoxicity, no studies were performed with BMN 270.”

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

“There were no ROCTAVIAN-related adverse changes on mating rates, maternal behavior, and fertility indices.”

“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.”

“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.”

“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.”

“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.”

“The CRL also included a recommendation for the applicant to provide additional data to address the risks of vector integration and insertional mutagenesis.”