Roctavian: which risks did reviewers probe?

“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.”

“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).”

“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.”