Hemgenix

“The toxicology data package of etranacogene dezaparvovec and AMT-060 included single IV dose toxicity studies up to duration of 6 months with 6 months observation period in C57Bl/6 mice and cynomolgus macaques, and a reproduction and developmental toxicity study in mice.”

“From the pharmacokinetic point of view, non-human primates were the most relevant species”

“AMT-060 instead of etranacogene dezaparvovec was used in several toxicological studies provided.”

“The toxicology data package of etranacogene dezaparvovec and AMT-060 included single IV dose toxicity studies up to duration of 6 months with 6 months observation period in C57Bl/6 mice and cynomolgus macaques, and a reproduction and developmental toxicity study in mice.”

“The risk of germline transmission of the HEMGENIX predecessor was evaluated in healthy male mice administered 2.3x1014 gc/kg and mated with healthy naïve female mice on Day 6 post-dose.”

“Dedicated studies on carcinogenicity were not conducted with AMT-061 (nor AMT-060).”

“AMT-060 instead of etranacogene dezaparvovec was used in several toxicological studies provided. This is regarded acceptable as AMT-060 differs only in two base pairs/one amino-acid to the final GTMP AMT-061”

“At 26 weeks following IV administration of 5x1012 to 9x1013 gc/kg HEMGENIX in NHPs, high levels of vector DNA were detected in a dose-dependent manner in the liver.”

“The single IV dose toxicology studies and the analysis of the safety parameters were performed under GLP compliance.”

“IV-route of administration, the clinical route, is used in all toxicological studies.”

“For both species, the majority of the identified vector DNA sequences represented episomal forms that were not integrated into the host DNA.”

“Studies to evaluate the carcinogenicity/tumorigenicity of HEMGENIX were not conducted. These studies are not warranted based on the nonclinical safety profile.”

“Integration site analysis was performed on host genomic DNA isolated from liver tissue collected at 180 days (healthy mice) and 26 weeks (NHPs) following IV administration of the HEMGENIX predecessor.”

“The applicant confirmed that dorsal root ganglia toxicity was not included in histopathological analyses.”

“However, there were no adverse effects on mating rates or fertility indices.”

“With regard to ECG readings no effects related to the test article were observed with AMT-060.”

“No traditional nonclinical carcinogenicity or mutagenicity studies were conducted with HEMGENIX; such studies were not indicated.”

“No traditional nonclinical carcinogenicity or mutagenicity studies were conducted with HEMGENIX; such studies were not indicated.”

“No traditional nonclinical carcinogenicity or mutagenicity studies were conducted with HEMGENIX; such studies were not indicated.”

“A low level of integrated vector DNA was distributed throughout the host genome with no predilection to specific integration sites, including in genes associated with malignant transformation in humans.”

“Studies to evaluate the carcinogenicity/tumorigenicity of HEMGENIX were not conducted. These studies are not warranted based on the nonclinical safety profile.”

“With regard to ECG readings no effects related to the test article were observed with AMT-060.”

“The supporting clinical data from the predecessor product that used a similar vector (AAV5) as HEMGENIX was used to inform dosing for later clinical studies, and assessments of vector viral kinetics.”

“The identified no-observed-adverse-effect-level was 9x1013 gc/kg.”

“Antigenicity endpoints were included in single dose toxicity studies, capsid antigens generally caused high titres of anti AAV5 antibodies. In addition, anti-human FIX antibodies were observed inconsistently in NHP.”

“Vector DNA was also identified in the adrenal glands and spinal cord, followed by limited vector presence in various tissue types.”

“Dose is considered a pivotal factor with regards to the frequency of integration and with that a main contributor to the risk of insertional oncogenesis.”

“Anti-hFIX antibodies developed in 5 out of 12 NHPs administered HEMGENIX, which correlated with a decline in circulating hFIX protein levels beginning at 13 weeks post-dose.”

“In the clinical efficacy study (N=54), sustained humoral immune response to infused AAV5 capsid was observed in all patients following treatment with HEMGENIX.”

“The supporting clinical data from the predecessor product that used a similar vector (AAV5) as HEMGENIX was used to inform dosing for later clinical studies, and assessments of vector viral kinetics.”

“No repeated dose toxicity studies were conducted. This is acceptable, as only a single etranacogene dezaparvovec administration is intended in patients”

“The single IV dose toxicology studies and the analysis of the safety parameters were performed under GLP compliance.”

“The risk of germline transmission of the HEMGENIX predecessor was evaluated in healthy male mice administered 2.3x1014 gc/kg and mated with healthy naïve female mice on Day 6 post-dose.”

“However, there were no adverse effects on mating rates or fertility indices.”

“As haemophilia B is almost exclusively limited to male patients, and as the current MAA only comprises adult patients, dedicated EFD and PPND studies are not required.”

“Dedicated studies on carcinogenicity were not conducted with AMT-061 (nor AMT-060).”

“A low level of integrated vector DNA was distributed throughout the host genome with no predilection to specific integration sites, including in genes associated with malignant transformation in humans.”

“Studies to evaluate the carcinogenicity/tumorigenicity of HEMGENIX were not conducted. These studies are not warranted based on the nonclinical safety profile.”

“Findings in animals dosed at 9x1013 gc/kg included prolonged prothrombin time, decreased activated partial thromboplastin time, and decreased heart rates; however, these changes were not statistically significant, and no adverse effects were observed. This dose level is 4.5-fold higher than the recommended dose level for HEMGENIX.”

“The identified no-observed-adverse-effect-level was 9x1013 gc/kg.”

“At 4 weeks following intravenous (IV) administration of 5x1011 to 2.3x1014 gc/kg of AMT-060 in the B6.129P2-F9tm1Dws mouse model of Hemophilia B, dose-dependent increases in vector transduction in the liver, plasma hFIX protein levels, and plasma hFIX activity were observed.”

“From the pharmacokinetic point of view, non-human primates were the most relevant species for nonclinical efficacy and safety studies, as natural hosts for AAVs.”

“Overall, the primary pharmacodynamic studies provided adequate evidence that murine and monkey hepatocytes are efficiently transduced by etranacogene dezaparvovec and produce hFIX dosedependently, enabling sustained and durable hFIX activity levels.”

“The non-clinical development programme was initiated with AMT-060, which has a similar vector backbone as etranacogene dezaparvovec (AMT-061), but lacks the 2-nucleotide change in the hFIX coding sequence (enhancing the FIX activity of Padua FIX variant).”

“HEMGENIX is an adeno-associated virus serotype 5 (AAV5) based gene therapy designed to deliver a copy of a gene encoding the Padua variant of human coagulation Factor IX (hFIX-Padua). Single intravenous infusion of HEMGENIX results in cell transduction and increase in circulating Factor IX activity in patients with Hemophilia B.”

“Initial U.S. Approval: 2022”