The FDA's approval of etranacogene dezaparvovec (Hemgenix) marks a significant milestone in gene therapy for hemophilia B. It is the first FDA-approved gene therapy for hemophilia and the first liver-targeted adeno-associated virus (AAV) vector gene therapy. The approval was based on nonclinical and clinical studies showing safety and efficacy. The therapy demonstrated a 96% success rate in stopping factor IX (FIX) prophylaxis, with noninferiority to FIX in terms of annualized bleeding rate. Key secondary endpoints, such as reduced infusion rates and increased plasma FIX activity, were also significant. The approval was not accelerated, and post-marketing requirements address preexisting antibodies to the AAV capsid. The therapy was developed by uniQure and marketed by CSL Behring. Nonclinical studies showed that the AAV5 capsid was less immunogenic, and the self-complementary AAV vector improved transduction efficiency. Clinical trials demonstrated durable FIX expression, with some participants maintaining therapeutic levels for over 10 years. Safety data showed mostly transient adverse reactions, with no evidence of vector-related insertional mutagenesis in a case of hepatocellular carcinoma. The therapy's long-term safety and efficacy are supported by data from phase 2b and 3 studies. The FDA's approval highlights the potential of gene therapy for hemophilia, with ongoing research into long-term safety and the impact of preexisting antibodies. The therapy's durability and variability in expression are important factors, with the AAV5 capsid showing less sensitivity to neutralizing antibodies. The risk of vector clearance from semen is managed through barrier birth control, and the risk of insertional mutagenesis is considered low based on current data. The approval of Hemgenix represents a major advancement in gene therapy for hemophilia, with ongoing studies to further understand its long-term safety and efficacy.The FDA's approval of etranacogene dezaparvovec (Hemgenix) marks a significant milestone in gene therapy for hemophilia B. It is the first FDA-approved gene therapy for hemophilia and the first liver-targeted adeno-associated virus (AAV) vector gene therapy. The approval was based on nonclinical and clinical studies showing safety and efficacy. The therapy demonstrated a 96% success rate in stopping factor IX (FIX) prophylaxis, with noninferiority to FIX in terms of annualized bleeding rate. Key secondary endpoints, such as reduced infusion rates and increased plasma FIX activity, were also significant. The approval was not accelerated, and post-marketing requirements address preexisting antibodies to the AAV capsid. The therapy was developed by uniQure and marketed by CSL Behring. Nonclinical studies showed that the AAV5 capsid was less immunogenic, and the self-complementary AAV vector improved transduction efficiency. Clinical trials demonstrated durable FIX expression, with some participants maintaining therapeutic levels for over 10 years. Safety data showed mostly transient adverse reactions, with no evidence of vector-related insertional mutagenesis in a case of hepatocellular carcinoma. The therapy's long-term safety and efficacy are supported by data from phase 2b and 3 studies. The FDA's approval highlights the potential of gene therapy for hemophilia, with ongoing research into long-term safety and the impact of preexisting antibodies. The therapy's durability and variability in expression are important factors, with the AAV5 capsid showing less sensitivity to neutralizing antibodies. The risk of vector clearance from semen is managed through barrier birth control, and the risk of insertional mutagenesis is considered low based on current data. The approval of Hemgenix represents a major advancement in gene therapy for hemophilia, with ongoing studies to further understand its long-term safety and efficacy.