HIGH IMPACT – CSL/uniQure’s Hemgenix (etranacogene dezaparvovec, Etranadez) was approved by the FDA for hemophilia B.

Key Takeaways

  • Hemgenix was approved for adults with hemophilia B who currently use FIX prophylaxis, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes
  • Hemgenix is the first hemophilia B gene therapy approved and the first hemophilia gene therapy approved in the U.S. (Roctavian was approved in August for hemophilia A in Europe)
  • CSL emphasized that Hemgenix is the first therapy for hemophilia B that offers patients and caregivers the possibility of freedom from regular, ongoing infusions
  • The initial reports suggest an initial list price of $3.5 million


  • Steven Pipe quote from CSL press release emphasized the freedom from regular infusions: “HEMGENIX is unique in its approach to increasing mean factor IX activity and hemostatic protection in those with hemophilia B, and today’s approval could fundamentally transform the treatment paradigm for this life-long condition,” said Dr. Steven Pipe … a lead investigator in the HOPE-B study. “As a clinician, I look forward to being able to provide a new treatment option that may help patients treated with HEMGENIX become free from the regular infusion schedule that many people living with hemophilia B rely on to protect them from the debilitating effects of the condition.”

Details of USPI

Indication:  Adults with hemophilia B who: currently use FIX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes


  • 2e13 genome copies (gc) per kg. Administered as an IV infusion at a rate of 500 ml/hr (8 mL/min). Provided in kits containing 10 to 48 single use vials. For an average 72kg patients, 144 mL and 15vials will be required
  • The USPI specifically states that Hemgenix can only be administered once

Patient Selection:

  • Perform FIX inhibitor testing – if test and retest are positive, do not administer Hemgenix
  • Perform liver health assessments including: ALT, AST, ALP, total bilirubin and hepatic ultrasound and elastography. In the case of liver abnormalities, consider consultation with a hepatologist to assess eligibility for Hemgenix.
  • The USPI states that the safety and efficacy of Hemgenix has not been studies in patients with advanced hepatic impairment and Hemgenix was not studied in patients with severe renal impairment
  • A test for AAV5 neutralizing antibodies is not required.  The USPI discusses the results in patients who were positive for preexisting AAV5 NAb using an unvalidated assay in the Hemgenix trials.  Patients intending to receive Hemgenix are encouraged to enroll in a CSL study to measure pre-existing NAb to AAV5 to determine any affect on the risk of bleeding
  • The prescribing information states that 6 geriatric subjects (age 68-75) were in the trials with no meaningful differences in safety and efficacy profiles

Monitoring and warnings

  • Monitor for infusion reactions during and for at least 3 hours after end of infusion.  If symptoms occur, slow or interrupt administration. Re-start at a slower rate once resolved
  • Closely monitor ALT and AST levels once per week for 3 months. Continue to monitor in all patients who developed elevated liver enzymes until they return to baseline.
  • Consider corticosteroids if liver enzyme elevation (above normal limits or 2x patient’s base level) occurs. Starting dose of 60mg with tape (week 2 – 50mg; week 3 – 30mg; week 4 – 30mg; maintenance until ALT returns to baseline – 20mg and then reduce by 5mg/week). Mean duration of steroid use in trials was 81.4 days (51-130 days)
  • Hepatocellular carcinogenicity: For patients with preexisiting risk factors (e.g. cirrhosis, advanced hepatic fibrosis, hepatitis B or C, NAFLD, chronic alcohol consumption, NASH, and advanced age) perform regular (annual) liver ultrasound and alpha-fetoprotein testing. The prescribing information states that integration of AAV vector DNA into the genome may carry the theoretical risk of hepatocellular carcinoma development. It also states that no Hemgenix associated clonal expansion or carcinogenicity has been observed in clinical studies
  • Monitor FIX activity – suggestion of weekly for 3 months.
  • Monitor for FIX inhibitors if bleeding is not controlled or FIX levels decrease


  • Shipped and stored at 2 to 8 degrees C

Adverse Reactions: elevated ALT, headache, blood creatine kinase elevations, flu-like symptoms, infusion-related reactions, fatigue, malaise and elevated AST

Clinical data

  • The USPI contains a chart with stable FIX levels out to month 24 with the median FIX activity at month 24 of 33.9 (4.7, 99.2) using a one-stage assay
  • Mean ABR from months 7 to 18 was 1.9 compared to 4.1 during the lead in period. Subjects with zero bleeds was 63% versus 26% in the lead-in study
  • 2 patients did not stop prophylaxis.  One additional patient received prophylaxis for 20 weeks between days 396 and 534.

inThought Analysis

The first gene therapy approved for hemophilia was BioMarin’s Roctavian in the EU. The FDA is also set to decide on Roctavian in 2023 and has reported plans to consult an advisory committee on the company’s approval application. While there are differences in the drugs, Hemgenix label appears to be less restrictive and more favorable in terms of appropriate patients and post-dose monitoring requirements compared to Roctavian’s SmPC.  FIX and liver enzyme monitoring are only being required for 3 months versus up to 2 years for Roctavian.  Unlike the Roctavian SmPC, the Hemgenix USPI does not mention restrictions such as active infections, refraining from drinking alcohol, and does not require testing for AAV5 NAbs. Also, this approval did not require an FDA adcomm.

Overall, regulatory agencies are showing they will not make class-wide restrictions on gene therapies, and are practicing flexibility in approving and labeling of two AAV gene therapies for the same disease.


Source: FDA Press Release, BiopharmaDive