Regulatory milestone moves CSL one step closer to bringing the promise of gene therapy for hemophilia B to patients in Europe
16 Dec 2022
Global biotechnology leader CSL (ASX: CSL) today announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending conditional marketing authorization (CMA) of etranacogene dezaparvovec. Etranacogene dezaparvovec is a one-time gene therapy for the treatment of appropriate adults with hemophilia B that reduces the rate of annual bleeds with a single infusion.1,2 If the marketing authorization for which CSL applied under the brand name HEMGENIX® is approved by the European Commission, etranacogene dezaparvovec would be the first gene therapy for people living with hemophilia B in the European Union (EU) and European Economic Area (EEA).
“The CHMP’s positive opinion moves us one step closer to bringing this ground-breaking innovation to hemophilia B patients in Europe,” said Emmanuelle Lecomte Brisset, Senior Vice President and Head of Global Regulatory Affairs at CSL. “Getting a new medicine to this stage of the regulatory process takes the support of many, including clinical trial participants, the hemophilia community in general, investigators, clinicians, regulatory agencies, our people, and our partners at uniQure to name a few. Thank you to all for the role you have played in helping us reach this regulatory milestone in Europe.”
The positive CHMP opinion is based on findings from the pivotal HOPE-B trial, the largest gene therapy trial in hemophilia B to date.3,4 These findings showed that hemophilia B patients treated with etranacogene dezaparvovec demonstrated stable and durable increases in mean Factor IX (FIX) activity levels (with a mean FIX activity of 36.9%) which led to an adjusted annualized bleed rate (ABR) reduction of 64%.1,2 Following infusion of etranacogene dezaparvovec, 96% of patients discontinued routine FIX prophylaxis.1,2
The HOPE-B study 24 months analysis showed a sustained and durable effect of etranacogene dezaparvovec.5,6 In a clinical setting, etranacogene dezaparvovec continued to be generally well-tolerated with no serious treatment-related adverse events.5,6
The positive opinion from the CHMP will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union member states.
The multi-year clinical development of etranacogene dezaparvovec was led by uniQure (Nasdaq: QURE) and sponsorship of the clinical trials transitioned to CSL after it licensed global rights to commercialize the treatment. Etranacogene dezaparvovec was recently approved by the U.S. Food and Drug Administration.
About Hemophilia B
Hemophilia B is a life-threatening rare disease. People with the condition are particularly vulnerable to bleeds in their joints, muscles, and internal organs, leading to pain, swelling, and joint damage. Current treatments for moderate to severe hemophilia B include life-long prophylactic infusions of factor IX to temporarily replace or supplement low levels of the blood-clotting factor.
About Etranacogene Dezaparvovec
Etranacogene dezaparvovec is an adeno-associated virus five (AAV5)-based gene therapy given as a one-time treatment for moderately severe to severe hemophilia B patients. Etranacogene dezaparvovec (also known as CSL222, previously known as AMT-061) uses a specific type of AAV, called AAV5, as its vector. The AAV5 vector carries the Padua gene variant of Factor IX (FIX-Padua), which generates FIX proteins that are 5x-8x more active than normal.
About the Pivotal HOPE-B Trial
The pivotal Phase III HOPE-B trial is an ongoing, multinational, open-label, single-arm study to evaluate the safety and efficacy of etranacogene dezaparvovec. Fifty-four adult hemophilia B patients classified as having a diagnosis of moderately severe or severe hemophilia B and requiring prophylactic FIX replacement therapy were enrolled in a prospective, six-month observational period during which time they continued to use their current standard of care therapy to establish a baseline Annual Bleeding Rate (ABR). After the six-month lead-in period, patients received a single intravenous administration of etranacogene dezaparvovec at the 2x10^13 gc/kg dose. Patients were not excluded from the trial based on pre-existing neutralizing antibodies (NAbs) to AAV5. A total of 54 patients received a single dose of etranacogene dezaparvovec in the pivotal trial, with 53 patients completing at least 18 months of follow-up. The primary endpoint in the pivotal HOPE-B study was 52-week ABR after achievement of stable FIX expression compared with the six-month lead-in period. For this endpoint, ABR was measured from month seven to month 18 after infusion, ensuring the observation period represented a steady-state FIX transgene expression.
Results from the pivotal HOPE-B study demonstrated that etranacogene dezaparvovec produced mean FIX activity of 36.9 IU/dL at 18 months post infusion. At 24 months follow-up, FIX activity remained stable at 36.7 IU/DL. After the six-month lead-in period post-infusion, the adjusted annualized bleeding rate (ABR) (1.51) for all bleeds was reduced by 64 percent (p=0.0002) and all FIX-treated bleeds was reduced by 77 percent (3.65 to 0.83; p<0.0001) over months seven to 18. 96 percent of subjects treated with a full dose of etranacogene dezaparvovec discontinued use of routine prophylaxis, with an overall 97 percent reduction in mean unadjusted annualized FIX consumption of 257338.8 IU/yr/participant to 8486.6 IU/yr/participant (from lead-in period to months 13-18).
Further analyses showed that there was no clinically meaningful correlation between patient AAV5 NAb levels at baseline and FIX activity.
No serious adverse reactions were reported. One death resulting from urosepsis and cardiogenic shock in a 77-year-old patient at 65 weeks following dosing was considered unrelated to treatment by investigators and the company sponsor. A serious adverse event of hepatocellular carcinoma was determined to be unrelated to treatment with etranacogene dezaparvovec by independent molecular tumor characterization and vector integration analysis. No inhibitors to FIX were reported.
CSL (ASX:CSL; USOTC:CSLLY) is a leading global biotechnology company with a dynamic portfolio of lifesaving medicines, including those that treat hemophilia and immune deficiencies, vaccines to prevent influenza, and therapies in iron deficiency, dialysis and nephrology. Since our start in 1916, we have been driven by our promise to save lives using the latest technologies. Today, CSL – including our three businesses, CSL Behring, CSL Seqirus and CSL Vifor – provides lifesaving products to patients in more than 100 countries and employs 30,000 people. Our unique combination of commercial strength, R&D focus and operational excellence enables us to identify, develop and deliver innovations so our patients can live life to the fullest. For inspiring stories about the promise of biotechnology, visit CSLBehring.com/Vita and follow us on Twitter.com/CSL.
For more information about CSL, visit CSL.com.
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1. Miesbach W et al. Oral presentation at 15th EAHAD meeting, February 2022
2. Summary of Product Characteristics: etranacogene dezaparvovec. Data on file.
3. ASH Clinical News. New HOPE for Hemophilia B: One-Time Gene Therapy Abolishes Bleeding in Most Patients. Available at: https://ashpublications.org/ashclinicalnews/news/5441/New-HOPE-for-Hemophilia-B-One-Time-Gene-Therapy. [Accessed December 2022]
4. ClinicalTrials.gov. HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT03569891. [Accessed December 2022]
5. Miesbach W et al. Poster presentation at ASH meeting, December 2022
6. Pipe S et al. Poster presentation at ASH meeting, December 2022