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Final Analysis of Pivotal HOPE-B Study Demonstrates Durable and Sustained Therapeutic Effect of Etranacogene Dezaparvovec Gene Therapy in Hemophilia B – Data Presented at EAHAD 2022

KING OF PRUSSIA, PA

- Data from the largest gene therapy study in Hemophilia B to date shows that etranacogene dezaparvovec is statistically superior in reducing annualized bleeding rate compared to baseline FIX prophylactic therapy
- Following a single administration of etranacogene dezaparvovec, participants maintained stable Factor IX (FIX) activity through 18 months
- Therapeutic benefit observed in patients with pre-existing anti-capsid neutralizing antibody levels up to a titer of 1:678

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KING OF PRUSSIA, PA – 4 February 2022 – Global biotherapeutics leader CSL Behring today announced positive long-term results from the Phase 3 HOPE-B clinical trial evaluating etranacogene dezaparvovec (EtranaDez), an investigational adeno-associated virus five (AAV5)-based gene therapy for people living with hemophilia B, a life-threatening bleeding disorder. Following a single infusion of etranacogene dezaparvovec, participants experienced a stable and durable increase in mean Factor IX (FIX) activity and hemostatic protection at 18 months. The final data, from the largest gene therapy study in hemophilia B, were presented as part of the latest clinical trial results session at the European Association of Haemophilia and Allied Disorders (EAHAD) 2022 Annual Meeting.

“The final 18-month results from the pivotal HOPE-B study continue to establish the durability of etranacogene dezaparvovec gene therapy, which produced Factor IX levels that remained stable and consistent over the course of the study, while also significantly reducing the rate of annual bleeds after a single infusion,” said Professor Wolfgang Miesbach, Head of the Department of Coagulation Disorders and the Comprehensive Care Centre from the University Hospital of Frankfurt, Germany, and an investigator for the HOPE-B trial. “Hemophilia B, like many other genetic diseases, is an ideal target for gene therapy because the disease stems from a single faulty gene, making its replacement with a fully functional F9 gene a robust therapeutic intervention.”

Key Data from the Phase 3 HOPE-B Study

The Phase 3, open label, single-dose, single arm HOPE-B trial, which included 54 male participants with severe or moderately severe hemophilia B, demonstrated that etranacogene dezaparvovec produced mean FIX activity of 39.0 IU/dL at six months and 36.9 IU/dL at 18 months post infusion. 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. In addition, 98 percent of subjects treated with a full dose of etranacogene dezaparvovec discontinued use of 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).

While progress in today’s FIX prophylaxis treatments has made meaningful improvements in the lives of people with hemophilia B, many patients remain at risk of serious bleeds and other complications, despite regular, ongoing treatment,” said Steven Pipe, M.D., Professor of Pediatrics and Pathology and Pediatric Medical Director of the Hemophilia and Coagulation Disorders Program at the University of Michigan, and the principal investigator of the HOPE-B trial. “Nearly all patients treated with gene therapy in this study were able to discontinue use of prophylaxis. The treatment was also effective in people who have pre-existing neutralizing antibodies, which would typically disqualify someone from this kind of treatment.”

Etranacogene dezaparvovec is generally well-tolerated with the majority of adverse events (80.4 percent) considered mild. 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, by independent molecular tumor characterization and vector integration analysis, to be unrelated to treatment with etranacogene dezaparvovec. No inhibitors to FIX were reported.

“The gene therapy platform builds on CSL Behring’s decades-long promise to improve the lives and well-being of people with hemophilia B, and the most recent data from the pivotal HOPE-B study demonstrates the transformative potential of this platform to further redefine how we treat this life-long condition,” said CSL Behring’s Vice President, Hematology Research and Development Brahm Goldstein, MD, MCR, “With this positive data and accelerated regulatory review pathways in the U.S. and in Europe, we look forward to expanding on the foundational work done by our partner, uniQure and working closely with regulatory authorities to bring the potentially life-changing benefits of gene therapy to the hemophilia B community.”

In addition to the presentation of the HOPE-B findings, the e-posters “Multiple-Year Durability Data From A Phase 2B Trial Of Gene Therapy With Etranacogene Dezaparvovec In Patients With Hemophilia B” [PO098] and “Unmet Needs in Hemophilia B: Perspectives From People Living With Hemophilia B, Healthcare Professionals and the Healthcare Industry” [PO142] were also shared.

About the Phase 3 HOPE-B Study

The pivotal Phase III HOPE-B trial is a multinational, open-label, single-arm study to evaluate the safety and efficacy of etranacogene dezaparvovec. Fifty-four adult hemophilia B patients classified as severe or moderately severe (defined as less than or equal to 2 percent of normal FIX activity) 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 ABR. No prophylactic immunosuppression was provided to patients upon entering the study. 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, considering all bleeds regardless of investigator adjudication as true bleeds. For this endpoint, ABR was measured from month seven to month 18 after infusion, ensuring the observation period represented likely steady-state FIX transgene expression. Secondary endpoints included assessment of FIX activity and statistical superiority of ABR after dosing.

The multi-year clinical development for etranacogene dezaparvovec is being jointly led by CSL Behring and uniQure (Nasdaq: QURE). CSL Behring acquired global rights to commercialize etranacogene dezaparvovec in May 2021.

About Hemophilia B

Hemophilia B is a life-threatening degenerative disease. People with the condition are particularly vulnerable to bleeds in their muscles, internal organs, and joints, leading to pain, swelling, and joint damage. Current treatment includes life-long prophylactic infusions of FIX to temporarily replace or supplement low levels of the blood-clotting factor. This can reduce joint bleeding events, prevent life-threatening bleeds, and preserve joint function. However, infusions can be cumbersome, painful and veins can fibrose over time, making ongoing treatment difficult. A person’s immune system may also generate inhibitors against the replacement factor, negating its benefit. In addition, many people receiving prophylaxis are forced to plan their lives around the highs and lows of their FIX levels, which rise immediately after an infusion but drop over time -- leaving them especially vulnerable to bleeds and pain in the days before their next infusion. Most troubling, prophylactic FIX replacement therapy sometimes fails to control unobservable micro-bleeds in the joints, meaning that the degeneration can continue despite regular infusions. Missing an infusion may also the increase their likelihood of a life-threatening bleed or even premature death.

About Gene Therapy in Hemophilia B

Gene therapy has the potential to make a functional cure possible in hemophilia B.  Gene therapy achieves this with modified non-infectious viruses called “vectors” that can enter certain cells.  Vectors act as delivery trucks, carrying a package of genetic instructions to specific cells. Once delivered, the package acts like a generator that plugs into the cellular machinery, allowing a person to produce their own stable levels of FIX. A certain type of vector, called an adeno-associated virus, or AAV, dissolves after delivering its package. The genetic instructions remain, but never actually become a part of a person’s own DNA.

About Etranacogene Dezaparvovec

Etranacogene dezaparvovec (also known as CSL222, previously known as AMT-061) uses a specific type of AAV, called AAV5, as its delivery vehicle. 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. Preclinical and clinical data show that AAV5-based gene therapies may be clinically effective in up to 95 percent of hemophilia B patients with pre-existing antibodies to AAV vectors, thereby potentially increasing patient eligibility for treatment compared to other AAV gene therapy product candidates.

About CSL Behring

CSL Behring is a global biotherapeutics leader driven by our promise to save lives. Focused on serving patients’ needs by using the latest technologies, we discover, develop and deliver innovative therapies for people living with conditions in the immunology, hematology, cardiovascular and metabolic, respiratory, and transplant therapeutic areas. We use three strategic scientific platforms of plasma fractionation, recombinant protein technology, and cell and gene therapy to support continued innovation and continually refine ways in which products can address unmet medical needs and help patients lead full lives.

CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. The parent company, CSL Limited (ASX:CSL;USOTC:CSLLY), headquartered in Melbourne, Australia, employs more than 25,000 people worldwide, and delivers its life-saving therapies to people in more than 100 countries. For inspiring stories about the promise of biotechnology, visit Vita CSLBehring.com/vita and follow us on Twitter.com/CSLBehring.

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